{"text":"Kits containing the diagnostic systems and diagnostic systems that rely on bioluminescence for visualizing tissues in situ are provided. The systems include compositions containing conjugates that include a tissue specific, particularly a tumor-specific, targeting agent linked to a targeted agent, a luciferase or luciferin. The systems also include a second composition that contains the remaining components of a bioluminescence generating reaction. Administration of the compositions results production of light by targeted tissues that permits the detection and localization of neoplastic tissue for surgical removal.\n\nThe present invention relates to bioluminescence generating agents, conjugates containing such agents linked to targeting agents, and methods of use of the conjugates for visualization neoplastic or specialty tissue during invasive and non-invasive surgical procedures.\nLuminescence is a phenomenon in which energy is specifically channeled to a molecule to produce an excited state. Return to a lower energy state is accompanied by release of a photon (hv). Luminescence includes fluorescence, phosphorescence, chemiluminescence and bioluminescence. Bioluminescence is the process by which living organisms emit light that is visible to other organisms. Luminescence may be represented as follows:\nA+Bxe2x86x92X*+Y\nX*xe2x86x92X+hv,\nwhere X* is an electronically excited molecule and hv represents light emission upon return of X* to a lower energy state. Where the luminescence is bioluminescence, creation of the excited state derives from an enzyme catalyzed reaction. The color of the emitted light in a bioluminescent (or chemiluminescent or other luminescent) reaction is characteristic of the excited molecule, and is independent from its source of excitation and temperature.\nAn essential condition for bioluminescence is the use of molecular oxygen, either bound or free in the presence of a luciferase. Luciferases, are oxygenases, that act on a substrate, luciferin, in the presence of molecular oxygen and transform the substrate to an excited state. Upon return to a lower energy level, energy is released in the form of light [for reviews see, e.g., McElroy et al. (1966) in Molecular Architecture in Cell Physiology, Hayashi et al., eds., Prentice-Hall, Inc., Englewood Cliffs, N.J., pp. 63-80; Ward et al., Chapter 7 in Chemi-and Bioluminescence, Burr, ed., Marcel Dekker, Inc. NY, pp.321-358; Hastings, J. W. in (1995) Cell Physiology:Source Book, N. Sperelakis (ed.), Academic Press, pp 665-681; Luminescence, Narcosis and Life in the Deep Sea, Johnson, Vantage Press, NY, see, esp. pp. 50-56].\nThough rare overall, bioluminescence is more common in marine organisms than in terrestrial organisms. Bioluminescence has developed from as many as thirty evolutionarily distinct origins and, thus, is manifested in a variety of ways so that the biochemical and physiological mechanisms responsible for bioluminescence in different organisms are distinct. Bioluminescent species span many genera and include microscopic organisms, such as bacteria [primarily marine bacteria including Vibrio species], fungi, algae and dinoflagellates, to marine organisms, including arthropods, mollusks, echinoderms, and chordates, and terrestrial organism including annelid worms and insects.\nBioluminescence, as well as other types of chemiluminescence, is used for quantitative determinations of specific substances in biology and medicine. For example, luciferase genes have been cloned and exploited as reporter genes in numerous assays, for many purposes. Since the different luciferase systems have different specific requirements, they may be used to detect and quantify a variety of substances. The majority of commercial bioluminescence applications are based on firefly [Photinus pyralis] luciferase. One of the first and still widely used assays involves the use of firefly luciferase to detect the presence of ATP. It is also used to detect and quantify other substrates or co-factors in the reaction. Any reaction that produces or utilizes NAD(H), NADP(H) or long chain aldehyde, either directly or indirectly, can be coupled to the light-emitting reaction of bacterial luciferase.\nAnother luciferase system that has been used commercially for analytical purposes is the Aequorin system. The purified jellyfish photoprotein, aequorin, is used to detect and quantify intracellular Ca2+ and its changes under various experimental conditions. The Aequorin photoprotein is relatively small [xcx9c20 kDa], nontoxic, and can be injected into cells in quantities adequate to detect calcium over a large concentration range [3xc3x9710xe2x88x927 to 10xe2x88x924 M].\nBecause of their analytical utility, many luciferases and substrates have been studied and well-characterized and are commercially available [e.g., firefly luciferase is available from Sigma, St. Louis, Mo., and Boehringer Mannheim Biochemicals, Indianapolis, Ind.; recombinantly produced firefly luciferase and other reagents based on this gene or for use with this protein are available from Promega Corporation, Madison, Wis.; the aequorin photoprotein luciferase from jellyfish and luciferase from Renilla are commercially available from Sealite Sciences, Bogart, Ga.; coelenterazine, the naturally-occurring substrate for these luciferases, is available from Molecular Probes, Eugene, Oreg.]. These luciferases and related reagents are used as reagents for diagnostics, quality control, environmental testing and other such analyses.\nOne difficulty encountered by surgeons during surgical procedures either for diagnosis or treatment is to find the tissue of interest. For example, during surgeries in which tumors are excised it is difficult to localize the neoplastic tissue and to be sure to remove all of it, yet not remove healthy tissue. It is also difficult to readily detect metastases, and also, for example to locate the embryo in ectopic pregnancies.\nFor these reasons and others, it is an object herein to provide means for visualizing neoplastic tissue and specialty tissue during surgical procedures. It is also an object herein to provide methods of detecting neoplastic and specialty tissue.\nDiagnostic systems that rely on bioluminescence for visualizing tissues in situ are provided. The systems are particularly useful for visualizing and detecting neoplastic tissue and specialty tissue, such as during non-invasive and invasive procedures. Kits that provide the components of the systems and methods using the systems for visualizing the tissue are also provided. Therapeutic methods in which photosensitizing compounds are administered are also provided.\nThe systems include compositions containing conjugates that include a tissue specific, particularly a tumor-specific, targeting agent linked to a targeted agent, a luciferase or luciferin. The systems also include a second composition that contains the remaining components of a bioluminescence generating reaction. In some embodiments, all components, except for activators, which are provided in situ or are present in the body or tissue, are included in a single composition.\nIn particular, the diagnostic systems include two compositions. A first composition that contains conjugates that, in preferred embodiments, include antibodies directed against tumor antigens conjugated to a component of the bioluminescence generating reaction, a luciferase or luciferin, preferably a luciferase are provided. In certain embodiments, conjugates containing tumor-specific targeting agents are linked to luciferases or luciferins. In other embodiments, tumor-specific targeting agents are linked to microcarriers that are coupled with, preferably more than one of the bioluminescence generating components, preferably more than one luciferase molecule.\nThe second composition contains the remaining components of a bioluminescence generating system, typically the luciferin or luciferase substrate. In some embodiments, these components, particularly the luciferin, are linked to a protein, such as a serum albumin, or other protein carrier. The carrier and time release formulations, permit systemically administered components to travel to the targeted tissue without interaction with blood cell components, such as hemoglobin that deactivate the luciferin or luciferase. Preferred bioluminescence generating systems include the Vargula luciferase\/luciferin.\nIn certain, the bioluminescence generating compositions are packaged in a time release formulation, such as cyclodextran, a liposome or other such vehicle, for delivery through the bloodstream to the tumor.\nThe compositions are useful in methods for the detection and localization of neoplastic tissue or other tissue, such as endometriotic or an ectopic pregnancy, in a mammal, particularly a human.\nThe conjugates permit the specific targeting of a bioluminescent agent to neoplastic tissue or other targeted tissue. Upon binding to or interaction with the tissue, when treated with an appropriate substrate (when luciferase is linked) or luciferase (when a luciferin is linked) in the presence of activators, if necessary, light is produced, thereby permitting detection and localization of neoplastic tissue or other targeted tissue. This can, for example, permit or aid in identification of neoplastic tissue, which may then be removed using noninvasive or invasive surgical procedures. In some embodiments, the conjugate may also include a chemotherapeutic agent that is delivered to the targeted tissue.\nThe conjugates contain one or more targeting agents [hereinafter TA] linked, either directly or via a linker, to one or more luciferases or luciferins are provided. For purposes herein, the targeting agent is any molecule that specifically interacts with a cell surface moiety that is present on a tumor cell or tissue or neoplastic cell or tissue or other targeted cell in a higher amount or concentration than on a non-tumor or non-neoplastic cell or non-targeted cell. The higher amount or concentration is any amount or concentration that permits tumor or neoplastic cells to be distinguished from non tumor or neoplastic cells or tissues using the methods and systems and compositions provided herein.\nThe conjugates provided herein contain the following components: (TA)n, (L)q, and (targeted agent)m in which: at least one TA moiety is linked with or without a linker (L) to at least one targeted agent, n is 1 or more, preferably 1-3, more preferably 1 or 2, but is any number whereby the resulting conjugate binds to the tumor or neoplastic cell or tissue, q is generally 1 to 4; m is 1 or more, generally 1 or 2; L refers to a linker, and the targeted agent is any agent that when treated with an activator, will produce light.\nIt is understood that the above description does not represent the order in which each component is linked or the manner in which each component is linked. The TA and targeted agent (or linker and targeted agent) may be linked in any order and through any appropriate linkage, as long as the resulting conjugate binds to a neoplastic cell or tissue receptor and can be visualized by the methods herein. The TA may be linked directly to the targeted agent, such as by a covalent bond, or may be linked through a linker. The TA may also be indirectly linked through a microcarrier that is coupled to the targeted agent.\nThe targeted agents for use herein are luciferases or photoproteins and substrates (luciferins) therefor.\nThe targeting agents [TAs] include any agent that will preferentially bind to a tumor or neoplastic cell or tissue compared to cell or tissue that is not a tumor or neoplastic or that target to specialty tissues such as ligaments, tendons, endometriotic tissue, ectopic pregnancies and other such tissues. Such agents include, but are not limited to tissue specific monoclonal antibodies, methotrexate and growth factors, such as FGF, EGF, HBEFG, that can be modified whereby internalization does not occur or is reduced and other such growth factors that bind to receptors that are present in greater amounts or concentrations on neoplastic or tumorous cells or tissues than non-tumorous or non-neoplastic tissues. Monoclonal antibodies specific for tumor cell surface proteins are presently preferred. Among the monoclonal antibodies, humanized monoclonal antibodies are preferred.\nMethods for diagnosis and visualization of tissues in vivo or in situ are provided. Included are methods of identifying metastatic tumors or other targeted tissue during an operative procedure, typically an exploratory procedure, by the preoperative administration of a targeting agent conjugated to one of the bioluminescence-generating components and followed by the topical or local application of the final components during surgery to illuminate areas of neoplasia. In the methods provided herein, bioluminescence is used to visualize the targeted tissue in an animal during surgical procedures, such as for surgical removal.\nMethods for the preparation of the conjugates and the resulting conjugates are provided. These methods include chemical conjugation methods and methods that rely on recombinant production of the conjugates. The chemical methods rely on derivatization of the targeted agent or TA with the desired linker and then reaction with a TA or targeted agent. Alternatively, the derivatized targeted agent is coupled to a microcarrier directly or through a linker and then coupled to a TA. The chemical methods of derivatization are particularly preferred. Direct linkage is presently preferred.\nPresently the methods for preparation of antibody-luciferase conjugates, such as those described in U.S. Pat. No. 5,486,455 are among the preferred methods.\nIf a linker is used it is selected such that it does not interfere with the activity of the targeted agent upon interaction of the conjugate with a cell surface protein. Any appropriate linker known to those of skill in this art may be used. The linker may be selected to improve activity by permitting the targeted agent to react with the activating composition. In some instances the linker is selected to increase the specificity, toxicity, solubility, serum stability, and\/or intracellular availability targeted moiety. In some embodiments, several linkers may be included in order to take advantage of desired properties of each linker.\nOther linkers are suited for incorporation into chemically produced conjugates. Linkers that are suitable for chemically linking conjugates include disulfide bonds, thioether bonds, hindered disulfide bonds, esters, and covalent bonds between free reactive groups, such as amine and thiol groups. These bonds are produced using heterobifunctional reagents to produce reactive thiol groups on one or both of the polypeptides and then reacting the thiol groups on one polypeptide with reactive thiol groups or amine groups on the other. Other linkers include, acid cleavable linkers, such as bismaleimideothoxy propane, acid labile-transferrin conjugates and adipic acid diihydrazide, that would be cleaved in more acidic environments; photocleavable cross linkers that are cleaved by visible or UV light. Linkers particularly suitable for coupling microcarriers to TA and targeted agents are chemical linking conjugates as well as avidin\/streptavidin-biotin conjugates.\nKits containing the compositions for use in the diagnostic systems are provided. In particular, the kits include a first composition that contains the conjugates, and a second that contains the activating composition, which contains any necessary activating agents, as well as the luciferase, if the targeted agent is a luciferin, or a luciferin, if the targeted agent is a luciferase.\nThus, the kits will typically include two compositions, a first composition containing the conjugate formulated for systemic administration (or in some embodiments local or topical application), and a second composition, formulated for systemic, topical or local administration depending upon the application. Instructions for administration will be included.\nMethods of detecting bioluminescent neoplasia and specialty tissues for surgical removal using surgical viewing devices are also provided. Methods of detecting and surgically removing bioluminescent neoplasia and specialty tissues using these surgical viewing devices are also provided. These devices include night vision binoculars, CCD arrays, tomographs, endoscopic devices and other such devices.\nSurgical instruments for detecting and surgically removing bioluminescent neoplastic and specialty tissue are provided. Methods of detecting and surgically removing bioluminescent neoplasia and specialty tissues using these surgical viewing devices are also provided. In particular, a surgical vision device, that includes: an optical detection system that is operatively associated with the image intensifier such that an image detected by the optical detection system is transmitted to the image intensifier for viewing; an image intensifier device highly sensitive to low intensity visible light; and an objective lens assembly.\nCompositions and methods of using bioluminescence targeting agents, as described herein, in conjunction with photodynamic methodologies for the treatment of neoplasms are also provided. In practicing the methods, a photodynamic drug is administered prior to the administration of a targeting agent conjugated to a component of a bioluminescence generating system. Binding of the targeting agent to the targeted neoplasia and initiation of the bioluminescent reaction results in in situ production of light at the surface of the cell thereby irradiating those neoplastic tissues that uptake the photodynamic drug. Photoactivation of the drug results in death of the targeted cell.\nIn practicing the methods, a conjugate containing a targeting agent linked to a luciferase or luciferin is administered to an animal prior to surgery or diagnosis. During surgery or the diagnostic procedure, when the tissues can be seen, they are contacted with a composition containing the remaining components of a bioluminescence generating system. Any tissues to which the targeting agent binds will glow, thereby permitting the surgeon to identify the tissues.\nIn other methods, a luciferase, such as red emitting luciferase, including those from Aristostomias, A. niger, Melanocostus and Pachystomias, that produces light that can be detected through tissue is conjugated to a targeting agent and administered prior to surgery or a diagnostic procedure. A composition containing the remaining components of the bioluminescence generating system is injected either locally or systemically prior to surgery or diagnosis. When systemically administered, the components, such as the luciferin can be provided in a time release formulation, or can include other components, such as an albumin that prevent it from getting into the blood cells or that prevent interaction with other blood components. Tissues to which the tumor-specific targeting agent binds are detected using a photomultiplier or other surgical viewing instrument directly through the skin without the need for invasive surgery.\nIn other methods, a luciferase that produces light that can be detected through tissue, e.g., Aristostomias, is conjugated to a targeting agent and administered prior to surgery. Light is detected from the targeted tissue using a surgical instrument, such as a laparoscope or tomogram, and the image of the targeted tissue is displayed and removed by one or more invasive or non-invasive surgical techniques.\nA. Definitions\nUnless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs. All patents and publications of referred to herein are incorporated by reference in their entirety.\nAs used herein, chemiluminescence refers to a chemical reaction in which energy is specifically channeled to a molecule causing it to become electronically excited and subsequently to release a photon thereby emitting visible light. Temperature does not contribute to this channeled energy. Thus, chemiluminescence involves the direct conversion of chemical energy to light energy.\nAs used herein, luminescence refers to the detectable EM radiation, generally, UV, IR or visible EM radiation that is produced when the excited product of an exergonic chemical process reverts to its ground state with the emission of light. Chemiluminescence is luminescence that results from a chemical reaction. Bioluminescence is chemiluminescence that results from a chemical reaction using biological molecules [or synthetic versions or analogs thereof] as substrates and\/or enzymes.\nAs used herein, bioluminescence, which is a type of chemiluminescence, refers to the emission of light by biological molecules, particularly proteins. The essential condition for bioluminescence is molecular oxygen, either bound or free in the presence of an oxygenase, a luciferase, which acts on a substrate, a luciferin. Bioluminescence is generated by an enzyme or other protein [luciferase] that is an oxygenase that acts on a substrate luciferin [a bioluminescence substrate] in the presence of molecular oxygen and transforms the substrate to an excited state, which upon return to a lower energy level releases the energy in the form of light.\nAs used herein, the substrates and enzymes for producing bioluminescence are generically referred to as luciferin and luciferase, respectively. When reference is made to a particular species thereof, for clarity, each generic term is used with the name of the organism from which it derives, for example, bacterial luciferin or firefly luciferase.\nAs used herein, luciferase refers to oxygenases that catalyze a light emitting reaction. For instance, bacterial luciferases catalyze the oxidation of flavin mononucleotide [FMN] and aliphatic aldehydes, which reaction produces light. Another class of luciferases, found among marine arthropods, catalyzes the oxidation of Cypridina [Vargula] luciferin, and another class of luciferases catalyzes the oxidation of Coleoptera luciferin.\nThus, luciferase refers to an enzyme or photoprotein that catalyzes a bioluminescent reaction [a reaction that produces bioluminescence]. The luciferases, such as firefly and Renilla luciferases, that are enzymes which act catalytically and are unchanged during the bioluminescence generating reaction. The luciferase photoproteins, such as the aequorin photoprotein to which luciferin is non-covalently bound, are changed, such as by release of the luciferin, during bioluminescence generating reaction. The luciferase is a protein that occurs naturally in an organism or a variant or mutant thereof, such as a variant produced by mutagenesis that has one or more properties, such as thermal stability, that differ from the naturally-occurring protein. Luciferases and modified mutant or variant forms thereof are well known. For purposes herein, reference to luciferase refers to either the photoproteins or luciferases.\nThus, reference, for example, to xe2x80x9cRenilla luciferasexe2x80x9d means an enzyme isolated from member of the genus Renilla or an equivalent molecule obtained from any other source, such as from another Anthozoa, or that has been prepared synthetically.\nThe luciferases and luciferin and activators thereof are referred to as bioluminescence generating reagents or components. Typically, a subset of these reagents will be provided or combined with an article of manufacture. Bioluminescence will be produced upon contacting the combination with the remaining reagents. Thus, as used herein, the component luciferases, luciferins, and other factors, such as O2, Mg2+, Ca2+ are also referred to as bioluminescence generating reagents [or agents or components].\nAs used herein, xe2x80x9cnot strictly catalyticallyxe2x80x9d means that the photoprotein acts as a catalyst to promote the oxidation of the substrate, but it is changed in the reaction, since the bound substrate is oxidized and bound molecular oxygen is used in the reaction. Such photoproteins are regenerated by addition of the substrate and molecular oxygen under appropriate conditions known to those of skill in this art.\nAs used herein, bioluminescence substrate refers to the compound that is oxidized in the presence of a luciferase, and any necessary activators, and generates light. These substrates are referred to as luciferins herein, are substrates that undergo oxidation in a bioluminescence reaction. These bioluminescence substrates include any luciferin or analog thereof or any synthetic compound with which a luciferase interacts to generate light. Preferred substrates are those that are oxidized in the presence of a luciferase or protein in a light-generating reaction. Bioluminescence substrates, thus, include those compounds that those of skill in the art recognize as luciferins. Luciferins, for example, include firefly luciferin, Cypridina [also known as Vargula] luciferin [coelenterazine], bacterial luciferin, as well as synthetic analogs of these substrates or other compounds that are oxidized in the presence of a luciferase in a reaction the produces bioluminescence.\nAs used herein, capable of conversion into a bioluminescence substrate means susceptible to chemical reaction, such as oxidation or reduction, that yields a bioluminescence substrate. For example, the luminescence producing reaction of bioluminescent bacteria involves the reduction of a flavin mononucleotide group (FMN) to reduced flavin mononucleotide (FMNH2) by a flavin reductase enzyme. The reduced flavin mononucleotide [substrate] then reacts with oxygen [an activator] and bacterial luciferase to form an intermediate peroxy flavin that undergoes further reaction, in the presence of a long-chain aldehyde, to generate light. With respect to this reaction, the reduced flavin and the long chain aldehyde are substrates.\nAs used herein, bioluminescence system [or bioluminescence generating system] refers to the set of reagents required to conduct a bioluminescent reaction. Thus, the specific luciferase, luciferin and other substrates, solvents and other reagents that may be required to complete a bioluminescent reaction form a bioluminescence system. Thus a bioluminescence system refers to any set of reagents that, under appropriate reaction conditions, yield bioluminescence. Appropriate reaction conditions refers to the conditions necessary for a bioluminescence reaction to occur, such as pH, salt concentrations and temperature. In general, bioluminescence systems include a bioluminescence substrate, luciferin, a luciferase, which includes enzymes luciferases and photoproteins, and one or more activators. A specific bioluminescence system may be identified by reference to the specific organism from which the luciferase derives; for example, the Vargula [also called Cypridina] bioluminescence system (or Vargula system) includes a Vargula luciferase, such as a luciferase isolated from the ostracod, Vargula or produced using recombinant means or modifications of these luciferases. This system would also include the particular activators necessary to complete the bioluminescence reaction, such as oxygen and a substrate with which the luciferase reacts in the presence of the oxygen to produce light.\nThe amino acids, which occur in the various amino acid sequences appearing herein, are identified according to their well-known, three-letter or one-letter abbreviations. The nucleotides, which occur in the various DNA fragments, are designated with the standard single-letter designations used routinely in the art.\nAs used herein, to target a targeted agent, such as a luciferase, means to direct it to a cell that expresses a selected receptor or other cell surface protein by linking the agent to a such agent. Upon binding to or interaction with the receptor or cell surface protein the targeted agent, can be reacted with an appropriate substrate and activating agents, whereby bioluminescent light is produced and the tumorous tissue or cells distinguished from non-tumorous tissue.\nAs used herein, an effective amount of a compound for treating a particular disease is an amount that is sufficient to ameliorate, or in some manner reduce the symptoms associated with the disease. Such amount may be administered as a single dosage or may be administered according to a regimen, whereby it is effective. The amount may cure the disease but, typically, is administered in order to ameliorate the symptoms of the disease. Repeated administration may be required to achieve the desired amelioration of symptoms.\nAs used herein, an effective amount of a conjugate for diagnosing a disease is an amount that will result in a detectable tissue. The tissues are detected by visualization either without aid from a detector more sensitive than the human eye, or with the use of a light source to excite any fluorescent products.\nAs used herein, visualizable means detectable by eye, particularly during surgery under normal surgical conditions, or, if necessary, slightly dimmed light.\nAs used herein, pharmaceutically acceptable salts, esters or other derivatives of the conjugates include any salts, esters or derivatives that may be readily prepared by those of skill in this art using known methods for such derivatization and that produce compounds that may be administered to animals or humans without substantial toxic effects and that either are pharmaceutically active or are prodrugs.\nAs used herein, treatment means any manner in which the symptoms of a conditions, disorder or disease are ameliorated or otherwise beneficially altered. Treatment also encompasses any pharmaceutical use of the compositions herein.\nAs used herein, amelioration of the symptoms of a particular disorder by administration of a particular pharmaceutical composition refers to any lessening, whether permanent or temporary, lasting or transient that can be attributed to or associated with administration of the composition.\nAs used herein, substantially pure means sufficiently homogeneous to appear free of readily detectable impurities as determined by standard methods of analysis, such as thin layer chromatography (TLC), gel electrophoresis and high performance liquid chromatography (HPLC), used by those of skill in the art to assess such purity, or sufficiently pure such that further purification would not detectably alter the physical and chemical properties, such as enzymatic and biological activities, of the substance. Methods for purification of the compounds to produce substantially chemically pure compounds are known to those of skill in the art. A substantially chemically pure compound may, however, be a mixture of stereoisomers or isomers. In such instances, further purification might increase the specific activity of the compound.\nAs used herein, a prodrug is a compound that, upon in vivo administration, is metabolized or otherwise converted to the biologically, pharmaceutically or therapeutically active form of the compound. To produce a prodrug, the pharmaceutically active compound is modified such that the active compound will be regenerated by metabolic processes. The prodrug may be designed to alter the metabolic stability or the transport characteristics of a drug, to mask side effects or toxicity, to improve the flavor of a drug or to alter other characteristics or properties of a drug. By virtue of knowledge of pharmacodynamic processes and drug metabolism in vivo, those of skill in this art, once a pharmaceutically active compound is known, can design prodrugs of the compound (see, e.g., Nogrady (1985) Medicinal Chemistry A Biochemical Approach, Oxford University Press, New York, pages 388-392).\nAs used herein, biological activity refers to the in vivo activities of a compound or physiological responses that result upon in vivo administration of a compound, composition or other mixture. Biological activity, thus, encompasses therapeutic effects and pharmaceutical activity of such compounds, compositions and mixtures.\nAs used herein, ED50 refers to the concentration at which 50% of the cells are killed following a 72-hour incubation with a cytotoxic conjugate, such as FGF-SAP.\nAs used herein, ID50 refers to the concentration of a cytotoxic conjugate required to inhibit protein synthesis in treated cells by 50% compared to protein synthesis in the absence of the protein.\nAs used herein, targeting agent refers to an agent that specifically or preferentially targets a linked targeted agent, a luciferin or luciferase, to a neoplastic cell or tissue.\nAs used herein, tumor antigen refers to a cell surface protein expressed or located on the surface of tumor cells.\nAs used herein, neoplastic cells include any type of transformed or altered cell that exhibits characteristics typical of transformed cells, such as a lack of contact inhibition and the acquisition of tumor-specific antigens. Such cells include, but are not limited to leukemic cells and cells derived from a tumor.\nAs used herein, neoplastic disease is any disease in which neoplastic cells are present in the individual afflicted with the disease. Such diseases include, any disease characterized as cancer.\nAs used herein, metastatic tumors refers to tumors that are not localized in one site.\nAs used herein, specialty tissue refers to non-tumorous tissue for which information regarding location is desired. Such tissues include, for example, endometriotic tissue, ectopic pregnancies, tissues associated with certain disorders and myopathies or pathologies.\nAs used herein, an antibody conjugate refers to a conjugate in which the targeting agent is an antibody.\nAs used herein, antibody activation refers to the process whereby activated antibodies are produced. Antibodies are activated upon reaction with a linker, such as heterobifunctional reagent.\nAs used herein, a surgical viewing refers to any procedure in which an opening is made in the body of an animal. Such procedures include traditional surgeries and diagnostic procedures, such as laparoscopies and arthroscopic procedures.\nAs used herein, humanized antibodies refer to antibodies that are modified to include xe2x80x9chumanxe2x80x9d sequences of amino acids so that administration to a human will not provoke an immune response. Methods for preparation of such antibodies are known. For example, the hybridoma that expresses the monoclonal antibody is altered by recombinant DNA techniques to express an antibody in which the amino acid composition of the non-variable regions is based on human antibodies. Computer programs have been designed to identify such regions.\nAs used herein, ATP, AMP, NAD+ and NADH refer to adenosine triphosphate, adenosine monophosphate, nicotinamide adenine dinucleotide (oxidized form) and nicotinamide adenine dinucleotide (reduced form), respectively.\nAs used herein, production by recombinant means by using recombinant DNA methods means the use of the well known methods of molecular biology for expressing proteins encoded by cloned DNA.\nAs used herein, substantially identical to a product means sufficiently similar so that the property of interest is sufficiently unchanged so that the substantially identical product can be used in place of the product.\nAs used herein, substantially pure means sufficiently homogeneous to appear free of readily detectable impurities as determined by standard methods of analysis, such as thin layer chromatography (TLC), gel electrophoresis and high performance liquid chromatography (HPLC), used by those of skill in the art to assess such purity, or sufficiently pure such that further purification would not detectably alter the physical and chemical properties, such as enzymatic and biological activities, of the substance. Methods for purification of the compounds to produce substantially chemically pure compounds are known to those of skill in the art. A substantially chemically pure compound may, however, be a mixture of stereoisomers. In such instances, further purification might increase the specific activity of the compound.\nAs used herein equivalent, when referring to two sequences of nucleic acids means that the two sequences in question encode the same sequence of amino acids or equivalent proteins. When xe2x80x9cequivalentxe2x80x9d is used in referring to two proteins or peptides, it means that the two proteins or peptides have substantially the same amino acid sequence with only conservative amino acid substitutions [see, e.g., Table 2, below] that do not substantially alter the activity or function of the protein or peptide. When xe2x80x9cequivalentxe2x80x9d refers to a property, the property does not need to be present to the same extent [e.g., two peptides can exhibit different rates of the same type of enzymatic activity], but the activities are preferably substantially the same. xe2x80x9cComplementary,xe2x80x9d when referring to two nucleotide sequences, means that the two sequences of nucleotides are capable of hybridizing, preferably with less than 25%, more preferably with less than 15%, even more preferably with less than 5%, most preferably with no mismatches between opposed nucleotides. Preferably the two molecules will hybridize under conditions of high stringency.\nAs used herein: stringency of hybridization in determining percentage mismatch is as follows:\n1) high stringency: 0.1xc3x97SSPE, 0.1% SDS, 65xc2x0 C.\n2) medium stringency: 0.2xc3x97SSPE, 0.1% SDS, 50xc2x0 C.\n3) low stringency: 1.0xc3x97SSPE, 0.1% SDS, 50xc2x0 C.\nIt is understood that equivalent stringencies may be achieved using alternative buffers, salts and temperatures.\nThe term xe2x80x9csubstantiallyxe2x80x9d identical or homologous or similar varies with the context as understood by those skilled in the relevant art and generally means at least 70%, preferably means at least 80%, more preferably at least 90%, and most preferably at least 95% identity.\nAs used herein, biological activity refers to the in vivo activities of a compound or physiological responses that result upon administration of a compound, composition or other mixture. Biological activities may be observed in in vitro systems designed to test or use such activities. Thus, for purposes herein the biological activity of a luciferase is its oxygenase activity whereby, upon oxidation of a substrate, light is produced.\nAs used herein, a composition refers to a any mixture. It may be a solution, a suspension, liquid, powder, a paste, aqueous, non-aqueous or any combination thereof.\nAs used herein, a combination refers to any association between two or among more items.\nAs used herein, fluid refers to any composition that can flow. Fluids thus encompass compositions that are in the form of semi-solids, pastes, solutions, aqueous mixtures, gels, lotions, creams and other such compositions.\nB. Preparation of the Conjugates\nThe conjugates that are provided herein contain a targeting agent, such as a tissue specific or tumor specific monoclonal antibody or fragment thereof linked either directly or via a linker to a targeted agent, a luciferase (including photoproteins or luciferase enzymes) or a luciferin. The targeted agent may be coupled to a microcarrier. The linking is effected either chemically, by recombinant expression of a fusion protein in instances when the targeted agent is a protein, and by combinations of chemical and recombinant expression. The targeting agent is one that will preferentially bind to a selected tissue or cell type, such as a tumor cell surface antigen or other tissue specific antigen.\nMethods for preparing conjugates are known to those of skill in the art. For example, aequorin that is designed for conjugation and conjugates containing such aequorin have been produced [see, e.g., International PCT application No. WO 94\/18342; see, also Smith et al. (1995) in American Biotechnology Laboratory]. Aequorin has been conjugated to an antibody molecule by means of a sulfhydryl-reacting binding agent (Stultz et al. (1992) Use of Recombinant Biotinylated Apoaequorin from Escherichia coli. Biochemistry 31, 1433-1442). Such methods may be adapted for use herein to produce aequorin coupled to protein or other such molecules, which are useful as targeting agents. Vargula luciferase has also been linked to other molecules [see, e.g., Japanese application No. JP 5064583, Mar. 19, 1993]. Such methods may be adapted for use herein to produce aequorin coupled to protein or other such molecules, which are useful as targeting agents.\nAequorin-antibody conjugates have been employed to detect the presence of or quantitate a particular antigen in a biological sample by direct correlation to the light emitted from the bioluminescent reaction.\nAs an alternative, a component of the bioluminescence generating system may be modified for linkage, such as by addition of amino acid residues that are particularly suitable for linkage to the selected substrate. This can be readily effected by modifying the DNA and expressing such modified DNA to produce luciferase with additional residues at the N- or C-terminus.\nSelection of the system depends upon factors such as the desired color and duration of the bioluminescence desired as well as the particular item. Selection of the targeting agent primarily depends upon the type and characteristics of neoplasia or tissue to be visualized and the setting in which visualization will be performed. For example, the luciferase isolated from Aristostomias emits red light, which is particularly beneficial for preoperative diagnosis because the red light is detectable through tissue using a photomultiplier.\n1 Bioluminescence Generating Systems\nA bioluminescence generating system refers to the components that are necessary and sufficient to generate bioluminescence. These include a luciferase, luciferin and any necessary co-factors or conditions. Virtually any bioluminescent system known to those of skill in the art will be amenable to use in the apparatus, systems, combinations and methods provided herein. Factors for consideration in selecting a bioluminescent-generating system, include, but are not limited to: the targeting agent used in combination with the bioluminescence; the medium in which the reaction is run; stability of the components, such as temperature or pH sensitivity; shelf life of the components; sustainability of the light emission, whether constant or intermittent; availability of components; desired light intensity; color of the light; and other such factors.\na. General Description\nIn general, bioluminescence refers to an energy-yielding chemical reaction in which a specific chemical substrate, a luciferin, undergoes oxidation, catalyzed by an enzyme, a luciferase. Bioluminescent reactions are easily maintained, requiring only replenishment of exhausted luciferin or other substrate or cofactor or other protein, in order to continue or revive the reaction. Bioluminescence generating reactions are well-known to those of skill in this art and any such reaction may be adapted for use in combination with articles of manufacture as described herein.\nThere are numerous organisms and sources of bioluminescence generating systems, and some representative genera and species that exhibit bioluminescence are set forth in the following table [reproduced in part from Hastings in (1995) Cell Physiology:Source Book, N. Sperelakis (ed.), Academic Press, pp 665-681]:\nOther bioluminescent organisms contemplated for use herein are Gonadostomias, Gaussia, Watensia, Halisturia, Vampire squid, Glyphus, Mycotophids (fish), Vinciguerria, Howella, Florenciella, Chaudiodus, Melanocostus and Sea Pens.\nIt is understood that a bioluminescence generating system may be isolated from natural sources, such as those in the above Table, or may be produced synthetically. In addition, for uses herein, the components need only be sufficiently pure so that mixture thereof, under appropriate reaction conditions, produces a glow so that cells and tissues can be visualized during a surgical procedure.\nThus, in some embodiments, a crude extract or merely grinding up the organism may be adequate. Generally, however, substantially pure components are used. Also, components may be synthetic components that are not isolated from natural sources. DNA encoding luciferases is available [see, e.g., SEQ ID Nos. 1-13] and has been modified [see, e.g., SEQ ID Nos. 3 and 10-13] and synthetic and alternative substrates have been devised. The DNA listed herein is only representative of the DNA encoding luciferases that is available.\nAny bioluminescence generating system, whether synthetic or isolated form natural sources, such as those set forth in Table 1, elsewhere herein or known to those of skill in the art, is intended for use in the combinations, systems and methods provided herein. Chemiluminescence systems per se, which do not rely on oxygenases [luciferases] are not encompassed herein.\n(1) Luciferases\nThe targeted agents herein include luciferases or luciferins. Luciferases refer to any compound that, in the presence of any necessary activators, catalyze the oxidation of a bioluminescence substrate [luciferin] in the presence of molecular oxygen, whether free or bound, from a lower energy state to a higher energy state such that the substrate, upon return to the lower energy state, emits light. For purposes herein, luciferase is broadly used to encompass enzymes that act catalytically to generate light by oxidation of a substrate and also photoproteins, such as aequorin, that act, though not strictly catalytically [since such proteins are exhausted in the reaction], in conjunction with a substrate in the presence of oxygen to generate light. These luciferases, including photoproteins, such as aequorin, are herein also included among the luciferases. These reagents include the naturally-occurring luciferases [including photoproteins], proteins produced by recombinant DNA, and mutated or modified variants thereof that retain the ability to generate light in the presence of an appropriate substrate, co-factors and activators or any other such protein that acts as a catalyst to oxidize a substrate, whereby light is produced.\nGenerically, the protein that catalyzes or initiates the bioluminescent reaction is referred to as a luciferase, and the oxidizable substrate is referred to as a luciferin. The oxidized reaction product is termed oxyluciferin, and certain luciferin precursors are termed etioluciferin. Thus, for purposes herein bioluminescence encompasses light produced by reactions that are catalyzed by [in the case of luciferases that act enzymatically] or initiated by [in the case of the photoproteins, such as aequorin, that are not regenerated in the reaction] a biological protein or analog, derivative or mutant thereof.\nFor clarity herein, these catalytic proteins are referred to as luciferases and include enzymes such as the luciferases that catalyze the oxidation of luciferin, emitting light and releasing oxyluciferin. Also included among luciferases are photoproteins, which catalyze the oxidation of luciferin to emit light but are changed in the reaction and must be reconstituted to be used again. The luciferases may be naturally occurring or may be modified, such as by genetic engineering to improve or alter certain properties. As long as the resulting molecule retains the ability to catalyze the bioluminescent reaction, it is encompassed herein.\nAny protein that has luciferase activity [a protein that catalyzes oxidation of a substrate in the presence of molecular oxygen to produce light as defined herein] may be used herein. The preferred luciferases are those that are described herein or that have minor sequence variations. Such minor sequence variations include, but are not limited to, minor allelic or species variations and insertions or deletions of residues, particularly cysteine residues. Suitable conservative substitutions of amino acids are known to those of skill in this art and may be made generally without altering the biological activity of the resulting molecule. Those of skill in this art recognize that, in general, single amino acid substitutions in non-essential regions of a polypeptide do not substantially alter biological activity (see, e.g., Watson et al. Molecular Biology of the Gene, 4th Edition, 1987, The Benjamin\/Cummings Pub. co., p.224). Such substitutions are preferably made in accordance with those set forth in TABLE 2 as follows:\nOther substitutions are also permissible and may be determined empirically or in accord with known conservative substitutions. Any such modification of the polypeptide may be effected by any means known to those of skill in this art.\nThe luciferases may be obtained commercially, isolated from natural sources, expressed in host cells using DNA encoding the luciferase, or obtained in any manner known to those of skill in the art. For purposes herein, crude extracts obtained by grinding up selected source organisms may suffice. Since large quantities of the luciferase may be desired, isolation of the luciferase from host cells is preferred. DNA for such purposes is widely available as are modified forms thereof.\nExamples of luciferases include, but are not limited to, those isolated from the ctenophores Mnemiopsis (mnemiopsin) and Beroe ovata (berovin), those isolated from the coelenterates Aequorea (aequorin), Obelia (obelin), Pelagia, the Renilla luciferase, the luciferases isolated from the mollusca Pholas (pholasin), the luciferases isolated from fish, such as Aristostomias, Pachystomias and Poricthys and from the ostracods, such as Cypridina (also referred to as Vargula). Preferred luciferases for use herein are the Aequorin protein, Renilla luciferase and Cypridina [also called Vargula] luciferase [see, e.g., SEQ ID Nos. 1, 2, and 4-13]. Also, preferred are luciferases which react to produce red and\/or near infrared light. These include luciferases found in species of Aristostomias, such as A. scintillans, Pachystomias, Malacosteus, such as M. niger. \n(2) Luciferins\nThe substrates for the reaction or for inclusion in the conjugates include any molecule(s) with which the luciferase reacts to produce light. Such molecules include the naturally-occurring substrates, modified forms thereof, and synthetic substrates [see, e.g., U.S. Pat. Nos. 5,374,534 and 5,098,828]. Exemplary luciferins include those described herein, as well as derivatives thereof, analogs thereof, synthetic substrates, such as dioxetanes [see, e.g., U.S. Pat. Nos. 5,004,565 and 5,455,357], and other compounds that are oxidized by a luciferase in a light-producing reaction [see, e.g., U.S. Pat. Nos. 5,374,534, 5,098,828 and 4,950,588]. Such substrates also may be identified empirically by selecting compounds that are oxidized in bioluminescent reactions.\n(3) Activators\nThe bioluminescent generating systems also require additional components discussed herein and known to those of skill in the art. All bioluminescent reactions require molecular oxygen in the form of dissolved or bound oxygen. Thus, molecular oxygen, dissolved in water or in air or bound to a photoprotein, is the activator for bioluminescence reactions. Depending upon the form of the components, other activators include, but are not limited to, ATP [for firefly luciferase], flavin reductase [bacterial systems] for regenerating FMNH2 from FMN, and Ca2+ or other suitable metal ion [aequorin].\nMost of the systems provided herein will generate light when the luciferase and luciferin are mixed and exposed to air or water. The systems that use photoproteins that have bound oxygen, such as aequorin, however, will require exposure to Ca2+ [or other suitable metal ion], which can be provided in the form of an aqueous composition of a calcium salt. In these instances, addition of a Ca2+ [or other suitable metal ion] to a mixture of luciferase [aequorin] and luciferin [such as coelenterazine] will result in generation of light. The Renilla system and other Anthozoa systems also require Ca2+ [or other suitable metal ion].\nIf crude preparations are used, such as ground up Cypridina [shrimp] or ground fireflies, it may be necessary to add only water. In instances in which fireflies [or a firefly or beetle luciferase] are used the reaction may only require addition ATP. The precise components will be apparent, in light of the disclosure herein, to those of skill in this art or may be readily determined empirically.\nIt is also understood that these mixtures will also contain any additional salts or buffers or ions that are necessary for each reaction to proceed. Since these reactions are well-characterized, those of skill in the art will be able to determine precise proportions and requisite components. Selection of components will depend upon the apparatus, article of manufacture and luciferase. Various embodiments are described and exemplified herein; in view of such description, other embodiments will be apparent.\n(4) Reactions\nIn all embodiments, all but one component, either the luciferase or luciferin, of a bioluminescence generating system will be mixed or packaged with or otherwise combined. The remaining component is conjugated to a targeting agent and is intended for administration to an animal.\nPrior to a surgical procedure, the conjugate is administered via any suitable route, whereby the targeting agent binds to the targeted tissue by virtue of its specific interaction with a tissue-specific cell surface protein. During surgery the tissue is contacted, with the remaining component(s), typically by spraying the area or local injection, and any tissue to which conjugate is bound will glow. The glow should be sufficient to see under dim light or, if necessary, in the dark.\nIn general, since the result to be achieved is the production of light visible to the naked eye for qualitative, not quantitative, diagnostic purposes, the precise proportions and amounts of components of the bioluminescence reaction need not be stringently determined or met. They must be sufficient to produce light. Generally, an amount of luciferin and luciferase sufficient to generate a visible glow is used; this amount can be readily determined empirically and is dependent upon the selected system and selected application. Where quantitative measurements are required, more precision may be required.\nFor purposes herein, such amount is preferably at least the concentrations and proportions used for analytical purposes by those of skill in the such arts. Higher concentrations may be used if the glow is not sufficiently bright. Alternatively, a microcarrier coupled to more than one luciferase molecule linked to a targeting agent may be utilized to increase signal output. Also because the conditions in which the reactions are used are not laboratory conditions and the components are subject to storage, higher concentration may be used to overcome any loss of activity. Typically, the amounts are 1 mg, preferably 10 mg and more preferably 100 mg, of a luciferase per liter of reaction mixture or 1 mg, preferably 10 mg, more preferably 100 mg. Compositions may contain at least about 0.01 mg\/l, and typically 0.1 mg\/l, 1 mg\/l, 10 mg\/l or more of each component on the item. The amount of luciferin is also between about 0.01 and 100 mg\/l, preferably between 0.1 and 10 mg\/l, additional luciferin can be added to many of the reactions to continue the reaction. In embodiments in which the luciferase acts catalytically and does not need to be regenerated, lower amounts of luciferase can be used. In those in which it is changed during the reaction, it also can be replenished; typically higher concentrations will be selected. Ranges of concentration per liter [or the amount of coating on substrate the results from contacting with such composition] of each component on the order of 0.1 to 20 mg, preferably 0.1 to 10 mg, more preferably between about 1 and 10 mg of each component will be sufficient. When preparing coated substrates, as described herein, greater amounts of coating compositions containing higher concentrations of the luciferase or luciferin may be used.\nThus, for example, in presence of calcium, 5 mg of luciferin, such as coelenterazine, in one liter of water will glow brightly for at least about 10 to 20 minutes, depending on the temperature of the water, when about 10 mgs of luciferase, such as aequorin photoprotein luciferase or luciferase from Renilla, is added thereto. Increasing the concentration of luciferase, for example, to 100 mg\/l, provides a particularly brilliant display of light.\nIt is understood, that concentrations and amounts to be used depend upon the selected bioluminescence generating system but these may be readily determined empirically. Proportions, particularly those used when commencing an empirical determination, are generally those used for analytical purposes, and amounts or concentrations are at least those used for analytical purposes, but the amounts can be increased, particularly if a sustained and brighter glow is desired.\nb. Ctenophore and Coelenterate Systems\nCtenophores, such as Mnemiopsis (mnemiopsin) and Beroe ovata (berovin), and coelenterates, such as Aequorea (aequorin), Obelia (obelin) and Pelagia, produce bioluminescent light using similar chemistries [see, e.g., Stephenson et al. (1981) Biochimica et Biophysica Acta 678:65-75; Hart et al. (1979) Biochemistry 18:2204-2210; International PCT Application No. WO 94\/18342, which is based on U.S. application Ser. No. 08\/017,116, U.S. Pat. No. 5,486,455 and other references and patents cited herein]. The Aequorin and Renilla systems are representative and are described in detail herein as exemplary and as among the presently preferred systems. The Aequorin and Renilla systems can use the same luciferin and produce light using the same chemistry, but each luciferase is different. The Aequorin luciferase aequorin, as well as, for example, the luciferases mnemiopsin and berovin, is a photoprotein that includes bound oxygen and bound luciferin, requires Ca2+ [or other suitable metal ion] to trigger the reaction, and must be regenerated for repeated use; whereas, the Renilla luciferase acts as a true enzyme because it is unchanged during the reaction and it requires dissolved molecular oxygen.\n(1) The Aequorin System\nThe aequorin system is well known [see, e.g., Tsuji et al. (1986) xe2x80x9cSite-specific mutagenesis of the calcium-binding photoprotein aequorin,xe2x80x9d Proc. Natl. Acad. Sci. USA 83:8107-8111; Prasher et al. (1985) xe2x80x9cCloning and Expression of the cDNA Coding for Aequorin, a Bioluminescent Calcium-Binding Protein,xe2x80x9d Biochemical and Biophysical Research Communications 126:1259-1268; Prasher et al. (1986) Methods in Enzymology 133:288-297; Prasher, et al. (1987) xe2x80x9cSequence Comparisons of cDNAs Encoding for Aequorin Isotypes,xe2x80x9d Biochemistry 26:1326-1332; Charbonneau et al. (1985) xe2x80x9cAmino Acid Sequence of the Calcium-Dependent Photoprotein Aequorin,xe2x80x9d Biochemistry 24:6762-6771; Shimomura et al. (1981) xe2x80x9cResistivity to denaturation of the apoprotein of aequorin and reconstitution of the luminescent photoprotein from the partially denatured apoprotein,xe2x80x9d Biochem. J. 199:825-828; Inouye et al. (1989) J. Biochem. 105:473-477; Inouye et al. (1986) xe2x80x9cExpression of Apoaequorin Complementary DNA in Escherichia coli,xe2x80x9d Biochemistry 25:8425-8429; Inouye et al. (1985) xe2x80x9cCloning and sequence analysis of cDNA for the luminescent protein aequorin,xe2x80x9d Proc. Natl. Acad. Sci. USA 82:3154-3158; Prendergast, et al. (1978) xe2x80x9cChemical and Physical Properties of Aequorin and the Green Fluorescent Protein Isolated from Aequorea forskaleaxe2x80x9d J. Am. Chem. Soc. 17:3448-3453; European Patent Application 0 540 064 A1; European Patent Application 0 226 979 A2, European Patent Application 0 245 093 A1 and European Patent Application 0 245 093 B1; U.S. Pat. No. 5,093,240; U.S. Pat. No. 5,360,728; U.S. Pat. No. 5,139,937; U.S. Pat. No. 5,422,266; U.S. Pat. No. 5,023,181; U.S. Pat. No. 5,162,227; and SEQ ID Nos. 5-13, which set forth DNA encoding the apoprotein; and a form, described in U.S. Pat. No. 5,162,227, European Patent Application 0 540 064 A1 and Sealite Sciences Technical Report No. 3 (1994), is commercially available from Sealite, Sciences, Bogart, Ga. as AQUALITE(copyright)].\nThis system is among the preferred systems for use herein. As will be evident, since the aequorin photoprotein includes noncovalently bound luciferin and molecular oxygen, it is suitable for storage in this form as a lyophilized powder or encapsulated into a selected delivery vehicle. The system can be encapsulated into pellets, such as liposomes or other delivery vehicles. When used, the vehicles are contacted with a composition, even tap water, that contains Ca2+ [or other suitable metal ion], to produce a mixture that glows.\n(a) Aequorin and Related Photoproteins\nThe photoprotein, aequorin, isolated from the jellyfish, Aequorea, emits light upon the addition of Ca2+ [or other suitable metal ion]. The aequorin photoprotein, which includes bound luciferin and bound oxygen that is released by Ca2+, does not require dissolved oxygen. Luminescence is triggered by calcium, which releases oxygen and the luciferin substrate producing apoaqueorin.\nThe bioluminescence photoprotein aequorin is isolated from a number of species of the jellyfish Aequorea. It is a 22 kilodalton [kD] molecular weight peptide complex [see, e.g., Shimomura et al. (1962) J. Cellular and Comp. Physiol. 59:233-238; Shimomura et al. (1969) Biochemistry 8:3991-3997; Kohama et al. (1971) Biochemistry 10:4149-4152; and Shimomura et al. (1972) Biochemistry 11:1602-1608]. The native protein contains oxygen and a heterocyclic compound coelenterazine, a luciferin, [see, below] noncovalently bound thereto. The protein contains three calcium binding sites. Upon addition of trace amounts Ca2+ [or other suitable metal ion, such as strontium] to the photoprotein, it undergoes a conformational change the catalyzes the oxidation of the bound coelenterazine using the protein-bound oxygen. Energy from this oxidation is released as a flash of blue light, centered at 469 nm. Concentrations of calcium ions as low as 10xe2x88x926 M are sufficient to trigger the oxidation reaction.\nNaturally-occurring apoaequorin is not a single compound but rather is a mixture of microheterogeneous molecular species. Aequoria jellyfish extracts contain as many as twelve distinct variants of the protein [see, e.g., Prasher et al. (187) Biochemistry 26:1326-1332; Blinks et al. (1975) Fed. Proc. 34:474]. DNA encoding numerous forms has been isolated [see, e.g., SEQ ID Nos. 5-9 and 13].\nThe photoprotein can be reconstituted [see, e.g., U.S. Pat. No. 5,023,181] by combining the apoprotein, such as a protein recombinantly produced in E. coli, with a coelenterazine, such as a synthetic coelenterazine, in the presence of oxygen and a reducing agent [see, e.g., Shimomura et al. (1975) Nature 256:236-238; Shimomura et al. (1981) Biochemistry J. 199:825-828], such as 2-mercaptoethanol, and also EDTA or EGTA [concentrations between about 5 to about 100 mM or higher for applications herein] tie up any Ca2+ to prevent triggering the oxidation reaction until desired. DNA encoding a modified form of the apoprotein that does not require 2-mercaptoethanol for reconstitution is also available [see, e.g., U.S. Pat. No. 5,093,240]. The reconstituted photoprotein is also commercially available [sold, e.g., under the trademark AQUALITE(copyright), which is described in U.S. Pat. No. 5,162,227].\nThe light reaction is triggered by adding Ca2+ at a concentration sufficient to overcome the effects of the chelator and achieve the 10xe2x88x926 M concentration. Because such low concentrations of Ca2+ can trigger the reaction, for use in the methods herein, higher concentrations of chelator may be included in the compositions of photoprotein. Accordingly, higher concentrations of added Ca2+ in the form of a calcium salt will be required. Precise amounts may be empirically determined. For use herein, it may be sufficient to merely add water to the photoprotein, which is provided in the form of a concentrated composition or in lyophilized or powdered form. Thus, for purposes herein, addition of small quantities of Ca2+, such as those present in phosphate buffered saline (PBS) or other suitable buffers or the moisture on the tissue to which the compositions are contacted, should trigger the bioluminescence reaction.\nNumerous isoforms of the aequorin apoprotein been identified isolated. DNA encoding these proteins has been cloned, and the proteins and modified forms thereof have been produced using suitable host cells [see, e.g., U.S. Pat. Nos. 5,162,227, 5,360,728, 5,093,240; see, also, Prasher et al. (1985) Biophys. Biochem. Res. Commun. 126:1259-1268; Inouye et al. (1986) Biochemistry 25:8425-8429]. U.S. Pat. No. 5,093,240; U.S. Pat. No. 5,360,728; U.S. Pat. No. 5,139,937; U.S. Pat. No. 5,288,623; U.S. Pat. No. 5,422,266, U.S. Pat. No. 5,162,227 and SEQ ID Nos. 5-13, which set forth DNA encoding the apoprotein; and a form is commercially available form Sealite, Sciences, Bogart, Ga. as AQUALITE(copyright)]. DNA encoding apoaequorin or variants thereof is useful for recombinant production of high quantities of the apoprotein. The photoprotein is reconstituted upon addition of the luciferin, coelenterazine, preferably a sulfated derivative thereof, or an analog thereof, and molecular oxygen [see, e.g., U.S. Pat. No. 5,023,181]. The apoprotein and other constituents of the photoprotein and bioluminescence generating reaction can be mixed under appropriate conditions to regenerate the photoprotein and concomitantly have the photoprotein produce light. Reconstitution requires the presence of a reducing agent, such as mercaptoethanol, except for modified forms, discussed below, that are designed so that a reducing agent is not required [see, e.g., U.S. Pat. No. 5,093,240].\nFor use herein, it is preferred aequorin is produced using DNA, such as that set forth in SEQ ID Nos. 5-13 and known to those of skill in the art or modified forms thereof. The DNA encoding aequorin is expressed in a host cell, such as E. coli, isolated and reconstituted to produce the photoprotein [see, e.g., U.S. Pat. Nos. 5,418,155, 5,292,658, 5,360,728, 5,422,266, 5,162,227].\nOf interest herein, are forms of the apoprotein that have been modified so that the bioluminescent activity is greater than unmodified apoaequorin [see, e.g., U.S. Pat. No. 5,360,728, SEQ ID Nos. 10-12]. Modified forms that exhibit greater bioluminescent activity than unmodified apoaequorin include proteins having sequences set forth in SEQ ID Nos. 10-12, in which aspartate 124 is changed to serine, glutamate 135 is changed to serine, and glycine 129 is changed to alanine, respectively. Other modified forms with increased bioluminescence are also available.\nFor use in certain embodiments herein, the apoprotein and other components of the aequorin bioluminescence generating system are packaged or provided as a mixture, which, when desired is subjected to conditions under which the photoprotein reconstitutes from the apoprotein, luciferin and oxygen [see, e.g., U.S. Pat. No. 5,023,181; and U.S. Pat. No. 5,093,240]. Particularly preferred are forms of the apoprotein that do not require a reducing agent, such as 2-mercaptoethanol, for reconstitution. These forms, described, for example in U.S. Pat. No. 5,093,240 [see, also Tsuji et al. (1986) Proc. Natl. Acad. Sci. U.S.A. 83:8107-8111], are modified by replacement of one or more, preferably all three cysteine residues with, for example serine. Replacement may be effected by modification of the DNA encoding the aequorin apoprotein, such as that set forth in SEQ ID No. 5, and replacing the cysteine codons with serine.\nThe photoproteins and luciferases from related species, such as Obelia are also contemplated for use herein. DNA encoding the Ca2+-activated photoprotein obelin from the hydroid polyp Obelia longissima is known and available [see, e.g., Illarionov et al. (1995) Gene 153:273-274; and Bondar et al. (1995) Biochim. Biophys. Acta 1231:29-32]. This photoprotein can also be activated by Mn2+ [see, e.g., Vysotski et al. (1995) Arch. Bioch. Biophys. 316:92-93, Vysotski et al. (1993) J. Bio-lumin. Chemilumin. 8:301-305].\nIn general for use herein, the components of the bioluminescence are packaged or provided so that there is insufficient metal ions to trigger the reaction. When used, the trace amounts of triggering metal ion, particularly Ca2+ is contacted with the other components. For a more sustained glow, aequorin can be continuously reconstituted or can be added or can be provided in high excess.\n(b) Luciferin\nThe aequorin luciferin is coelenterazine and analogs therein, which include molecules having the structure [formula (I)]: \nin which R1 is CH2C6H5 or CH3; R2 is C6H5, and R3 is p-C6H4OH or CH3 or other such analogs that have activity. Preferred coelenterazine has the structure in which R1 is p-CH2C6H4OH, R2 is C6H5, and R3 is p-C6H4OH, which can be prepared by known methods [see, e.g., Inouye et al. (1975) Jap. Chem. Soc., Chemistry Lttrs. pp 141-144; and Halt et al. (1979) Biochemistry 18:2204-2210]. Among the preferred analogs, are those that are modified, whereby the spectral frequency of the resulting light is shifted to another frequency.\nThe preferred coelenterazine has the structure (formula (II)): \nand sulfated derivatives thereof.\nThe reaction of coelenterazine when bound to the aequorin photoprotein with bound oxygen and in the presence of Ca2+ can represented as follows: \nThe photoprotein aequorin [which contains apoaequorin bound to a coelenterate luciferin molecule] and Renilla luciferase, discussed below, can use the same coelenterate luciferin. The aequorin photoprotein catalyses the oxidation of coelenterate luciferin [coelenterazine] to oxyluciferin [coelenteramide] with the concomitant production of blue light [lambdamax=469 nm].\nImportantly, the sulfate derivative of the coelenterate luciferin [lauryl-luciferin] is particularly stable in water, and thus may be used in a coelenterate-like bioluminescent system. In this system, adenosine diphosphate (ADP) and a sulpha-kinase are used to convert the coelenterazine to the sulphated form. Sulfatase is then used to reconvert the lauryl-luciferin to the native coelenterazine. Thus, the more stable lauryl-luciferin is used in the item to be illuminated and the luciferase combined with the sulfatase are added to the luciferin mixture when illumination is desired.\nThus, the bioluminescent system of Aequorea is particularly suitable for use in the methods herein. The particular amounts and the manner in which the components are provided depends upon the type of neoplasia or specialty tissue to be visualized. This system can be provided in lyophilized form, that will glow upon addition of Ca2+. It can be encapsulated, linked to microcarriers, such as microbeads, or in as a compositions, such as a solution or suspension, preferably in the presence of sufficient chelating agent to prevent triggering the reaction. The concentration of the aequorin photoprotein will vary and can be determined empirically. Typically concentrations of at least 0.1 mg\/l, more preferably at least 1 mg\/l and higher, will be selected. In certain embodiments, 1-10 mg luciferin\/100 mg of luciferase will be used in selected volumes and at the desired concentrations will be used.\n(2) The Renilla System\nRepresentative of coelenterate systems is the Renilla system. Renilla, also known as sea pansies, are members of the class of coelenterates Anthozoa, which includes other bioluminescent genera, such as Cavarnularia, Ptilosarcus, Stylatula, Acanthoptilum, and Parazoanthus. Bioluminescent members of the Anthozoa genera contain luciferases and luciferins that are similar in structure [see, e.g., Cormier et al. (1973) J. Cell. Physiol. 81:291-298; see, also Ward et al. (1975) Proc. Natl. Acad. Sci. U.S.A. 72:2530-2534]. The luciferases and luciferins from each of these anthozoans crossreact with one another and produce a characteristic blue luminescence.\nRenilla luciferase and the other coelenterate and ctenophore luciferases, such as the aequorin photoprotein, use imidazopyrazine substrates, particularly the substrates generically called coelenterazine [see, formulae (I) and (II), above]. Other genera that have luciferases that use a coelenterazine include: squid, such as Chiroteuthis, Eucleoteuthis, Onychoteuthis, Watasenia, cuttlefish, Sepiolina; shrimp, such as Oplophorus, Acanthophyra, Sergestes, and Gnathophausia; deep-sea fish, such as Argyropelecus, Yarella, Diaphus, Gonadostomias and Neoscopelus.\nRenilla luciferase does not, however, have bound oxygen, and thus requires dissolved oxygen in order to produce light in the presence of a suitable luciferin substrate. Since Renilla luciferase acts as a true enzyme [i.e., it does not have to be reconstituted for further use] the resulting luminescence can be long-lasting in the presence of saturating levels of luciferin. Also, Renilla luciferase is relatively stable to heat.\nRenilla luciferase, DNA encoding Renilla luciferase, and use of the DNA to produce recombinant luciferase, as well as DNA encoding luciferase from other coelenterates, are well known and available [see, e.g., SEQ ID No. 1, U.S. Pat. Nos. 5,418,155 and 5,292,658; see, also, Prasher et al. (1985) Biochem. Biophys. Res. Commun. 126:1259-1268; Cormier (1981) xe2x80x9cRenilla and Aequorea bioluminescencexe2x80x9d in Bioluminescence and Chemiluminescence, pp. 225-233; Charbonneau et al. (1979) J. Biol. Chem. 254:769-780; Ward et al. (1979) J. Biol. Chem. 254:781-788; Lorenz et al. (1981) Proc. Natl. Acad. Sci. U.S.A. 88:4438-4442; Hori et al. (1977) Proc. Natl. Acad. Sci. U.S.A. 74:4285-4287; Hori et al. (1975) Biochemistry 14:2371-2376; Hori et al. (1977) Proc. Natl. Acad. Sci. U.S.A. 74:4285-4287; Inouye et al. (1975) Jap. Soc. Chem. Lett. 141-144; and Matthews et al. (1979) Biochemistry 16:85-91]. The DNA encoding Renilla luciferase and host cells containing such DNA provide a convenient means for producing large quantities of the enzyme [see, e.g., U.S. Pat. Nos. 5,418,155 and 5,292,658, which describe recombinant production of Renilla luciferase and the use of the DNA to isolate DNA encoding other luciferases, particularly those from related organisms].\nWhen used herein, the Renilla luciferase can be packaged in lyophilized form, encapsulated in a vehicle, either by itself or in combination with the luciferin substrate. Prior to use the mixture is contacted with an aqueous composition, preferably a phosphate buffered saline pH 7-8; dissolved O2 will activate the reaction. Final concentrations of luciferase in the glowing mixture will be on the order of 0.01 to 1 mg\/l or more. Concentrations of luciferin will be at least about 10xe2x88x928 M, but 1 to 100 or more orders of magnitude higher to produce a long lasting bioluminescence.\nIn certain embodiments herein, about 1 to 10 mg, or preferably 2-5 mg, more preferably about 3 mg of coelenterazine will be used with about 100 mg of Renilla luciferase. The precise amounts, of course can be determined empirically, and, also will depend to some extent on the ultimate concentration and application. In particular, about addition of about 0.25 ml of a crude extract from the bacteria that express Renilla to 100 ml of a suitable assay buffer and about 0.005 xcexcg was sufficient to produce a visible and lasting glow [see, U.S. Pat. Nos. 5,418,155 and 5,292,658, which describe recombinant production of Renilla luciferase].\nLyophilized mixtures, and compositions containing the Renilla luciferase are also provided. The luciferase or mixtures of the luciferase and luciferin may also be encapsulated into a suitable delivery vehicle, such as a liposome, glass particle, capillary tube, drug delivery vehicle, gelatin, time release coating or other such vehicle. The luciferase may also be linked to a substrate, such as biocompatible materials.\nc. Crustacean, Particularly Cyrpidina Systems\nThe ostracods, such as Vargula serratta, hilgendorfii and noctiluca are small marine crustaceans, sometimes called sea fireflies. These sea fireflies are found in the waters off the coast of Japan and emit light by squirting luciferin and luciferase into the water, where the reaction, which produces a bright blue luminous cloud, occurs. The reaction involves only luciferin, luciferase and molecular oxygen, and, thus, is very suitable for application herein.\nThe systems, such as the Vargula bioluminescent systems, are particularly preferred herein because the components are stable at room temperature if dried and powdered and will continue to react even if contaminated. Further, the bioluminescent reaction requires only the luciferin\/luciferase components in concentrations as low as 1:40 parts per billion to 1:100 parts per billion, water and molecular oxygen to proceed. An exhausted system can renewed by addition of luciferin.\n(1) Vargula Luciferase\nThe Vargula luciferase is water soluble and is among those preferred for use in the methods herein. Vargula luciferase is a 555-amino acid polypeptide that has been produced by isolation from Vargula and also using recombinant technology by expressing the DNA in suitable bacterial and mammalian host cells [see, e.g., Thompson et al. (1989) Proc. Natl. Acad. Sci. U.S.A. 86:6567-6571; Inouye et al. (1992) Proc. Natl. Acad. Sci. U.S.A. 89:9584-9587; Johnson et al. (1978) Methods in Enzymology LVII:331-349; Tsuji et al. (1978) Methods Enzymol. 57:364-72; Tsuji (19740 Biochemistry 13:5204-5209; Japanese Patent Application No. JP 3-30678 Osaka; and European Patent Application No. EP 0 387 355 A1].\n(a) Purification from Cypridina\nMethods for purification of Vargula [Cypridina] luciferase are well known. For example, crude extracts containing the active can be readily prepared by grinding up or crushing the Vargula shrimp. In other embodiments, a preparation of Cypridina hilgendorfi luciferase can be prepared by immersing stored frozen C. hilgendorfi in distilled water containing, 0.5-5.0 M salt, preferably 0.5-2.0 M sodium or potassium chloride, ammonium sulfate, at 0-30xc2x0 C., preferably 0-10xc2x0 C., for 1-48 hr, preferably 10-24 hr, for extraction followed by hydrophobic chromatography and then ion exchange or affinity chromatography [TORAY IND INC, Japanese patent application JP 4258288, published Sep. 14, 1993; see, also, Tsuji et al. (1978) Methods Enzymol. 57:364-72 for other methods].\nThe luciferin can be isolated from ground dried Vargula by heating the extract, which destroys the luciferase but leaves the luciferin intact [see, e.g., U.S. Pat. No. 4,853,327].\n(b) Preparation by Recombinant Methods\nThe luciferase is preferably produced by expression of cloned DNA encoding the luciferase [European Patent Application No. 0 387 355 A1; International PCT Application No. WO 95\/001542; see, also SEQ ID No. 5, which sets forth the sequence from Japanese Patent Application No. JP 3-30678 and Thompson et al. (1989) Proc. Natl. Acad. Sci. U.S.A. 86:6567-6571] DNA encoding the luciferase or variants thereof is introduced into E. coli using appropriate vectors and isolated using standard methods.\n(2) Vargula Luciferin\nThe natural luciferin in a substituted imidazopyrazine nucleus, such a compound of formula (III): \nAnalogs thereof and other compounds that react with the luciferase in a light producing reaction also may be used.\nOther bioluminescent organisms that have luciferases that can react with the Vargula luciferin include, the genera Apogon, Parapriacanthus and Porichthys.\n(3) Reaction\nThe luciferin upon reaction with oxygen forms a dioxetanone intermediate [which includes a cyclic peroxide similar to the firefly cyclic peroxide molecule intermediate]. In the final step of the bioluminescent reaction, the peroxide breaks down to form CO2 and an excited carbonyl. The excited molecule then emits a blue to blue-green light.\nThe optimum pH for the reaction is about 7. For purposes herein, any pH at which the reaction occurs may be used. The concentrations of reagents are those normally used for analytical reactions or higher [see, e.g., Thompson et al. (1990) Gene 96:257-262]. Typically concentrations of the luciferase between 0.1 and 10 mg\/l, preferably 0.5 to 2.5 mg\/l will be used. Similar concentrations or higher concentrations of the luciferin may be used.\nd. Insect Bioluminescent Systems Including Fireflies, Click Beetles, and Other Insect System\nThe biochemistry of firefly bioluminescence was the first bioluminescent system to be characterized [see, e.g., Wienhausen et al. (1985) Photochemistry and Photobiology 42:609-611; McElroy et al. (1966) in Molecular Architecture in cell Physiology, Hayashi et al., eds. Prentice Hall, Inc., Englewood Cliffs, N.J., pp. 63-80] and it is commercially available [e.g., from Promega Corporation, Madison, Wis., see, e.g., Leach et al. (1986) Methods in Enzymology 133:51-70, esp. Table 1]. Luciferases from different species of fireflies are antigenically similar. These species include members of the genera Photinus, Photurins and Luciola. Further, the bioluminescent reaction produces more light at 30xc2x0 C. than at 20xc2x0 C., the luciferase is stabilized by small quantities of bovine albumin serum, and the reaction can be buffered by tricine.\n(1) Luciferase\nDNA clones encoding luciferases from various insects and the use to produce the encoded luciferase is well known. For example, DNA clones that encode luciferase from Photinus pyralis, Luciola cruciata [see, e.g., de Wet et al. (1985) Proc. Natl. Acad. Sci. U.S.A. 82:7870-7873; de We et al. (1986) Methods in Enzymology 133:3; U.S. Pat. No. 4,968,613, see, also SEQ ID No. 3] are available. The DNA has also been expressed in Saccharomyces [see, e.g., Japanese Application No. JP 63317079, published Dec. 26, 1988, KIKKOMAN CORP] and in tobacco.\nIn addition to the wild-type luciferase modified insect luciferases have been prepared. For example, heat stable luciferase mutants, DNA-encoding the mutants, vectors and transformed cells for producing the luciferases are available. A protein with 60% amino acid sequence homology with luciferases from Photinus pyralis, Luciola mingrelica, L. cruciata or L. lateralis and having luciferase activity is available [see, e.g., International PCT Application No. WO 95\/25798]. It is more stable above 30xc2x0 C. than naturally-occurring insect luciferases and may also be produced at 37xc2x0 C. or above, with higher yield.\nModified luciferases that generate light at different wavelengths [compared with native luciferase], and thus, may be selected for their color-producing characteristics. For example, synthetic mutant beetle luciferase(s) and DNA encoding such luciferases that produce bioluminescence at a wavelength different from wild-type luciferase are known [Promega Corp, International PCT Application No. WO 95\/18853, which is based on U.S. application Ser. No. 08\/177,081]. The mutant beetle luciferase has an amino acid sequence differing from that of the corresponding wild-type Luciola cruciata [see, e.g., U.S. Pat. Nos. 5,182,202, 5,219,737, 5,352,598, see, also SEQ ID No.3] by a substitution(s) at one or two positions. The mutant luciferase produces a bioluminescence with a wavelength of peak intensity that differs by at least 1 nm from that produced by wild-type luciferases.\nOther mutant luciferase have also been produced. Mutant luciferases with the amino acid sequence of wild-type luciferase, but with at least one mutation in which valine is replaced by isoleucine at the amino acid number 233, valine by isoleucine at 239, serine by asparagine at 286, glycine by serine at 326, histidine by tyrosine at 433 or proline by serine at 452 are known [see, e.g., U.S. Pat. Nos. 5,219,737, and 5,330,906]. The luciferases are produced by expressing DNA-encoding each mutant luciferase in E. coli and isolating the protein. These luciferases produce light with colors that differ from wild-type. The mutant luciferases catalyze luciferin to produce red [xcex609 nm and 612 nm], orange[xcex595 and 607 nm] or green [xcex 558 nm] light. The other physical and chemical properties of mutant luciferase are substantially identical to native wild type-luciferase. The mutant luciferase has the amino acid sequence of Luciola cruciata luciferase with an alteration selected from Ser 286 replaced by Asn, Gly 326 replaced by Ser, His 433 replaced by Tyr or Pro 452 replaced by Ser. Thermostable luciferases are also available [see, e.g., U.S. Pat. No. 5,229,285; see, also International PCT Application No. WO 95\/25798, which provides Photinus luciferase in which the glutamate at position 354 is replaced lysine and Luciola luciferase in which the glutamate at 356 is replaced with lysine].\nThese mutant luciferases as well as the wild type luciferases are among those preferred herein, particularly in instances when a variety of colors are desired or when stability at higher temperatures is desired. \nAnalogs of this luciferin and synthetic firefly luciferins are also known to those of skill in art [see, e.g., U.S. Pat. No. 5,374,534 and 5,098,828]. These include compounds of formula (IV) [see, U.S. Pat. No. 5,098,828]: \nin which:\nR1 is hydroxy, amino, linear or branched C1-C20 alkoxy, C2-C20 alkyenyloxy, an L-amino acid radical bond via the xcex1-amino group, an oligopeptide radical with up to ten L-amino acid units linked via the xcex1-amino group of the terminal unit;\nR2 is hydrogen, H2PO3, HSO3, unsubstituted or phenyl substituted linear or branched C1-C20 alkyl or C2-C20alkenyl, aryl containing 6 to 18 carbon atoms, or R3xe2x80x94C(O)xe2x80x94; and\nR3 is an unsubstituted or phenyl substituted linear or branched C1-C20 alkyl or C2-C20alkenyl, aryl containing 6 to 18 carbon atoms, a nucleotide radical with 1 to 3 phosphate groups, or a glycosidically attached mono- or disaccharide, except when formula (IV) is a D-luciferin or D-luciferin methyl ester.\nModified luciferins that have been modified to produce light of shifted frequencies are known to those of skill in the art.\n(3) Reaction\nThe reaction catalyzed by firefly luciferases and related insect luciferases requires ATP, Mg2+ as well as molecular oxygen. Luciferin must be added exogenously. Firefly luciferase catalyzes the firefly luciferin activation and the subsequent steps leading to the excited product. The luciferin reacts with ATP to form a luciferyl adenylate intermediate. This intermediate then reacts with oxygen to form a cyclic luciferyl peroxy species, similar to that of the coelenterate intermediate cyclic peroxide, which breaks down to yield CO2 and an excited state of the carbonyl product. The excited molecule then emits a yellow light; the color, however, is a function of pH. As the pH is lowered the color of the bioluminescence changes from yellow-green to red.\nDifferent species of fireflies emit different colors of bioluminescence so that the color of the reaction will be dependent upon the species from which the luciferase is obtained. Additionally, the reaction is optimized at pH 7.8.\nAddition of ATP and luciferin to a reaction that is exhausted produces additional light emission. Thus, the system, once established, is relatively easily maintained. Therefore, it is highly suitable for use herein in embodiments in which a sustained glow is desired.\ne. Bacterial Systems\nLuminous bacteria typically emit a continuous light, usually blue-green. When strongly expressed, a single bacterium may emit 104 to 105 photons per second. Bacterial bioluminescence systems include, among others, those systems found in the bioluminescent species of the genera Photobacterium, Vibrio and Xenorhabdus. These systems are well known and well characterized [see, e.g., Baldwin et al. (1984) Biochemistry 23:3663-3667; Nicoli et al. (1974) J. Biol. Chem. 249:2393-2396; Welches et al. (1981) Biochemistry 20:512-517; Engebrecht et al. (1986) Methods in Enzymology 133:83-99; Frackman et al. (1990) J. of Bacteriology 172:5767-5773; Miyamoto et al. (1986) Methods in Enzymology 133:70; U.S. Pat. No. 4,581,3351.\n(1) Luciferases\nBacterial luciferase, as exemplified by luciferase derived from Vibrio harveyi [EC 22.214.171.124, alkanol reduced-FMN-oxygen oxidoreductase 1-hydroxylating, luminescing], is a mixed function oxidase, formed by the association of two different protein subunits xcex1 and xcex2. The xcex1-subunit has an apparent molecular weight of approximately 42,000 kD and the xcex2-subunit has an apparent molecular weight of approximately 37,000 kD [see, e.g., Cohn et al. (1989) Proc. Natl. Acad. Sci. U.S.A. 90:102-123]. These subunits associate to form a 2-chain complex luciferase enzyme, which catalyzes the light emitting reaction of bioluminescent bacteria, such as Vibrio harveyi [U.S. Pat. No. 4,581,335; Belas et al. (1982) Science 218:791-793], Vibrio fischeri [Engebrecht et al. (1983) Cell 32:773-781; Engebrecht et al. (1984) Proc. Natl. Acad. Sci. U.S.A. 81:4154-4158] and other marine bacteria.\nBacterial luciferase genes have been cloned [see, e.g., U.S. Pat. No. 5,221,623; U.S. Pat. No. 4,581,335; European Patent Application No. EP 386 691 A]. Plasmids for expression of bacterial luciferase, such as Vibrio harveyi, include pFIT001 (NRRL B-18080), pPALE001 (NRRL B-18082) and pMR19 (NRRL B-18081)] are known. For example the sequence of the entire lux regulon from Vibiro fisheri has been determined [Baldwin et al. (1984), Biochemistry 23:3663-3667; Baldwin et al. (1981) Biochem. 20:512-517; Baldwin et al. (1984) Biochem. 233663-3667; see, also, e.g., U.S. Pat. Nos. 5,196,318, 5,221,623, and 4,581,335]. This regulon includes luxI gene, which encodes a protein required for autoinducer synthesis [see, e.g., Engebrecht et al. (1984) Proc. Natl. Acad. Sci. U.S.A. 81:4154-4158], the luxC, luxD, and luxE genes, which encode enzymes that provide the luciferase with an aldehyde substrate, and the luxA and luxB genes, which encode the alpha and beta subunits of the luciferase.\nLux genes from other bacteria have also been cloned and are available [see, e.g., Cohn et al. (1985) J. Biol. Chem. 260:6139-6146; U.S. Pat. No. 5,196,524, which provides a fusion of the luxA and luxB genes from Vibrio harveyi]. Thus, luciferase alpha and beta subunit-encoding DNA is provided and can be used to produce the luciferase. DNA encoding the xcex1 [1065 bp] and xcex2 [984 bp] subunits, DNA encoding a luciferase gene of 2124 bp, encoding the alpha and beta subunits, a recombinant vector containing DNA encoding both subunits and a transformed E. coli and other bacterial hosts for expression and production of the encoded luciferase are available. In addition, bacterial luciferases are commercially available.\n(2) Luciferins\nBacterial luciferins include: \nin which the tetradecanal with reduced flavin mononucleotide are considered luciferin since both are oxidized during the light emitting reaction.\n(3) Reactions\nThe bacterial systems require, in addition to reduced flavin, five polypeptides to complete the bioluminescent reaction: two subunits, xcex1 and xcex2, of bacterial luciferin and three units of a fatty acid reductase system complex, which supplies the tetradecanal aldehyde. Examples of bacterial bioluminescent systems useful in the apparatus and methods provided herein include those derived from Vibrio fisheri and Vibrio harveyi. One advantage to this system is its ability to operate at cold temperatures; certain surgical procedures are performed by cooling the body to lower temperatures.\nBacterial luciferase catalyzes the flavin-mediated hydroxylation of a long-chain aldehyde to yield carboxylic acid and an excited flavin; the flavin decays to ground state with the concomitant emission of blue green light [xcexmax=490 nm; see, e.g., Legocki et al. (1986) Proc. Natl. Acad. Sci. USA 81:9080; see U.S. Pat. No. 5,196,524]: \nThe reaction can be initiated by contacting reduced flavin mononucleotide [FMNH2] with a mixture of the bacterial luciferase, oxygen, and a long-chain aldehyde, usually n-decyl aldehyde.\nDNA encoding luciferase from the fluorescent bacterium Alteromonas hanedai is known [CHISSO CORP; see, also, Japanese application JP 7222590, published Aug. 22, 1995]. The reduced flavin mononucleotide [FMNH2; luciferin] reacts with oxygen in the presence of bacterial luciferase to produce an intermediate peroxy flavin. This intermediate reacts with a long-chain aldehyde [tetradecanal] to form the acid and the luciferase-bound hydroxy flavin in its excited state. The excited luciferase-bound hydroxy flavin then emits light and dissociates from the luciferase as the oxidized flavin mononucleotide [FMN] and water. In vivo FMN is reduced again and recycled, and the aldehyde is regenerated from the acid.\nFlavin reductases have been cloned [see, e.g., U.S. Pat. No. 5,484,723; see, SEQ ID No. 14 for a representative sequence from this patent]. These as well as NAD(P)H can be included in the reaction to regenerate FMNH2 for reaction with the bacterial luciferase and long chain aldehyde. The flavin reductase catalyzes the reaction of FMN, which is the luciferase reaction, into FMNH2; thus, if luciferase and the reductase are included in the reaction system, it is possible to maintain the bioluminescent reaction. Namely, since the bacterial luciferase turns over many times, bioluminescence continues as long as a long chain aldehyde is present in the reaction system.\nThe color of light produced by bioluminescent bacteria also results from the participation of a protein blue-florescent protein [BFP] in the bioluminescence reaction. This protein, which is well known [see, e.g., Lee et al. (1978) Methods in Enzymology LVII: 226-234], may also be added to bacterial bioluminescence reactions in order to cause a shift in the color.\nf. Other Systems\n(1) Dinoflagellate Bioluminescence Generating Systems\nIn dinoflagellates, bioluminescence occurs in organelles termed scintillons. These organelles are outpocketings of the cytoplasm into the cell vacuole. The scintillons contain only dinoflagellate luciferase and luciferin [with its binding protein], other cytoplasmic components being somehow excluded. The dinoflagellate luciferin is a tetrapyrrole related to chlorophyll: \nor an analog thereof.\nThe luciferase is a 135 kD single chain protein that is active at pH 6.5, but inactive at pH 8 [see, e.g., Hastings (1981) Bioluminescence and Chemiluminescence, DeLuca et al., eds. Academic Press, NY, pp.343-360]. Luminescent activity can be obtained in extracts made at pH 8 by simply shifting the pH from 8 to 6. This occurs in soluble and particulate fractions. Within the intact scintillon, the luminescent flash occurs for xcx9c100 msec, which is the duration of the flash in vivo. In solution, the kinetics are dependent on dilution, as in any enzymatic reaction. At pH 8, the luciferin is bound to a protein [luciferin binding protein] that prevents reaction of the luciferin with the luciferase. At pH 6, however, the luciferin is released and free to react with the enzyme.\n(2) Systems from Molluscs, such as Latia and Pholas\nMolluscs Latia neritoides and species of Pholas are bioluminescent animals. The luciferin has the structure: \nand has been synthesized [see, e.g., Shimomura et al. (1968) Biochemistry 7:1734-1738; Shimomura et al. (1972) Proc. Natl. Acad. Sci. U.S.A. 69:2086-2089]. In addition to a luciferase and luciferin the reaction has a third component, a xe2x80x9cpurple proteinxe2x80x9d. The reaction, which can be initiated by an exogenous reducing agent is represented by the following scheme: \nXH2 is a reducing agent.\nThus for practice herein, the reaction will require the purple protein as well as a reducing agent.\n(3) Earthworms and Other Annelids\nEarthworm species, such as Diplocardia longa, Chaetopterus and Harmothoe, exhibit bioluminescence. The luciferin has the structure: \nThe reaction requires hydrogen peroxide in addition to luciferin and luciferase. The luciferase is a photoprotein.\n(4) Glow Worms\nThe luciferase\/luciferin system from the glow worms that are found in Great Britain, and in Australian and New Zealand caves are also intended for use herein.\n(5) Marine Polycheate Worm Systems\nMarine polycheate worm bioluminescence generating systems, such as Phyxotrix and Chaetopterus, are also contemplated for use herein.\n(6) South American Railway Beetle\nThe bioluminescence generating system from the South American railway beetle is also intended for use herein.\n(7) Fish\nOf interest herein, are luciferases and bioluminescence generating systems that generate red light. These include luciferases found in species of Aristostomias, such as A. scintillans [see, e.g., O\"\"Day et al. (1974) Vision Res. 14:545-550], Pachystomias, Malacosteus, such as M. niger. \nBlue\/green emitters include cyclthone, myctophids, hatchet fish (agyropelecus), vinciguerria, howella, florenciella, and Chauliodus.\ng. Other Fluorescent Proteins\n(1) Green and Blue Fluorescent Proteins\nAs described herein, blue light is produced using the Renilla luciferase or the Aequorea photoprotein in the presence of Ca2+ and the coelenterazine luciferin or analog thereof. This light can be converted into a green light if a green fluorescent protein (GFP) is added to the reaction. Green fluorescent proteins, which have been purified [see, e.g., Prasher et al. (1992) Gene 111:229-233] and also cloned [see, e.g., International PCT Application No. WO 95\/07463, which is based on U.S. application Ser. No. 08\/119,678 and U.S. application Ser. No. 08\/192,274, which are herein incorporated by reference], are used by cnidarians as energy-transfer acceptors. GFPs fluoresce in vivo upon receiving energy from a luciferase-oxyluciferin excited-state complex or a Ca2+-activated photoprotein. The chromophore is modified amino acid residues within the polypeptide. The best characterized GFPs are those of Aequorea and Renilla [see, e.g., Prasher et al. (1992) Gene 111 :229-233; Hart, et al. (1979)Biochemistry 18:2204-2210]. For example, a green fluorescent protein [GFP] from Aequorea victoria contains 238 amino acids, absorbs blue light and emits green light. Thus, inclusion of this protein in a composition containing the aequorin photoprotein charged with coelenterazine and oxygen, can, in the presence of calcium, result in the production of green light. Thus, it is contemplated that GFPs may be included in the bioluminescence generating reactions that employ the aequorin or Renilla luciferases or other suitable luciferase in order to enhance or alter color of the resulting bioluminescence.\nGFPs are activated by blue light to emit green light and thus may be used in the absence of luciferase and in conjunction with an external light source to illuminate neoplasia and specialty tissues, as described herein. Similarly, blue fluorescent proteins (BFPs), such as from Vibrio fischeri, Vibrio harveyi or Photobacterium phosphoreum, may be used in conjunction with an external light source of appropriate wavelength to generate blue light. (See for example, Karatani, et al., xe2x80x9cA blue fluorescent protein from a yellow-emitting luminous bacterium,xe2x80x9d Photochem. Photobiol. 55(2):293-299 (1992); Lee, et al., xe2x80x9cPurification of a blue-fluorescent protein from the bioluminescent bacterium Photobacterium phosphoreumxe2x80x9d Methods Enzymol. (Biolumin. Chemilumin.) 57:226-234 (1978); and Gast, et al. xe2x80x9cSeparation of a blue fluorescence protein from bacterial luciferasexe2x80x9d Biochem. Biophys. Res. Commun. 80(1): 14-21 (1978), each incorporated in its entirety by reference herein.) In particular, GFPs, and\/or BFPs or other such fluorescent proteins may be used in the methods described herein using a targeting agent conjugate by illuminating the conjugate with light of an appropriate wavelength to cause the fluorescent proteins to fluoresce.\nSuch systems are particularly of interest because no luciferase is needed to activate the photoprotein. These fluorescent proteins may also be used in addition to bioluminescence generating systems to enhance or create an array of different colors.\n(2) Phycobiliproteins\nPhycobiliproteins are water soluble fluorescent proteins derived from cyanobacteria and eukaryotic algae [see, e.g., Apt et al. (1995) J. Mol. Biol. 238:79-96; Glazer (1982) Ann. Rev. Microbiol. 36:173-198; and Fairchild et al. (1994) J. of Biol. Chem. 269:8686-8694]. These proteins have been used as fluorescent labels in immunoassay [see, Kronick (1986) J. of Immunolog. Meth. 92:1-13], the proteins have been isolated and DNA encoding them is also available [see, e.g., Pilot et al. (1984) Proc. Natl. Acad. Sci. U.S.A. 81:6983-6987; Lui et al. (1993) Plant Physiol 103:293-294; and Houmard et al. (1988) J. Bacteriol. 170:5512-5521; the proteins are commercially available from, for example, ProZyme, Inc., San Leandro, Calif.].\nIn these organisms, the phycobiliproteins are arranged in subcellular structures termed phycobilisomes, and function as accessory pigments that participate in photosynthetic reactions by absorbing visible light and transferring the derived energy to chlorophyll via a direct fluorescence energy transfer mechanism.\nTwo classes of phycobiliproteins are known based on their color: phycoerythrins (red) and phycocyanins (blue), which have reported absorption maxima between 490 and 570 nm and between 610 and 665 nm, respectively. Phycoerythrins and phycocyanins are heterogenous complexes composed of different ratios of alpha and beta monomers to which one or more class of linear tetrapyrrole chromophores are covalently bound. Particular phycobiliproteins may also contain a third xcex3-subunit which often associated with (xcex1,xcex2)6 aggregate proteins.\nAll phycobiliproteins contain either phycothrombilin or phycoerythobilin chromophores, and may also contain other bilins phycourobilin, cryptoviolin or the 697 nm bilin. The xcex3-subunit is covalently bound with phycourobilin which results in the 495-500 nm absorption peak of B- and R-phycoerythrins. Thus, the spectral characteristics of phycobiliproetins may be influenced by the combination of the different chromophores, the subunit composition of the apophycobiliproteins and\/or the local environment effecting the tertiary and quaternary structure of the phycobiliproteins.\nAs described above for GFPs and BFPs, phycobiliproteins are also activated by visible light of the appropriate wavelength and, thus, may be used in the absence of luciferase and in conjunction with an external light source to illuminate neoplasia and specialty tissues, as described herein. Furthermore, the attachment of phycobiliproteins to solid support matrices is known (e.g., see U.S. Pat. Nos. 4,714,682; 4,767,206; 4,774,189 and 4,867,908). As noted above, these proteins may be used in combination with other fluorescent proteins and\/or bioluminescence generating systems to produce an array of colors or to provide different colors over time.\nAs described above, attachment of phycobiliproteins to solid support matrices is known (e.g., see U.S. Pat. Nos. 4,714,682; 4,767,206; 4,774,189 and 4,867,908). Therefore, phycobiliproteins may be coupled to microcarriers coupled to one or more components of the bioluminescent reaction, preferably a luciferase, to convert the wavelength of the light generated from the bioluminescent reaction. Microcarriers coupled to one or more phycobiliproteins may be used in any of the methods provided herein.\nThe conversion of blue or green light to light of a longer wavelength, i.e., red or near infra-red, is particularly preferred for the visualization of deep neoplasias or specialty tissues using a laparoscope or computer tomogram imaging system, as described herein.\nThus, when a change in the frequency of emitted light is desired, the phycobiliprotein, or other spectral shifter, such as synthetic fluorochrome, green fluorescent proteins, red fluorescent proteins, and substrates altered chemically or enzymatically to cause shifts in frequency of emission can be included with the bioluminescent generating components.\n2. Linkers\nAny linker known to those of skill in the art may be used herein. Other linkers are suitable for incorporation into chemically produced conjugates. Linkers that are suitable for chemically linked conjugates include disulfide bonds, thioether bonds, hindered disulfide bonds, and covalent bonds between free reactive groups, such as amine and thiol groups. These bonds are produced using heterobifunctional reagents to produce reactive thiol groups on one or both of the polypeptides and then reacting the thiol groups on one polypeptide with reactive thiol groups or amine groups to which reactive maleimido groups or thiol groups can be attached on the other. Other linkers include, acid cleavable linkers, such as bismaleimideothoxy propane, acid labile-transferrin conjugates and adipic acid diihydrazide, that would be cleaved in more acidic intracellular compartments; cross linkers that are cleaved upon exposure to UV or visible light and linkers, such as the various domains, such as CH1, CH2, and CH3, from the constant region of human IgG, (see, Batra et al. (1993) Molecular Immunol. 30:379-386). In some embodiments, several linkers may be included in order to take advantage of desired properties of each linker.\nChemical linkers and peptide linkers may be inserted by covalently coupling the linker to the TA and the targeted agent. The heterobifunctional agents, described below, may be used to effect such covalent coupling. Peptide linkers may also be linked by expressing DNA encoding the linker and TA, linker and targeted agent, or linker, targeted agent and TA as a fusion protein.\nFlexible linkers and linkers that increase solubility of the conjugates are contemplated for use, either alone or with other linkers are contemplated herein.\nNumerous heterobifunctional cross-linking reagents that are used to form covalent bonds between amino groups and thiol groups and to introduce thiol groups into proteins, are known to those of skill in this art (see, e.g., the PIERCE CATALOG, ImmunoTechnology Catalog and Handbook, 1992-1993, which describes the preparation of and use of such reagents and provides a commercial source for such reagents; see, also, e.g., Cumber et al. (1992) Bioconjugate Chem. 3:397-401; Thorpe et al. (1987) Cancer Res. 47:5924-5931; Gordon et al. (1987) Proc. Natl. Acad Sci. 84:308-312; Walden et al. (1986) J. Mol. Cell Immunol. 2:191-197; Carlsson et al. (1978) Biochem. J. 173:723-737; Mahan et al. (1987) Anal. Biochem. 162:163-170; Wawryznaczak et al. (1992) Br. J. Cancer 66:361-366; Fattom et al. (1992) Infection and Immun. 60:584-589). These reagents may be used to form covalent bonds between the TA and targeted agent. These reagents include, but are not limited to: N-succinimidyl-3-(2-pyridyldithio)propionate (SPDP; disulfide linker); sulfosuccinimidyl 6-[3-(2-pyridyldithio)propionamido]hexanoate (sulfo-LC-SPDP); succinimidyloxycarbonyl-xcex1-methyl benzyl thiosulfate (SMBT, hindered disulfate linker); succinimidyl 6-[3-(2-pyridyldithio) propionamido]hexanoate (LC-SPDP); sulfosuccinimidyl 4-(N-maleimidomethyl)cyclohexane-1-carboxylate (sulfo-SMCC); succinimidyl 3-(2-pyridyldithio)butyrate (SPDB; hindered disulfide bond linker); sulfosuccinimidyl 2-(7-azido-4-methylcoumarin-3-acetamide) ethyl-1,3xe2x80x2-dithiopropionate (SAED); sulfo-succinimidyl 7-azido-4-methylcoumarin-3-acetate (SAMCA); sulfosuccinimidyl 6-[alpha-methyl-alpha-(2-pyridyldithio)toluamido]-hexanoate (sulfo-LC-SMPT); 1,4-di-[3xe2x80x2-(2xe2x80x2-pyridyldithio)propionamido]butane (DPDPB); 4-succinimidyloxycarbonyl-xcex1-methyl-xcex1-(2-pyridylthio)toluene (SMPT, hindered disulfate linker);sulfosuccinimidyl6[xcex1-methyl-xcex1-(2-pyridyldithio)toluamido]hexanoate (sulfo-LC-SMPT); m-maleimidobenzoyl-N-hydroxysuccinimide ester (MBS); m-maleimidobenzoyl-N-hydroxysulfosuccinimide ester (sulfo-MBS); N-succinimidyl(4-iodoacetyl)aminobenzoate (SIAB; thioether linker); sulfosuccinimidyl(4-iodoacetyl)amino benzoate (sulfo-SIAB); succinimidyl4(p-maleimidophenyl)butyrate (SMPB); sulfosuccinimidyl4-(p-maleimidophenyl)butyrate (sulfo-SMPB); azidobenzoyl hydrazide (ABH).\nAcid cleavable linkers, photocleavable and heat sensitive linkers may also be used, particularly where it may be necessary to cleave the targeted agent to permit it to be more readily accessible to reaction. Acid cleavable linkers include, but are not limited to, bismaleimideothoxy propane; and adipic acid dihydrazide linkers (see, e.g., Fattom et al. (1992) Infection and Immun. 60:584-589) and acid labile transferrin conjugates that contain a sufficient portion of transferrin to permit entry into the intracellular transferrin cycling pathway (see, e.g., Welhxc3x6ner et al. (1991) J. Biol. Chem. 266:4309-4314).\nPhotocleavable linkers are linkers that are cleaved upon exposure to light (see, e.g., Goldmacher et al. (1992) Bioconj. Chem. 3:104-107, which linkers are herein incorporated by reference), thereby releasing the targeted agent upon exposure to light. Photocleavable linkers that are cleaved upon exposure to light are known (see, e.g., Hazum et al. (1981) in Pept., Proc. Eur. Pept. Symp., 16th, Brunfeldt, K (Ed), pp. 105-110, which describes the use of a nitrobenzyl group as a photocleavable protective group for cysteine; Yen et al. (1989) Makromol. Chem 190:69-82, which describes water soluble photocleavable copolymers, including hydroxypropylmethacrylamide copolymer, glycine copolymer, fluorescein copolymer and methylrhodamine copolymer; Goldmacher et al. (1992) Bioconj. Chem. 3:104-107, which describes a cross-linker and reagent that undergoes photolytic degradation upon exposure to near UV light (350 nm); and Senter et al. (1985) Photochem. Photobiol 42:231-237, which describes nitrobenzyloxycarbonyl chloride cross linking reagents that produce photocleavable linkages), thereby releasing the targeted agent upon exposure to light. Such linkers would have particular use in treating dermatological or ophthalmic conditions that can be exposed to light using fiber optics. After administration of the conjugate, the eye or skin or other body part can be exposed to light, resulting in release of the targeted moiety from the conjugate. Such photocleavable linkers are useful in connection with diagnostic protocols in which it is desirable to remove the targeting agent to permit rapid clearance from the body of the animal.\n3. Targeting Agents\nTargeting agents include any agent that will interact with and localize the targeted agent cells in a tumor or specialized tissue [targeted tissue]. Such agents include any agent that specifically interacts with a cell surface protein or receptor that is present at sufficiently higher concentrations or amounts on the targeted tissue, whereby, when contacted with an appropriate bioluminescence generating reagent and activators. These agents include, but are not limited to, growth factors, preferentially modified to not internalize, methotrexate, and antibodies, particularly, antibodies raised against tumor specific antigens. A plethora of tumor-specific antigens have been identified from a number of human neoplasias. Among the antigens suitable for use in raising antibodies are those set forth in Table 3. below.\nAnti-tumor Antigen Antibodies\nPolyclonal and monoclonal antibodies may be produced against selected antigens. Alternatively, many such antibodies are presently available. An exemplary list of antibodies and the tumor antigen for which each has been directed against is provided in Table 3. It is contemplated that any of the antibodies listed may be conjugated with a bioluminescence generating component following the methods provided herein.\nAmong the preferred antibodies for use in the methods herein are those of human origin or, more preferably, are humanized monoclonal antibodies. These are preferred for diagnosis of humans.\nAny method for linking proteins may be used. For example, methods for linking a luciferase to an antibody is described in U.S. Pat. No. 5,486,455. As noted above, the targeting agent and luciferin or luciferase may be linked directly, such as through covalent bonds, i.e., sulfhyryl bonds or other suitable bonds, or they may be linked through a linker. There may be more than one luciferase or luciferin per targeting agent, or more than one targeting agent per luciferase or luciferin.\nAlternatively, an antibody, or F(Ab)2 antigen-binding fragment thereof or other protein targeting agent may be fused (directly or via a linking peptide) to the luciferase using recombinant DNA technology. For example, the DNA encoding any of the anti-tumor antibodies of Table 3 may be ligated in the same translational reading frame to DNA encoding any of the above-described luciferases, e.g., SEQ ID NOs. 1-14 and inserted into an expression vector. The DNA encoding the recombinant antibody-luciferase fusion may be introduced into an appropriate host, such as bacteria or yeast, for expression.\nC. Formulation and Administration of the Compositions for Use in the Diagnostic Systems\nIn most embodiments, the components of the diagnostic systems provided herein are formulated into two compositions: a first composition containing the conjugate; and a second composition containing the remaining components of the bioluminescence generating system. The compositions are formulated in any manner suitable for administration to an animal, particularly a mammal, and more particularly a human. Such formulations include those suitable for topical, local, enteric, parenteral, intracystal, intracutaneous, intravitreal, subcutaneous, intramuscular, or intraveneous administration.\nFor example, the conjugates, which in preferred embodiments, are a targeting agent linked to a luciferase (or photoprotein) are formulated for systemic or local administration. The remaining components are formulated in a separate second composition for topical or local application. The second composition will typically contain any other agents, such as spectral shifters that will be included in the reaction. It is preferred that the components of the second composition are formulated in a time release manner or in some other manner that prevents degradation and\/or interaction with blood components.\nAs noted above, the conjugates either contain a luciferase or luciferin and a targeting agents. The preferred conjugates are formed between a targeting agent and a luciferase or photoprotein. The conjugates may be formulated into pharmaceutical compositions suitable for topical, local, intravenous and systemic application. Effective concentrations of one or more of the conjugates are mixed with a suitable pharmaceutical carrier or vehicle. The concentrations or amounts of the conjugates that are effective requires delivery of an amount, upon administration, that results in a sufficient amount of targeted moiety linked to the targeted cells or tissue whereby the cells or tissue can be visualized during the surgical procedure. Typically, the compositions are formulated for single dosage administration. Effective concentrations and amounts may be determined empirically by testing the conjugates in known in vitro and in vivo systems, such as those described here; dosages for humans or other animals may then be extrapolated therefrom.\nUpon mixing or addition of the conjugate(s) with the vehicle, the resulting mixture may be a solution, suspension, emulsion or the like. The form of the resulting mixture depends upon a number of factors, including the intended mode of administration and the solubility of the conjugate in the selected carrier or vehicle. The effective concentration is sufficient for targeting a sufficient amount of targeted agent to the site of interest, whereby when combined with the remaining reagents during a surgical procedure the site will glow. Such concentration or amount may be determined based upon in vitro and\/or in vivo data, such as the data from the mouse xenograft model for tumors or rabbit ophthalmic model. If necessary, pharmaceutically acceptable salts or other derivatives of the conjugates may be prepared.\nPharmaceutical carriers or vehicles suitable for administration of the conjugates provided herein include any such carriers known to those skilled in the art to be suitable for the particular mode of administration. In addition, the conjugates may be formulated as the sole pharmaceutically ingredient in the composition or may be combined with other active ingredients.\nThe conjugates can be administered by any appropriate route, for example, orally, parenterally, intravenously, intradermally, subcutaneously, or topically, in liquid, semi-liquid or solid form and are formulated in a manner suitable for each route of administration. Intravenous or local administration is presently preferred. Tumors and vascular proliferative disorders, will typically be visualized by systemic, intradermal or intramuscular, modes of administration.\nThe conjugate is included in the pharmaceutically acceptable carrier in an amount sufficient to produce detectable tissue and to not result in undesirable side effects on the patient or animal. It is understood that number and degree of side effects depends upon the condition for which the conjugates are administered. For example, certain toxic and undesirable side effects are tolerated when trying to diagnose life-threatening illnesses, such as tumors, that would not be tolerated when diagnosing disorders of lesser consequence.\nThe concentration of conjugate in the composition will depend on absorption, inactivation and excretion rates thereof, the dosage schedule, and amount administered as well as other factors known to those of skill in the art. Typically an effective dosage should produce a serum concentration of active ingredient of from about 0.1 ng\/ml to about 50-1000 xcexcg\/ml, preferably 50-100 xcexcg\/ml. The pharmaceutical compositions typically should provide a dosage of from about 0.01 mg to about 100-2000 mg of conjugate, depending upon the conjugate selected, per kilogram of body weight per day. Typically, for intravenous administration a dosage of about between 0.05 and 1 mg\/kg should be sufficient. Local application for, such as visualization of ophthalmic tissues or local injection into joints, should provide about 1 ng up to 1000 xcexcg, preferably about 1 xcexcg to about 100 xcexcg, per single dosage administration. It is understood that the amount to administer will be a function of the conjugate selected, the indication, and possibly the side effects that will be tolerated. Dosages can be empirically determined using recognized models.\nThe active ingredient may be administered at once, or may be divided into a number of smaller doses to be administered at intervals of time. It is understood that the precise dosage and duration of administration is a function of the disease condition being diagnosed and may be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test data. It is to be noted that concentrations and dosage values may also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that the concentration ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed compositions.\nSolutions or suspensions used for parenteral, intradermal, subcutaneous, or topical application can include any of the following components: a sterile diluent, such as water for injection, saline solution, fixed oil, polyethylene glycol, glycerine, propylene glycol or other synthetic solvent; antimicrobial agents, such as benzyl alcohol and methyl parabens; antioxidants, such as ascorbic acid and sodium bisulfite; chelating agents, such as ethylenediaminetetraacetic acid (EDTA); buffers, such as acetates, citrates and phosphates; and agents for the adjustment of tonicity such as sodium chloride or dextrose. Parental preparations can be enclosed in ampules, disposable syringes or multiple dose vials made of glass, plastic or other suitable material.\nIf administered intravenously, suitable carriers include physiological saline or phosphate buffered saline (PBS), and solutions containing thickening and solubilizing agents, such as glucose, polyethylene glycol, and polypropylene glycol and mixtures thereof. Liposomal suspensions may also be suitable as pharmaceutically acceptable carriers. These may be prepared according to methods known to those skilled in the art.\nThe conjugates may be prepared with carriers that protect them against rapid elimination from the body, such as time release formulations or coatings. Such carriers include controlled release formulations, such as, but not limited to, implants and microencapsulated delivery systems, and biodegradable, biocompatible polymers, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, polyorthoesters, polylacetic acid and others. These are particularly useful for application to the eye for ophthalmic indications following or during surgery in which only a single administration is possible. Methods for preparation of such formulations are known to those skilled in the art.\nThe conjugates may be formulated for local or topical application, such as for topical application to the skin and mucous membranes, such as in the eye, in the form of gels, creams, and lotions and for application to the eye or for intracisternal or intraspinal application. Such solutions, particularly those intended for ophthalmic use, may be formulated as 0.01%-10% isotonic solutions, pH about 5-7, with appropriate salts. The ophthalmic compositions may also include additional components, such as hyaluronic acid. The conjugates may be formulated as aerosols for topical application (see, e.g., U.S. Pat. Nos. 4,044,126, 4,414,209, and 4,364,923).\nAlso, the compositions for activation of the conjugate in vivo during surgical procedures may be formulated as an aerosol. These compositions contain the activators and also the remaining bioluminescence generating agent, such as luciferin, where the conjugate targets a luciferase, or a luciferase, where the conjugate targets a luciferin, such as coelenterazine.\nIf oral administration is desired, the conjugate should be provided in a composition that protects it from the acidic environment of the stomach. For example, the composition can be formulated in an enteric coating that maintains its integrity in the stomach and releases the active compound in the intestine. Oral compositions will generally include an inert diluent or an edible carrier and may be compressed into tablets or enclosed in gelatin capsules. For the purpose of oral administration, the active compound or compounds can be incorporated with excipients and used in the form of tablets, capsules or troches. Pharmaceutically compatible binding agents and adjuvant materials can be included as part of the composition.\nTablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder, such as microcrystalline cellulose, gum tragacanth and gelatin; an excipient such as starch and lactose, a disintegrating agent such as, but not limited to, alginic acid and corn starch; a lubricant such as, but not limited to, magnesium stearate; a glidant, such as, but not limited to, colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; and a flavoring agent such as peppermint, methyl salicylate, and fruit flavoring.\nWhen the dosage unit form is a capsule, it can contain, in addition to material of the above type, a liquid carrier such as a fatty oil. In addition, dosage unit forms can contain various other materials which modify the physical form of the dosage unit, for example, coatings of sugar and other enteric agents. The conjugates can also be administered as a component of an elixir, suspension, syrup, wafer, chewing gum or the like. A syrup may contain, in addition to the active compounds, sucrose as a sweetening agent and certain preservatives, dyes and colorings and flavors.\nThe active materials can also be mixed with other active materials that do not impair the desired action, or with materials that supplement the desired action, such as cis-platin for treatment of tumors.\nFinally, the compounds may be packaged as articles of manufacture containing packaging material, one or more conjugates or compositions as provided herein within the packaging material, and a label that indicates the indication for which the conjugate is provided.\nThe second composition will include the remaining components of the bioluminescence generating reaction. In preferred embodiments in which these components are administered systemically, the remaining components include the luciferin or substrate, and optionally additional agents, such as spectral shifters. These components, such as the luciferin, can be formulated as described above for the conjugates. In some embodiments, the luciferin or luciferase in this composition will be linked to a protein carrier or other carrier to prevent degradation or dissolution into blood cells or other cellular components.\nFor embodiments, in which the second composition is applied locally or topically, they can be formulated in a spray or aerosol or other suitable means for local or topical application.\nIn certain embodiments described herein, all components, except an activator are formulated together, such as by encapsulation in a time release formulation that is targeted to the tissue. Upon release the composition will have been localized to the desired site, and will begin to glow.\nIn practice, the two compositions can be adminstered simultaneously or sequentially. Typically, the first composition, which contains the conjugate is adminstered first, generally an hour or two before the surgery, and the second composition is then adminstered, either pre-operatively or during surgery.\nD. Practice of the Reactions in Combination with Targeting Agents\nThe particular manner in which each bioluminescence system will be combined with a selected targeting agent will be a function of the agent and the neoplasia or tissue to be visualized. In general, however, a luciferin or luciferase, of the reaction will be conjugated to the targeting agent, administered to an animal prior to surgery. During the surgery, the tissues of interest are contacted with the remaining component(s) of a bioluminescence generating system. Any tissue to which or with which the targeting agent reacts will glow.\nAny color of visible light produced by a bioluminescence generating system is contemplated for use in the methods herein. Preferably the visible light is a combination of blue, green and\/or red light of varying intensities and wavelengths. For visualizing neoplasia or specialty tissues through mammalian tissues or tumors deeply embedded in tissue, longer wavelengths of visible light, i.e., red and near infrared light, is preferred because wavelengths of near infrared light of about 700-1300 nm are known to penetrate soft tissue and bone [e.g., see U.S. Pat. No. 4,281,645].\nIn the simplest embodiments, the targeting agent conjugate may be visualized by adding one or more of the bioluminescence generating components in crude mixture. For example, the organisms can be ground up and dried and administered topically. Light will be emitted by ground up fireflies when mixed with water and ATP. Light will also be emitted by combining ground up Vargula shrimp and adding water, preferably cool water [room temperature or lower]. The only caveat is that the water must not be too hot; high temperatures destroy activity of the luciferases.\nGenerally, the remaining bioluminescence generating components will be formulated in a vehicle suitable for topical administration to tissues during surgery and will be applied as an aerosol. Alternatively, they can be injected into the tissue or administered intravenously.\nIn other embodiments, the conjugate can be applied to the tissues during surgery, such as by spraying a sterile solution over the tissues, followed by application of the remaining components. Tissues that express the targeted antigen will glow.\nThe reagents may be provided in compositions, such as suspensions, as powders, as pastes or any in other suitable sterile form. They may be provided as sprays, aerosols, or in any suitable form. The reagents may be linked to a matrix, particularly microbeads suitable for in vivo use and of size that they pass through capillaries. Typically all but one or more, though preferably all but one, of the components necessary for the reaction will be mixed and provided together; reaction will be triggered contacting the mixed component(s) with the remaining component(s), such as by adding Ca2+, FMN with reductase, FMNH2, ATP, air or oxygen.\nIn preferred embodiments the luciferase or luciferase\/luciferin, such as the aequorin photoprotein, will be provided in combination with the targeting agent before administration to the patient. The targeting agent conjugate will then be contacted in vivo with the remaining components. As will become apparent herein, there are a multitude of ways in which each system may be combined with a selected targeting agent.\nE. Kits and Compositions\nKits containing the diagnostic systems are provided. The kits comprise compositions containing the conjugates and remaining bioluminescence generating system components. The first composition in the kit typically contains the targeting agent conjugated to a luciferase (i.e., a luciferase or photoprotein). The second composition, contains at least the luciferin (substrate). Both compositions are formulated for systemic, local or topical application to a mammal. In alternative embodiments, the first composition contains the luciferin linked to a targeting agent, and the second composition contains the luciferase.\nIn general, the packaging is non-reactive with the compositions contained therein and where needed should exclude water and or air to the degree those substances are required for the luminescent reaction to proceed.\nDiagnostic applications may require specific packaging. The bioluminescence generating reagents may be provided in pellets, encapsulated as micro or macro-capsules, linked to matrices, preferably biocompatible, more preferably biodegradable matrices, and included in or on articles of manufacture, or as mixtures in chambers within an article of manufacture or in some other configuration. For example, a composition containing luciferase conjugate will be provided separately from, and for use with, a separate composition containing a bioluminescence substrate and bioluminescence activator.\nSimilarly, the luciferase or luciferin may be provided in a composition that is a mixture, suspension, solution, powder, paste or other suitable composition separately from or in combination with the remaining components, but in the absence of an activating component. Upon contacting the conjugate, which has been targeted to a selected tissue, with this composition the reaction commences and the tissue glows. The luciferase and bioluminescence substrate, for example, are packaged to exclude water and\/or air, the bioluminescence activator. Upon administration and release at the targeted site, the reaction with salts or other components at the site, including air in the case of surgical procedures, will activate the components.\n1. Dispensing and Packaging Apparatus for Combination with the Bioluminescent System Components\nThe kits may include a bioluminescent apparatus systems provided herein are bioluminescence [or bioluminescent] systems in combination with dispensing or packaging apparatus. The bioluminescence systems, described in detail elsewhere herein, include three components: a bioluminescence substrate [e.g., a luciferin], a luciferase [e.g., a luciferase or photoprotein], and a bioluminescence activator or activators [e.g., molecular oxygen or Ca2+]. The dispensing and packaging apparatus are configured to keep at least one of the three components separate from the other two components, until generation of bioluminescence is desired. Detailed descriptions of such apparatus are described in copending, commonly owned U.S. application Ser. Nos. 08\/757,046 and 08\/597,274, which are incorporated by reference herein.\nTwo of the components will be mixed to form a suitable composition for targeting to tissues, and the third, will be administered when visualization or detection is desired.\nIn general, the dispensing and packaging apparatus are non-reactive with the bioluminescent system components contained therein and can exclude moisture, air or other activators, such as O2 or Ca2+, or in some manner keep all necessary components that are required for the bioluminescent reaction to come into contact until desired.\n2. Capsules, Pellets, Liposomes, Endosomes, Vacuoles, Micronized Particles\nIn certain embodiments sequestering of the components of one of the compositions from the environment prior to use or provision of the components in particulate form, such as microparticles, may be necessary. Examples of suitable means for such use include encapsulating bioluminescent generating system components in one or micro- [up to about 100 xcexcm in size] or macroparticles [larger than 100 xcexcM] of material that permits release of the contents, such as by diffusion or by dissolution of the encapsulating material. Microparticles to which a plurality of conjugates can be linked are among the preferred embodiments. The microparticles are biocompatible and preferably of a size that can pass through capillary walls.\nLiposomes and other encapsulating vehicles [see, e.g., U.S. Pat. No. 4,525,306, which describes encapsulation of compounds in gelatin; U.S. Pat. Nos. 4,021,364, 4,225,581, 4,269,821, 4,322,311, 4,324,683, 4,329,332, 4,525,306, 4,963,368 describe encapsulation of biologically active materials in various polymers] known to those of skill in the art, including those discussed herein and known to those of skill in the art [such as soluble paper, see U.S. Pat. No. 3,859,125].\na. Encapsulating Vehicles in General\nAll components of the bioluminescence generating system, except for the oxygen or water or Ca2+, depending upon the selected system can be incorporated into encapsulating material, such as liposomes, that protect the contents from the environment until placed into conditions that cause release of the contents into the environment. Encapsulating material contemplated for use herein includes liposomes and other such materials used for encapsulating chemicals, such as drug delivery vehicles.\nb. Encapsulating Vehicles -liposomes\nFor example, liposomes that dissolve and slowly release the components into the medium, such as the blood, which contains dissolved oxygen or Ca 2+ or even ATP for the luciferase system are contemplated herein. They can be formulated in compositions, such as solutions, suspensions, gels, lotions, creams, and ointments, for topical application, such as procedures for diagnosing or visualizing melanomas. Liposomes and other slow release encapsulating compositions are well known and can be adapted for use in for slow release delivery of bioluminescence generating components. Typically the luciferin and luciferase will be encapsulated in the absence of oxygen or Ca2+ or ATP or other activating component. Upon release into the environment or medium containing this component at a suitable concentration, the reaction will proceed and a glow will be produced. Generally the concentrations of encapsulated components should be relatively high, perhaps 0.1-1 mg\/ml or more, to ensure high enough local concentrations upon release to be visible.\nLiposomes or other sustained release delivery system that are formulated in an ointment or sustained release topical vehicle, for example, would be suitable for use in a body paint, lotion. Those formulated as a suspension would be useful as a spray. Numerous ointments and suitable liposome formulations are known [see, e.g., Liposome Technology, Targeted Drug Delivery and Biological Interaction, vol. III, G. Gregoriadis ed., CRC Press, Inc., 1984; U.S. Pat. Nos. 5,470,881; 5,366,881; 5,296,231; 5,272,079; 5,225,212; 5,190,762; 5,188,837; 5,188,837; 4,921,757; 4,522,811]. For example, an appropriate ointment vehicle would contain petrolatum, mineral oil and\/or anhydrous liquid lanolin. Sustained release vehicles such as liposomes, membrane or contact lens delivery systems, or gel-forming plastic polymers would also be suitable delivery vehicles. Liposomes for topical delivery are well known [see, e.g., U.S. Pat. No. 5,296,231; Mezei et al. (1980) xe2x80x9cLiposomes -A selective drug delivery system for the topical route of administration, I. lotion dosage formxe2x80x9d Life Sciences 26:1473-1477; Mezei et al. (1981) xe2x80x9cLiposomes -A selective drug delivery system for the topical route of administration: gel dosage formxe2x80x9d Journal of Pharmacy and Pharmacology 34:473-474; Gesztes et al. (1988) xe2x80x9cTopical anaesthesia of the skin by liposome-encapsulated tetracainexe2x80x9d Anesthesia and Analgesia 67:1079-1081; Patel (1985) xe2x80x9cLiposomes as a controlled-release systemxe2x80x9d,Biochemical Soc. Trans. 13:513-516; Wohlrab et al. (1987) xe2x80x9cPenetration kinetics of liposomal hydrocortisone in human skinxe2x80x9d Dermatologica 174:18-22].\nLiposomes are microcapsules [diameters typically on the order of less than 0.1 to 20 xcexcm] that contain selected mixtures and can slowly release their contents in a sustained release fashion. Targeted liposomes or other capsule, particularly a time release coating, that dissolve upon exposure to oxygen, air, moisture, visible or ultraviolet [UV] light or a particular pH or temperature [see, e.g., U.S. Pat. No. 4,882,165; Kusumi et al. (1989) Chem. Lett. no.3 433-436; Koch Troels et al. (1990) Bioconjugate Chem. 4:296-304; U.S. Pat. No. 5,482,719; U.S. Pat. No. 5,411,730; U.S. Pat. No. 4,891,043; Straubinger et al. (1983) Cell 32:1069-1079; and Straubinger et a. (1985) FEBS Lttrs. 179:148-154; and Duzgunes et al. in Chapter 11 of the book CELL FUSION, edited by A. E. Sowers; Ellens et al. (1984) Biochemistry 23:1532-1538; Yatvin et al. (1987) Methods in Enzymology 149:77-87] may be used. Liposome formulations for use in baking [see, e.g., U.S. Pat. No. 4,999,208] are available. They release their contents when eaten or heated. Such liposomes may be suitable for intravenous or local administration.\nLiposomes be prepared by methods known to those of skill in the art [see, e.g., Kimm et al. (1983) Bioch. Bioph. Acta 728:339-398; Assil et al. (1987) Arch Ophthalmol. 105:400; and U.S. Pat. No. 4,522,811, and other citations herein and known to those of skill in the art].\nLiposomes that are sensitive to low pH [see, e.g., U.S. Pat. Nos. 5,352,448, 5,296,231; 5,283,122; 5,277,913, 4,789,633] are particularly suitable for use with alkaline agents. Upon contact with the low pH detergent or soap composition or a high pH composition, the contents of the liposome will be released. Other components, particularly Ca+ or the presence of dissolved O2 in the water will cause the components to glow as they are released. Temperature sensitive liposomes are also suitable for use in bath powders for release into the warm bath water.\nc. Encapsulating Vehicles -Gelatin and Polymeric Vehicles\nMacro or microcapsules made of gelatin or other such polymer that dissolve or release their contents on contact with air or light or changes in temperature may also be used to encapsulate components of the bioluminescence generating systems.\nSuch microcapsules or macrocapsules may also be conjugated to a targeting agent, e.g., an antibody, such that the bioluminescence generating components are delivered to the target by the antibody and then the components are released to produce a glow.\nThe aequorin system is particularly suitable for this application. It can be encapsulated in suspension or solution or as a paste, or other suitable form, of buffer with sufficient chelating agent, such as EDTA, to prevent discharge of the bioluminescence. Upon exposure of the capsule [microcapsule or macrocapsule] to moisture that contains Ca2+, such as in a buffer or blood, the released components will glow.\nThus, encapsulated bioluminescence generating components can be used in combination with a variety of targeting agents and thereby release the luciferase\/luciferin, such as the Renilla system, which will light upon exposure to air], and other such items.\nOther encapsulating containers or vehicles for use with the bioluminescence systems are those that dissolve sufficiently in water to release their contents, or that are readily opened when squeezed in the hand or from which the contents diffuse when mixed with a aqueous mixture. These containers can be made to exclude water, so that the bioluminescent system components may be desiccated and placed therein. Upon exposure to water, such as in an aqueous composition solution or in the atmosphere, the vehicle dissolves or otherwise releases the contents, and the components react and glow. Similarly, some portion less than all of the bioluminescence generating components may themselves be prepared in pellet form. For example, the component(s) may be mixed with gelatin or similar hardening agent, poured into a mold, if necessary and dried to a hard, water soluble pellet. The encapsulating containers or vehicles may be formed from gelatin or similar water soluble material that is biocompatible.\nd. Endosomes and Vacuoles\nVehicles may be produced using endosomes or vacuoles from recombinant host cells in which the luciferase is expressed using method known to those of skill in the art [see, e.g., U.S. Pat. Nos. 5,284,646, 5,342,607, 5,352,432, 5,484,589, 5,192,679, 5,206,161, and 5,360,726]. For example, aequorin that is produced by expression in a host, such as E. coli, can be isolated within vesicles, such as endosomes or vacuoles, after protein synthesis. Using routine methods the cells are lysed and the vesicles are released with their contents intact. The vesicles will serve as delivery vehicles. When used they will be charged with a luciferin, such as a coelenterazine, and dissolved oxygen, such as by diffusion, under pressure, or other appropriate means.\ne. Micronized Particles\nThe bioluminescence generating system components that are suitable for lyophilization, such as the aequorin photoprotein, the Renilla system, and the Vargula systems, can be micronized to form fine powder and stored under desiccating conditions, such as with a desiccant. Contact with dissolved oxygen or Ca2+ in the air or in a mist that can be supplied or in added solution will cause the particles to dissolve and glow.\n3. Immobilized Systems\na. Matrix Materials\nIn some embodiments, it will be desirable to provide at least one component of the bioluminescence generating system linked to a matrix substrate, which can then be locally or systemically administered. The matrix substrate will be biocompatible. When desired, a mixture or mixtures(s) containing the remaining components, typically a liquid mixture is applied, as by pouring or spraying onto the matrix substrate, to produce a glow. For example, the aequorin photoprotein, including coelenterazine and oxygen, is linked to the substrate. When desired, a liquid containing Ca2+, such as tap water or, preferably, a liquid mixture containing the Ca2+ in an appropriate buffer, is contacted, such as by spraying, with the matrix with linked luciferase. Upon contact the material glows.\nIn other embodiments, the luciferase, such as a Vargula luciferase, is linked to the substrate material, and contacted with a liquid mixture containing the luciferin in an appropriate buffer. Contacting can be effected by spraying or pouring or other suitable manner. The matrix material is incorporated into, onto or is formed into an article of manufacture, such as surgical sponge or as part of a microbead.\nThe kits may also include containers containing compositions of the linked components which can be provided in a form, such as sprayed on as a liquid and air dried, that can be applied to the substrate so that the item can be made to glow again. Thus, kits containing a first composition containing the targeting agent and a luciferase or a luciferin or both and luciferin, and a second composition containing the remaining components. The item as provided in the kit can be charged with the first composition, such as having the composition applied and dried, or may require charging prior to the first use. Alternatively, the item may be sprayed with both compositions when desired to produce a glow.\nIt is understood that the precise components and optimal means for application or storage are a function of the selected bioluminescence system. The concentrations of the components, which can be determined empirically, are not critical, but must be sufficient to produce a visible glow when combined. Typical concentrations are as low as nanomoles\/l, preferably on the order of mg\/l or higher. The concentration on the substrate is produced when a composition containing such typical concentration is applied to the material. Again, such ideal concentrations can be readily determined empirically by applying the first composition, letting it dry, spraying the second composition, and observing the result.\nThe matrix material substrates contemplated herein are generally insoluble materials used to immobilize ligands and other molecules, and are those that used in many chemical syntheses and separations. Such matrices are fabricated preferably from biocompatible, more preferably from biodegradable materials. Such substrates, also called matrices, are used, for example, in affinity chromatography, in the immobilization of biologically active materials, and during chemical syntheses of biomolecules, including proteins, amino acids and other organic molecules and polymers. The preparation of and use of matrices is well known to those of skill in this art; there are many such materials and preparations thereof known. For example, naturally-occurring matrix materials, such as agarose and cellulose, may be isolated from their respective sources, and processed according to known protocols, and synthetic materials may be prepared in accord with known protocols. Other matrices for use herein may comprise proteins, for example carrier molecules, such as albumin.\nThe substrate matrices are typically insoluble materials that are solid, porous, deformable, or hard, and have any required structure and geometry, including, but not limited to: beads, pellets, disks, capillaries, hollow fibers, needles, solid fibers, random shapes, thin films and membranes. Thus, the item may be fabricated from the matrix material or combined with it, such by coating all or part of the surface or impregnating particles.\nTypically, when the matrix is particulate, the particles are at least about 10-2000 xcexcM, but may be smaller or larger, depending upon the selected application. Selection of the matrices will be governed, at least in part, by their physical and chemical properties, such as solubility, functional groups, mechanical stability, surface area swelling propensity, hydrophobic or hydrophilic properties and intended use. For use herein, the matrices are preferably biocompatible, more preferably biodegradable matrices.\nIf necessary the support matrix material can be treated to contain an appropriate reactive moiety or in some cases the may be obtained commercially already containing the reactive moiety, and may thereby serve as the matrix support upon which molecules are linked. Materials containing reactive surface moieties such as amino silane linkages, hydroxyl linkages or carboxysilane linkages may be produced by well established surface chemistry techniques involving silanization reactions, or the like. Examples of these materials are those having surface silicon oxide moieties, covalently linked to gamma-aminopropylsilane, and other organic moieties; N-[3-(triethyoxysilyl)propyl]phthelamic acid; and bis-(2-hydroxyethyl)aminopropyltriethoxysilane. Exemplary of readily available materials containing amino group reactive functionalities, include, but are not limited to, para-aminophenyltriethyoxysilane. Also derivatized polystyrenes and other such polymers are well known and readily available to those of skill in this art [e.g., the Tentagel(copyright) Resins are available with a multitude of functional groups, and are sold by Rapp Polymere, Tubingen, Germany; see, U.S. Pat. No. 4,908,405 and U.S. Pat. No. 5,292,814; see, also Butz et al. (1994) Peptide Res. 7:20-23; Kleine et al. (1994) Immunobiol. 190:53-66].\nThese matrix materials include any material that can act as a support matrix for attachment of the molecules of interest. Such materials are known to those of skill in this art, and include those that are used as a support matrix. These materials include, but are not limited to, inorganics, natural polymers, and synthetic polymers, including, but are not limited to: cellulose, cellulose derivatives, acrylic resins, glass, silica gels, polystyrene, gelatin, polyvinyl pyrrolidone, co-polymers of vinyl and acrylamide, polystyrene cross-linked with divinylbenzene or the like [see, Merrifield (1964) Biochemistry 3:1385-1390], polyacrylamides, latex gels, polystyrene, dextran, polyacrylamides, rubber, silicon, plastics, nitrocellulose, celluloses, natural sponges. Of particular interest herein, are highly porous glasses [see, e.g., U.S. Pat. No. 4,244,721] and others prepared by mixing a borosilicate, alcohol and water.\nSynthetic matrices include, but are not limited to: acrylamides, dextran-derivatives and dextran co-polymers, agarose-polyacrylamide blends, other polymers and co-polymers with various functional groups, methacrylate derivatives and co-polymers, polystyrene and polystyrene copolymers [see, e.g., Merrifield (1964) Biochemistry 3:1385-1390; Berg et al. (1990) in Innovation Perspect. Solid Phase Synth. Collect. Pap., Int. Symp., 1st, Epton, Roger (Ed), pp. 453-459; Berg et al. (1989) in Pept., Proc. Eur. Pept. Symp., 20th, Jung, G. et al. (Eds), pp. 196-198; Berg et al. (1989) J. Am. Chem. Soc. 111:8024-8026; Kent et al. (1979) Isr. J. Chem. 17:243-247; Kent et al. (1978) J. Org. Chem. 43:2845-2852; Mitchell et al. (1976) Tetrahedron Lett. 42:3795-3798; U.S. Pat. No. 4,507,230; U.S. Pat. No. 4,006,117; and U.S. Pat. No. 5,389,449]. Methods for preparation of such matrices are well-known to those of skill in this art.\nSynthetic matrices include those made from polymers and co-polymers such as polyvinylalcohols, acrylates and acrylic acids such as polyethylene-co-acrylic acid, polyethylene-co-methacrylic acid, polyethylene-co-ethylacrylate, polyethylene-co-methyl acrylate, polypropylene-co-acrylic acid, polypropylene-co-methyl-acrylic acid, polypropylene-co-ethylacrylate, polypropylene-co-methyl acrylate, polyethylene-co-vinyl acetate, polypropylene-co-vinyl acetate, and those containing acid anhydride groups such as polyethylene-co-maleic anhydride, polypropylene-co-maleic anhydride and the like. Liposomes have also been used as solid supports for affinity purifications [Powell et al. (1989) Biotechnol. Bioeng. 33:173].\nFor example, U.S. Pat. No. 5,403,750, describes the preparation of polyurethane-based polymers. U.S. Pat. No. 4,241,537 describes a plant growth medium containing a hydrophilic polyurethane gel composition prepared from chain-extended polyols; random copolymerization is preferred with up to 50% propylene oxide units so that the prepolymer will be a liquid at room temperature. U.S. Pat. No. 3,939,123 describes lightly crosslinked polyurethane polymers of isocyanate terminated prepolymers containing poly(ethyleneoxy) glycols with up to 35% of a poly(propyleneoxy) glycol or a poly(butyleneoxy) glycol. In producing these polymers, an organic polyamine is used as a crosslinking agent. Other matrices and preparation thereof are described in U.S. Pat. Nos. 4,177,038, 4,175,183, 4,439,585, 4,485,227, 4,569,981, 5,092,992, 5,334,640, 5,328,603.\nU.S. Pat. No. 4,162,355 describes a polymer suitable for use in affinity chromatography, which is a polymer of an aminimide and a vinyl compound having at least one pendant halo-methyl group. An amine ligand, which affords sites for binding in affinity chromatography is coupled to the polymer by reaction with a portion of the pendant halo-methyl groups and the remainder of the pendant halo-methyl groups are reacted with an amine containing a pendant hydrophilic group. A method of coating a substrate with this polymer is also described. An exemplary aminimide is 1,1-dimethyl-1-(2-hydroxyoctyl)amine methacrylimide and vinyl compound is a chloromethyl styrene.\nU.S. Pat. No. 4,171,412 describes specific matrices based on hydrophilic polymeric gels, preferably of a macroporous character, which carry covalently bonded D-amino acids or peptides that contain D-amino acid units. The basic support is prepared by copolymerization of hydroxyalkyl esters or hydroxyalkylamides of acrylic and methacrylic acid with crosslinking acrylate or methacrylate comonomers are modified by the reaction with diamines, aminoacids or dicarboxylic acids and the resulting carboxyterminal or aminoterminal groups are condensed with D-analogs of aminoacids or peptides. The peptide containing D-amino-acids also can be synthesized stepwise on the surface of the carrier.\nU.S. Pat. No. 4,178,439 describes a cationic ion exchanger and a method for preparation thereof. U.S. Pat. No. 4,180,524 describes chemical syntheses on a silica support.\nImmobilized Artificial Membranes [IAMs; see, e.g., U.S. Pat. Nos. 4,931,498 and 4,927,879] may also be used. IAMs mimic cell membrane environments and may be used to bind molecules that preferentially associate with cell membranes [see, e.g., Pidgeon et al. (1990) Enzyme Microb. Technol. 12:149].\nThese materials are also used for preparing articles of manufacture, surgical sponges soaps, and other items, and thus are amenable to linkage of molecules, either the luciferase, luciferin, mixtures of both. For example, matrix particles may be impregnated into items that will then be contacted with an activator.\nKits containing the item including the matrix material with or without the coating of the bioluminescence generating components, and compositions containing the remaining components are provided.\nb. Immobilization and Activation\nNumerous methods have been developed for the immobilization of proteins and other biomolecules onto insoluble or liquid supports [see, e.g., Mosbach (1976) Methods in Enzymology 44; Weetall (1975) Immobilized Enzymes, Antigens, Antibodies, and Peptides; and Kennedy et al. (1983) Solid Phase Biochemistry, Analytical and Synthetic Aspects, Scouten, ed., pp. 253-391; see, generally, Affinity Techniques. Enzyme Purification: Part B. Methods in Enzymology, Vol. 34, ed. W. B. Jakoby, M. Wilchek, Acad. Press, N.Y. (1974); Immobilized Biochemicals and Affinity Chromatography, Advances in Experimental Medicine and Biology, vol. 42, ed. R. Dunlap, Plenum Press, N.Y. (1974)].\nAmong the most commonly used methods are absorption and adsorption or covalent binding to the support, either directly or via a linker, such as the numerous disulfide linkages, thioether bonds, hindered disulfide bonds, and covalent bonds between free reactive groups, such as amine and thiol groups, known to those of skill in art [see, e.g., the PIERCE CATALOG, ImmunoTechnology Catalog and Handbook, 1992-1993, which describes the preparation of and use of such reagents and provides a commercial source for such reagents; and Wong (1993) Chemistry of Protein Conjugation and Cross Linking, CRC Press; see, also DeWitt et al. (1993) Proc. Natl. Acad. Sci. U.S.A. 90:6909; Zuckermann et al. (1992) J. Am. Chem. Soc. 114:10646; Kurth et al. (1994) J. Am. Chem. Soc. 116:2661; Ellman et al. (1994) Proc. Natl. Acad. Sci. U.S.A. 91:4708; Sucholeiki (1994) Tetrahedron Lttrs. 35:7307; and Su-Sun Wang (1976) J. Org. Chem. 41:3258; Padwa et al. (1971) J. Org. Chem. 41:3550 and Vedejs et al. (1984) J. Org. Chem. 49:575, which describe photosensitive linkers].\nTo effect immobilization, a solution of the protein or other biomolecule is contacted with a support material such as alumina, carbon, an ion-exchange resin, cellulose, glass or a ceramic. Fluorocarbon polymers have been used as supports to which biomolecules have been attached by adsorption [see, U.S. Pat. No. 3,843,443; Published International PCT Application WO\/86 03840]. For purposes herein, the support material will be biocompatible (i.e., suitable for use in the body).\nA large variety of methods are known for attaching biological molecules, including proteins and nucleic acids, molecules to solid supports [see. e.g., U.S. Pat. No. 5,451,683]. For example, U.S. Pat. No. 4,681,870 describes a method for introducing free amino or carboxyl groups onto a silica matrix. These groups may subsequently be covalently linked to other groups, such as a protein or other anti-ligand, in the presence of a carbodiimide. Alternatively, a silica matrix may be activated by treatment with a cyanogen halide under alkaline conditions. The anti-ligand is covalently attached to the surface upon addition to the activated surface. Another method involves modification of a polymer surface through the successive application of multiple layers of biotin, avidin and extenders [see, e.g., U.S. Pat. No. 4,282,2871; other methods involve photoactivation in which a polypeptide chain is attached to a solid substrate by incorporating a light-sensitive unnatural amino acid group into the polypeptide chain and exposing the product to low-energy ultraviolet light [see, e.g., U.S. Pat. No. 4,762,881]. Oligonucleotides have also been attached using a photochemically active reagents, such as a psoralen compound, and a coupling agent, which attaches the photoreagent to the substrate [see, e.g., U.S. Pat. No. 4,542,102 and U.S. Pat. No. 4,562,157]. Photoactivation of the photoreagent binds a nucleic acid molecule to the substrate to give a surface-bound probe.\nCovalent binding of the protein or other biomolecule or organic molecule or biological particle to chemically activated solid matrix supports such as glass, synthetic polymers, and cross-linked polysaccharides is a more frequently used immobilization technique. The molecule or biological particle may be directly linked to the matrix support or linked via linker, such as a metal [see, e.g., U.S. Pat. No. 4,179,402; and Smith et al. (1992) Methods: A Companion to Methods in Enz. 4:73-78]. An example of this method is the cyanogen bromide activation of polysaccharide supports, such as agarose. The use of perfluorocarbon polymer-based supports for enzyme immobilization and affinity chromatography is described in U.S. Pat. No. 4,885,250]. In this method the biomolecule is first modified by reaction with a perfluoroalkylating agent such as perfluorooctylpropylisocyanate described in U.S. Pat. No. 4,954,444. Then, the modified protein is adsorbed onto the fluorocarbon support to effect immobilization.\nThe activation and use of matrices are well known and may be effected by any such known methods [see, e.g., Hermanson et al. (1992) Immobilized Affinity Ligand Techniques, Academic Press, Inc., San Diego]. For example, the coupling of the amino acids may be accomplished by techniques familiar to those in the art and provided, for example, in Stewart and Young, 1984, Solid Phase Synthesis, Second Edition, Pierce Chemical Co., Rockford.\nOther suitable methods for linking molecules to solid supports are well known to those of skill in this art [see, e.g., U.S. Pat. No. 5,416,193]. These include linkers that are suitable for chemically linking molecules, such as proteins, to supports and include, but are not limited to, disulfide bonds, thioether bonds, hindered disulfide bonds, and covalent bonds between free reactive groups, such as amine and thiol groups. These bonds can be produced using heterobifunctional reagents to produce reactive thiol groups on one or both of the moieties and then reacting the thiol groups on one moiety with reactive thiol groups or amine groups to which reactive maleimido groups or thiol groups can be attached on the other. Other linkers include, acid cleavable linkers, such as bismaleimideothoxy propane, acid labile-transferrin conjugates and adipic acid diihydrazide, that would be cleaved in more acidic intracellular compartments; cross linkers that are cleaved upon exposure to UV or visible light and linkers, such as the various domains, such as CH1, CH2, and CH3, from the constant region of human IgG, (see, Batra et al. (1993) Molecular Immunol. 30:379-386). Presently preferred linkages are direct linkages effected by adsorbing the molecule to the surface of the matrix. Other linkages are photocleavable linkages that can be activated by exposure to light [see, e.g., Goldmacher et al. (1992) Bioconj. Chem. 3:104-107, which linkers are herein incorporated by reference]. The photocleavable linker is selected such that the cleaving wavelength that does not damage linked moieties. Photocleavable linkers are linkers that are cleaved upon exposure to light [see, e.g., Hazum et al. (1981) in Pept., Proc. Eur. Pept. Symp., 16th, Brunfeldt, K (Ed), pp. 105-110, which describes the use of a nitrobenzyl group as a photocleavable protective group for cysteine; Yen et al. (1989) Makromol. Chem 190:69-82, which describes water soluble photocleavable copolymers, including hydroxypropylmethacrylamide copolymer, glycine copolymer, fluorescein copolymer and methylrhodamine copolymer; Goldmacher et al. (1992) Bioconj. Chem. 3:104-107, which describes a cross-linker and reagent that undergoes photolytic degradation upon exposure to near UV light (350 nm); and Senter et al. (1985) Photochem. Photobiol 42:231-237, which describes nitrobenzyloxycarbonyl chloride cross linking reagents that produce photocleavable linkages]. The selected linker will depend upon the particular application and, if needed, may be empirically selected.\nThese methods for linking molecules to supports may be adapted for use to link the targeting agents to the targeted agents.\nF. Surgical Devices and Instruments\na. A Surgical Viewing Device for Visualizing Bioluminescent Neoplasia and Specialty Tissues\n(1) Background\nMonocular and binocular night vision devices have been developed to enable a viewer to observe objects at night and under low light conditions. These night vision devices may be battery powered, modular or solid-state, hand-held, such a telescope or night viewer, or mounted on a gun or helmet, such as a weapon sight or binoculars\/goggles or other head gear (e.g., see U.S. Pat. Nos. 3,509,344; 4,449,783; 4,629,295; 4,642,452; 4,734,939; 4,822,994; 4,948,210; 4,953,963; 5,029,963; 5,084,780; 5,117,553; 5,146,077, 5,396,069; and, 5,535,053).\nSeveral night vision devices are commercially available that detect low intensity visible and infrared light [e.g., monocular and binocular goggles, pocketscopes and viewers; Stano Components, Carson City, Nev.; Star-Tron Technology Corp., Pittsburgh, Pa., Excalibur Enterprises; RETRON night vision devices, Surveillance Technology Group, Mamaroneck, N.Y.; Princeton Instruments, MA.]. These night vision devices may be passive, relying only on ambient light, or active, where an external light source provides illumination for enhanced viewing.\nIn general, active night vision devices are contain of a power source and an infrared illuminator, e.g., a laser, that projects a beam of near infrared light [U.S. Pat. No. 4,948,210 describes an infrared zoom illuminator means]. Infrared and low intensity visible light is received from the surrounding environment through an objective camera lens that focuses and transmits images in the viewing area onto an image intensifier tube [e.g., GEN II and III image intensifiers are described in U.S. Pat. No. 5,146,077]. The GEN II and III intensifier tubes are commercially available (ITT Electro-Optical Products Division, Roanoke, Va.). The GEN III intensifier tube, preferred of the existing intensifier tubes, results in greater than a 50,000-fold amplification in light intensity (with xcx9c30-50% quantum efficiency between 600-700 nm) and a lifetime use of about 10,000 hours.\nAn image intensifier may contain a S-20 or S-25 photocathode, a photoemissive wafer that is extremely sensitive to low radiation levels of light in the 580-900 nm spectral range. The photocathode may be optionally coated with gallium arsenide, which increases the light amplification 4-fold (e.g., as available in the GEN III intensifier tube). The intensified image may be projected, for example, onto a phosphor screen of a photosensor, which converts the electronic emissions into visible light for viewing. The intensified images are viewed on the phosphor screen through an ocular lens assembly.\nIn addition, a microchannel plate (MCP) may be placed between the photocathode and the phosphor screen to enhance the brightness of the image. For example, 18 mm and 25 mm MCP second generation imager intensifiers are commercially available (Stano Components, Carson City, Nev.).\nAlternatively, a charged coupled device (CCD) detector array may be used in association with the video camera\/image intensifier system. In this instance, the intensified image may be transmitted through the CCD imager of a video camera which is connected to a display apparatus via a control unit [e.g., see U.S. Pat. No. 4,642,452].\n(2) Surgical Vision Device\nA surgical vision device useful for detecting low intensity visible light from bioluminescent neoplasia and specialty tissue is provided. The surgical vision device is analogous to the above-described night vision devices in that the image intensifier preferably receives or detects low intensity visible light, particularly wavelengths between 500-900 nm. Preferred for the in vivo detection of neoplasia and specialty tissue are wavelengths of visible light, preferably those wavelengths between 500-900 nm, more preferably green, red and near infrared wavelengths. In particularly preferred embodiments, the surgical night vision device is highly sensitive to low intensity visible red light.\nAny night vision device that detects low intensity visible light is contemplated for use in the methods described herein. In addition, an existing vision device may be modified for use herein, such as by replacing the infrared-sensitive CCD imager or photocathode of the image intensifier, with a corresponding component that has an exceptionally high sensitivity to low intensity visible light. The GEN III image intensifier adequately detects light in the desired wavelengths, especially red and near infrared light (e.g., light wavelengths greater than xcex650 nm). The selection of the appropriate image intensifier or requisite modifications will depend on the wavelength and intensity of the light generated by the bioluminescent reaction which may be determined empirically by one of skill in the art using the teachings herein.\nTo minimize undesired wavelengths of light, an optical interference filter may also be employed in conjunction with these devices to allow only the desired wavelengths of light to pass through to the image intensifier or other equivalent imager. Such a filter may be included between the optical detector and the image intensifier to minimize the level of background light, i.e., wavelengths less than 500 nm or greater than 1000 nm.\nThe monocular and binocular night vision devices described in U.S. Pat. Nos. 5,396,069 or 5,535,053 are particularly suited for use in the methods described herein, particularly the modular apparatus described in U.S. Pat. No. 5,535,053. As described therein, a GEN III image intensifier (i.e., item 40 in FIG. 2) is contained in a tubular housing flanked on one end by an adjustable objective lens assembly and an adjustable ocular lens assembly attached to the opposite end of the housing. The intensified image produced by the GEN III intensifier tube is viewed on the phosphor screen through the adjustable ocular lens assembly. The GEN III image intensifier may be used or replaced with a modified image intensifier that has a higher sensitivity low intensity visible light.\n(3) Methods of Use\nThe surgical vision device provides the surgeon a means for visualizing the image of a tumor or specialty tissue from the low intensity visible light produced at the target site from a selected bioluminescence generating system. For example, a targeting agent conjugated to a component of the bioluminescence generating system, preferably a luciferase, may be administered to a patient followed by the remaining components of the bioluminescence generating system. After exposure of the target area for surgical viewing, the image of the glowing tumor or specialty tissue is captured by the objective lens and focused onto the photocathode tube of a GEN III or equivalent image intensifier. In a dark, sterile room, the glowing image is readily detected against the dark background of the body cavity and the image projected on the phosphor screen is viewed through the ocular lens assembly. Metastatic tumors may also be rapidly identified by visual inspection of the exposed surrounding tissues and organs. Surgical removal of the target may occur in the absence or presence of the assistance of the surgical vision device.\nIn particularly preferred embodiments, the surgical vision device is used for the detection of deep tumors and metastases using a bioluminescence generating system that produces red light at the target site. Presently preferred are the bioluminescence generating systems isolated from Aristostomias, such as A. scintillans, Pachystomias and Malacosteus, such as M. niger, all of which produce red light [i.e., light of a wavelength between 650 and 750 nm, peaking at 705 nm; Widder et al. (19??) Science News 150(14): 214].\nIn alternative embodiments, blue or green light may produced at the target site using a bioluminescence generating system, e.g., using Renilla bioluminescence generating system, and converted to red light by further including a fluorescent protein, such as a phycobiliprotein, which converts green light to red light. The concentration of the bioluminescence generating components necessary to generate red light of sufficient intensity to be detected by the surgical vision device will vary but may be determined empirically by one of skill in the art using methods described herein and those known to those of skill in the art.\nb. Miniature Surgical Imaging Instruments\n(1) Background\nOptical images of the interior of a living body may also be generated by a surgeon using a surgical imaging instrument. Examples of instruments used for surgically viewing the internal organs of a patient include, but are not limited to, laparoscopes, endoscopes, cytoscopes, arthoscopes and thorascopes [e.g., see U.S. Pat. Nos. 5,511,564; 5,311,859; 5,313,306 and 5,331,950].\nThe application of these instruments requires only a minimally invasive surgical procedure. In general, the surgeon makes a small incision in the patient nearby the targeted viewing area into which the elongated tube of the instrument is inserted. The instruments are guided through the body to the viewing area by the surgeon or by remote controlled means [e.g., see U.S. Pat. No. 5,540,649 describing a device for remotely controlling surgical instruments]. Light is transmitted from a light source through the insertion tube using a fiber optic bundle to illuminate internal objects of the body cavity. The illuminated images are focused by a lens housed at the distal end of the insertion tube onto an image forming surface of a CCD imager or other equivalent imager. The optical image is then converted to an electric output signal that is displayed on a video monitor, LED monitor or phosphor screen.\nIn addition, a wide angled lens may be used to increase the available viewing area, and any image distortion from such lenses may be optically corrected using an omniview transformation system, which allows for multiple simultaneous images to be outputted from a single location [e.g., see U.S. Pat. No. 5,313,306].\n(2) Surgical Viewing Instruments for Detecting Bioluminescent Neoplasia and Specialty Tissue\nSurgical instruments for detecting bioluminescent neoplasia and specialty tissue are provided herein. More particularly, surgical instruments containing miniaturized imagers that are specifically designed to detect bioluminescence inside the body cavity of a patient are provided herein.\nAny surgical imaging device capable of detecting emissions generated from a bioluminescent generating system is contemplated for use in the methods and EXAMPLES provided herein. For example, surgical instruments that detect emissions generated throughout the human scotopic and photopic range, e.g., ultraviolet through infrared wavelengths, are contemplated for use herein. In preferred embodiments the instruments are highly sensitive to broad spectrum visible light, and in more preferred embodiments, the instruments are highly sensitive to narrow ranges visible light, particularly blue, green or red wavelengths.\nIn especially preferred embodiments, surgical viewing instruments contain a modified CCD imager or other equivalent imager that is useful for the detection of bioluminescence. Particularly preferred instruments are those described in U.S. Pat. No. 5,313,306 (endoscope), U.S. Pat. Nos. 5,311,859 and 5,331,950 (laparoscopes). For example, U.S. Pat. No. 5,331,950 describes a video laparoscope assembly in which a miniature camera, containing a lens assembly, focuses an image of a target onto an image forming surface of CCD video camera imager. The intensified image is converted to an output signal which is sent to a video processing unit. The reproduced image is displayed on an accompanying video monitor.\nExisting CCD imagers and other equivalent image intensifiers may be used in the methods that are sensitive to low intensity visible and infrared light. These CCD imagers are commercially available and well known to those of skill in the art (e.g., Tektronics TEK Nos. 25, 27 and 32 CCD imager intensifiers; Generation II and III image intensifier tubes, ITT Electro Optics Division, Roanoke, Va.; cooled CCD arrays and image intensifiers, Princeton Instruments, Inc., Fremont, Calif.; SenSys 1400 and 1600 digital cameras, Photometrics, Ltd; Model 221, Javelin Electronics and, 18 and 25 mm MCP second generation image intensifier tubes, Stano Components, Inc, Carson City, Nev.). Any of these imager intensifiers may be used in the apparatus described herein.\nThe selection of the appropriate CCD imager for use in the methods herein will depend on means of visualizing the tumor and the wavelength and intensity of the light generated by the bioluminescent reaction. These parameters may be determined empirically by one of skill in the art using the teachings provided herein. For the detection of extremely low levels of light emission, the surgical instrument may optionally contain an image intensifier tube, e.g., a GEN III image intensifier tube or red-sensitive Model 221 image intensifier, and the intensified image visualized on a phosphor screen or other equivalent display means.\nUsing these surgical instruments, an external light source is not required for viewing the bioluminescent target because the tumor or specialty tissue targeted for surgical removal glows in the absence of excitation by an external illumination source. When necessary, a light source may be used that generates broad spectrum light or monochromatic light of narrow spectral bands. In addition, the color of the broad spectrum light may be filtered to reduce background and light scattering. Color wheel filters adaptable for use in these instruments are known [e.g., see U.S. Pat. No. 4,523,224]. Alternatively, in order to minimize undesired wavelengths of light from reaching the CCD imager or intensifier tube, an appropriate optical interference filter may be placed between the video camera and the imager.\nIn a preferred embodiment, the CCD imager of the surgical instrument is highly sensitive to visible light, preferably blue or green light [xcex400-600 nm]. A tumor-specific targeting agent, e.g., an antibody directed against a colon cancer specific-antigen, is coupled to a component of the Aequorin or Renilla bioluminescence generating system, preferably the photoprotein or luciferase, respectively. In the presence of the remaining components, bluish-green light is produced at the site of the tumor. The remaining components, i.e. an appropriate substrate and\/or any necessary activators, may be added intravenously or using a laparoscope or trocar that allows for local administration of fluid to the target site through the insertion tube [e.g., see International Patent Application No. WO 95\/32012]. A laparoscope that contains a CCD imager that is highly sensitive to low intensity visible light in these wavelengths, is used by the surgeon to detect and visualize the image of the glowing tumor. The target tissue may be removed surgically or removed using a medical ablation device [e.g., see U.S. Pat. Nos. 5,486,161 and 5,511,564 describing laparoscopic medical ablation devices].\nIn another preferred embodiment, the CCD imager of the surgical imaging instrument is replaced with an imager containing a CCD array that is highly sensitive to low intensity red light [e.g., xcex650-750 nm]. Wavelengths of red and near infrared light of about 700-1300 nm are known to easily penetrate through the skull, soft tissue and into bone [e.g., see U.S. Pat. No. 4,281,645]. In this embodiment, a tumor-specific targeting agent is coupled to a component of a red emitting bioluminescent generating system, e.g., Aristostomias, and the remaining components of the reaction are added as described above. Red light emitted from the tumor is detected using the modified laparoscope or endoscope. The glowing image of the tumor may be visualized through surrounding and nearby tissues, even in deep tissue tumors such as breast cancer, eliminating the need to surgically view the targeted tissue.\nc. Computer Tomographs\n(1) Background\nA computer tomograph is a non-invasive, medical imaging device capable of generating prescribed sectional pictures of the interior of a living body. These sectional images, i.e., computer tomograms, are arranged in different planes from which a three dimensional computer image of the internal organs and tissues of the body may be constructed.\nIn general, a computer assisted tomograph, e.g., an X-ray CT scanner, is composed of a patient support, an X-ray radiator and detector array capable of being rotated 360 degrees around the patient axis and a computer processing unit for image re-construction. In preparing computer tomograms, a subject is placed horizontally on the patient support and irradiated with a narrow beam of X-rays. The X-ray radiator and detector array, fixed in space relative to one another, are rotated 360 degrees around the patient. The circumferential output signals from the detector array are relayed to a computer processing unit which reconstructs an image of the target. The reproduced image is viewed on a video monitor or other suitable display means [e.g., see U.S. Pat. Nos. 5,113,077; 5,315,628; 5,533,082].\nIn addition to images generated using X-rays, apparatus for optically inspecting the human body using light are also known. For example, spectrophotometric methods and apparatus for optically monitoring biological processes, such as blood metabolism, are known [e.g., see U.S. Pat. Nos. 4,281,645; 5,148,022; 5,337,745; 5,413,098; International Patent Application Publication No. WO 93\/13395; Amato (1992) Science 258:892-893]. Furthermore, optical tomography using laser-emitting apparatus that pulse wavelengths of near infrared light has been employed to visualize images of phantom objects placed in tissue and also the internal organs of animals [Benaron et al. (1994) in Oxygen Transport to Tissue, Ed. Hogan et al., pp. 207-222 Plenum Press, NY].\nConventional tomographic and spectrophotometric apparatus require an external source of radiation for image detection and construction. For example, traditional computer tomography requires an irradiation source for generating X-rays. Optical tomographs require one or more lasers to generate a narrow beam of light in the near infrared region of the spectrum to minimize scattering and absorption of photons by tissues. Computer software containing algorithms for forward and inverse problems of image re-construction in optical tomography has been developed, such as time-of-flight absorbance [TOFA; e.g., see Benaron et al. (1993) Science 259:1463-1466; Benaron et al. (1994) in Oxygen Transport to Tissue, Ed. Hogan et al., pp. 207-222 Plenum Press, NY] or time-resolved optical absorption and scattering tomography [TOAST; e.g., Arridge et al. (1991) Proc. SPIE 1431:204-215; Arridge et al. (1993) Proc. SPIE 2035:218-229].\n(2) Computer Apparatus for the Non-invasive Detection of Bioluminescent Neoplasia and Specialty Tissue\nA computerized apparatus and non-invasive methods for optically inspecting the interior of a living body are provided herein. More particularly, a computerized optical imaging apparatus and non-invasive methods for optically imaging bioluminescent neoplasia and specialty tissues are provided herein.\nIt is to be appreciated that any apparatus that is capable of detecting electromagnetic radiation generated from a bioluminescent reaction and calculating an image of the bioluminescent target is contemplated for use in the methods described herein. For example, the computerized optical imaging apparatus may be analogous to a computer tomograph except that bioluminescence is used as the radiation source and an optical detector as the image detector. Image reconstruction may be performed using a computer processing unit containing software that uses algorithms and principles employed in X-ray CT scanners and optical computer tomography, such as time-of flight optical imaging, convolution integration and Fourier analysis [e.g., see Benaron et al. (1993) Science 259: 1463-1466; U.S. Pat. Nos. 5,113,077; 5,315,628; 5,533,082].\nAlternatively, the apparatus may contain any optical detector known to those of skill in the art capable of detecting electromagnetic radiation through tissue or other biological medium. Visible light may be detected directly through animal tissue using a photon detector or digital camera.[e.g., see Travis (1996) Science News 150:220-221]. Thus, the instant apparatus may contain an array of digital cameras may be used to detect light emission from the bioluminescent neoplasia or specialty tissue. In this exemplary embodiment, digital cameras may be placed at any angle or any position nearby a targeted viewing area or, alternatively, a complete scan of the entire patient may be performed. The electromagnetic radiation detected by the digital camera may be relayed to a computer processing unit and computer image of the bioluminescent neoplasia or specialty tissue is re-constructed based from the intensity of the detected light emissions using one or more of the above-described computer algorithms.\nBy moving one or more digital camera, several computer images may be produced and overlaid upon one another to generate a three dimensional image of the bioluminescent neoplasia or specialty tissue. The imaging of the bioluminescent tumors or specialty tissues may be also be performed by overlaying against images obtained using other non-invasive diagnostic imaging methods. Particularly preferred is the projection of bioluminescent neoplasms on images obtained using standard ultrasound techniques, such as sonograms [e.g., see U.S. Pat. Nos. 5,575,288; 5,619,995; 5,619,999; 5,622,172; 5,630,426].\nIn preferred embodiments, the optical imaging apparatus is capable of detecting low intensity visible light emissions from the interior of a patient. One or more digital camera is used to detect light output from the bioluminescent target, and the detected images are relayed to a computer processing unit that generates an image of the bioluminescent neoplasia or specialty tissue. In especially preferred embodiments, the optical detector of the apparatus is highly sensitive to wavelengths of low intensity red and near infrared light, which wavelengths are known to undergo the least amount of scattering through tissue or other biological medium.\nG. Photodynamic Therapy\n1. Background\nThe bioluminescent targeting agent conjugates may also be used the detection and treatment of neoplasia in conjunction with photodynamic therapy techniques. These techniques involve the administration of a photosensitizing drug to a patient. The drugs or chemicals subsequently localize in neoplastic cells which are then illuminated from an external source with light of an appropriate wavelength to activate the drug or chemicals. This photoactivation results in photochemical reactions in the neoplastic tissue that ultimately cause cytotoxic injury and\/or death of the targeted tissue.\nA wide variety of compounds suitable for use as photosensitizing drugs are commercially available or may be prepared using methods known to those of skill in the art. For example, the compounds may be derived from natural sources (e.g., porphyrins, chlorins and purpurins) or from known chemicals originating in the dyestuffs industries (e.g., cyanine dyes). Specific examples of photosensitizing drugs include, but are not limited to, phyhalocyanines (merocyanine 540), substituted purpurines, xanthenes (Rhodamine 1236GandB), cationic cyanine dyes, chlorine polymers, chalcogenapyrylium dyes containing selenium or tellurium atoms in the chromophore, phenothiazolium derivatives, benzophenoxoniums (Nile Blue A) and triarylmethanes (Victoria Blue BO) [e.g., see U.S. Pat. Nos. 4,861,876; 4,961,920; 5,132,101; 5,179,120; 5,189,029; 5,344,928; 5,409,900; 5,433,896; 5,446,157; 5,532,171 and International Patent Application Publication Nos. WO 95\/24930 and WO 96\/31451].\nThe photosensitizing drugs may be formulated, for example, for topical, local, parenteral or systemic intravenous administration. In addition, the specificity of the photosensitizing drug for neoplastic cells can also be increased by conjugation to a known anti-tumor targeting agent. For example, the photosensitizing drug may be conjugated to an antibody or other peptide. The method of conjugating a porphyrin dye to an anti-cancer antigen antibody is known [e.g., see European Patent Application No. EP 252683].\nThe exact mechanism used by the above-mentioned chemicals to destroy neoplastic cells upon exposure to an external excitatory light source is currently unknown. There are two generally proposed mechanisms by which photosensitizing drugs are chemically altered upon illumination. The first mechanism typically involves hydrogen atom abstraction from the drugs, thereby producing free radicals that react with organic products or oxygen, which results in biochemical destruction of the neoplastic cells. The other reaction mechanism normally involves energy transfer from the electronically excited drugs to oxygen producing a singlet oxygen. The singlet oxygen reacts with a variety of substrates to produce oxygenated products in combination with superoxide ions that results in disruption of the target cell wall or mitochondria and destruction of the neoplastic cell.\nExternal light sources, such as white light sources and lasers, are typically used as the radiation source. The time and duration and repetition of irradiation varies depending on the particular photosensitizing compound selected, the means of administration and the neoplasia to be treated. For example, irradiation takes place not less than one hour nor more than four days after parenteral administration of a porphyrin derivative; whereas radiation may commence as soon as 10 minutes after topical application of the same or similar compound [e.g., see U.S. Pat. No. 5,409,900]. Photodynamic therapy is usually initiated about 3 to 48 hours after administration of the photosensitizing drug and may be performed using invasive as well as non-invasive surgical procedures. Apparatus for irradiating living cells are well known to those of skill in the art [e.g., see International Patent Application Publication No. WO 96\/24406].\nNot all neoplasia are suitable candidates for photodynamic therapy. Nevertheless, photodynamic therapy has been used to treat bladder, bronchial, bone marrow and skin tumors as well as severe psoriasis [e.g., see U.S. Pat. No. 5,179,120]. Specific examples of skin malignancies include basal and squamous cell cancers, malignant melanoma, Kaposi\"\"s sarcoma, mycosis, fungoides, metastatic epidermoid, and recurrent breast cancer. Head and neck cancers, such as nasopharyngeal, tongue and other oropharyngeal tumors may also be treated. Other examples of neoplastic tissue that may be treated are endobronchial cancer (such as adenocarcinoma or small cell carcinoma), esophageal cancers, gynecologic tumors (such as cervical carcinoma, vaginal cancer and vulvar malignancies) as well as brain tumors (such as glioblastoma and astrocytoma) and metastatic malignancies [e.g., see U.S. Pat. No. 5,446,157].\n2. Methods of Using Photodynamic Therapy in Conjunction with Bioluminescent Targeting Agents\nThe photosensitizing drugs used in photodynamic therapy may also be used in methods with the bioluminescent targeting agent conjugates, as described herein, in the detection and treatment of neoplasia and specialty tissue. These methods differ from traditional photodynamic therapy in that light required to activate the photosensitizing drug is generated in situ by a bioluminescent reaction. Thus, irradiation of the drug occurs directly at the surface of the neoplastic cell by light emitted by the targeting agent-luciferase conjugate, which has been localized on the surface of the targeted cell through the specific interaction of the targeting agent and the target. Therefore, the present method may be used with a wide variety of compounds and photodynamic therapies, and provides non-invasive surgical procedures for treating a diverse array of neoplasia.\nFor practice in the methods, an effective amount of a photosensitizing drug may be administered to a patient successively or simultaneously with an anti-tumor antigen antibody conjugated to one or more component of a bioluminescence generating system, preferably a luciferase. After allowing an amount of time sufficient for binding of the antibody conjugate to the neoplastic tissue and subsequent sequestration of the photosensitizing drug by the neoplastic tissue, e.g., 10 min to 24 hr, the remaining components of the bioluminescent reaction, e.g., luciferin and any necessary activators, are administered to initiate the bioluminescent reaction. Light production activates the photosensitizing drug resulting the death of the targeted neoplastic cell.\nThe bioluminescence generating system used to activate the photosensitizing drug will vary depending on the biochemical properties of the drug [e.g., the absorption maxima] and the type of neoplasia to be detected or treated. The selection of the drug and bioluminescence system may be determined empirically based on the teachings herein. In addition, the targeting agent may also include the use of a fluorophore or fluorescent protein, e.g., GFP, to alter the wavelength of the emitted light to provide a wider range of wavelengths for treatment.\nThis method is particularly advantageous for detecting and treating metastatic tumors using photodynamic methodologies. For example, metastases may be located quite distant from the primary site of irradiation used in traditional photodynamic techniques and, thus, metastatic regions may not receive a sufficient dose of irradiation for photoactivation of the drug. In the instant method, light may be continuously produced at any location in which the targeting agent binds. Therefore, sufficient quantities of light may be generated throughout the body to eliminate those neoplastic cells that have metastasized from the location of the primary tumor.\nPresently preferred compounds for use in the methods herein are those that have absorption maxima between 400 and 900 nm wavelengths and particularly preferred bioluminescence generating systems are those that emit wavelengths of light greater than 500 nm, Aristostomias and Malecostus. In addition, methods using photodynamic therapy with one or more fluorescent protein and the bioluminescent generating systems of Renilla and the photoprotein aequorin are also preferred.\nH. Practice of the Methods\nAmong the embodiments herein, are those in which a bioluminescence generating component, preferably a luciferase, is conjugated to an antibody directed against a human tumor antigen. A patient is administered a pre-operative dose of the antibody-luciferase conjugate, which binds to the tumor antigen. During the surgical procedure, the final components, i.e., a luciferin and any activators, are applied topically to the suspected area of the neoplasia, causing the tumor-antigen expressing cells to be illuminated. The illuminated area may be detected visually or using one of the above-described surgical instruments.\nIn the case of melanoma, for example, the antibody-luciferase conjugate may be applied topically in a lotion, ointment, cream or other such formulation, and the unbound and non-specifically bound antibody conjugate removed by washing or administered i.c.v or i.p. The remaining bioluminescence-generating components are topically applied to visualize the location and margins of the neoplastic melanoma cells for surgical removal.\nThe light intensity of the bioluminescent reaction may be amplified by coupling more than a single luciferase molecule to a microcarrier (e.g., microparticles or microbeads). The luciferase-coupled microcarrier may be covalently or non-covalently linked to a target agent and injected into an animal or human patient. Upon binding to the target, the remaining components of the bioluminescent reaction are added and the light production from the tumor or specialty tissue will be greatly enhanced compared to a targeting agent-luciferase protein conjugate (e.g., an aequorin-Mab conjugate, see U.S. Pat. No. 5,486,455).\nUsing the coupling methods described herein, a set of microcarriers may be designed containing one or more type of luciferase for the rapid production of a single targeting agent linked to one or more luciferase each having different biochemical properties (i.e., emit light of a different wavelength). In addition, more than one of the bioluminescence generating components may be coupled to the microcarrier. For example, aequorin or Renilla luciferase may be coupled, concurrently or successively, with a GFP, which absorbs light of one wavelength (xcexmax=480 nm) and emits light of a different wavelength (xcexmax=509 nm). Thus, Renilla luciferase bound to a microcarrier would emit blue light whereas a microcarrier containing Renilla luciferase and GFP would emit green light. Alternatively, the coupling a component of the Aristostomias, Pachystomias or Malacosteus bioluminescence generating system to a microcarrier would result in the production of red light.\nThe targeting agent may be conjugated to one or more components of the bioluminescence generating system contained on the microcarrier through a biotin-streptavidin complex. The interaction between avidin\/streptavidin and biotin is well documented and has been exploited as a research tool across several scientific disciplines (e.g., see Bayer and Wichek (1980) The Use of Avidin\/Biotin Complex as a Tool in Molecular Biology. Meth. Biochem. Anal. 26, 1-45).\nThe coupling of proteins and small molecules to biotin is well known and bioluminescence generating components are amendable to biotinylation. For example, biotinylated aequorin has been reported (Stultz et al. (1992) Use of Recombinant Biotinylated Apoaequorin from Escherichia coli. Biochemistry 31, 1433-1442; Smith et al. (1991) A Microplate Assay for Analysis of Solution Phase Glycosyltransferase Reactions: Determination of Kinetics Constants. Anal. Biochem. 199, 286-292). In addition, reagents are commercially available for coupling biotin to primary amines, sulfhydryl groups, carboxyl groups and the side chains of the amino acids tyrosine and histidine (see Pierce Catalog, pp. T123-T154, 1994). Kits designed for biotinylating compounds are also commercially available (e.g., Boehringer Mannheim Corp., Indianapolis, Ind.).\nIn addition, streptavidin matrices useful as microcarriers may be purchased or synthesized starting with the matrices described in Section 3(C)(3)(a) herein. Thus, the streptavidin-biotin coupling method is amendable to any targeting agent that may be coupled to biotin and any streptavidin matrix suitable as a microcarrier that may be coupled to at least one or more luciferase molecule.\nThe following examples are included for illustrative purposes only and are not intended to limit the scope of the invention.","meta":{"bibliographic_information":{"document_kind":"B2","document_number":"06596257","document_date":"20030722","publishing_country_or_organization":"US","title_of_invention":"Detection and visualization of neoplastic tissues and other tissues"},"source_file":"https:\/\/bulkdata.uspto.gov\/data\/patent\/grant\/redbook\/fulltext\/2003\/pg030722.zip","abstract":["Kits containing the diagnostic systems and diagnostic systems that rely on bioluminescence for visualizing tissues in situ are provided. The systems include compositions containing conjugates that include a tissue specific, particularly a tumor-specific, targeting agent linked to a targeted agent, a luciferase or luciferin. The systems also include a second composition that contains the remaining components of a bioluminescence generating reaction. Administration of the compositions results production of light by targeted tissues that permits the detection and localization of neoplastic tissue for surgical removal."],"citations":[{"DNUM":"3509344","DATE":"19700400","KIND":"A","CITING_PARTY":"other","US_PARTY_NAME":"Bouwers","PNC":"250 833"},{"DNUM":"3539794","DATE":"19701100","KIND":"A","CITING_PARTY":"other","US_PARTY_NAME":"Rauhut et al.","PNC":"240  225"},{"DNUM":"3597877","DATE":"19710800","KIND":"A","CITING_PARTY":"other","US_PARTY_NAME":"Speers","PNC":" 46116"},{"DNUM":"3843443","DATE":"19741000","KIND":"A","CITING_PARTY":"other","US_PARTY_NAME":"Fishman","PNC":"195 63"},{"DNUM":"3859125","DATE":"19750100","KIND":"A","CITING_PARTY":"other","US_PARTY_NAME":"Miller","PNC":"117155"},{"DNUM":"3939123","DATE":"19760200","KIND":"A","CITING_PARTY":"other","US_PARTY_NAME":"Matthews","PNC":"260 775"},{"DNUM":"4006117","DATE":"19770200","KIND":"A","CITING_PARTY":"other","US_PARTY_NAME":"Merrifield et al.","PNC":"260 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{"text":"Apparatuses and methods for removing solid tissue from beneath a tissue surface are described. The methods rely on positioning an energy conductive element at a target site beneath the tissue surface and energizing the element so that it can vaporize tissue. The element is then moved in a pattern which provides the desired tissue removal geometry, such as spherical, ovoid, or cylindrical. Usually, the shaft is moved, typically rotated or reciprocated, and the energy conductive element is moved relative to the shaft, typically by pivoting a rigid element or bowing a flexible element.\n\n1. Field of the Invention\nThe present invention relates generally to medical devices, kits, and methods. More particularly, the present invention relates to apparatuses and methods for removing tissue from tissue regions beneath a tissue surface.\nThe removal of diseased and other tissues is the basis for many surgical procedures and is accomplished in many different ways. Most commonly, the target tissue is excised using a cutting blade, such as a scalpel, in open surgical procedures. Typically, the cutting blade is advanced into a tissue through an exposed tissue surface, and the target tissue is simply cut out and removed. While very effective for tissue removal at or near an exposed tissue surface, this approach is less effective for tissue removal from sites spaced below the closest exposed tissue surface.\nFor removal of target tissue below a tissue surface, a surgeon can simply cut down to the level of the target tissue and cut out and remove the tissue at that level. The need to cut down through xe2x80x9cnon-targetxe2x80x9d tissue is, however, disadvantageous in several respects. First, surgically cutting through the overlying healthy tissue can create a much bigger incision than is necessary for simply removing the target tissue. Moreover, the need to penetrate through relatively thick layers of overlying tissue can complicate identification of the target region, often requiring that larger volumes of tissue be removed to assure to complete removal. Additionally, the ability to cut down into internal organs during minimally invasive endoscopic procedures is significantly more limited than in open surgical procedures.\nSurgical instruments for removing tissue beneath a tissue surface have been developed. For example, instruments employing specialized cutting blades for chopping or xe2x80x9cmorcellatingxe2x80x9d tissue into small pieces and aspirating the resulting debris have been developed. While such instruments are at least theoretically capable of being manipulated to remove a defined volume of tissue beneath a tissue surface, their performance suffers in various ways. Most importantly, tissue morcellation can result in significant bleeding which is difficult to staunch. Thus, these techniques would not be useful in highly vascularized tissues, such as many muscle and organ tissues. Even when combined with electrosurgical coagulation, such tissue morcellation devices are probably not useful for the removal of large tissue volumes beneath a tissue surface where bleeding control is problematic.\nFor all of these reasons, it would be desirable to provide improved apparatuses and methods for tissue removal beneath tissue surfaces. In particular, the devices and methods should be suitable for use in minimally invasive procedures, such as procedures where the devices are introduced through a port and viewed under endoscopic viewing. The methods and devices should further allow access to a target tissue region with minimum disruption and damage to the overlying xe2x80x9cnon-targetxe2x80x9d tissue. Additionally, it would be desirable to provide tissue removal regions with a simplified approach for removing the debris resulting from the tissue removal. It would be particularly desirable to provide such tissue removal methods and devices which result in minimum or easily controlled bleeding at the tissue removal site. Such methods and apparatuses should still further provide for removal of controlled volumes, even relatively large volumes of at least 0.5 cm3, preferably at least 50 cm3, and still more preferably at least 500 cm3, or more. The methods and apparatuses should also be useful on a wide variety of tissue types and for a wide variety of specific procedures. At least some of these objectives will be met by the invention described hereinafter.\n2. Description of the Background Art\nA loop electrode for radiofrequency electrosurgical excision of a tissue volume in solid tissue is described in Lorentzen et al. (1996) Min. Invas. Ther. and Allied Tecnol. 5:511-516.\nThree-dimensional electrode arrays for deployment in solid tissue followed by the application of radiofrequency energy to necrose tissue volumes are described in U.S. Pat. Nos. 5,827,276; 5,735,847; and 5,728,143.\nAtherectomy catheters having radially expansible blade structures intended for rotational stenotic excision in blood vessels are described in U.S. Pat. Nos. 5,556,408; 5,554,163; 5,527,326; 5,318,576; 5,100,423; and 5,030,201. In particular, U.S. Pat. No. 5,554,163, describes a catheter having a flexible xe2x80x9ccuttingxe2x80x9d element that may be radially deployed from the catheter body. U.S. Pat. No. 5,100,423, describes a cutting structure comprising a plurality of helically-shaped cutting wires that can be connected to an electrosurgical power supply to effect cutting of obstructing matter in a blood vessel. The following patents describe other electrosurgical instruments: U.S. Pat. Nos. 2,022,065; 4,660,571; 5,217,458; 5,578,007; 5,702,390; 5,715,817; 5,730,704; 5,738,683; and 5,782,828.\nThe present invention provides improved methods, devices, and kits for removing tissue from internal target sites disposed beneath a tissue surface. The present invention can provide a number of advantages when compared to prior tissue removal techniques, including minimizing disruption of the tissue overlying the target site, i.e., between the tissue surface and an outer periphery of the target volume which is to be removed. In the preferred examples described below, access through the overlying tissue can be achieved with a single percutaneous or transcutaneous tissue tract sufficient to accommodate a single shaft of the apparatus. In addition to minimizing disruption of overlying tissue, the present invention can significantly reduce bleeding at the target site after tissue removal. In particular, by employing electrocautery as part of the tissue excision process, bleeding of the surrounding tissues can be substantially staunched. Other advantages provided by the present invention include the ability to remove relatively large tissue volumes, typically, at least 0.5 cm3, often at least 50 cm3, and sometimes as large as 500 cm3, or larger. While the present invention is particularly suited for removing large volumes. The tissue removal can be effected in many tissue types, including those specifically set forth below, and tissue debris remaining after removal can be transported from the site, typically through the single access tract described above, usually by aspirating vapors and cellular debris which are produced as the tissue excision and vaporization stages occur. In addition or as an alternative to vapor aspiration, the tissue void which is being created may optionally be flushed with a suitable liquid or gas, preferably an electrically non-conductive liquid, such as sorbitol. Further optionally, the flushing medium may carry medications or other biologically active substances, such as antibiotics, pain killers, hemostatic agents, and the like. Such flushing may occur concurrently with the cutting, during brief periods when cutting is ceased, and\/or after all cutting has been completed.\nThe present invention is suitable for removing defined volumes of tissue from a variety of different tissue types, including breast tissue, liver tissue, kidney tissue, prostate tissue, lung, uterine, and the like. Thus, the tissue surface may be on the patient\"\"s skin, e.g., in the case of breast tissue removal, or the tissue surface may be located subcutaneously, e.g., in the case of internal body organs. In the former case, access to the target site may be achieved transcutaneously or subcutaneously, where the removal device penetrates directly through the skin. In the latter case, a secondary procedure is needed to access the tissue surface of the internal body organ. The secondary procedure may be an open surgical procedure where the overlying skin and body structures are surgically opened. Alternatively, the secondary procedure may itself be minimally invasive where small incisions or ports are used to introduce the devices of the present invention together with any necessary or useful auxiliary devices for performing the tissue removal. Typically, such minimally invasive surgeries will be performed under endoscopic visualization where the treating physician views the procedure on a video screen. As a still further alternative, access to internal body organs may be achieved intraluminally, preferably endoscopically. Typically, such intraluminal, endoscopic access will be obtained through body lumens having natural orifices, such as the esophagus, colon, uterus, fallopian tubes, sinuses, uterus, ureter, and urethra. Such access will typically be achieved using a flexible catheter which can provide a platform for advancing the energy conductive elements, as described in more detail below.\nThe depth of the target site will depend on the nature of the tissue and the nature of the disease or other condition being treated. Typically, the closest periphery of the target site will be located between the adjacent or available tissue surface by distance in the range from 0.5 cm to 15 cm, usually from 5 cm to 7 cm. The volume of tissue to be removed will typically be in the range from 0.5 cm3 to 500 cm3, typically being from 5 cm3 to 300 cm3. As described in more detail below, the geometry or shape of the removal volume, i.e., the void left in tissue following tissue removal, will generally be spherical, ovoid, cylindrical, or other shape characterized by at least one axis of symmetry. The axis of symmetry will usually arise because of the manner in which the tissue removal devices are used, as described in more detail below.\nIn a first aspect, methods according to the present invention comprise positioning an energy conductive element at a target site in tissue beneath a tissue surface. The energy conductive element is energized and moved through successive tissue layers, where the element is energized with sufficient energy to vaporize tissue in said successive layers. Such sequential removal of successive layers of tissues will produce a desired removal volume, typically having the geometries and sizes set forth above.\nIn a second aspect, methods according to the present invention comprise providing an instrument having a shaft and a repositionable energy conductive element on the shaft. The element is advanced through the tissue surface to a target site in solid tissue, where the element is in a low profile configuration (e.g., radially collapsed into the shaft) and the proximal end of the shaft remains outside of the solid tissue to permit manipulation. The shaft is moved relative to the tissue surface and the element repositioned relative to the shaft while the element is being energized with sufficient energy to remove tissue. The combined movements of the shaft and the element relative to the shaft cause the element to pass through successive tissue layers at or near the target site and to vaporize said layers to produce the desired removal volume.\nUsually, the methods for removing tissue as described above will further comprise imaging the solid tissue and positioning the energy conductive element based on the image. The imaging may be any type of conventional, two-dimensional or three-dimensional medical imaging, including fluoroscopic imaging, ultrasonic imaging, magnetic resonance imaging, computer-assisted tomographic imaging, optical imaging, and the like. Positioning of the energy conductive device may be entirely manual, where the user may view the image of the target site either in real time, as a pre-operative image only, or a combination of real time and pre-operative images. Alternatively, the energy conductive device may be automatically positioned based directly or indirectly on the image using robotic or other automatic positioning equipment. Optionally, such automatic positioning equipment can be programmed based on a pre-operative or real time image of the target region.\nThe methods of the present invention will preferably further comprise collecting vapors and cellular debris produced by the tissue vaporization and removing those vapors through the overlying tissue and the tissue surface. Usually, vapor removal will comprise aspirating the vapors from the site or volume of tissue removal as the vapors are being produced. Usually, the vapors will be aspirated through a tissue tract between the tissue surface and the target site, more typically being through a lumen in the shaft of the device used for removing the tissue.\nThe energy conductive element is moved through a pattern of successive tissue layers which, in the aggregate, will form the desired tissue removal volume. The energy conductive element may be moved in any manner, typically being moved by manipulation of the shaft upon which it is mounted. For example, the energy conductive element may be moved relative to the shaft while the shaft itself is moved so that the combined motions of the element and the shaft define the desired removal geometry. Alternatively, the energy conductive element could be moved on the shaft while the shaft remains stationary. In the latter case, a servo or other drive mechanism could be provided within the shaft to move the energy conductive element through its desired pattern.\nThe shaft will usually be rotated and\/or axially reciprocated in order move the energy conductive element through tissue along or about one axis. In turn, the energy conductive element may be pivoted, bowed, or otherwise moved or deflected relative to the shaft to provide further axes or dimensions of the removal volume. In a first exemplary removal method, a shaft having a rigid energy conductive member is introduced to an internal tissue target site with the element lying coaxial to the shaft. The shaft is then rotated and the element pivoted to provide a spherical or partial spherical tissue removal geometry. In a second exemplary embodiment, the energy conductive element comprises one or more flexible elements which may be bowed to form a series of arcuate tissue removal paths as the shaft is rotated. Other approaches include disposing a lateral energy conductive element beneath tissue and simultaneously rotating and reciprocating the support shaft so that a cylindrical removal volume is formed, with the length of the cylinder determined by the length of reciprocation. Other combinations of motion between the shaft and energy conductive element may also be utilized.\nThe type of energy transmitted or provided through the energy conductive element will preferably provide for heating of the tissue. For example, high frequency energy, such as radiofrequency or microwave energy, may be delivered in a monopolar or bipolar manner to vaporize the tissue. Typically, the radiofrequency energy will be applied with a cutting waveform at a frequency in the range from 100 kHz to 2 MHz, and a current in the range from 1 mA to 50 A, 0.5 mA to 10 A, depending on surface contact area and tissue type. Alternatively, energizing can comprise directly heating the element, typically to a temperature in the range from 100xc2x0 C. to 300xc2x0 C., usually 600xc2x0 C. to 2000xc2x0 C. Heating is preferably achieved using optical energy, e.g., laser energy, delivered through a fiberoptic element within the energy conductive element. Alternatively, heating can be achieved using an electrical resistance heater which comprises or is disposed within the energy conductive element.\nThe present invention further provides apparatus for removing tissue. In a first instance, a tissue ablation device comprises a shaft having a proximal end, a distal end, and a lumen therethrough. At least one flexible energy conductive element is disposed near the distal end of the shaft, and a means for bowing the element between a substantially linear profile (where the element lies directly over the shaft) and a series of arcuate profiles spaced progressively further from the shaft is provided. The bowing means will typically include a mechanism for axially advancing a proximal end of the flexible energy conductive element. By preventing or limiting axial movement of a distal end of the flexible energy conductive element, the element will be caused to bow radially outwardly in the desired arcuate configuration. Alternatively, a proximal end of the flexible energy conductive element may be fixed or limited relative to the shaft and a rod or other device for proximally retracting a distal end of the energy conductive element provided. It would further be possible to simultaneously draw both ends of the element together. Other mechanisms, such as expandable cages, parallel linkages, shape heat memory drivers, or the like, may also be provided for bowing the element radially outwardly. The tissue ablation device will further comprise an aspiration connector coupled to the lumen for aspirating vapors produced at the distal end. A power supply connector is further provided to permit electrical coupling of the energy conductive element to a desired power supply.\nThe shaft of such devices may be substantially rigid, typically having a diameter in the range from 0.5 mm to 20 mm, typically 2 mm to 7 mm, and a length in the range from 2 cm to 50 cm, usually 5 cm to 25 cm. The devices will also typically have a handle secured at or near the proximal end of the shaft, and at least one of the aspiration and power supply connectors will usually be disposed on the handle. Optionally, a motor may be provided in the handle or separate from the handle to help drive the device. For example, the motor could be connected to rotate and\/or reciprocate the shaft relative to the handle in order to drive the device in a desired manner. Alternatively or additionally, the motor could be connected to bow the flexible energy conductive element in a controlled manner. In the exemplary embodiments, however, all motions of both the shaft and the energy conductive element will be manual.\nThe shaft of such devices may also be flexible, typically in the form of a catheter having a diameter in the range from 0.5 mm to 10 mm, and a length in the range from 25 cm to 250 cm. Usually, when used for access to natural body lumens, such as the colon, uterus, esophagus, fallopian tubes, sinuses, uterus, ureter, and the urethra, the shafts will be introduced through or as part of an endoscope. The cutting elements for performing the tissue removal will then be deployed from or near the distal end of the catheter. Typically, the cutting elements will be deployed laterally from the catheter and a stylet or other introducer will be utilized to permit subcutaneous introduction as required by the present invention. In other cases, the devices may be introduced intravascularly, typically through the femoral or other veins, to target organs, such as liver, kidney, prostate, lung, and uterus. The cutting elements can then be deployed from the catheters through the blood vessel wall into the target organ.\nThe energy conductive elements may be configured to provide for any of the energy delivery modes set forth above. In particular, energy conductive elements may comprise electrodes suitable for the delivery of high frequency electrical energy, typically radiofrequency energy having the particular frequencies and other characteristics set forth above. Alternatively, the energy conductive elements may be configured to provide for direct heating of the elements themselves, usually comprising either an optical fiber for delivering light energy or comprising an electrical resistance heater together with the necessary wiring to connect the resistance heater to a suitable power source.\nThe flexible energy conductive elements may take a wide variety of forms. A first exemplary form will be a simple elastic or super elastic metal wire, typically having a diameter in the range from 0.1 mm to 5 mm, preferably from 0.5 mm to 2 mm. The wire may be formed from any suitable material, including stainless steel, nickel titanium alloy, tungsten, or the like. The wire may be composed of single material or may be a composite material, e.g., where a portion of the wire is selected for high electrical conductivity while another portion of the wire selected for elastic or other properties. The electrically conductive elements may also be in the form of ribbons, i.e., having a width substantially greater than its thickness. Such ribbon structures will have greater mechanical rigidity when they are radially expanded through their narrow dimension. Often times, different types of energy conductive elements may be combined in a single device. In an exemplary device, a pair of wire elements are disposed on opposite sides of the shaft with a pair of ribbon elements offset by 90xc2x0. Each of the four elements is coupled to the other so that they open and close (be xe2x80x9cbowedxe2x80x9d and relaxed) synchronously. Usually, such structures will be formed for bipolar operation, where the ribbon elements will have a much greater surface area than the wire elements so that the ribbons connect as a dispersible electrode, i.e., an electrode where minimum cutting takes place. In such cases, the ribbon electrode can also serve to act as a surface coagulation electrode to help control bleeding. In some instances, it will be desired that the wire cutting electrodes be advanced slightly radially ahead of the ribbon electrodes. Such a design allows the ribbons to open under a spring force to xe2x80x9cautomaticallyxe2x80x9d expand as the wire electrodes remove successive layers of tissue.\nA second exemplary tissue ablation device comprises a shaft having a proximal end, a distal end, and lumen therethrough. A substantially rigid energy conductive element is pivotally attached to the shaft near its distal end. The device further includes a means for causing the element to pivot, such as a push wire, pull wire, rack and pinion driver, gear driver, or the like. The device will further include aspiration and power supply connectors, both as generally described above.\nThe nature of the shaft and the types of energy conductive elements which may be deployed are all similar to corresponding aspects of the first embodiment of the tissue ablation device described above. The nature of the pivotally connected energy conductive element will, however, differ. The pivotally attached energy conductive element will usually be straight, typically being in the form of a cylindrical pin having a length in the range from 1 mm to 75 mm, and a width or diameter in the range from 0.5 mm to 5 mm. A preferred geometry includes a circular or flat cross-section. The rigid element may be pivotally attached near its middle, near one end thereof, or anywhere else along its length. In an illustration example, the element is pivotally attached near its middle in order to effect a spherical tissue removal volume as the device is rotated and the pin pivoted through 90xc2x0 or more, as described in detail below.\nThe present invention still further provides kits comprising a device having an energy conductive element which is connectable to a power supply and which provides energy sufficient to vaporize successive layers of tissue as the element is moved therethrough. The device may have any of the configurations described above. The kit will further comprise instructions for use setting forth a method as in any of the methods described above. Typically, at least the device will be present in a sterile package, and the instructions for use may printed on a portion of the package or may be on a separate instruction sheet accompanying the package. Suitable packages include pouches, trays, boxes, tubes, or the like. Suitable sterilization techniques include gamma radiation, ethylene oxide treatment, or the like.","meta":{"bibliographic_information":{"document_kind":"B2","document_number":"06663626","document_date":"20031216","publishing_country_or_organization":"US","title_of_invention":"Apparatuses and methods for interstitial tissue removal"},"source_file":"https:\/\/bulkdata.uspto.gov\/data\/patent\/grant\/redbook\/fulltext\/2003\/pg031216.zip","abstract":["Apparatuses and methods for removing solid tissue from beneath a tissue surface are described. The methods rely on positioning an energy conductive element at a target site beneath the tissue surface and energizing the element so that it can vaporize tissue. The element is then moved in a pattern which provides the desired tissue removal geometry, such as spherical, ovoid, or cylindrical. Usually, the shaft is moved, typically rotated or reciprocated, and the energy conductive element is moved relative to the shaft, typically by pivoting a rigid element or bowing a flexible element."],"citations":[{"DNUM":"2022065","DATE":"19351100","KIND":"A","CITING_PARTY":"other","US_PARTY_NAME":"Wappler"},{"DNUM":"3850175","DATE":"19741100","KIND":"A","CITING_PARTY":"other","US_PARTY_NAME":"Iglesias"},{"DNUM":"3942530","DATE":"19760300","KIND":"A","CITING_PARTY":"other","US_PARTY_NAME":"Northeved"},{"DNUM":"4108182","DATE":"19780800","KIND":"A","CITING_PARTY":"other","US_PARTY_NAME":"Hartman et al."},{"DNUM":"4660571","DATE":"19870400","KIND":"A","CITING_PARTY":"other","US_PARTY_NAME":"Hess et al."},{"DNUM":"4986825","DATE":"19910100","KIND":"A","CITING_PARTY":"other","US_PARTY_NAME":"Bays et 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{"text":"A flexible connection unit for spinal stabilization, including: a first end portion having a first longitudinal channel and configured to be coupled to a first securing member secured to a patient's spine; a second end portion having a second longitudinal channel and configured to be coupled to a second securing member secured to the patient's spine; and a flexible wire extending through at least a portion of the first and second longitudinal channels and flexibly linking the first and second end portions.\n\n1. Field of the Invention\nThe present invention relates to a method and system for fixing and stabilizing a spinal column and, more particularly, to a method and system of spinal fixation in which one or more screw type fixing members are implanted and fixed into a portion of a patient's spinal column and flexible, semi-rigid rods or plates are connected and fixed to the upper ends of the fixing members to provide dynamic stabilization of the spinal column.\n2. Description of the Related Art\nDegenerative spinal column diseases, such as disc degenerative diseases (DDD), spinal stenosis, spondylolisthesis, and so on, need surgical operation if they do not take a turn for the better by conservative management. Typically, spinal decompression is the first surgical procedure that is performed. The primary purpose of decompression is to reduce pressure in the spinal canal and on nerve roots located therein by removing a certain tissue of the spinal column to reduce or eliminate the pressure and pain caused by the pressure. If the tissue of the spinal column is removed the pain is reduced but the spinal column is weakened. Therefore, fusion surgery (e.g., ALIF, PLIF or posterolateral fusion) is often necessary for spinal stability following the decompression procedure. However, following the surgical procedure, fusion takes additional time to achieve maximum stability and a spinal fixation device is typically used to support the spinal column until a desired level of fusion is achieved. Depending on a patient's particular circumstances and condition, a spinal fixation surgery can sometimes be performed immediately following decompression, without performing the fusion procedure. The fixation surgery is performed in most cases because it provides immediate postoperative stability and, if fusion surgery has also been performed, it provides support of the spine until sufficient fusion and stability has been achieved.\nConventional methods of spinal fixation utilize a rigid spinal fixation device to support an injured spinal part and prevent movement of the injured part. These conventional spinal fixation devices include: fixing screws configured to be inserted into the spinal pedicle or sacral of the backbone to a predetermined depth and angle, rods or plates configured to be positioned adjacent to the injured spinal part, and coupling elements for connecting and coupling the rods or plates to the fixing screws such that the injured spinal part is supported and held in a relatively fixed position by the rods or plates.\nU.S. Pat. No. 6,193,720 discloses a conventional spinal fixation device, in which connection members of a rod or plate type are mounted on the upper ends of at least one or more screws inserted into the spinal pedicle or sacral of the backbone. The connection units, such as the rods and plates, are used to stabilize the injured part of the spinal column which has been weakened by decompression. The connection units also prevent further pain and injury to the patient by substantially restraining the movement of the spinal column. However, because the connection units prevent normal movement of the spinal column, after prolonged use, the spinal fixation device can cause ill effects, such as \"junctional syndrome\" (transitional syndrome) or \"fusion disease\" resulting in further complications and abnormalities associated with the spinal column. In particular, due to the high rigidity of the rods or plates used in conventional fixation devices, the patient's fixed joints are not allowed to move after the surgical operation, and the movement of the spinal joints located above or under the operated area is increased. Consequently, such spinal fixation devices cause decreased mobility of the patient and increased stress and instability to the spinal column joints adjacent to the operated area.\nIt has been reported that excessive rigid spinal fixation is not helpful to the fusion process due to load shielding caused by rigid fixation. Thus, trials using load sharing semi-rigid spinal fixation devices have been performed to eliminate this problem and assist the bone fusion process. For example, U.S. Pat. No. 5,672,175, U.S. Pat. No. 5,540,688, and U.S. Pub No 2001\/0037111 disclose dynamic spine stabilization devices having flexible designs that permit axial load translation (i.e., along the vertical axis of the spine) for bone fusion promotion. However, because these devices are intended for use following a bone fusion procedure, they are not well-suited for spinal fixation without fusion. Thus, in the end result, these devices do not prevent the problem of rigid fixation resulting from fusion.\nTo solve the above-described problems associated with rigid fixation, non-fusion technologies have been developed. The Graf band is one example of a non-fusion fixation device that is applied after decompression without bone fusion. The Graf band is composed of a polyethylene band and pedicle screws to couple the polyethylene band to the spinal vertebrae requiring stabilization. The primary purpose of the Graf band is to prevent sagittal rotation (flexion instability) of the injured spinal parts. Thus, it is effective in selected cases but is not appropriate for cases that require greater stability and fixation. See, Kanayarna et al, Journal of Neurosurgery 95(1 Suppl):5-10, 2001, Markwalder & Wenger, Acta Neurochrgica 145(3):209-14.). Another non-fusion fixation device called \"Dynesys\" has recently been introduced. See Stoll et al, European Spine Journal 11 Suppl 2:S170-8, 2002, Schmoelz et al, J of spinal disorder & techniques 16(4):418-23, 2003. The Dynesys device is similar to the Graf band except it uses a polycarburethane spacer between the screws to maintain the distance between the heads of two corresponding pedicle screws and, hence, adjacent vertebrae in which the screws are fixed. Early reports by the inventors of the Dynesys device indicate it has been successful in many cases. However, it has not yet been determined whether the Dynesys device can maintain long-term stability with flexibility and durability in a controlled study. Because it has polyethylene components and interfaces, there is a risk of mechanical failure. Furthermore, due to the mechanical configuration of the device, the surgical technique required to attach the device to the spinal column is complex and complicated.\nU.S. Pat. Nos. 5,282,863 and 4,748,260 disclose a flexible spinal stabilization system and method using a plastic, non-metallic rod. U.S. patent publication no. 2003\/0083657 discloses another example of a flexible spinal stabilization device that uses a flexible elongate member. These devices are flexible but they are not well-suited for enduring long-term axial loading and stress. Additionally, the degree of desired flexibility vs. rigidity may vary from patient to patient. The design of existing flexible fixation devices are not well suited to provide varying levels of flexibility to provide optimum results for each individual candidate. For example, U.S. Pat. No. 5,672,175 discloses a flexible spinal fixation device which utilizes a flexible rod made of metal alloy and\/or a composite material. Additionally, compression or extension springs are coiled around the rod for the purpose of providing de-rotation forces on the vertebrae in a desired direction. However, this patent is primarily concerned with providing a spinal fixation device that permits \"relative longitudinal translational sliding movement along [the] vertical axis\" of the spine and neither teaches nor suggests any particular designs of connection units (e.g., rods or plates) that can provide various flexibility characteristics. Prior flexible rods such as that mentioned in U.S. Pat. No. 5,672,175 typically have solid construction with a relatively small diameter in order to provide a desired level of flexibility. Because they are typically very thin to provide suitable flexibility, such prior art rods are prone to mechanical failure and have been known to break after implantation in patients.\nTherefore, conventional spinal fixation devices have not provided a comprehensive and balanced solution to the problems associated with curing spinal diseases. Many of the prior devices are characterized by excessive rigidity, which leads to the problems discussed above while others, though providing some flexibility, are not well-adapted to provide varying degrees of flexibility. Additionally, existing flexible fixation devices utilize non-metallic components that are not proven to provide long-term stability and durability. Therefore, there is a need for an improved dynamic spinal fixation device that provides a desired level of flexibility to the injured parts of the spinal column, while also providing long-term durability and consistent stabilization of the spinal column.\nAdditionally, in a conventional surgical method for fixing the spinal fixation device to the spinal column, a doctor incises the midline of the back to about 10-15 centimeters, and then, dissects and retracts it to both sides. In this way, the doctor performs muscular dissection to expose the outer part of the facet joint. Next, after the dissection, the doctor finds an entrance point to the spinal pedicle using radiographic devices (e.g., C-arm flouroscopy), and inserts securing members of the spinal fixation device (referred to as \"spinal pedicle screws\") into the spinal pedicle. Thereafter, the connection units (e.g., rods or plates) are attached to the upper portions of the pedicle screws in order to provide support and stability to the injured portion of the spinal column. Thus, in conventional spinal fixation procedures, the patient's back is incised about 10\u02dc15 cm, and as a result, the back muscle, which is important for maintaining the spinal column, is incised or injured, resulting in significant post-operative pain to the patient and a slow recovery period.\nRecently, to reduce patient trauma, a minimally invasive surgical procedure has been developed which is capable of performing spinal fixation surgery through a relatively small hole or \"window\" that is created in the patient's back at the location of the surgical procedure.\nThrough the use of an endoscope, or microscope, minimally invasive surgery allows a much smaller incision of the patient's affected area. Through this smaller incision, two or more securing members (e.g., pedicle screws) of the spinal fixation device are screwed into respective spinal pedicle areas using a navigation system. Thereafter, special tools are used to connect the stabilizing members (e.g., rods or plates) of the fixation device to the securing members. Alternatively, or additionally, the surgical procedure may include inserting a step dilator into the incision and then gradually increasing the diameter of the dilator. Thereafter, a tubular retractor is inserted into the dilated area to retract the patient's muscle and provide a visual field for surgery. After establishing this visual field, decompression and, if desired, fusion procedures may be performed, followed by a fixation procedure, which includes the steps of finding the position of the spinal pedicle, inserting pedicle screws into the spinal pedicle, using an endoscope or a microscope, and securing the stabilization members (e.g., rods or plates) to the pedicle screws in order to stabilize and support the weakened spinal column.\nOne of the most challenging aspects of performing the minimally invasive spinal fixation procedure is locating the entry point for the pedicle screw under endoscopic or microscopic visualization. Usually anatomical landmarks and\/or radiographic devices are used to find the entry point, but clear anatomical relationships are often difficult to identify due to the confined working space. Additionally, the minimally invasive procedure requires that a significant amount of the soft tissue must be removed to reveal the anatomy of the regions for pedicle screw insertion. The removal of this soft tissue results in bleeding in the affected area, thereby adding to the difficulty of finding the correct position to insert the securing members and causing damage to the muscles and soft tissue surrounding the surgical area. Furthermore, because it is difficult to accurately locate the point of insertion for the securing members, conventional procedures are unnecessarily traumatic.\nRadiography techniques have been proposed and implemented in an attempt to more accurately and quickly find the position of the spinal pedicle in which the securing members will be inserted. However, it is often difficult to obtain clear images required for finding the corresponding position of the spinal pedicle using radiography techniques due to radiographic interference caused by metallic tools and equipment used during the surgical operation. Moreover, reading and interpreting radiographic images is a complex task requiring significant training and expertise. Radiography poses a further problem in that the patient is exposed to significant amounts of radiation.\nAlthough some guidance systems have been developed which guide the insertion of a pedicle screw to the desired entry point on the spinal pedicle, these prior systems have proven difficult to use and, furthermore, hinder the operation procedure. For example, prior guidance systems for pedicle screw insertion utilize a long wire that is inserted through a guide tube that is inserted through a patient's back muscle and tissue. The location of insertion of the guide tube is determined by radiographic means (e.g., C-arm flouroscope) and driven until a first end of the guide tube reaches the desired location on the surface of the pedicle bone. Thereafter, a first end of the guide wire, typically made of a biocompatible metal material, is inserted into the guide tube and pushed into the pedicle bone, while the opposite end of the wire remains protruding out of the patient's back. After the guide wire has been fixed into the pedicle bone, the guide tube is removed, and a hole centered around the guide wire is dilated and retracted. Finally, a pedicle screw having an axial hole or channel configured to receive the guide wire therethrough is guided by the guide wire to the desired location on the pedicle bone, where the pedicle screw is screw-driven into the pedicle.\nAlthough the concept of the wire guidance system is a good one, in practice, the guide wire has been very difficult to use. Because it is a relatively long and thin wire, the structural integrity of the guide wire often fails during attempts to drive one end of the wire into the pedicle bone, making the process unnecessarily time-consuming and laborious. Furthermore, because the wire bends and crimps during insertion, it does not provide a smooth and secure anchor for guiding subsequent tooling and pedicle screws to the entry point on the pedicle. Furthermore, current percutaneous wire guiding systems are used in conjunction with C-arm flouroscopy (or other radiographic device) without direct visualization with the use of an endoscope or microscope. Thus, current wire guidance systems pose a potential risk of misplacement or pedicle breakage. Finally, because one end of the wire remains protruding out of the head of the pedicle screw, and the patient's back, this wire hinders freedom of motion by the surgeon in performing the various subsequent procedures involved in spinal fixation surgery. Thus, there is a need to provide an improved guidance system, adaptable for use in minimally invasive pedicle screw fixation procedures under endoscopic or microscopic visualization, which is easier to implant into the spinal pedicle and will not hinder subsequent procedures performed by the surgeon.\nAs discussed above, existing methods and devices used to cure spinal diseases are in need of much improvement. Most conventional spinal fixation devices are too rigid and inflexible. This excessive rigidity causes further abnormalities and diseases of the spine, as well as significant discomfort to the patient. Although some existing spinal fixation devices do provide some level of flexibility, these devices are not designed or manufactured so that varying levels of flexibility may be easily obtained to provide a desired level of flexibility for each particular patient. Additionally, prior art devices having flexible connection units (e.g., rods or plates) pose a greater risk of mechanical failure and do not provide long-term durability and stabilization of the spine. Furthermore, existing methods of performing the spinal fixation procedure are unnecessarily traumatic to the patient due to the difficulty in finding the precise location of the spinal pedicle or sacral of the backbone where the spinal fixation device will be secured.","meta":{"bibliographic_information":{"country":"US","doc-number":"11650260","kind":"B2","date":"20070104","invention_title":"Method and apparatus for flexible fixation of a spine"},"source_file":"https:\/\/bulkdata.uspto.gov\/data\/patent\/grant\/redbook\/fulltext\/2015\/ipg150303.zip","abstract":["A flexible connection unit for spinal stabilization, including: a first end portion having a first longitudinal channel and configured to be coupled to a first securing member secured to a patient's spine; a second end portion having a second longitudinal channel and configured to be coupled to a second securing member secured to the patient's spine; and a flexible wire extending through at least a portion of the first and 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{"text":"A new and distinct variety of peach Prunus persica, tree having the following unique combination of desirable features:\n\nThe new peach tree (Prunus persica) (hereinafter referred to as the P.F. 20-007 peach tree) was originated by Paul Friday in the experimental orchard, which is maintained for the purpose of breeding peach trees, at Paul Friday Farms Inc., located in Coloma, Mich. Coloma is located in the southwest section of Michigan.\nIn an ongoing mass selection breeding program, superior seedlings of unrecorded parentage are maintained as seed sources for the production of seeds which are collected and planted in mass. The seed producing parent trees are maintained solely as proprietary trees for breeding purposes and have not been released from the experimental orchard, where such trees can be evaluated for their adaptability to local and regional growing conditions. Seeds resulting from open pollination of the trees in the experimental orchard are regularly planted in mass to produce new populations of seedlings which are cultured and monitored to maturity. Trees with superior attributes are retained for further observation and testing, and contribute seeds to advancing generations of new populations of seedlings.\nThe tree of this application, P.F. 20-007, was a selection from one such cultivated seedling population, and was based on the numerous superior genetic attributes of this tree which are described in the botanical descriptions to follow. While not exhaustive, the botanical descriptions to follow are believed to represent a reasonably complete botanical description of the new peach tree which is sufficiently detailed to distinguish the tree from the most closely related trees within the same market class.\nThe new and distinct variety of peach tree was asexually propagated by budding onto xe2x80x98Baileyxe2x80x99 rootstock as performed in the experimental orchard of Paul Friday Farms Inc., located in Coloma, Mich. The so stated propagation demonstrates that such reproduction of the characteristics of the tree are consistent and are established and transmitted through succeeding propagation.\nThe new and distinct variety of peach tree is of moderate spreading growth. A distinct characteristic of the P.F. 20-007 peach tree is that it has large, strong right angle branching to support its heavy crops of large fruit. While fruit set is medium, this variety yields very big crops due to large fruit size, providing extraordinary yields and is a regular and productive bearer of large peaches.\nThe blossoms of the present peach tree bloom in mid-season and are characterized as being non-showy and do not open much past a vertical state only, opening to a diameter of about xc2xd inch diameter during full bloom with its pistil protruding beyond the plane of the opened blossom petals.\nThe fruit at maturity has crisp flesh of very clear yellow with red around the pit.\nThe skin is smooth, having little down, and is sixty to eighty percent red or more overlying medium-yellow color. At maturity, the peach is spherical, having an average diameter ranging between 2xc2xd inches to 3 inches.\nThe fruit has a firm flesh and may be described as resilient to the extent that the flesh is yieldable and restorable to its original state when subjected to impact forces which may cause permanent deformities in peaches of commercial varieties. The firmness of fruit facilitates handling and packaging of the peaches without damaging the same for shipment. This results in less spoilage and also increases the shelf life.\nThe fruit matures in the mid-part of the peach growing season in southwestern Michigan.","meta":{"bibliographic_information":{"document_kind":"P2","document_number":"PP012331","document_date":"20020101","publishing_country_or_organization":"US","title_of_invention":"Peach tree named xe2x80x98P.F. 20-007xe2x80x99"},"source_file":"https:\/\/bulkdata.uspto.gov\/data\/patent\/grant\/redbook\/fulltext\/2002\/pg020101.zip","abstract":["A new and distinct variety of peach Prunus persica, tree having the following unique combination of desirable features:","1. The new and distinct variety of peach is of spreading growth and a regular and productive bearer of large peaches having a diameter of between 2xc2xdxe2x80x3 and 3xe2x80x3 while bearing heavy crops exceeding 600 bushels per acre in a test block in Michigan. The tree planting was based on 300 trees per acre.","2. Producing a very firm fruit having a resilient flesh texture.","3. Blossoms are non-showy when in full bloom.","4. A substantially spherical to oblate fruit with skin of red overlaying a medium yellow color at maturity.","5. Mid-season maturing fruit of good taste.","6. A mid-season maturing fruit of good storage and shelf life."],"citations":[{"DNUM":"PP1925","DATE":"19600300","KIND":"P","CITING_PARTY":"examiner","US_PARTY_NAME":"Tremmel et al.","PNC":"PLT 198"},{"DNUM":"PP9895","DATE":"19970500","KIND":"P","CITING_PARTY":"examiner","US_PARTY_NAME":"Friday","PNC":"PLT 198"}],"classifications":{"main_or_locrano_class":["A01H  500"],"ipc_edition":["7"],"domestic_main_classification":["PLT 198"],"national_classifications":["PLT 198"]},"inventors":[{"first_name":"Paul Jan","sir_name":"Friday","street":"P.O. Box 850","city":"Coloma","state":"MI","post_code":"49038"}],"dup_signals":{"dup_doc_count":225,"dup_dump_count":18,"dup_details":{"curated_sources":2,"2015-27":10,"2015-22":12,"2015-14":10,"2014-52":12,"2014-49":17,"2014-42":35,"2014-41":19,"2014-35":15,"2014-23":12,"2014-15":12,"2023-14":1,"2024-10":1,"2015-18":17,"2015-11":17,"2015-06":16,"2014-10":9,"2013-48":7,"2024-30":1}}},"subset":"uspto"}
{"text":"The present invention provides systems and methods for secure transaction management and electronic rights protection. Electronic appliances such as computers equipped in accordance with the present invention help to ensure that information is accessed and used only in authorized ways, and maintain the integrity, availability, and\/or confidentiality of the information. Such electronic appliances provide a distributed virtual distribution environment (VDE) that may enforce a secure chain of handling and control, for example, to control and\/or meter or otherwise monitor use of electronically stored or disseminated information. Such a virtual distribution environment may be used to protect rights of various participants in electronic commerce and other electronic or electronic-facilitated transactions. Distributed and other operating systems, environments and architectures, such as, for example, those using tamper-resistant hardware-based processors, may establish security at each node. These techniques may be used to support an all-electronic information distribution, for example, utilizing the \u201celectronic highway.\u201d\n\nTelecommunications, financial transactions, government processes, business operations, entertainment, and personal business productivity all now depend on electronic appliances. Millions of these electronic appliances have been electronically connected together. These interconnected electronic appliances comprise what is increasingly called the \"information highway.\" Many businesses, academicians, and government leaders are concerned about how to protect the rights of citizens and organizations who use this information (also \"electronic\" or \"digital\") highway.\nElectronic Content\nToday, virtually anything that can be represented by words, numbers, graphics, or system of commands and instructions can be formatted into electronic digital information. Television, cable, satellite transmissions, and on-line services transmitted over telephone lines, compete to distribute digital information and entertainment to homes and businesses. The owners and marketers of this content include software developers, motion picture and recording companies, publishers of books, magazines, and newspapers, and information database providers. The popularization of on-line services has also enabled the individual personal computer user to participate as a content provider. It is estimated that the worldwide market for electronic information in 1992 was approximately $40 billion and is expected to grow to $200 billion by 1997, according to Microsoft Corporation. The present invention can materially enhance the revenue of content providers, lower the distribution costs and the costs for content, better support advertising and usage information gathering, and better satisfy the needs of electronic information users. These improvements can lead to a significant increase in the amount and variety of electronic information and the methods by which such information is distributed.\nThe inability of conventional products to be shaped to the needs of electronic information providers and users is sharply in contrast to the present invention. Despite the attention devoted by a cross-section of America's largest telecommunications, computer, entertainment and information provider companies to some of the problems addressed by the present invention, only the present invention provides commercially secure, effective solutions for configurable, general purpose electronic commerce transaction\/distribution control systems.\nControlling Electronic Content\nThe present invention provides a new kind of \"virtual distribution environment\" (called \"VDE\" in this document) that secures, administers, and audits electronic information use. VDE also features fundamentally important capabilities for managing content that travels \"across\" the \"information highway.\" These capabilities comprise a rights protection solution that serves all electronic community members. These members include content creators and distributors, financial service providers, end-users, and others. VDE is the first general purpose, configurable, transaction control\/rights protection solution for users of computers, other electronic appliances, networks, and the information highway.\nA fundamental problem for electronic content providers is extending their ability to control the use of proprietary information. Content providers often need to limit use to authorized activities and amounts. Participants in a business model involving, for example, provision of movies and advertising on optical discs may include actors, directors, script and other writers, musicians, studios, publishers, distributors, retailers, advertisers, credit card services, and content end-users. These participants need the ability to embody their range of agreements and requirements, including use limitations, into an \"extended\" agreement comprising an overall electronic business model. This extended agreement is represented by electronic content control information that can automatically enforce agreed upon rights and obligations. Under VDE, such an extended agreement may comprise an electronic contract involving all business model participants. Such an agreement may alternatively, or in addition, be made up of electronic agreements between subsets of the business model participants. Through the use of VDE, electronic commerce can function in the same way as traditional commerce\u2014that is commercial relationships regarding products and services can be shaped through the negotiation of one or more agreements between a variety of parties.\nCommercial content providers are concerned with ensuring proper compensation for the use of their electronic information. Electronic digital information, for example a CD recording, can today be copied relatively easily and inexpensively. Similarly, unauthorized copying and use of software programs deprives rightful owners of billions of dollars in annual revenue according to the International Intellectual Property Alliance. Content providers and distributors have devised a number of limited function rights protection mechanisms to protect their rights. Authorization passwords and protocols, license servers, \"lock\/unlock\" distribution methods, and non-electronic contractual limitations imposed on users of shrink-wrapped software are a few of the more prevalent content protection schemes. In a commercial context, these efforts are inefficient and limited solutions.\nProviders of \"electronic currency\" have also created protections for their type of content. These systems are not sufficiently adaptable, efficient, nor flexible enough to support the generalized use of electronic currency. Furthermore, they do not provide sophisticated auditing and control configuration capabilities. This means that current electronic currency tools lack the sophistication needed for many real-world financial business models. VDE provides means for anonymous currency and for \"conditionally\" anonymous currency, wherein currency related activities remain anonymous except under special circumstances.\nVDE Control Capabilities\nVDE allows the owners and distributors of electronic digital information to reliably bill for, and securely control, audit, and budget the use of, electronic information. It can reliably detect and monitor the use of commercial information products. VDE uses a wide variety of different electronic information delivery means: including, for example, digital networks, digital broadcast, and physical storage media such as optical and magnetic disks. VDE can be used by major network providers, hardware manufacturers, owners of electronic information, providers of such information, and clearinghouses that gather usage information regarding, and bill for the use of, electronic information.\nVDE provides comprehensive and configurable transaction management, metering and monitoring technology. It can change how electronic information products are protected, marketed, packaged, and distributed. When used, VDE should result in higher revenues for information providers and greater user satisfaction and value. Use of VDE will normally result in lower usage costs, decreased transaction costs, more efficient access to electronic information, re-usability of rights protection and other transaction management implementations, greatly improved flexibility in the use of secured information, and greater standardization of tools and processes for electronic transaction management. VDE can be used to create an adaptable environment that fulfills the needs of electronic information owners, distributors, and users; financial clearinghouses; and usage information analyzers and resellers.\nRights and Control Information\nIn general, the present invention can be used to protect the rights of parties who have:                (a) proprietary or confidentiality interests in electronic information. It can, for example, help ensure that information is used only in authorized ways;        (b) financial interests resulting from the use of electronically distributed information. It can help ensure that content providers will be paid for use of distributed information, and        (c) interests in electronic credit and electronic currency storage, communication, and\/or use including electronic cash, banking, and purchasing.        \nProtecting the rights of electronic community members involves a broad range of technologies VDE combines these technologies in a way that creates a \"distributed\" electronic rights protection \"environment.\" This environment secures and protects transactions and other processes important for rights protection. VDE, for example, provides the ability to prevent, or impede, interference with and\/or observation of, important rights related transactions and processes. VDE, in its preferred embodiment, uses special purpose tamper resistant Secure Processing Units (SPUs) to help provide a high level of security for VDE processes and information storage and communication.\nThe rights protection problems solved by the present invention are electronic versions of basic societal issues. These issues include protecting property rights, protecting privacy rights, properly compensating people and organizations for their work and risk, protecting money and credit, and generally protecting the security of information VDE employs a system that uses a common set of processes to manage rights issues in an efficient, trusted, and cost-effective way.\nVDE can be used to protect the rights of parties who create electronic content such as, for example: records, games, movies, newspapers, electronic books and reference materials, personal electronic mail, and confidential records and communications. The invention can also be used to protect the rights of parties who provide electronic products, such as publishers and distributors; the rights of parties who provide electronic credit and currency to pay for use of products, for example, credit clearinghouses and banks; the rights to privacy of parties who use electronic content (such as consumers, business people, governments); and the privacy rights of parties described by electronic information, such as privacy rights related to information contained in a medical record, tax record, or personnel record.\nIn general, the present invention can protect the rights of parties who have:                (a) commercial interests in electronically distributed information\u2014the present invention can help ensure, for example, that parties, will be paid for use of distributed information in a, manner consistent with their agreement;        (b) proprietary and\/or confidentiality interests in electronic information\u2014the present invention can, for example, help ensure that data is used only in authorized ways;        (c) interests in electronic credit and electronic currency storage, communication, and\/or use\u2014this can include electronic cash, banking, and purchasing; and        (d) interests in electronic information derived, at least in part, from use of other electronic information.        \nVDE Functional Properties\nVDE is a cost-effective and efficient rights protection solution that provides a unified, consistent system for securing and managing transaction processing. VDE can:                (a) audit and analyze the use of content,        (b) ensure that content is used only in authorized ways; and        (c) allow information regarding content usage to be used only in ways approved by content users.        \nIn addition, VDE:                (a) is very configurable, modifiable, and re-usable;        (b) supports a wide range of useful capabilities that may be combined in different ways to accommodate most potential applications;        (c) operates on a wide variety of electronic appliances ranging from hand-held inexpensive devices to large mainframe computers;        (d) is able to ensure the various rights of a number of different parties, and a number of different rights protection schemes, simultaneously;        (e) is able to preserve the rights of parties through a series of transactions that may occur at different times and different locations;        (f) is able to flexibly accommodate different ways of securely delivering information and reporting usage; and        (g) provides for electronic analogues to \"real\" money and credit, including anonymous electronic cash, to pay for products and services and to support personal (including home) banking and other financial activities.        \nVDE economically and efficiently fulfills the rights protection needs of electronic community members. Users of VDE will not require additional rights protection systems for different information highway products and rights problems\u2014nor will they be required to install and learn a new system for each new information highway application.\nVDE provides a unified solution that allows all content creators, providers, and users to employ the same electronic rights protection solution. Under authorized circumstances, the participants can freely exchange content and associated content control sets. This means that a user of VDE may, if allowed, use the same electronic system to work with different kinds of content having different sets of content control information. The content and control information supplied by one group can be used by people who normally use content and control information supplied by a different group. VDE can allow content to be exchanged \"universally\" and users of an implementation of the present invention can interact electronically without fear of incompatibilities in content control, violation of rights, or the need to get, install, or learn a new content control system.\nThe VDE securely administers transactions that specify protection of rights. It can protect electronic rights including, for example:                (a) the property rights of authors of electronic content,        (b) the commercial rights of distributors of content,        (c) the rights of any parties who facilitated the distribution of content,        (d) the privacy rights of users of content,        (e) the privacy rights of parties portrayed by stored and\/or distributed content, and        (f) any other rights regarding enforcement of electronic agreements.        \nThe VDE can enable a very broad variety of electronically enforced commercial and societal agreements. These agreements can include electronically implemented contracts, licenses, laws, regulations, and tax collection.\nContrast With Traditional Solutions\nTraditional content control mechanisms often require users to purchase more electronic information than the user needs or desires. For example, infrequent users of shrink-wrapped software are required to purchase a program at the same price as frequent users, even though they may receive much less value from their less frequent use. Traditional systems do not scale cost according to the extent or character of usage and traditional systems can not attract potential customers who find that a fixed price is too high. Systems using traditional mechanisms are also not normally particularly secure. For example, shrink-wrapping does not prevent the constant illegal pirating of software once removed from either its physical or electronic package.\nTraditional electronic information rights protection systems are often inflexible and inefficient and may cause a content provider to choose costly distribution channels that increase a product's price. In general these mechanisms restrict product pricing, configuration, and marketing flexibility. These compromises are the result of techniques for controlling information which cannot accommodate both different content models and content models which reflect the many, varied requirements, such as content delivery strategies, of the model participants. This can limit a provider's ability to deliver sufficient overall value to justify a given product's cost in the eyes of many potential users. VDE allows content providers and distributors to create applications and distribution networks that reflect content providers' and users' preferred business models. It offers users a uniquely cost effective and feature rich system that supports the ways providers want to distribute information and the ways users want to use such information. VDE supports content control models that ensure rights and allow content delivery strategies to be shaped for maximum commercial results.\nChain of Handling and Control\nVDE can protect a collection of rights belonging to various parties having in rights in, or to, electronic information. This information may be at one location or dispersed across (and\/or moving between) multiple locations. The information may pass through a \"chain\" of distributors and a \"chain\" of users. Usage information may also be reported through one or more \"chains\" of parties. In general, VDE enables parties that (a) have rights in electronic information, and\/or (b) act as direct or indirect agents for parties who have rights in electronic information, to ensure that the moving, accessing, modifying, or otherwise using of information can be securely controlled by rules regarding how, when, where, and by whom such activities can be performed.\nVDE Applications and Software\nVDE is a secure system for regulating electronic conduct and commerce. Regulation is ensured by control information put in place by one or more parties. These parties may include content providers, electronic hardware manufacturers, financial service providers, or electronic \"infrastructure\" companies such as cable or telecommunications companies. The control information implements \"Rights Applications.\" Rights applications \"run on\" the \"base software\" of the preferred embodiment. This base software serves as a secure, flexible, general purpose foundation that can accommodate many different rights applications, that is, many different business models and their respective participant requirements.\nA rights application under VDE is made up of special purpose pieces, each of which can correspond to one or more basic electronic processes needed for a rights protection environment. These processes can be combined together like building blocks to create electronic agreements that can protect the rights, and may enforce fulfillment of the obligations, of electronic information users and providers. One or more providers of electronic information can easily combine selected building blocks to create a rights application that is unique to a specific content distribution model. A group of these pieces can represent the capabilities needed to fulfill the agreement(s) between users and providers. These, pieces accommodate many requirements of electronic commerce including:                the distribution of permissions to use electronic information;        the persistence of the control information and sets of control information managing these permissions;        configurable control set information that can be selected by users for use with such information,        data security and usage auditing of electronic information, and        a secure system for currency, compensation and debit management.        \nFor electronic commerce, a rights application, under the preferred embodiment of the present invention, can provide electronic enforcement of the business agreements between all participants. Since different groups of components can be put together for different applications, the present invention can provide electronic control information for a wide variety of different products and markets. This means the present invention can provide a \"unified,\" efficient, secure, and cost-effective system for electronic commerce and data security. This allows VDE to serve as a single standard for electronic rights protection, data security, and electronic currency and banking.\nIn a VDE, the separation between a rights application and its foundation permits the efficient selection of sets of control information that are appropriate for each of many different types of applications and uses. These control sets can reflect both rights of electronic community members, as well as obligations (such as providing a history of one's use of a product or paying taxes on one's electronic purchases). VDE flexibility allows its users to electronically implement and enforce common social and commercial ethics and practices. By providing a unified control system, the present invention supports a vast range of possible transaction related interests and concerns of individuals, communities, businesses, and governments. Due to its open design, VDE allows (normally under securely controlled circumstances) applications using technology independently created by users to be \"added\" to the system and used in conjunction with the foundation of the invention. In sum, VDE provides a system that can fairly reflect and enforce agreements among parties. It is a broad ranging and systematic solution that answers the pressing need for a secure, cost-effective, and fair electronic environment.\nVDE Implementation\nThe preferred embodiment of the present invention includes various tools that enable system designers to directly insert VDE capabilities into their products. These tools include an Application Programmer's Interface (\"API\") and a Rights Permissioning and Management Language (\"RPML\"). The RPML provides comprehensive and detailed control over the use of the invention's features. VDE also includes certain user interface subsystems for satisfying the needs of content providers, distributors, and users.\nInformation distributed using VDE may take many forms. It may, for example, be \"distributed\" for use on an individual's own computer, that is the present invention can he used to provide security for locally stored data. Alternatively, VDE may be used with information that is dispersed by authors and\/or publishers to one or more recipients. This information may take many forms including: movies, audio recordings, games, electronic catalog shopping, multimedia, training materials, E-mail and personal documents, object oriented libraries, software programming resources, and reference\/record keeping information resources (such as business, medical, legal, scientific, governmental, and consumer databases).\nElectronic rights protection provided by the present invention will also provide an important foundation for trusted and efficient home and commercial banking, electronic credit processes, electronic purchasing, true or conditionally anonymous electronic cash, and EDI (Electronic Data Interchange). VDE provides important enhancements for improving data security in organizations by providing \"smart\" transaction management features that can be far more effective than key and password based \"go\/no go\" technology.\nVDE normally employs an integration of cryptographic and other security technologies (e.g. encryption, digital signatures, etc.), with other technologies including: component, distributed, and event driven operating system technology, and related communications, object container, database, smart agent, smart card, and semiconductor design technologies.\nI. Overview\nA. VDE Solves Important Problems and Fills Critical Needs\nThe world is moving towards an integration of electronic information appliances. This interconnection of appliances provides a foundation for much greater electronic interaction and the evolution of electronic commerce. A variety of capabilities are required to implement an electronic commerce environment. VDE is the first system that provides many of these capabilities and therefore solves fundamental problems related to electronic dissemination of information\nElectronic Content\nVDE allows electronic arrangements to be created involving two or more parties. These agreements can themselves comprise a collection of agreements between participants in a commercial value chain and\/or a data security chain model for handling, auditing, reporting, and payment. It can provide efficient, reusable, modifiable, and consistent means for secure electronic content: distribution, usage control, usage payment, usage auditing, and usage reporting. Content may, for example, include:                financial information such as electronic currency and credit;        commercially distributed electronic information such as reference databases, movies, games, and advertising and        electronic properties produced by persons and organizations, such as documents, e-mail, and proprietary database information.VDE enables an electronic commerce marketplace that supports differing, competitive business partnerships, agreements, and evolving overall business models.        \nThe features of VDE allow it to function as the first trusted electronic information control environment that can conform to, and support, the bulk of conventional electronic commerce and data security requirements. In particular, VDE enables the participants in a business value chain model to create an electronic version of traditional business agreement terms and conditions and further enables these participants to shape' and evolve their electronic commerce models as they believe appropriate to their business requirements.\nVDE offers an architecture that avoids reflecting specific distribution biases, administrative and control perspectives, and content types. Instead, VDE provides a broad-spectrum, fundamentally configurable and portable, electronic transaction control, distributing, usage, auditing, reporting, and payment operating environment. VDE is not limited to being an application or application specific toolset that covers only a limited subset of electronic interaction activities and participants. Rather, VDE supports systems by which such applications can be created, modified, and\/or reused. As a result, the present invention answers pressing, unsolved needs by offering a system that supports a standardized control environment which facilitates interoperability of electronic appliances, interoperability of content containers, and efficient creation of electronic commerce applications and models through the use of a programmable, secure electronic transactions management foundation and reusable and extensible executable components. VDE can support a single electronic \"world\" within which most forms of electronic transaction activities can be managed.\nTo answer the developing needs of rights owners and content providers and to provide a system that can accommodate the requirements and agreements of all parties that may be involved in electronic business models (creators, distributors, administrators, users, credit providers, etc.), VDE supplies an efficient, largely transparent, low cost and sufficiently secure system (supporting both hardware\/software and software only models). VDE provides the widely varying secure control and administration capabilities required for:\n1. Different types of electronic content,\n2. Differing electronic content delivery schemes,\n3. Differing electronic content usage schemes,\n4. Different content usage platforms, and\n5. Differing content marketing and model strategies.\nVDE may be combined with, or integrated into, many separate computers and\/or other electronic appliances. These appliances typically include a secure subsystem that can enable control of content use such as displaying, encrypting, decrypting, printing, copying, saving, extracting, embedding, distributing, auditing usage, etc. The secure subsystem in the preferred embodiment comprises one or more \"protected processing environments\", one or more secure databases, and secure \"component assemblies\" and other items and processes that need to be kept secured. VDE can, for example, securely control electronic currency, payments, and\/or credit management (including electronic credit and\/or currency receipt, disbursement, encumbering, and\/or allocation) using such a \"secure subsystem.\"\nVDE provides a secure, distributed electronic transaction management system for controlling the distribution and\/or other usage of electronically provided and\/or stored information. VDE controls auditing and reporting of electronic content and\/or appliance usage. Users of VDE may include content creators who apply content usage, usage reporting, and\/or usage payment related control information to electronic content and\/or appliances for users such as end-user organizations, individuals, and content and\/or appliance distributors. VDE also securely supports the payment of money owed (including money owed for content and\/or appliance usage) by one or more parties to one or more other parties, in the form of electronic credit and\/or currency.\nElectronic appliances under control of VDE represent VDE 'nodes' that securely process and control; distributed electronic information and\/or appliance usage, control information formulation, and related transactions. VDE can securely manage the integration of control information provided by two or more parties. As a result, VDE can construct an electronic agreement between VDE participants that represent a \"negotiation\" between, the control requirements of, two or more parties and enacts terms and conditions of a resulting agreement. VDE ensures the rights of each party to an electronic agreement regarding a wide range of electronic activities related to electronic information and\/or appliance usage.\nThrough use of VDE's control system, traditional content providers and users can create electronic relationships that reflect traditional, non-electronic relationships. They can shape and modify commercial relationships to accommodate the evolving needs of, and agreements among, themselves. VDE does not require electronic content providers and users to modify their business practices and personal preferences to conform to a metering and control application program that supports limited, largely fixed functionality. Furthermore, VDE permits participants to develop business models not feasible with non-electronic commerce, for example, involving detailed reporting of content usage information, large numbers of distinct transactions at hitherto infeasibly low price points, \"pass-along\" control information that is enforced without involvement or advance knowledge of the participants, etc.\nThe present invention allows content providers and users to formulate their transaction environment to accommodate:                (1) desired content models, content control models, and content usage information pathways,        (2) a complete range of electronic media and distribution means,        (3) a broad range of pricing, payment, and auditing strategies,        (4) very flexible privacy and\/or reporting models,        (5) practical and effective security architectures, and        (6) other administrative procedures that together with steps (1) through (5) can enable most \"real world\" electronic commerce and data security models, including models unique to the electronic world.        \nVDE's transaction management capabilities can enforce:                (1) privacy rights of users related to information regarding their usage of electronic information and\/or appliances,        (2) societal policy such as laws that protect rights of content users or require the collection of taxes derived from electronic transaction revenue, and        (3) the proprietary and\/or other rights of parties related to ownership of, distribution of, and\/or other commercial rights related to, electronic information.        \nVDE can support \"real\" commerce in an electronic form, that is the progressive creation of commercial relationships that form, over time, a network of interrelated agreements representing a value chain business model. This is achieved in part by enabling content control information to develop through the interaction of (negotiation between) securely created and independently submitted sets of content and\/or appliance control information. Different sets of content and\/or appliance control information can be submitted by different parties in an electronic business value chain enabled by the present invention. These parties create control information sets through the use of their respective VDE installations. Independently, securely deliverable, component based control information allows efficient interaction among control information sets supplied by different parties.\nVDE permits multiple, separate electronic arrangements to be formed between subsets of parties in a VDE supported electronic value chain model. These multiple agreements together comprise a VDE value chain \"extended\" agreement. VDE allows such constituent electronic agreements, and therefore overall VDE extended agreements, to evolve and reshape over time as additional VDE participants become involved in VDE content and\/or appliance control information handling. VDE electronic agreements may also be extended as new control information is submitted by existing participants. With VDE, electronic commerce participants are free to structure and restructure their electronic commerce business activities and relationships. As a result, the present invention allows a competitive electronic commerce marketplace to develop since the use of VDE enables different, widely varying business models using the same or shared content.\nA significant facet of the present invention's ability to broadly support electronic commerce is its ability to securely manage independently delivered VDE component objects containing control information (normally in the form of VDE objects containing one or more methods, data, or load module VDE components). This independently delivered control information can be integrated with senior and other pre-existing content control information to securely form derived control information using the negotiation mechanisms of the present invention. All requirements specified by this derived control information must be satisfied before VDE controlled content can be accessed or otherwise used. This means that, for example, all load modules and any mediating data which are listed by the derived control information as required must be available and securely perform their required function. In combination with other aspects of the present invention, securely, independently delivered control components allow electronic commerce participants to freely stipulate their business requirements and trade offs. As a result, much as with traditional, non-electronic commerce, the present invention allows electronic commerce (through a progressive stipulation of various control requirements by VDE participants) to evolve into forms of business that are the most efficient, competitive and useful.\nVDE provides capabilities that rationalize the support of electronic commerce and electronic transaction management. This rationalization stems from the reusability of control structures and user interfaces for a wide variety of transaction management related activities. As a result, content usage control, data security, information auditing, and electronic financial activities, can be supported with tools that are reusable, convenient, consistent, and familiar. In addition, a rational approach\u2014a transaction\/distribution control standard\u2014allows all participants in VDE the same foundation set of hardware control and security, authoring, administration, and management tools 'to support widely varying types of information, business market model, and\/or personal objectives.\nEmploying VDE as a general purpose electronic transaction\/distribution control system allows users to maintain a single transaction management control arrangement on each of their computers, networks, communication nodes, and\/or other electronic appliances. Such a general purpose system can serve the needs of many electronic transaction management applications without requiring distinct, different installations for different purposes. As a result, users of VDE can avoid the confusion and expense and other inefficiencies of different, limited purpose transaction control applications for each different content and\/or business model. For example, VDE allows content creators to use the same VDE foundation control arrangement for both content authoring and for licensing content from other content creators for inclusion into their products or for other use. Clearinghouses, distributors, content creators, and other VDE users can all interact, both with the applications running on their VDE installations, and with each other, in an entirely consistent manner, using and reusing (largely transparently) the same distributed tools, mechanisms, and consistent user interfaces, regardless of the type of VDE activity.\nVDE prevents many forms of unauthorized use of electronic information, by controlling and auditing (and other administration of use) electronically stored and\/or disseminated information. This includes, for example, commercially distributed content, electronic currency, electronic credit, business transactions (such as EDI), confidential communications, and the like. VDE can further be used to enable commercially provided electronic content to be made available to users in user defined portions, rather than constraining the user to use portions of content that were \"predetermined\" by a content creator and\/or other provider for billing purposes.\nVDE, for example, can employ:                (1) Secure metering means for budgeting and\/or auditing electronic content and\/or appliance usage;        (2) Secure flexible means for enabling compensation and\/or billing rates for content and\/or appliance usage, including electronic credit and\/or currency mechanisms for payment means;        (3) Secure distributed database means for storing control and usage related information (and employing validated compartmentalization and tagging schemes);        (4) Secure electronic appliance control means;                    A distributed, secure, \"virtual black box\" comprised of nodes located at every user (including VDE content container creators, other content providers, client users, and recipients of secure VDE content usage information) site. The nodes of said virtual black box normally include a secure subsystem having at least one secure hardware element (a semiconductor element or other hardware module for securely executing VDE control processes), said secure subsystems being distributed at nodes along a pathway of information storage, distribution, payment, usage, and\/or auditing. In some embodiments, the functions of said hardware element, for certain or all nodes, may be performed by software, for example, in host processing environments of electronic appliances;                        (6) Encryption and decryption means;        (7) Secure communications means employing authentication, digital signaturing, and encrypted transmissions. The secure subsystems at said user nodes utilize a protocol that establishes and authenticates each node's and\/or participant's identity, and establishes one or more secure host-to-host encryption keys for communications between the secure subsystems; and        (8) Secure control means that can allow each VDE installation to perform VDE content authoring (placing content into VDE containers with associated control information), content distribution, and content usage; as well as clearinghouse and other administrative and analysis activities employing content usage information.        \nVDE may be used to migrate most non-electronic, traditional information delivery models (including entertainment, reference materials, catalog shopping, etc.) into an adequately secure digital distribution and usage management and payment context. The distribution and financial pathways managed by a VDE arrangement may include:                content creator(s),        distributor(s),        redistributor(s),        client administrator(s),        client user(s),        financial and\/or other clearinghouse(s),        and\/or government agencies.These distribution and financial pathways may also include:        advertisers,        market survey organizations, and\/or        other parties interested in the user usage of information securely delivered and\/or stored using VDE.Normally, participants in a VDE arrangement will employ the same secure VDE foundation. Alternate embodiments support VDE arrangements employing differing VDE foundations. Such alternate embodiments may employ procedures to ensure certain interoperability requirements are met.        \nSecure VDE hardware (also known as SPUs for Secure Processing Units), or VDE installations that use software to substitute for, or complement, said hardware (provided by Host Processing Environments (HPEs)), operate in conjunction with secure communications, systems integration software, and distributed software control information and support structures, to achieve the electronic contract\/rights protection environment of the present invention. Together, these VDE components comprise a secure, virtual, distributed content and\/or appliance control, auditing (and other administration), reporting, and payment environment. In some embodiments and where commercially acceptable, certain VDE participants, such as clearinghouses that normally maintain sufficiently physically secure non-VDE processing environments, may be allowed to employ HPEs rather VDE hardware elements and interoperate, for example, with VDE end-users and content providers. VDE components together comprise a configurable, consistent, secure and \"trusted\" architecture for distributed, asynchronous control of electronic content and\/or appliance usage. VDE supports a \"universe wide\" environment for electronic content delivery, broad dissemination, usage reporting, and usage related payment activities.\nVDE provides generalized configurability. This results, in part, from decomposition of generalized requirements for supporting electronic commerce and data security into a broad range of constituent \"atomic\" and higher level components (such as load modules, data elements, and methods) that may be variously aggregated together to form control methods for electronic commerce applications, commercial electronic agreements, and data security arrangements. VDE provides a secure operating environment employing VDE foundation elements along with secure independently deliverable VDE components that enable electronic commerce models and relationships to develop. VDE specifically supports the unfolding of distribution models in which content providers, over time, can expressly agree to, or allow, subsequent content providers and\/or users to participate in shaping the control information for, and consequences of use of electronic content and\/or appliances. A very broad range of the functional attributes important for supporting simple to very complex electronic commerce and data security activities are supported by capabilities of the present invention. As a result, VDE supports most types of electronic information and\/or appliance: usage control (including distribution), security, usage auditing, reporting, other administration, and payment arrangements.\nVDE, in its preferred embodiment, employs object software technology and uses object technology to form \"containers\" for delivery of information that is (at least in part) encrypted or otherwise secured. These containers may contain electronic content products or other electronic information and some or all of their associated permissions (control) information. These container objects may be distributed along pathways involving content providers and\/or content users. They may be securely moved among nodes of a Virtual Distribution Environment (VDE) arrangement, which nodes operate VDE foundation software and execute control methods to enact electronic information usage control and\/or administration models. The containers delivered through use of the preferred embodiment of the present invention may be employed both for distributing VDE control instructions (information) and\/or to encapsulate and electronically distribute content that has been at least partially secured.\nContent providers who employ the present invention may include, for example, software application and game publishers, database publishers, cable, television, and radio broadcasters, electronic shopping vendors, and distributors of information in electronic document, book, periodical, e-mail and\/or other forms. Corporations, government agencies, and\/or individual \"end-users\" who act as storers of, and\/or distributors of, electronic information, may also be VDE content providers (in a restricted model, a user provides content only to himself and employs VDE to secure his own confidential information against unauthorized use by other parties). Electronic information may include proprietary and\/or confidential information for personal or internal organization use, as well as information, such as software applications, documents, entertainment materials, and\/or reference information, which may be provided to other parties. Distribution may be by, for example, physical media delivery, broadcast and\/or telecommunication means, and in the form of \"static\" files and\/or streams of data. VDE may also be used, for example, for multi-site \"real-time\" interaction such as teleconferencing, interactive games, or on-line bulletin boards, where restrictions on, and\/or auditing of, the use of all or portions of communicated information is enforced.\nVDE provides important mechanisms for both enforcing commercial agreements and enabling the protection of privacy rights. VDE can securely deliver information from one party to another concerning the use of commercially distributed electronic content. Even if parties are separated by several \"steps\" in a chain (pathway) of handling for such content usage information, such information is protected by VDE through encryption and\/or other secure processing. Because of that protection, the accuracy of such information is guaranteed by VDE, and the information can be trusted by all parties to whom it is delivered. Furthermore, VDE guarantees that all parties can trust that such information cannot be received by anyone other than the intended, authorized, party(ies) because it is encrypted such that only an authorized party, or her agents, can decrypt it. Such information may also be derived through a secure VDE process at a previous pathway-of-handling location to produce secure VDE reporting information that is then communicated securely to its intended recipient's VDE secure subsystem. Because VDE can deliver such information securely, parties to an electronic agreement need not trust the accuracy of commercial usage and\/or other information delivered through means other than those under control of VDE.\nVDE participants in a commercial value, chain can be \"commercially\" confident (that is, sufficiently confident for commercial purposes) that the direct (constituent) and\/or \"extended\" electronic agreements they entered into through the use of VDE can be enforced reliably. These agreements may have both \"dynamic\" transaction management related, aspects, such as content usage control information enforced through budgeting, metering, and\/or reporting of electronic information and\/or appliance use, and\/or they may include \"static\" electronic assertions, such as an end-user using the system to assert his or her agreement to pay for services, not to pass to unauthorized parties electronic information derived from usage of content or systems, and\/or agreeing to observe copyright laws. Not only can electronically reported transaction related information be trusted under the present invention, but payment may be automated by, the passing of payment tokens through a pathway of payment (which may or may not be the same as a pathway for reporting). Such payment can be contained within a VDE container created automatically by a VDE installation in response to control information (located, in the preferred embodiment, in one or more permissions records) stipulating the \"withdrawal\" of credit or electronic currency (such as tokens) from an electronic account (for example, an account securely maintained by a user's VDE installation secure subsystem) based upon usage of VDE controlled electronic content and\/or appliances (such as governments, financial credit providers, and users).\nVDE allows the needs of electronic commerce participants to be served and it can bind such participants together in a universe wide, trusted commercial network that can be secure enough to support very large amounts of commerce. VDE's security and metering secure subsystem core will be present at all physical locations where VDE related content is (a) assigned usage related control information (rules and mediating data), and\/or (b) used. This core can perform security and auditing functions (including metering) that operate within a \"virtual black box,\" a collection of distributed, very secure VDE related hardware instances that are interconnected by secured information exchange (for example, telecommunication) processes and distributed database means. VDE further includes highly configurable transaction operating system technology, one or more associated libraries of load modules along with affiliated data, VDE related administration, data preparation, and analysis applications, as well as system software designed to enable VDE integration into host environments and applications. VDE's usage control information, for example, provide for property content and\/or appliance related: usage authorization, usage auditing (which may include audit reduction), usage billing, usage payment, privacy filtering, reporting, and security related communication 'and encryption techniques.\nVDE extensively employs methods in the form of software objects to augment configurability, portability, and security of the VDE environment. It also employs a software object architecture for VDE content containers that carries protected content and may also carry both freely available information (e.g, summary, table of contents) and secured content control information which ensures the performance of control information. Content control information governs content usage according to criteria set by holders of rights to an object's contents and\/or according to parties who otherwise have rights associated with distributing such content (such as governments, financial credit providers; and users).\nIn part, security is enhanced by object methods employed by the present invention because the encryption schemes used to protect an object can efficiently be further used to protect the associated content control information (software control information and relevant data) from modification. Said object techniques also enhance portability between various computer and\/or other appliance environments because electronic information in the form of content can be inserted along with (for example, in the same object container as) content control information (for said content) to produce a \"published\" object. As a result, various portions of said control information may be specifically adapted for different environments, such as for diverse computer platforms and operating systems, and said various portions may all be carried by a VDE container.\nAn objective of VDE is supporting a transaction\/distribution control standard. Development of such a standard has many obstacles, given the security requirements and related hardware and communications issues, widely differing environments, information types, types of information usage, business and\/or data security goals, varieties of participants, and properties of delivered information. A significant feature of VDE accommodates the many, varying distribution and other transaction variables by, in part, decomposing electronic commerce and data security functions into generalized capability modules executable within a secure hardware SPU and\/or corresponding software subsystem and further allowing extensive flexibility in assembling, modifying, and\/or replacing, such modules (e.g. load modules and\/or methods) in applications run on a VDE installation foundation. This configurability and reconfigurability allows electronic commerce and data security participants to reflect their priorities and requirements through a process of iteratively shaping an evolving extended electronic agreement (electronic control model). This shaping can occur as content control information passes from one VDE participant to another and to the extent allowed by \"in place\" content control information. This process allows users of VDE to recast existing control information and\/or add new control information as necessary (including the elimination of no longer required elements).\nVDE supports trusted (sufficiently secure) electronic information distribution and usage control models for both commercial electronic content distribution and data security applications. It can be configured to meet the diverse requirements of a network of interrelated participants that may include content creators, content distributors, client administrators, end users, and\/or clearinghouses and\/or other content usage information users. These parties may constitute a network of participants involved in simple to complex electronic content dissemination, usage control, usage reporting, and\/or usage payment. Disseminated content may include both originally provided and VDE generated information (such as content usage information) and content control information may persist through both chains (one or more pathways) of content and content control information handling, as well as the direct usage of content. The configurability provided by the present invention is particularly critical for supporting electronic commerce, that is enabling businesses to create relationships and evolve strategies that offer, competitive value. Electronic commerce tools that are not inherently configurable and interoperable will ultimately fail to produce products (and services) that meet both basic requirements and evolving needs of most commerce applications.\nVDE's fundamental configurability will allow a broad range of competitive electronic commerce business models to flourish. It allows business models to be shaped to maximize revenues sources, end-user product value, and operating efficiencies. VDE can be employed to support multiple, differing models, take advantage of new revenue opportunities, and deliver product configurations most desired by users. Electronic commerce technologies that do not, as the present invention does:                support a broad range of possible, complementary revenue activities,        offer a flexible array of content usage features most desired by customers, and        exploit opportunities for operating efficiencies,will result in products that are often intrinsically more costly and less appealing and therefore less competitive in the marketplace.        \nSome of the key factors contributing to the configurability intrinsic to the present invention include:                (a) integration into the fundamental control environment of a broad range of electronic appliances through portable API and programming language tools that efficiently support merging of control and auditing capabilities in nearly any electronic appliance environment while maintaining overall system security;        (b) modular data structures;        (c) generic content model;        (d) general modularity and independence of foundation architectural components;        (e) modular security structures;        (f) variable length and multiple branching chains of control; and        (g) independent, modular control structures in the form of executable load modules that can be maintained in one or more libraries, and assembled into control methods and models, and where such model control schemes can \"evolve\" as control information passes through the VDE installations of participants of a pathway of VDE content control information handling.        \nBecause of the breadth of issues resolved by the present invention, it can provide the emerging \"electronic highway\" with a single transaction\/distribution control system that can, for a very broad range of commercial and data security models, ensure against unauthorized use of confidential and\/or proprietary information and commercial electronic transactions. VDE's electronic transaction management mechanisms can enforce the electronic rights and agreements of all parties participating in widely varying business and data security models, and this can be efficiently achieved through a single VDE implementation within each VDE participant's electronic appliance. VDE supports widely varying business and\/or data security models that can involve a broad range of participants at various \"levels\" of VDE content and\/or content control information pathways of handling. Different content control and\/or auditing models and agreements may be available on the same VDE installation. These models and agreements may control content in relationship to, for example, VDE installations and\/or users in general; certain specific users, installations, classes and\/or other groupings of installations and\/or users; as well as to electronic content generally on a given installation, to specific properties, property portions, classes and\/or other groupings of content.\nDistribution using VDE may package both the electronic content and control information into the same VDE container, and\/or may involve the delivery to an end-user site of different pieces of the same VDE managed property from plural separate remote locations and\/or in plural separate VDE content containers and\/or employing plural different delivery means. Content control information may be partially or fully delivered separately from its associated content to a user VDE installation in one or more VDE administrative objects. Portions of said control information may be delivered from one or more sources. Control information may also be available for use by access from a user's VDE installation secure sub-system to one or more remote VDE secure sub-systems and\/or VDE compatible, certified secure remote locations. VDE control processes such as metering, budgeting, decrypting and\/or fingerprinting, may as relates to a certain user content usage activity, be performed in a user's local VDE installation secure subsystem, or said processes may be divided amongst plural secure subsystems which may be located in the same user VDE installations and\/or in a network server and in the user installation. For example, a local VDE installation may perform decryption and save any, or all of, usage metering information related to content and\/or electronic appliance usage at such user installation could be performed at the server employing secure (e.g., encrypted) communications between said secure subsystems. Said server location may also be used for near real time, frequent, or more periodic secure receipt of content usage information from said user installation, with, for example, metered information being maintained only temporarily at a local user installation.\nDelivery means for VDE managed content may include electronic data storage means such as optical disks for delivering one portion of said information and broadcasting and\/or telecommunicating means for other portions of said information. Electronic data storage means may include magnetic media, optical media, combined magneto-optical systems, flash RAM memory, bubble memory, and\/or other memory storage means such as huge capacity optical storage systems employing holographic, frequency, and\/or polarity data storage techniques. Data storage means may also employ layered disc techniques, such as the use of generally transparent and\/or translucent materials that pass light through layers of data carrying discs which themselves are physically packaged together as one thicker disc. Data carrying locations on such discs may be, at least in part, opaque.\nVDE supports a general purpose foundation for secure transaction management, including usage control, auditing, reporting, and\/or payment. This general purpose foundation is called \"VDE Functions\" (\"VDEFs\"). VDE also supports a collection of \"atomic\" application elements (e.g., load modules) that can be selectively aggregated together to form various VDEF capabilities called control methods and which serve as VDEF applications and operating system functions. When a host operating environment of an electronic appliance includes VDEF capabilities, it is called a \"Rights Operating System\" (ROS) VDEF load modules, associated data, and methods form a body of information that for the purposes of the present invention are called \"control information.\" VDEF control information may be specifically associated with one or more pieces of electronic content and\/or it may be employed as a general component of the operating system capabilities of a VDE installation.\nVDEF transaction control elements reflect and enact content specific and\/or more generalized administrative (for example, general operating system) control information. VDEF capabilities which can generally take the form of applications (application models) that have more or less configurability which can be shaped by VDE participants, through the use, for example, of VDE templates, to employ specific capabilities, along, for example, with capability parameter data to reflect the elements of one or more express electronic agreements between VDE participants in regards to the use of electronic content such as commercially distributed products. These control capabilities manage the use of, and\/or auditing of use of, electronic content, as well as reporting information based upon content use, and any payment for said use. VDEF capabilities may \"evolve\" to reflect the requirements of one or more successive parties who receive or otherwise contribute to a given set of control information. Frequently, for a VDE application for a given content model (such as distribution of entertainment on CD-ROM, content delivery from an Internet repository, or electronic catalog shopping and advertising, or some combination of the above) participants would be able to securely select from amongst available, alternative control methods and apply related parameter data, wherein such selection of control method and\/or submission of data would constitute their \"contribution\" of control information. Alternatively, or in addition, certain control methods that have been expressly certified as securely interoperable and compatible with said application may be independently submitted by a participant as part of such a contribution. In the most general example, a generally certified load module (certified for a given VDE arrangement and\/or content class) may be used with many or any VDE application that operates in nodes of said arrangement. These parties, to the extent they are allowed, can independently and securely add, delete, and\/or otherwise modify the specification of load modules and methods, as well as add, delete or otherwise modify related information.\nNormally the party who creates a VDE content container defines the general nature of the VDEF capabilities that will and\/or may apply to certain electronic information. A VDE content container is an object that contains both content (for example, commercially distributed electronic information products such as computer software programs, movies, electronic publications or reference materials, etc.) and certain control information related to the use of the object's content. A creating party may make a VDE container available to other parties. Control information delivered by, and\/or otherwise available for use with, VDE content containers comprise (for commercial content distribution purposes) VDEF control capabilities (and any associated parameter data) for electronic content. These capabilities may constitute one or more \"proposed\" electronic agreements (and\/or agreement functions available for selection and\/or use with parameter data) that manage the use and\/or the consequences of use of such content and which can enact the terms and conditions of agreements involving multiple parties and their various rights and obligations.\nA VDE electronic agreement may be explicit, through a user interface acceptance by one or more parties, for example by a \"junior\" party who has received control information from a \"senior\" party, or it may be a process amongst equal, parties who individually assert their agreement. Agreement may also result from an automated electronic process during which terms and conditions are \"evaluated\" by certain VDE participant control information that assesses whether certain other electronic terms and conditions attached to content and\/or submitted by another party are acceptable (do not violate acceptable control information criteria). Such an evaluation process may be quite simple, for example a comparison to ensure compatibility between a portion of, or all senior, control terms and conditions in a table of terms and conditions and the submitted control information of a subsequent participant in a pathway of content control information handling, or it may be a more elaborate process that evaluates the potential outcome of, and\/or implements a negotiation process between, two or more sets of control information submitted by two or more parties. VDE also accommodates a semi-automated process during which one or more VDE participants directly, through user interface means, resolve \"disagreements\" between control information sets by accepting and\/or proposing certain control information that may be acceptable to control information representing one or more other parties interests and\/or responds to certain user interface queries for selection of certain alternative choices and\/or for certain parameter information, the responses being adopted if acceptable to applicable senior control information.\nWhen another party (other than the first applier of rules), perhaps through a negotiation process, accepts, and\/or adds to and\/or otherwise modifies, \"in place\" content control information, a VDE agreement between two or more parties related to the use of such electronic content may be created (so long as any modifications are consistent with senior control information). Acceptance of terms and conditions related to certain electronic content may be direct and express, or it may be implicit as a result of use of content (depending, for example, on legal requirements, previous exposure to such terms and conditions, and requirements of in place control information).\nVDEF capabilities may be employed, and a VDE agreement may be entered into, by a plurality of parties without the VDEF capabilities being directly associated with the controlling of certain, specific electronic information. For example, certain one or more VDEF capabilities may be present at a VDE installation, and certain VDE agreements may have been entered into during the registration process for a content distribution application, to be used by such installation for securely controlling VDE content usage, auditing, reporting and\/or payment. Similarly, a specific VDE participant may enter into a VDE user agreement with a VDE content or electronic appliance provider when the user and\/or her appliance register with such provider as a VDE installation and\/or user. In such events, VDEF in place control information available to the user VDE installation may require that certain VDEF methods are employed, for example in a certain sequence, in order to be able to use all and\/or certain classes, of electronic content and\/or VDE applications.\nVDE ensures that certain prerequisites necessary for a given transaction to occur are met. This includes the secure execution of any required load modules and the availability of any required, associated data. For example, required load modules and data (e.g. in the form of a method) might specify that sufficient credit from an authorized source must be confirmed as available. It might further require certain one or more load modules execute as processes at an appropriate time to ensure that such credit will be used in order to pay for user use of the content. A certain content provider might, for example, require metering the number of copies made for distribution to employees of a given software program (a portion of the program might be maintained in encrypted form and require the presence of a VDE installation to run). This would require the execution of a metering method for copying of the property each time a copy was made for another employee. This same provider might also charge fees based on the total number of different properties licensed from them by the user and, a metering history of their licensing of properties might be required to maintain this information.\nVDE provides organization, community, and\/or universe wide secure environments whose integrity is assured by processes securely controlled in VDE participant user installations (nodes). VDE installations, in the preferred embodiment, may include both software and tamper resistant hardware semiconductor elements. Such a semiconductor arrangement comprises, at least in part, special purpose circuitry that has been designed to protect against tampering with, or unauthorized observation of, the information and functions used in performing the VDE's control functions. The special purpose secure circuitry provided by the present invention includes at least one of a dedicated semiconductor arrangement known as a Secure Processing Unit (SPU) and\/or a standard microprocessor, microcontroller, and\/or other processing logic that accommodates the requirements of the present invention and functions as an SPU. VDE's secure hardware may be found incorporated into, for example, a fax\/modem chip or chip pack, I\/O controller, video display controller, and\/or other available digital processing arrangements. It is anticipated that portions of the present invention's VDE secure hardware capabilities may ultimately be standard design elements of central processing units (CPUs) for computers and various other electronic devices.\nDesigning VDE capabilities into one or more standard microprocessor, microcontroller and\/or other digital processing components may materially reduce VDE related hardware costs by employing the same hardware resources for both the transaction management uses contemplated by the present invention and for other, host electronic appliance functions. This means that a VDE SPU can employ (share) circuitry elements of a \"standard\" CPU. For example, if a \"standard\" processor can operate in protected mode and can execute VDE related instructions as a protected activity, then such an embodiment may provide sufficient hardware security for a variety of applications and the expense of a special purpose processor might be avoided. Under one preferred embodiment of the present invention, certain memory (e.g., RAM, ROM, NVRAM) is maintained during VDE related instruction processing in a protected mode (for example, as supported by protected mode microprocessors). This memory is located in the same package as the processing logic (e.g. processor). Desirably, the packaging and memory of such a processor would be designed using security techniques that enhance its resistance to tampering.\nThe degree of overall security of the VDE system is primarily dependent on the degree of tamper resistance and concealment of VDE control process execution and related data storage activities. Employing special purpose semiconductor packaging techniques can significantly contribute to the degree of security. Concealment and tamper-resistance in semiconductor memory (e.g., RAM, ROM, NVRAM) can be achieved, in part, by employing such memory within an SPU package, by encrypting data before it is sent to external memory (such as an external RAM package) and decrypting encrypted data within the CPU\/RAM package before it is executed. This process is used for important VDE related data when such data is stored on unprotected media, for example, standard host storage, such as random access memory, mass storage, etc. In that event, a VDE SPU would encrypt data that results from a secure VDE execution before such data was stored in external memory.\nSummary of some Important Features Provided by VDE in Accordance with the Present Invention\nVDE employs a variety of capabilities that serve as a foundation for a general purpose, sufficiently secure distributed electronic commerce solution. VDE enables an electronic commerce marketplace that supports divergent, competitive business partnerships, agreements, and evolving overall business models. For example, VDE includes features that:                \"sufficiently\" impede unauthorized and\/or uncompensated use of electronic information and\/or appliances through the use of secure communication, storage, and transaction management technologies. VDE supports a model wide, distributed security implementation which creates a single secure \"virtual\" transaction processing and information storage environment. VDE enables distributed VDE installations to securely store and communicate information and remotely control the execution processes and the character of use of electronic information at other VDE installations and in a wide variety of ways;        support low-cost, efficient, and effective security architectures for transaction control, auditing, reporting, and related communications and information storage. VDE may employ tagging related security techniques, the time-ageing of encryption keys, the compartmentalization of both stored control information (including differentially tagging such stored information to ensure against substitution and tampering) and distributed content (to, for many content applications, employ one or more content encryption keys that are unique to the specific VDE installation and\/or user), private key techniques such as triple DES to encrypt content, public key techniques such as RSA to protect communications and to provide the benefits of digital signature and authentication to securely bind together the nodes of a VDE arrangement, secure processing of important transaction management executable code, and a combining of a small amount of highly secure, hardware protected storage space with a much larger \"exposed\" mass media storage space storing secured (normally encrypted and tagged) control and audit information. VDE employs special purpose hardware distributed throughout some or all locations of a VDE implementation: a) said hardware controlling important elements of: content preparation (such as causing such content to be placed in a VDE content container and associating content control information with said content), content and\/or electronic appliance usage auditing, content usage analysis, as well as content usage control; and b) said hardware having been designed to securely handle processing load module control activities, wherein said control processing activities may involve a sequence of required control factors;        support dynamic user selection of information subsets of a VDE electronic information product (VDE controlled content). This contrasts with the constraints of having to use a few high level individual, pre-defined content provider information increments such as being required to select a whole information product or product section in order to acquire or otherwise use a portion of such product or section. VDE supports metering and usage control over a variety of increments (including \"atomic\" increments, and combinations of different increment types) that are selected ad hoc by a user and represent a collection of pre-identified one or more increments (such as one or more blocks of a preidentified nature, e.g., bytes, images, logically related blocks) that form a generally arbitrary, but logical to a user, content \"deliverable.\" VDE control information (including budgeting, pricing and metering) can be configured so that it can specifically apply, as appropriate, to ad hoc selection of different, unanticipated variable user selected aggregations of information increments and pricing levels can be, at least in part, based on quantities and\/or nature of mixed increment selections (for example, a certain quantity of certain text could mean associated images might be discounted by 15%; a greater quantity of text in the \"mixed\" increment selection might mean the images are discounted 20%). Such user selected aggregated information increments can reflect the actual requirements of a user for information and is more flexible than being limited to a single, or a few, high level, (e.g. product, document, database record) predetermined increments. Such high level increments may include, quantities of information not desired by the user and as a result be more costly than the subset of information needed by the user if such a subset was available. In sum, the present invention allows information contained in electronic information products to be supplied according to user specification. Tailoring to user specification allows the present invention to provide the greatest value to users, which in turn will generate the greatest amount of electronic commerce activity. The user, for example, would be able to define an aggregation of content derived from various portions of an available content product, but which, as a deliverable for use by the user, is an entirely unique aggregated increment. The user may, for example, select certain numbers of bytes of information from various portions of an information product, such as a reference work, and copy them to disc in unencrypted form and be billed based on total number of bytes plus a surcharge on the number of \"articles\" that provided the bytes. A content provider might reasonably charge less for such a user defined information increment since the user does not require all of the content from all of the articles that contained, desired information. This process of defining a user desired information increment may involve artificial intelligence database search tools that contribute to the location of the most relevant portions of information from an information product and cause the automatic display to the user of information describing search criteria bits for user selection or the automatic extraction and delivery of such portions to the user. VDE further supports a wide variety of predefined increment types including:        bytes,        images,        content over time for audio or video, or any other increment that can be identified by content provider data mapping efforts, such as:        sentences,        paragraphs,        articles,        database records, and        byte offsets representing increments of logically related information.VDE supports as many simultaneous predefined increment types as may be practical for a given type of content and business model.        securely store at a user's site potentially highly detailed information reflective of a user's usage of a variety of different content segment types and employing both inexpensive \"exposed\" host mass storage for maintaining detailed information in the form of encrypted data and maintaining summary information for security testing in highly secure special purpose VDE installation nonvolatile memory (if available).        support trusted chain of handling capabilities for pathways of distributed electronic information and\/or for content usage related information. Such chains may extend, for example, from a content creator, to a distributor, a redistributor, a client user, and then may provide a pathway for securely reporting the same and\/or differing usage information to one or more auditors, such as to one or more independent clearinghouses and then back to the content providers, including content creators. The same and\/or different pathways employed for certain content handling, and related content control information and reporting information handling, may also be employed as one or more pathways for electronic payment handling (payment is characterized in the present invention as administrative content) for electronic content and\/or appliance usage. These pathways are used for conveyance of all or portions of content, and\/or content related control information. Content creators and other providers can specify the pathways that, partially or fully, must be used to disseminate commercially distributed property content, content control information, payment administrative content, and\/or associated usage reporting information. Control information specified by content providers may also specify which specific parties must or may (including, for example, a group of eligible parties from which a selection may be made) handle conveyed information. It may also specify what transmission means (for example telecommunication carriers or media types) and transmission hubs must or may be used.        support flexible auditing mechanisms, such as employing \"bitmap meters,\" that achieve a high degree of efficiency of operation and throughput and allow, in a practical manner, the retention and ready recall of information related to previous usage activities and related patterns. This flexibility is adaptable to a wide variety of billing and security control strategies such as:        upgrade pricing (e.g. suite purchases),        pricing discounts (including quantity discounts),        billing related time duration variables such as discounting new purchases based on the timing of past purchases, and        security budgets based on quantity of different, logically related units of electronic information used over an interval of time.                    Use of bitmap meters (including \"regular\" and \"wide\" bitmap meters) to record usage and\/or purchase of information, in conjunction with other elements of the preferred embodiment of the present invention, uniquely supports efficient maintenance of usage history for: (a) rental, (b) flat fee licensing or purchase, (c) licensing or purchase discounts based upon historical usage variables, and (d) reporting to users in a manner enabling users to determine whether a certain item was acquired, or acquired within a certain time period (without requiring the use of conventional database mechanisms, which are highly inefficient for these applications). Bitmap meter methods record activities associated with electronic appliances, properties, objects, or portions thereof, and\/or administrative activities that are independent of specific properties, objects, etc., performed by a user and\/or electronic appliance such that a content and\/or appliance provider and\/or controller of an administrative activity can determine whether a certain activity has occurred at some point, or during a certain period, in the past (for example, certain use of a commercial electronic content product and\/or appliance). Such determinations can then be used as part of pricing and\/or control strategies of a content and\/or appliance provider, and\/or controller of an administrative activity. For example, the content provider may choose to charge only once for access to a portion of a property, regardless of the number of times that portion of the property is accessed by a user.                        support \"launchable\" content, that is content that can be provided by a content provider to an end-user, who can then copy or pass along the content to other end-user parties without requiring the direct participation of a content provider to register and\/or otherwise initialize the content for use. This content goes \"out of (the traditional distribution) channel\" in the form of a \"traveling object.\" Traveling objects are containers that securely carry at least some permissions information and\/or methods that are required for their use (such methods need not be carried by traveling objects if the required methods will be available at, or directly available to, a destination VDE installation). Certain travelling objects may be used at some or all VDE installations of a given VDE arrangement since they can make available the content control information necessary for content use without requiring the involvement of a commercial VDE value chain participant or data security administrator (e.g. a control officer or network administrator). As long as traveling object control information requirements are available at the user VDE installation secure subsystem (such as the presence of a sufficient quantity of financial credit from an authorized credit provider), at least some travelling object content may be used by a receiving party without the need to establish a connection with a remote VDE authority (until, for example, budgets are exhausted or a time content usage reporting interval has occurred). Traveling objects can travel \"out-of-channel,\" allowing, for example, a user to give a copy of a traveling object whose content is a software program, a movie or a game, to a neighbor, the neighbor being able to use the traveling object if appropriate credit (e.g. an electronic clearinghouse account from a clearinghouse such as VISA or AT&T) is available. Similarly, electronic information that is generally available on an Internet, or a similar network, repository might be provided in the form of a traveling object that can be downloaded and subsequently copied by the initial downloader and then passed along to other parties who may pass the object on to additional parties.        provide very flexible and extensible user identification according to individuals, installations, by groups such as classes, and by function and hierarchical identification employing a hierarchy of levels of client identification (for example, client organization ID, client department ID, client network ID, client project ID, and client employee ID, or any appropriate subset of the above).        provide a general purpose, secure, component based content control and distribution system that functions as a foundation transaction operating system environment that employs executable code pieces crafted for transaction control and auditing. These code pieces can be reused to optimize efficiency in creation and operation of trusted, distributed transaction management arrangements. VDE supports providing such executable code in the form of \"atomic\" load modules and associated data. Many such load modules are inherently configurable, aggregatable, portable, and extensible and singularly, or in combination (along with associated data), run as control methods under the VDE transaction operating environment. VDE can satisfy the requirements of widely differing electronic commerce and data security applications by, in part, employing this general purpose transaction management foundation to securely process VDE transaction related control methods. Control methods are created primarily through the use of one or more of said executable, reusable load module code pieces (normally in the form of executable object components) and associated data. The component nature of control methods allows the present invention to efficiently operate as a highly configurable content control system. Under the present invention, content control models can be iteratively and asynchronously shaped, and otherwise updated to accommodate the needs of VDE participants to the extent that such shaping and otherwise updating conforms to constraints applied by a VDE application, if any (e.g., whether new component assemblies are accepted and, if so, what certification requirements exist for such component assemblies or whether any or certain participants may shape any or certain control information by selection amongst optional control information (permissions record) control methods. This iterative (or concurrent) multiple participant process occurs as a result of the submission and use of secure, control information components (executable code such as load modules and\/or methods, and\/or associated data). These components may be contributed independently by secure communication between each control information influencing VDE participant's VDE installation and may require certification for use with a given application, where such certification was provided by a certification service manager for the VDE arrangement who ensures secure interoperability and\/or reliability (e.g., bug control resulting from interaction) between appliances and submitted control methods. The transaction management control functions of a VDE electronic appliance transaction operating environment interact with non-secure transaction management operating system functions to properly direct transaction processes and data related to electronic information security, usage control, auditing, and usage reporting. VDE provides the capability to manages resources related to secure VDE content and\/or appliance control information execution and data storage.        facilitate creation of application and\/or system functionality under VDE and to facilitate integration into electronic appliance environments of load modules and methods created under the present invention. To achieve this, VDE employs an Application Programmer's Interface (API) and\/or a transaction operating system (such as a ROS) programming language with incorporated functions, both of which support the use of capabilities and can be used to efficiently and tightly integrate VDE functionality into commercial and user applications.        support user interaction through: (a) \"Pop-Up\" applications which, for example, provide messages to users and enable users to take specific actions such as approving a transaction, (b) stand-alone VDE applications that provide administrative environments for user activities such as: end-user preference specifications for limiting the price per transaction, unit of time, and\/or session, for accessing history information concerning previous transactions, for reviewing financial information such as budgets, expenditures (e.g. detailed and\/or summary) and usage analysis information, and (c) VDE aware applications which, as a result of the use of a VDE API and\/or a transaction management (for example, ROS based) programming language embeds VDE \"awareness\" into commercial or internal software (application programs, games, etc.) so that VDE user control information and services are seamlessly integrated into such software and can be directly accessed by a user since the underlying functionality has been integrated into the commercial software's native design. For example, in a VDE aware word processor application, a user may be able to \"print\" a document into a VDE content container object, applying specific control information by selecting from amongst a series of different menu templates for different purposes (for example, a confidential memo template for internal organization purposes may restrict the ability to \"keep,\" that is to make an electronic copy of the memo).        employ \"templates\" to ease the process of configuring capabilities of the present invention as they relate to specific industries or businesses. Templates are applications or application add-ons under the present invention. Templates support the efficient specification and\/or manipulation of criteria related to specific content types, distribution approaches, pricing mechanisms, user interactions with content and\/or administrative activities, and\/or the like. Given the very large range of capabilities and configurations supported by the present invention, reducing the range of configuration opportunities to a manageable subset particularly appropriate for a given business model allows the full configurable power of the present invention to be easily employed by \"typical\" users who would be otherwise burdened with complex programming and\/or configuration design responsibilities template applications can also help ensure that VDE related processes are secure and optimally bug free by reducing the risks associated with the contribution of independently developed load modules, including unpredictable aspects of code interaction between independent modules and applications, as well as security risks associated with possible presence of viruses in such modules. VDE, through the use of templates, reduces typical user configuration responsibilities to an appropriately focused set of activities including selection of method types (e.g. functionality) through menu choices such as multiple choice, icon selection, and\/or prompting for method parameter data (such as identification information, prices, budget limits, dates, periods of time, access rights to specific content, etc.) that supply appropriate and\/or necessary data for control information purposes. By limiting the typical (non-programming) user to a limited subset of configuration activities whose general configuration environment (template) has been preset to reflect general requirements corresponding to that user, or a content or other business model can very substantially limit difficulties associated with content containerization (including placing initial control information on content), distribution, client administration, electronic agreement implementation, end-user interaction, and clearinghouse activities, including associated interoperability problems (such as conflicts resulting from security, operating system, and\/or certification incompatibilities). Use of appropriate VDE templates can assure users that their activities related to content VDE containerization, contribution of other control information, communications, encryption techniques and\/or keys, etc. will be in compliance with specifications for their distributed VDE arrangement. VDE templates constitute preset configurations that can normally be reconfigurable to allow for new and\/or modified templates that reflect adaptation into new industries as they evolve or to reflect the evolution or other change of an existing industry. For example, the template concept may be used to provide individual, overall frameworks for organizations and individuals that create, modify, market, distribute, consume, and\/or otherwise use movies, audio recordings and live performances, magazines, telephony based retail sales, catalogs, computer software, information data bases, multimedia, commercial communications, advertisements, market surveys, infomercials, games, CAD\/CAM services for numerically controlled machines, and the like. As the context surrounding these templates changes or evolves, template applications provided under the present invention may be modified to meet these changes for broad use, or for more focused activities. A given VDE participant may have a plurality of templates available for different tasks. A party that places content in its initial VDE container may have a variety of different, configurable templates depending on the type of content and\/or business model related to the content. An end-user may have different configurable templates that can be applied to different document types (e-mail, secure internal documents, database records, etc.) and\/or subsets of users (applying differing general sets of control information to different bodies of users, for example, selecting a list of users who may, under certain preset criteria, use a certain document). Of course, templates may, under certain circumstances have fixed control information and not provide for user selections or parameter data entry.        support plural, different control models regulating the use and\/or auditing of either the same specific copy of electronic information content and\/or differently regulating different copies (occurrences) of the same electronic information content. Differing models for billing, auditing, and security can be applied to the same piece of electronic information content and such differing sets of control information may employ, for control purposes, the same, or differing, granularities of electronic information control increments. This includes supporting variable control information for budgeting and auditing usage as applied to a variety of predefined increments of electronic information, including employing a variety of different budgets and\/or metering increments for a given electronic information deliverable for: billing units of measure, credit limit, security budget limit and security content metering increments, and\/or market surveying and customer profiling content metering increments. For example, a CD-ROM disk with a database of scientific articles, might be in part billed according to a formula based on the number of bytes decrypted, number of articles containing said bytes decrypted, while a security budget might limit the use of said database to no more than 5% of the database per month for users on the wide area network it is installed on.        provide mechanisms to persistently maintain trusted content usage and reporting control information through both a sufficiently secure chain of handling of content and content control information and through various forms of usage of such content wherein said persistence of control may survive such use. Persistence of control includes the ability to extract information from a VDE container object by creating a new container whose contents are at least in part secured and that contains both the extracted content and at least a portion of the control information which control information of the original container and\/or are at least in part produced by control information of the original container for this purpose and\/or VDE installation control information stipulates should persist and\/or control usage of content in the newly formed container. Such control information can continue to manage usage of container content if the container is \"embedded\" into another VDE managed object, such as an object which contains plural embedded VDE containers, each of which contains content derived (extracted) from a different source.        enables users, other value chain participants (such as clearinghouses and government agencies), and\/or user organizations, to specify preferences or requirements related to their use of electronic content and\/or appliances. Content users, such as end-user customers using commercially distributed content (games, information resources, software programs, etc.), can define, if allowed by senior control information, budgets, and\/or other control information, to manage their own internal use of content. Uses include, for example, a user setting a limit on the price for electronic documents that the user is willing to pay without prior express user authorization, and the user establishing the character of metering information he or she is willing to allow to be collected (privacy protection). This includes providing the means for content users to protect the privacy of information derived from their use of a VDE installation and content and\/or appliance usage auditing. In particular, VDE can prevent information related to a participant's usage of electronic content from being provided to other parties without the participant's tacit or explicit agreement.        provide mechanisms that allow control information to \"evolve\" and be modified according, at least in part, to independently, securely delivered further control information. Said control information may include executable code (e.g., load modules) that has been certified as acceptable (e.g., reliable and trusted) for use with a specific VDE application, class of applications, and\/or a VDE distributed arrangement. This modification (evolution) of control information can occur upon content control information (load modules and any associated data) circulating to one or more VDE participants in a pathway of handling of control information, or it may occur upon control information being received from a VDE participant. Handlers in a pathway of handling of content control information, to the extent each is authorized, can establish, modify, and\/or contribute to, permission, auditing, payment, and reporting control information related to controlling, analyzing, paying for, and\/or reporting usage of, electronic content and\/or appliances (for example, as related to usage of VDE controlled property content). Independently delivered (from an independent source which is independent except in regards to certification), at least in part secure, control information can be employed to securely modify content control information when content control information has flowed from one party to another party in a sequence of VDE content control information handling. This modification employs, for example, one or more VDE component assemblies being securely processed in a VDE secure subsystem. In an alternate embodiment, control information may be modified by a senior party through use of their VDE installation secure sub-system after receiving submitted, at least in part secured, control information from a \"junior\" party, normally in the form of a VDE administrative object. Control information passing along VDE pathways can represent a mixed control set, in that it may include: control information that persisted through a sequence of control information handlers, other control information that was allowed to be modified, and further control information representing new control information and\/or mediating data. Such a control set represents an evolution of control information for disseminated content. In this example the overall content control set for a VDE content container is \"evolving\" as it securely (e.g. communicated in encrypted form and using authentication and digital signaturing techniques) passes, at least in part, to a new participant's VDE installation where the proposed control information is securely received and handled. The received control information may be integrated (through use of the receiving parties' VDE installation secure sub-system) with in-place control information through a negotiation process involving both control information sets. For example, the modification, within the secure sub-system of a content provider's VDE installation, of content control information for a certain VDE content container may have occurred as a result of the incorporation of required control information provided by a financial credit provider. Said credit provider may have employed their VDE installation to prepare and securely communicate (directly or indirectly) said required control information to said content provider. Incorporating said required control information enables a content provider to allow the credit provider's credit to be employed by a content end-user to compensate for the end-user's use of VDE controlled content and\/or appliances, so long as said end-user has a credit account with said financial credit provider and said credit account has sufficient credit available. Similarly, control information requiring the payment of taxes and\/or the provision of revenue information resulting from electronic commerce activities may be securely received by a content provider. This control information may be received, for example, from a government agency. Content providers might be required by law to incorporate such control information into the control information for commercially distributed content and\/or services related to appliance usage. Proposed control information is used to an extent allowed by senior control information and as determined by any negotiation trade-offs that satisfy priorities stipulated by each set (the received set and the proposed set). VDE also accommodates different control schemes specifically applying to different participants (e.g., individual participants and\/or participant classes (types)) in a network of VDE content handling participants.        support multiple simultaneous control models for the same content property and\/or property portion. This allows, for example, for concurrent business activities which are dependent on electronic commercial product content distribution, such as acquiring detailed market survey information and\/or supporting advertising, both of which can increase revenue and result in lower content costs to users and greater value to content providers. Such control information and\/or overall control models may be applied, as determined or allowed by control information, in differing manners to different participants in a pathway of content, reporting, payment, and\/or related control information handling. VDE supports applying different content control information to the same and\/or different content and\/or appliance usage related activities, and\/or to different parties in a content and\/or appliance usage model, such that different parties (or classes of VDE users, for example) are subject to differing control information managing their use of electronic information content. For example, differing control models based on the category of a user as a distributor of a VDE controlled content object or an end-user of such content may result in different budgets being applied. Alternatively, for example, a one distributor may have the right to distribute a different array of properties than another distributor (from a common content collection provided, for example, on optical disc). An individual, and\/or a class or other grouping of end-users, may have different costs (for example, a student, senior citizen, and\/or poor citizen user of content who may be provided with the same or differing discounts) than a \"typical\" content user.        support provider revenue information resulting from customer use of content and\/or appliances, and\/or provider and\/or end-user payment of taxes, through the transfer of credit and\/or electronic currency from said end-user and\/or provider to a government agency, might occur \"automatically\" as a result of such received control information causing the generation of a VDE content container whose content includes customer content usage information reflecting secure, trusted revenue summary information and\/or detailed user transaction listings (level of detail might depend, for example on type or size of transaction\u2014information regarding a bank interest payment to a customer or a transfer of a large (e.g. over $10,000) might be, by law, automatically reported to the government). Such summary and\/or detailed information related to taxable events and\/or currency, and\/or creditor currency transfer, may be passed along a pathway of reporting and\/or payment to the government in a VDE container. Such a container may also be used for other VDE related content usage reporting information.        support the flowing of content control information through different \"branches\" of content control information handling so as to accommodate, under the present invention's preferred embodiment, diverse controlled distributions of VDE controlled content. This allows different parties to employ the same initial electronic content with differing (perhaps competitive) control strategies. In this instance, a party who first placed control information on content can make certain control assumptions and these assumptions would evolve into more specific and\/or extensive control assumptions. These control assumptions can evolve during the branching sequence upon content model participants submitting control information changes, for example, for use in \"negotiating\" with \"in place\" content control information. This can result in new or modified content control information and\/or it might involve the selection of certain one or more already \"in-place\" content usage control methods over in-place alternative methods, as well as the submission of relevant control information parameter data. This form of evolution of different control information sets applied to different copies of the same electronic property content and\/or appliance results from VDE control information flowing \"down\" through different branches in an overall pathway of handling and control and being modified differently as it diverges down these different pathway branches. This ability of the present invention to support multiple pathway branches for the flow of both VDE content control information and VDE managed content enables an electronic commerce marketplace which supports diverging, competitive business partnerships, agreements, and evolving overall business models which can employ the same content properties combined, for example, in differing collections of content representing differing at least in part competitive products.        enable a user to securely extract, through the use of the secure subsystem at the user's VDE installation, at least a portion of the content included within a VDE content container to produce a new, secure object (content container), such that the extracted information is maintained in a continually secure manner through the extraction process. Formation of the new VDE container containing such extracted content shall result in control information consistent with, or specified by, the source VDE content container, and\/or local VDE installation secure subsystem as appropriate, content control information. Relevant control information, such as security and administrative information, derived, at least in part, from the parent (source) object's control information, will normally be automatically inserted into a new VDE content container object containing extracted VDE content. This process typically occurs under the control framework of a parent object and\/or VDE installation control information executing at the user's VDE installation secure subsystem (with, for example, at least a portion of this inserted control information being stored securely in encrypted form in one or more permissions records). In an alternative embodiment, the derived content control information applied to extracted content may be in part or whole derived from, or employ, content control information stored remotely from the VDE installation that performed the secure extraction such as at a remote server location. As with the content control information for most VDE managed content, features of the present invention allows the content's control information to:        (a) \"evolve,\" for example, the extractor of content may add new control methods and\/or modify control parameter data, such as VDE application compliant methods, to the extent allowed by the content's in-place control information. Such new control information might specify, for example, who may use at least a portion of the new object, and\/or how said at least a portion of said extracted content may be used (e.g. when at least a portion may be used, or what portion or quantity of portions may be used);        (b) allow a user to combine additional content with at least a portion of said extracted content, such as material authored by the extractor and\/or content (for example, images, video, audio, and\/or text) extracted from one or more other VDE container objects for placement directly into the new container;        (c) allow a user to securely edit at least a portion of said content while maintaining said content in a secure form within said VDE content container;        (d) append extracted content to a pre-existing VDE content container object and attach associated control information\u2014in these cases, user added information may be secured, e.g., encrypted, in part or as a whole, and may be subject to usage and\/or auditing control information that differs from the those applied to previously in place object content;        (e) preserve VDE control over one or more portions of extracted content after various forms of usage of said portions, for example, maintain content in securely stored form while allowing \"temporary\" on screen display of content or allowing a software program to be maintained in secure form but transiently decrypt any encrypted executing portion of said program (all, or only a portion, of said program may be encrypted to secure the program).        \nGenerally, the extraction features of the present invention allow users to aggregate and\/or disseminate and\/or otherwise use protected electronic content information extracted from content container sources while maintaining secure VDE capabilities thus preserving the rights of providers in said content information after various content usage processes.                support the aggregation of portions of VDE controlled content, such portions being subject to differing VDE content container control information, wherein various of said portions may have been provided by independent, different content providers from one or more different locations remote to the user performing the aggregation. Such aggregation, in the preferred embodiment of the present invention, may involve preserving at least a portion of the control information (e.g., executable code such as load modules) for each of various of said portions by, for example, embedding some or all of such portions individually as VDE content container objects within an overall VDE content container and\/or embedding some or all of such portions directly into a VDE content container. In the latter case, content control information of said content container may apply differing control information sets to various of such portions based upon said portions original control information requirements before aggregation. Each of such embedded VDE content containers may have its own control information in the form of one or more permissions records. Alternatively, a negotiation between control information associated with various aggregated portions of electronic content, may produce a control information set that would govern some or all of the aggregated content portions. The VDE content control information produced by the negotiation may be uniform (such as having the same load modules and\/or component assemblies, and\/or it may apply differing such content control information to two or more portions that constitute an aggregation of VDE controlled content such as differing metering, budgeting, billing and\/or payment models. For example, content usage payment may be automatically made, either through a clearinghouse, or directly, to different content providers for different potions.        enable flexible metering of, or other collection of information related to, use of electronic content and\/or electronic appliances. A feature of the present invention enables such flexibility of metering control mechanisms to accommodate a simultaneous, broad array of: (a) different parameters related to electronic information content use; (b) different increment units (bytes, documents, properties, paragraphs, images, etc.) and\/or other organizations of such electronic content; and\/or (c) different categories of user and\/or VDE installation types, such as client organizations, departments, projects, networks, and\/or individual users, etc. This feature of the present invention can be employed for content security, usage analysis (for example, market surveying), and\/or compensation based upon the use and\/or exposure to VDE managed content. Such metering is a flexible basis for ensuring payment for content royalties, licensing, purchasing, and\/or advertising. A feature of the present invention provides for payment means supporting flexible electronic currency and credit mechanisms, including the ability to securely maintain audit trails reflecting information related to use of such currency or credit. VDE supports multiple differing hierarchies of client organization control information wherein an organization client administrator distributes control information specifying the usage rights of departments, users, and\/or projects. Likewise, a department (division) network manager can function as a distributor (budgets, access rights, etc.) for department networks, projects, and\/or users, etc.        provide scalable, integratable, standardized control means for use on electronic appliances ranging from inexpensive consumer (for example, television set-top appliances) and professional devices (and hand-held PDAs) to servers, mainframes, communication switches, etc. The scalable transaction management\/auditing technology of the present invention will result in more efficient and reliable interoperability amongst devices functioning in electronic commerce and\/or data security environments. As standardized physical containers have become essential to the shipping of physical goods around the world, allowing these physical containers to universally \"fit\" unloading equipment, efficiently use truck and train space, and accommodate known arrays of objects (for example, boxes) in an efficient manner, so VDE electronic content containers may, as provided by the present invention, be able to efficiently move electronic information content (such as commercially published properties, electronic currency and credit, and content audit information), and associated content control information, around the world. Interoperability is fundamental to efficient electronic commerce. The design of the VDE foundation, VDE load modules, and VDE containers, are important features that enable the VDE node operating environment to be compatible with a very broad range of electronic appliances. The ability, for example, for control methods based on load modules to execute in very \"small\" and inexpensive secure sub-system environments, such as environments with very little read\/write memory, while also being able to execute in large memory sub-systems that may be used in more expensive electronic appliances, supports consistency across many machines. This consistent VDE operating environment, including its control structures and container architecture, enables the use of standardized VDE content containers across a broad range of device types and host operating environments. Since VDE capabilities can be seamlessly integrated as extensions, additions, and\/or modifications to fundamental capabilities of electronic appliances and host operating systems, VDE containers, content control information, and the VDE foundation will be able to work with many device types and these device types will be able to consistently and efficiently interpret and enforce VDE control information. Through this integration users can also benefit from a transparent interaction with many of the capabilities of VDE. VDE integration with software operating on a host electronic appliance supports a variety of capabilities that would be unavailable or less secure without such integration. Through integration with one or more device applications and\/or device operating environments, many capabilities of the present invention can be presented as inherent capabilities of a given electronic appliance, operating system, or appliance application. For example, features of the present invention include: (a) VDE system software to in part extend and\/or modify host operating systems such that they possesses VDE capabilities, such as enabling secure transaction processing and electronic information storage; (b) one or more application programs that in part represent tools associated with VDE operation; and\/or (c) code to be integrated into application programs, wherein such code incorporates references into VDE system software to integrate VDE capabilities and makes such applications VDE aware (for example, word processors, database retrieval applications, spreadsheets, multimedia presentation authoring tools, film editing software, music editing software such as MIDI applications and the like, robotics control systems such as those associated with CAD\/CAM environments and NCM software and the like, electronic mail systems, teleconferencing software, and other data authoring, creating, handling, and\/or usage applications including combinations of the above). These one or more features (which may also be implemented in firmware or hardware) may be employed in conjunction with a VDE node secure hardware processing capability, such as a microcontroller(s), microprocessor(s), other CPU(s) or other digital processing logic.        employ audit reconciliation and usage pattern evaluation processes that assess, through certain, normally network based, transaction processing reconciliation and threshold checking activities, whether certain violations of security of a VDE arrangement have occurred. These processes are performed remote to VDE controlled content end-user VDE locations by assessing, for example, purchases, and\/or requests, for electronic properties by a given VDE installation. Applications for such reconciliation activities include assessing whether the quantity of remotely delivered VDE controlled content corresponds to the amount of financial credit and\/or electronic currency employed for the use of such content. A trusted organization can acquire information from content providers concerning the cost for content provided to a given VDE installation and\/or user and compare this cost for content with the credit and\/or electronic currency disbursements for that installation and\/or user. Inconsistencies in the amount of content delivered versus the amount of disbursement can prove, and\/or indicate, depending on the circumstances, whether the local VDE installation has been, at least to some degree, compromised (for example, certain important system security functions, such as breaking encryption for at least some portion of the secure subsystem and\/or VDE controlled content by uncovering one or more keys). Determining whether irregular patterns (e.g. unusually high demand) of content usage, or requests for delivery of certain kinds of VDE controlled information during a certain time period by one or more VDE installations and\/or users (including, for example, groups of related users whose aggregate pattern of usage is suspicious) may also be useful in determining whether security at such one or more installations, and\/or by such one or more users, has been compromised, particularly when used in combination with an assessment of electronic credit and\/or currency provided to one or more VDE users and\/or installations, by some or all of their credit and\/or currency suppliers, compared with the disbursements made by such users and\/or installations.        support security techniques that materially increase the time required to \"break\" a system's integrity. This includes using a collection of techniques that minimizes the damage resulting from comprising some aspect of the security features of the present inventions.        provide a family of authoring, administrative, reporting, payment, and billing tool user applications that comprise components of the present invention's trusted\/secure, universe wide, distributed transaction control and administration system. These components support VDE related: object creation (including placing control information on content), secure object distribution and management (including distribution control information, financial related, and other usage analysis), client internal VDE activities administration and control, security management, user interfaces, payment disbursement, and clearinghouse related functions. These components are designed to support highly secure, uniform, consistent, and standardized: electronic commerce and\/or data security pathway(s) of handling, reporting, and\/or payment; content control and administration; and human factors (e.g. user interfaces).        support the operation of a plurality of clearinghouses, including, for example, both financial and user clearinghouse activities, such as those performed by a client administrator in a large organization to assist in the organization's use of a VDE arrangement, including usage information analysis, and control of VDE activities by individuals and groups of employees such as specifying budgets and the character of usage rights available under VDE for certain groups of and\/or individual, client personnel, subject to control information series to control information submitted by the client administrator. At a clearinghouse, one or more VDE installations may operate together with a trusted distributed database environment (which may include concurrent database processing means). A financial clearinghouse normally receives at its location securely delivered content usage information, and user requests (such as requests for further credit, electronic currency, and\/or higher credit limit). Reporting of usage information and user requests can be used for supporting electronic currency, billing, payment and credit related activities, and\/or for user profile analysis and\/or broader market survey analysis and marketing (consolidated) list generation or other information derived, at least in part, from said usage information. this information can be provided to content providers or other parties, through secure, authenticated encrypted communication to the VDE installation secure subsystems. Clearinghouse processing means would normally be connected to specialized I\/O means, which may include high speed telecommunication switching means that may be used for secure communications between a clearinghouse and other VDE pathway participants.        securely support electronic currency and credit usage control, storage, and communication at, and between, VDE installations. VDE further supports automated passing of electronic currency and\/or credit information, including payment tokens (such as in the form of electronic currency or credit) or other payment information, through a pathway of payment, which said pathway may or may not be the same as a pathway for content usage information reporting. Such payment may be placed into a VDE container created automatically by a VDE installation in response to control information stipulating the \"withdrawal\" of credit or electronic currency from an electronic credit or currency account based upon an amount owed resulting from usage of VDE controlled electronic content and\/or appliances. Payment credit or currency may then be automatically communicated in protected (at least in part encrypted) form through telecommunication of a VDE container to an appropriate party such as a clearinghouse, provider of original property content or appliance, or an agent for such provider (other than a clearinghouse). Payment information may be packaged in said VDE content container with, or without, related content usage information, such as metering information. An aspect of the present invention further enables certain information regarding currency use to be specified as unavailable to certain, some, or all VDE parties (\"conditionally\" to fully anonymous currency) and\/or further can regulate certain content information, such as currency and\/or credit use related information (and\/or other electronic information usage data) to be available only under certain strict circumstances, such as a court order (which may itself require authorization through the use of a court controlled VDE installation that may be required to securely access \"conditionally\" anonymous information). Currency and credit information, under the preferred embodiment of the present invention, is treated as administrative content;        support fingerprinting (also known as watermarking) for embedding in content such that when content protected under the present invention is released in clear form from a VDE object (displayed, printed, communicated, extracted, and\/or saved), information representing the identification of the user and\/or VDE installation responsible for transforming the content into clear form is embedded into the released content. Fingerprinting is useful in providing an ability to identify who extracted information in clear form a VDE container, or who made a copy of a VDE object or a portion of its contents. Since the identity of the user and\/or other identifying information may be embedded in an obscure or generally concealed manner, in VDE container content and\/or control information, potential copyright violators may be deterred from unauthorized extraction or copying. Fingerprinting normally is embedded into unencrypted electronic content or control information, though it can be embedded into encrypted content and later placed in unencrypted content in a secure VDE installation sub-system as the encrypted content carrying the fingerprinting information is decrypted. Electronic information, such as the content of a VDE container, may be fingerprinted as it leaves a network (such as Internet) location bound for a receiving party. Such repository information may be maintained in unencrypted form prior to communication and be encrypted as it leaves the repository. Fingerprinting would preferably take place as the content leaves the repository, but before the encryption step. Encrypted repository content can be decrypted, for example in a secure VDE sub-system, fingerprint information can be inserted, and then the content can be re-encrypted for transmission. Embedding identification information of the intended recipient user and\/or VDE installation into content as it leaves, for example, an Internet repository, would provide important information that would identify or assist in identifying any party that managed to compromise the security of a VDE installation or the delivered content. If a party produces an authorized clear form copy of VDE controlled content, including making unauthorized copies of an authorized clear form copy, fingerprint information would point back to that individual and\/or his or her VDE installation. Such hidden information will act as a strong disincentive that should dissuade a substantial portion of potential content \"pirates\" from stealing other parties electronic information. Fingerprint information identifying a receiving party and\/or VDE installation can be embedded into a VDE object before, or during, decryption, replication, or communication of VDE content objects to receivers. Fingerprinting electronic content before it is encrypted for transfer to a customer or other user provides information that can be very useful for identifying who received certain content which may have then been distributed or made available in unencrypted form. This information would be useful in tracking who may have \"broken\" the security of a VDE installation and was illegally making certain electronic content available to others. Fingerprinting may provide additional, available information such as time and\/or date of the release (for example extraction) of said content information. Locations for inserting fingerprints may be specified by VDE installation and\/or content container control information. This information may specify that certain areas and\/or precise locations within properties should be used for fingerprinting, such as one or more certain fields of information or information types. Fingerprinting information may be incorporated into a property by modifying in a normally undetectable way color frequency and\/or the brightness of certain image pixels, by slightly modifying certain audio signals as to frequency, by modifying font character formation, etc. Fingerprint information, itself, should be encrypted so as to make it particularly difficult for tampered fingerprints to be interpreted as valid. Variations in fingerprint locations for different copies of the same property; \"false\" fingerprint information; and multiple copies of fingerprint information within a specific property or other content which copies employ different fingerprinting techniques such as information distribution patterns, frequency and\/or brightness manipulation, and encryption related techniques, are features of the present invention for increasing the difficulty of an unauthorized individual identifying fingerprint locations and erasing and\/or modifying fingerprint information.        provide smart object agents that can carry requests, data, and\/or methods, including budgets, authorizations, credit or currency, and content. For example, smart objects may travel to and\/or from remote information resource locations and fulfill requests for electronic information content. Smart objects can, for example, be transmitted to a remote location to perform a specified database search on behalf of a user or otherwise \"intelligently\" search remote one or more repositories of information for user desired information. After identifying desired information at one or more remote locations, by for example, performing one or more database searches, a smart object may return via communication to the user in the form of a secure \"return object\" containing retrieved information. A user may be charged for the remote retrieving of information, the returning of information to the user's VDE installation, and\/or the use of such information. In the latter case, a user may be charged only for the information in the return object that the user actually uses. Smart objects may have the means to request use of one or more services and\/or resources. Services include locating other services and\/or resources such as information resources, language or format translation, processing, credit (or additional credit) authorization, etc. Resources include reference databases, networks, high powered or specialized computing resources (the smart object may carry information to another computer to be efficiently processed and then return the information to the sending VDE installation), remote object repositories, etc. Smart objects can make efficient use of remote resources (e.g. centralized databases, super computers, etc.) while providing a secure means for charging users based on information and\/or resources actually used.        support both \"translations\" of VDE electronic agreements elements into modern language printed agreement elements (such as English language agreements) and translations of electronic rights protection\/transaction management modern language agreement elements to electronic VDE agreement elements. This feature requires maintaining a library of textual language that corresponds to VDE load modules and\/or methods and\/or component assemblies. As VDE methods are proposed and\/or employed for VDE agreements, a listing of textual terms and conditions can be produced by a VDE user application which, in a preferred embodiment, provides phrases, sentences and\/or paragraphs that have been stored and correspond to said methods and\/or assemblies. This feature preferably employs artificial intelligence capabilities to analyze and automatically determine, and\/or assist one or more users to determine, the proper order and relationship between the library elements corresponding to the chosen methods and\/or assemblies so as to compose some or all portions of a legal or descriptive document. One or more users, and\/or preferably an attorney (if the document a legal, binding agreement), would review the generated document material upon completion and employ such additional textual information and\/or editing as necessary to describe non electronic transaction elements of the agreement and make any other improvements that may be necessary. These features further support employing modern language tools that allow one or more users to make selections from choices and provide answers to questions and to produce a VDE electronic agreement from such a process. This process can be interactive and the VDE agreement formulation process may employ artificial intelligence expert system technology that learns from responses and, where appropriate and based at least in part on said responses, provides further choices and\/or questions which \"evolves\" the desired VDE electronic agreement.        support the use of multiple VDE secure subsystems in a single VDE installation. Various security and\/or performance advantages may be realized by employing a distributed VDE design within a single VDE installation. For example, designing a hardware based VDE secure subsystem into an electronic appliance VDE display device, and designing said subsystem's integration with said display device so that it is as close as possible to the point of display, will increase the security for video materials by making it materially more difficult to \"steal\" decrypted video information as it moves from outside to inside the video system. Ideally, for example, a VDE secure hardware module would be in the same physical package as the actual display monitor, such as within the packaging of a video monitor or other display device, and such device would be designed, to the extent commercially practical, to be as tamper resistant as reasonable. As another example, embedding a VDE hardware module into an I\/O peripheral may have certain advantages from the standpoint of overall system throughput. If multiple VDE instances are employed within the same VDE installation, these instances will ideally share resources to the extent practical, such as VDE instances storing certain control information and content and\/or appliance usage information on the same mass storage device and in the same VDE management database.        requiring reporting and payment compliance by employing exhaustion of budgets and time ageing of keys. For example, a VDE commercial arrangement and associated content control information may involve a content provider's content and the use of clearinghouse credit for payment for end-user usage of said content. Control information regarding said arrangement may be delivered to a user's (of said content) VDE installation and\/or said financial clearinghouse's VDE installation. Said control information might require said clearinghouse to prepare and telecommunicate to said content provider both content usage based information in a certain form, and content usage payment in the form of electronic credit (such credit might be \"owned\" by the provider after receipt and used in lieu of the availability or adequacy of electronic currency) and\/or electronic currency. This delivery of information and payment may employ trusted VDE installation secure subsystems to securely, and in some embodiments, automatically, provide in the manner specified by said control information, said usage information and payment content. Features of the present invention help ensure that a requirement that a clearinghouse report such usage information and payment content will be observed. For example, if one participant to a VDE electronic agreement fails to observe such information reporting and\/or paying obligation, another participant can stop the delinquent party from successfully participating in VDE activities related to such agreement. For example, if required usage information and payment was not reported as specified by content control information, the \"injured\" party can fail to provide, through failing to securely communicate from his VDE installation secure subsystem, one or more pieces of secure information necessary for the continuance of one or more critical processes. For example, failure to report information and\/or payment from a clearinghouse to a content provider (as well as any security failures or other disturbing irregularities) can result in the content provider not providing key and\/or budget refresh information to the clearinghouse, which information can be necessary to authorize use of the clearinghouse's credit for usage of the provider's content and which the clearinghouse would communicate to end-user's during a content usage reporting communication between the clearinghouse and end-user. As another example, a distributor that failed to make payments and\/or report usage information to a content provider might find that their budget for creating permissions records to distribute the content provider's content to users, and\/or a security budget limiting one or more other aspect of their use of the provider's content, are not being refreshed by the content provider, once exhausted or timed-out (for example, at a predetermined date). In these and other cases, the offended party might decide not to refresh time ageing keys that had \"aged out.\" Such a use of time aged keys has a similar impact as failing to refresh budgets or time-aged authorizations.        support smart card implementations of the present invention in the form of portable electronic appliances, including cards that can be employed as secure credit, banking, and\/or money cards. A feature of the present invention is the use of portable VDEs as transaction cards at retail and other establishments, wherein such cards can \"dock\" with an establishment terminal that has a VDE secure sub-system and\/or an online connection to a VDE secure and\/or otherwise secure and compatible subsystem, such as a \"trusted\" financial clearinghouse (e.g., VISA, Mastercard). The VDE card and the terminal (and\/or online connection) can securely exchange information related to a transaction, with credit and\/or electronic currency being transferred to a merchant and\/or clearinghouse and transaction information flowing back to the card. Such a card can be used for transaction activities of all sorts. A docking station, such as a PCMCIA connector on an electronic appliance, such as a personal computer, can receive a consumer's VDE card at home. Such a station\/card combination can be used for on-line transactions in the same manner as a VDE installation that is permanently installed in such an electronic appliance. The card can be used as an \"electronic wallet\" and contain electronic currency as well as credit provided by a clearinghouse. The card can act as a convergence point for financial activities of a consumer regarding many, if not all, merchant, banking, and on-line financial transactions, including supporting home banking activities. A consumer can receive his paycheck and\/or investment earnings and\/or \"authentic\" VDE content container secured detailed information on such receipts, through on-line connections. A user can send digital currency to another party with a VDE arrangement, including giving away such currency. A VDE card can retain details of transactions in a highly secure and database organized fashion so that financially related information is both consolidated and very easily retrieved and\/or analyzed. Because of the VDE security, including use of effective encryption, authentication, digital signaturing, and secure database structures, the records contained within a VDE card arrangement may be accepted as valid transaction records for government and\/or corporate recordkeeping requirements. In some embodiments of the present invention a VDE card may employ docking station and\/or electronic appliance storage means and\/or share other VDE arrangement means local to said appliance and\/or available across a network, to augment the information storage capacity of the VDE card, by for example, storing dated, and\/or archived, backup information. Taxes relating to some or all of an individual's financial activities may be automatically computed based on \"authentic\" information securely stored and available to said VDE card. Said information may be stored in said card, in said docking station, in an associated electronic appliance, and\/or other device operatively attached thereto, and\/or remotely, such as at a remote server site. A card's data, e.g. transaction history, can be backed up to an individual's personal computer or other electronic appliance and such an appliance may have an integrated VDE installation of its own. A current transaction, recent transactions (for redundancy), or all or other selected card data may be backed up to a remote backup repository, such a VDE compatible repository at a financial clearinghouse, during each or periodic docking for a financial transaction and\/or information communication such as a user\/merchant transaction. Backing up at least the current transaction during a connection with another party's VDE installation (for example a VDE installation that is also on a financial or general purpose electronic network), by posting transaction information to a remote clearinghouse and\/or bank, can ensure that sufficient backup is conducted to enable complete reconstruction of VDE card internal information in the event of a card failure or loss.        support certification processes that ensure authorized interoperability between various VDE installations so as to prevent VDE arrangements and\/or installations that unacceptably deviate in specification protocols from other VDE arrangements and\/or installations from interoperating in a manner that may introduce security (integrity and\/or confidentiality of VDE secured information), process control, and\/or software compatibility problems. Certification validates the identity of VDE installations and\/or their components, as well as VDE users. Certification data can also serve as information that contributes to determining the decommissioning or other change related to VDE sites.        support the separation of fundamental transaction control processes through the use of event (triggered) based method control mechanisms. These event methods trigger one or more other VDE methods (which are available to a secure VDE sub-system) and are used to carry out VDE managed transaction related processing. These triggered methods include independently (separably) and securely processable component billing management methods, budgeting management methods, metering management methods, and related auditing management processes. As a result of this feature of the present invention, independent triggering of metering, auditing, billing, and budgeting methods, the present invention is able to efficiently, concurrently support multiple financial currencies (e.g. dollars, marks, yen) and content related budgets, and\/or billing increments as well as very flexible content distribution models.        support, complete, modular separation of the control structures related to (1) content event triggering, (2) auditing, (3) budgeting (including specifying no right of use or unlimited right of use), (4) billing, and (5) user identity (VDE installation, client name, department, network, and\/or user, etc.). The independence of these VDE control structures provides a flexible system which allows plural relationships between two or more of these structures, for example, the ability to associate a financial budget with different event trigger structures (that are put in place to enable controlling content based on its logical portions). Without such separation between these basic VDE capabilities, it would be more difficult to efficiently maintain separate metering, budgeting, identification, and\/or billing activities which involve the same, differing (including overlapping), or entirely different, portions of content for metering, billing, budgeting, and user identification, for example, paying fees associated with usage of content, performing home banking, managing advertising services, etc. VDE modular separation of these basic capabilities supports the programming of plural, \"arbitrary\" relationships between one or differing content portions (and\/or portion units) and budgeting, auditing, and\/or billing control information. For example, under VDE, a budget limit of $200 dollars or 300 German Marks a month may be enforced for decryption of a certain database and 2 U.S. Dollars or 3 German Marks may be charged for each record of said database decrypted (depending on user selected currency). Such usage can be metered while an additional audit for user profile purposes can be prepared recording the identity of each filed displayed. Additionally, further metering can be conducted regarding the number of said database bytes that have been decrypted, and a related security budget may prevent the decrypting of more than 5% of the total bytes of said database per year. The user may also, under VDE (if allowed by senior control information), collect audit information reflecting usage of database fields by different individuals and client organization departments and ensure that differing rights, of access and differing budgets limiting database usage can be applied to these client individuals and groups. Enabling content providers and users to practically employ such diverse sets of user identification, metering, budgeting, and billing control information results, in part, from the use of such independent control capabilities. As a result, VDE can support great configurability in creation of plural control models applied to the same electronic property and the same and\/or plural control models applied to differing or entirely different content models (for example, home banking versus electronic shopping).Methods, Other Control Information, and VDE Objects        \nVDE control information (e.g., methods) that collectively control use of VDE managed properties (database, document, individual commercial product), are either shipped with the content itself (for example, in a content container) and\/or one or more portions of such control information is shipped to distributors and\/or other users in separably deliverable \"administrative objects.\" A subset of the methods for a property may in part be delivered with each property while one or more other subsets of methods can be delivered separately to a user or otherwise made available for use (such as being available remotely by telecommunication means). Required methods (methods listed as required for property and\/or appliance use) must be available as specified if VDE controlled content (such as intellectual property distributed within a VDE content container) is to be used. Methods that control content may apply to a plurality of VDE container objects, such as a class or other grouping of such objects. Methods may also be required by certain users or classes of users and\/or VDE installations and\/or classes of installations for such parties to use one or more specific, or classes of, objects.\nA feature of VDE provided by the present invention is that certain one or more methods can be specified as required in order for a VDE installation and\/or user to be able to use certain and\/or all content. For example, a distributor of a certain type of content might be allowed by \"senior\" participants (by content creators, for example) to require a method which prohibits end-users from electronically saving decrypted content, a provider of credit for VDE transactions might require an audit method that records the time of an electronic purchase, and\/or a user might require a method that summarizes usage information for reporting to a clearinghouse (e.g. billing information) in a way that does not convey confidential, personal information regarding detailed usage behavior.\nA further feature of VDE provided by the present invention is that creators, distributors, and users of content can select from among a set of predefined methods (if available) to control container content usage and distribution functions and\/or they may have the right to provide new customized methods to control at least certain usage functions (such \"new\" methods may be required to be certified for trustedness and interoperability to the VDE installation and\/or for of a group of VDE applications). As a result, VDE provides a very high degree of configurability with respect to how the distribution and other usage of each property or object (or one or more portions of objects or properties as desired and\/or applicable) will be controlled. Each VDE participant in a VDE pathway of content control information may set methods for some or all of the content in a VDE container, so long as such control information does not conflict with senior control information already in place with respect to:                (1) certain or all VDE managed content,        (2) certain one or more VDE users and\/or groupings of users,        (3) certain one or more VDE nodes and\/or groupings of nodes, and\/or        (4) certain one or more VDE applications and\/or arrangements.        \nFor example, a content creator's VDE control information for certain content can take precedence over other submitted VDE participant control information and, for example, if allowed by senior control information, a content distributor's control information may itself take precedence over a client administrator's control information, which may take precedence over an end-user's control information. A path of distribution participant's ability to set such electronic content control information can be limited to certain control information (for example, method mediating data such as pricing and\/or sales dates) or it may be limited only to the extent that one or more of the participant's proposed control information conflicts with control information set by senior control information submitted previously by participants in a chain of handling of the property, or managed in said participant's VDE secure subsystem.\nVDE control information may, in part or in full, (a) represent control information directly put in place by VDE content control information pathway participants, and\/or (b) comprise control information put in place by such a participant on behalf of a party who does not directly handle electronic content (or electronic appliance) permissions records information (for example control information inserted by a participant on behalf of a financial clearinghouse or government agency). Such control information methods (and\/or load modules and\/or mediating data and\/or component assemblies) may also be put in place by either an electronic automated, or a semi-automated and human assisted, control information (control set) negotiating process that assesses whether the use of one or more pieces of submitted control information will be integrated into and\/or replace existing control information (and\/or chooses between alternative control information based upon interaction with in-place control information) and how such control information may be used.\nControl information may be provided by a party who does not directly participate in the handling of electronic content (and\/or appliance) and\/or control information for such content (and\/or appliance). Such control information may be provided in secure form using VDE installation secure sub-system managed communications (including, for example, authenticating the deliverer of at least in part encrypted control information) between such not directly participating one or more parties' VDE installation secure subsystems, and a pathway of VDE content control information participant's VDE installation secure subsystem. This control information may relate to, for example, the right to access credit supplied by a financial services provider, the enforcement of regulations or laws enacted by a government agency, or the requirements of a customer of VDE managed content usage information (reflecting usage of content by one or more parties other than such customer) relating to the creation, handling and\/or manner of reporting of usage information received by such customer. Such control information may, for example, enforce societal requirements such as laws related to electronic commerce.\nVDE content control information may apply differently to different pathway of content and\/or control information handling participants. Furthermore, permissions records rights may be added, altered, and\/or removed by a VDE participant if they are allowed to take such action. Rights of VDE participants may be defined in relation to specific parties and\/or categories of parties and\/or other groups of parties in a chain of handling of content and\/or content control information (e.g., permissions records). Modifications to control information that may be made by a given, eligible party or parties, may be limited in the number of modifications, and\/or degree of modification, they may make.\nAt least one secure subsystem in electronic appliances of creators, distributors, auditors, clearinghouses, client administrators, and end-users (understanding that two or more of the above classifications may describe a single user) provides a \"sufficiently\" secure (for the intended applications) environment for:                1. Decrypting properties and control information;        2. Storing control and metering related information;        3. Managing communications;        4. Processing core control programs, along with associated data, that constitute control information for electronic content and\/or appliance rights protection, including the enforcing of preferences and requirements of VDE participants.        \nNormally, most usage, audit, reporting, payment, and distribution control methods are themselves at least in part encrypted and are executed by the secure subsystem of a VDE installation. Thus, for example, billing and metering records can be securely generated and updated, and encryption and decryption keys are securely utilized, within a secure subsystem. Since VDE also employs secure (e.g. encrypted and authenticated) communications when passing information between the participant location (nodes) secure subsystems of a VDE arrangement, important components of a VDE electronic agreement can be reliably enforced with sufficient security (sufficiently trusted) for the intended commercial purposes. A VDE electronic agreement for a value chain can be composed, at least in part, of one or more subagreements between one or more subsets of the value chain participants. These subagreements are comprised of one or more electronic contract \"compliance\" elements (methods including associated parameter data) that ensure the protection of the rights of VDE participants.\nThe degree of trustedness of a VDE arrangement will be primarily based on whether hardware SPUs are employed at participant location secure subsystems and the effectiveness of the SPU hardware security architecture, software security techniques when an SPU is emulated in software, and the encryption algorithm(s) and keys that are employed for securing content, control information, communications, and access to VDE node (VDE installation) secure subsystems. Physical facility and user identity authentication security procedures may be used instead of hardware SPUs at certain nodes, such as at an established financial clearinghouse, where such procedures may provide sufficient security for trusted interoperability with a VDE arrangement employing hardware SPUs at user nodes.\nThe updating of property management files at each location of a VDE arrangement, to accommodate new or modified control information, is performed in the VDE secure subsystem and under the control of secure management file updating programs executed by the protected subsystem. Since all secure communications are at least in part encrypted and the processing inside the secure subsystem is concealed from outside observation and interference, the present invention ensures that content control information can be enforced. As a result, the creator and\/or distributor and\/or client administrator and\/or other contributor of secure control information for each property (for example, an end-user restricting the kind of audit information he or she will allow to be reported and\/or a financial clearinghouse establishing certain criteria for use of its credit for payment for use of distributed content) can be confident that their contributed and accepted control information will be enforced (within the security limitations of a given VDE security implementation design). This control information can determine, for example:                (1) How and\/or to whom electronic content can be provided, for example, how an electronic property can be distributed;        (2) How one or more objects and\/or properties, or portions of an object or property, can be directly used, such as decrypted, displayed, printed, etc;        (3) How payment for usage of such content and\/or content portions may or must be handled; and        (4) How audit information about usage information related to at least a portion of a property should be collected, reported, and\/or used.        \nSeniority of contributed control information, including resolution of conflicts between content control information submitted by multiple parties, is normally established by:                (1) the sequence in which control information is put in place by various parties (in place control information normally takes precedence over subsequently submitted control information),        (2) the specifics of VDE content and\/or appliance control information. For example, in-place control information can stipulate which subsequent one or more piece of control from one or more parties or class of parties will take precedence over control information submitted by one or more yet different parties and\/or classes of parties, and\/or        (3) negotiation between control information sets from plural parties, which negotiation establishes what control information shall constitute the resulting control information set for a given piece of VDE managed content and\/or VDE installation.Electronic Agreements and Rights Protection        \nAn important feature of VDE is that it can be used to assure the administration of, and adequacy of security and rights protection for, electronic agreements implemented through the use of the present invention. Such agreements may involve one or more of:                (1) creators, publishers, and other distributors, of electronic information,        (2) financial service (e.g. credit) providers,        (3) users of (other than financial service providers) information arising from content usage such as content specific demographic information and user specific descriptive information. Such users may include market analysts, marketing list compilers for direct and directed marketing, and government agencies,        (4) end users of content,        (5) infrastructure service and device providers such as telecommunication companies and hardware manufacturers (semiconductor and electronic appliance and\/or other computer system manufacturers) who receive compensation based upon the use of their services and\/or devices, and        (6) certain parties described by electronic information.        \nVDE supports commercially secure \"extended\" value chain electronic agreements. VDE can be configured to support the various underlying agreements between parties that comprise this extended agreement. These agreements can define important electronic commerce considerations including:                (1) security,        (2) content use control, including electronic distribution,        (3) privacy (regarding, for example, information concerning parties described by medical, credit, tax, personal, and\/or of other forms of confidential information),        (4) management of financial processes, and        (5) pathways of handling for electronic content, content and\/or appliance control information, electronic content and\/or appliance usage information and payment and\/or credit.        \nVDE agreements may define the electronic commerce relationship of two or more parties of a value chain, but such agreements may, at times, not directly obligate or otherwise directly involve other VDE value chain participants. For example, an electronic agreement between a content creator and a distributor may establish both the price to the distributor for a creator's content (such as for a property distributed in a VDE container object) and the number of copies of this object that this distributor may distribute to end-users over a given period of time. In a second agreement, a value chain end-user may be involved in a three party agreement in which the end-user agrees to certain requirements for using the distributed product such as accepting distributor charges for content use and agreeing to observe the copyright rights of the creator. A third agreement might exist between the distributor and a financial clearinghouse that allows the distributor to employ the clearinghouse's credit for payment for the product if the end-user has a separate (fourth) agreement directly with the clearinghouse extending credit to the end-user. A fifth, evolving agreement may develop between all value chain participants as content control information passes along its chain of handling. This evolving agreement can establish the rights of all parties to content usage information, including, for example, the nature of information to be received by each party and the pathway of handling of content usage information and related procedures. A sixth agreement in this example, may involve all parties to the agreement and establishes certain general assumptions, such as security techniques and degree of trustedness (for example, commercial integrity of the system may require each VDE installation secure subsystem to electronically warrant that their VDE node meets certain interoperability requirements). In the above example, these six agreements could comprise agreements of an extended agreement for this commercial value chain instance.\nVDE agreements support evolving (\"living\") electronic agreement arrangements that can be modified by current and\/or new participants through very simple to sophisticated \"negotiations\" between newly proposed content control information interacting with control information already in place and\/or by negotiation between concurrently proposed content control information submitted by a plurality of parties. A given model may be asynchronously and progressively modified over time in accordance with existing senior rules and such modification may be applied to all, to classes of, and\/or to specific content, and\/or to classes and\/or specific users and\/or user nodes. A given piece of content may be subject to different control information at different times or places of handling, depending on the evolution of its content control information (and\/or on differing, applicable VDE installation content control information). The evolution of control information can occur during the passing along of one or more VDE control information containing objects, that is control information may be modified at one or more points along a chain of control information handling, so long as such modification is allowed. As a result, VDE managed content may have different control information applied at both different \"locations\" in a chain of content handling and at similar locations in differing chains of the handling of such content. Such different application of control information may also result from content control information specifying that a certain party or group of parties shall be subject to content control information that differs from another party or group of parties. For example, content control information for a given piece of content may be stipulated as senior information and therefore not changeable, might be put in place by a content creator and might stipulate that national distributors of a given piece of their content may be permitted to make 100,000 copies per calendar quarter, so long as such copies are provided to boni fide end-users, but may pass only a single copy of such content to a local retailers and the control information limits such a retailer to making no more than 1,000 copies per month for retail sales to end-users. In addition, for example, an end-user of such content might be limited by the same content control information to making three copies of such content, one for each of three different computers he or she uses (one desktop computer at work, one for a desktop computer at home, and one for a portable computer).\nElectronic agreements supported by the preferred embodiment of the present invention can vary from very simple to very elaborate. They can support widely diverse information management models that provide for electronic information security, usage administration, and communication and may support:                (a) secure electronic distribution of information, for example commercial literary properties,        (b) secure electronic information usage monitoring and reporting,        (c) secure financial transaction capabilities related to both electronic information and\/or appliance usage and other electronic credit and\/or currency usage and administration capabilities,        (d) privacy protection for usage information a user does not wish to release, and        (e) \"living\" electronic information content dissemination models that flexibly accommodate:        (1) a breadth of participants,        (2) one or more pathways (chains) for: the handling of content, content and\/or appliance control information, reporting of content and\/or appliance usage related information, and\/or payment,        (3) supporting an evolution of terms and conditions incorporated into content control information, including use of electronic negotiation capabilities,        (4) support the combination of multiple pieces of content to form new content aggregations, and        (5) multiple concurrent models.Secure Processing Units        \nAn important part of VDE provided by the present invention is the core secure transaction control arrangement, herein called an SPU (or SPUs), that typically must be present in each user's computer, other electronic appliance, or network. SPUs provide a trusted environment for generating decryption keys, encrypting and decrypting information, managing the secure communication of keys and other information between electronic appliances (i.e. between VDE installations and\/or between plural VDE instances within a single VDE installation), securely accumulating and managing audit trail, reporting, and budget information in secure and\/or non-secure non-volatile memory, maintaining a secure database of control information management instructions, and providing a secure environment for performing certain other control and administrative functions.\nA hardware SPU (rather than a software emulation) within a VDE node is necessary if a highly trusted environment for performing certain VDE activities is required. Such a trusted environment may be created through the use of certain control software, one or more tamper resistant hardware modules such as a semiconductor or semiconductor chipset (including, for example, a tamper resistant hardware electronic appliance peripheral device), for use within, and\/or operatively connected to, an electronic appliance. With the present invention, the trustedness of a hardware SPU can be enhanced by enclosing some or all of its hardware elements within tamper resistant packaging and\/or by employing other tamper resisting techniques (e.g. microfusing and\/or thin wire detection techniques). A trusted environment of the present invention implemented, in part, through the use of tamper resistant semiconductor design, contains control logic, such as a microprocessor, that securely executes VDE processes.\nA VDE node's hardware SPU is a core component of a VDE secure subsystem and may employ some or all of an electronic appliance's primary control logic, such as a microcontroller, microcomputer or other CPU arrangement. This primary control logic may be otherwise employed for non VDE purposes such as the control of some or all of an electronic appliance's non-VDE functions. When operating in a hardware SPU mode, said primary control logic must be sufficiently secure so as to protect and conceal important VDE processes. For example, a hardware SPU may employ a host electronic appliance microcomputer operating in protected mode while performing VDE related activities, thus allowing portions of VDE processes to execute with a certain degree of security. This alternate embodiment is in contrast to the preferred embodiment wherein a trusted environment is created using a combination of one or more tamper resistant semiconductors that are not part of said primary control logic. In either embodiment, certain control information (software and parameter data) must be securely maintained within the SPU, and further control information can be stored externally and securely (e.g. in encrypted and tagged form) and loaded into said hardware SPU when needed. In many cases, and in particular with microcomputers, the preferred embodiment approach of employing special purpose secure hardware for executing said VDE processes, rather than using said primary control logic, may be more secure and efficient. The level of security and tamper resistance required for trusted SPU hardware processes depends on the commercial requirements of particular markets or market niches, and may vary widely.","meta":{"bibliographic_information":{"country":"US","doc-number":"12780702","kind":"B2","date":"20100514","invention_title":"Systems and methods for secure transaction management and electronic rights protection"},"source_file":"https:\/\/bulkdata.uspto.gov\/data\/patent\/grant\/redbook\/fulltext\/2013\/ipg131029.zip","abstract":["The present invention provides systems and methods for secure transaction management and electronic rights protection. Electronic appliances such as computers equipped in accordance with the present invention help to ensure that information is accessed and used only in authorized ways, and maintain the integrity, availability, and\/or confidentiality of the information. Such electronic appliances provide a distributed virtual distribution environment (VDE) that may enforce a secure chain of handling and control, for example, to control and\/or meter or otherwise monitor use of electronically stored or disseminated information. Such a virtual distribution environment may be used to protect rights of various participants in electronic commerce and other electronic or electronic-facilitated transactions. Distributed and other operating systems, environments and architectures, such as, for example, those using tamper-resistant hardware-based processors, may establish security at each node. These techniques may be used to support an all-electronic information distribution, for example, utilizing the \u201celectronic highway.\u201d"],"citations":[{"country":"US","doc-number":"3790700","kind":"A","name":"Callais et al.","date":"19740200","category":"cited by applicant"},{"country":"US","doc-number":"4162483","kind":"A","name":"Entenman","date":"19790700","category":"cited by applicant"},{"country":"US","doc-number":"4254483","kind":"A","name":"Vidovic","date":"19810300","category":"cited by applicant"},{"country":"US","doc-number":"4310720","kind":"A","name":"Check","date":"19820100","category":"cited by applicant"},{"country":"US","doc-number":"4393269","kind":"A","name":"Konheim et al.","date":"19830700","category":"cited by applicant"},{"country":"US","doc-number":"4558413","kind":"A","name":"Schmidt et al.","date":"19851200","category":"cited by applicant"},{"country":"US","doc-number":"4658093","kind":"A","name":"Hellman","date":"19870400","category":"cited by 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{"text":"Multiple component polymer compositions for fabrication into articles. In particular, polymeric compositions comprising a heat resistant polymer; a radio frequency (xe2x80x9cRFxe2x80x9d) susceptible polymer; and a compatibilizing polymer.\n\n1. Technical Field\nThe present invention relates generally to thermoplastic polymer alloys for fabricating into films, containers, tubing, and other devices.\n2. Background Prior Art\nIn the medical field, where beneficial agents are collected, processed and stored in containers, transported, and ultimately delivered through tubes by infusion to patients to achieve therapeutic effects, materials which are used to fabricate the containers and tubes must have a unique combination of properties. For example, in order to visually inspect solutions for particulate contaminants, the container or tubing must be optically transparent. To infuse a solution from a container by collapsing the container walls, without introducing air into the container, the material which forms the walls must be sufficiently flexible. The material must be functional over a wide range of temperatures. The material must function at low temperatures by maintaining its flexibility and toughness because some solutions, for example, certain premixed drug solutions are stored and transported in containers at temperatures such as xe2x88x9225 to xe2x88x9230xc2x0 C. to minimize the drug degradation. The material must also be functional at high temperatures to withstand the heat of sterilization; a process which most medical packages and nutritional products are subjected to prior to shipment. The sterilization process usually includes exposing the container to steam at temperatures typically 121xc2x0 C. and at elevated pressures. Thus, the material needs to withstand the temperature and pressures without significant distortions (xe2x80x9cheat distortion resistancexe2x80x9d).\nFor ease of manufacture into useful articles, it is desirable that the material be sealable using radio frequency (xe2x80x9cRFxe2x80x9d) generally at about 27.12 MHz. Therefore, the material should possess sufficient dielectric loss properties to convert the RF energy to thermal energy.\nA further requirement is to minimize the environmental impact upon the disposal of the article fabricated from the material after its intended use. For those articles that are disposed of in landfills, it is desirable to use as little material as possible and avoid the incorporation of low molecular weight leachable components to construct the article. Thus, the material should be light weight and have good mechanical strength. Further benefits are realized by using a material which may be recycled by thermoplastically reprocessing the post-consumer article into other useful articles.\nFor those containers which are disposed of through incineration, it is necessary to use a material which helps to eliminate the dangers of biological hazards, and to minimize or eliminate entirely the formation of inorganic acids which are environmentally harmful, irritating, and corrosive, or other products which are harmful, irritating, or otherwise objectionable upon incineration.\nIt is also desirable that the material be free from or have a low content of low molecular weight additives such as plasticizers, stabilizers and the like which could be released into the medications or biological fluids or tissues thereby causing danger to patients using such devices or are contaminating such substances being stored or processed in such devices. For containers which hold solutions for transfusion, such contamination could make its way into the transfusion pathway and into the patient causing injury or death to the patient.\nTraditional flexible polyvinyl chloride materials meets a number of, and in some cases, most of the above-mentioned requirements. Polyvinyl chloride (xe2x80x9cPVCxe2x80x9d) also offers the distinct advantage of being one of the most cost effective materials for constructing devices which meet the above requirements. However, PVC may generate objectionable amounts of hydrogen chloride (or hydrochloric acid when contacted with water) upon incineration, causing corrosion of the incinerator. PVC sometimes contains plasticizers which may leach into drugs or biological fluids or tissues that come in contact with PVC formulations. Thus, many materials have been devised to replace PVC. However, most alternate materials are too expensive to implement and still do not meet all of the above requirements.\nThere have been many attempts to develop a film material to replace PVC, but most attempts have been unsuccessful for one reason or another. For example, in U.S. Pat. No. 4,966,795 which discloses multi-layer film compositions capable of withstanding the steam sterilization, cannot be welded by radio frequency dielectric heating thus cannot be assembled by this rapid, low costs, reliable and practical process. European Application No. EP 0 310 143 A1 discloses multilayer films that meet most of the requirements, and can be RF welded. However, components of the disclosed film are cross-linked by radiation and, therefore, cannot be recycled by the standard thermoplastic processing methods. In addition, due to the irradiation step, appreciable amounts of acetic acid is liberated and trapped in the material. Upon steam sterilization, the acetic acid migrates into the packaging contents as a contaminant and by altering the pH of the contents acts as a potential chemical reactant to the contents or as a catalyst to the degradation of the contents.\nThe main objective of the present invention is the creation of thermoplastic materials which are, overall, superior to those materials, of which we are aware, which have been heretofore known to the art or have been commercially used or marketed. The properties of such materials includes flexibility, extensibility, and strain recoverability, not just at room temperatures, but through a wide range of ambient and refrigerated temperatures. The material should be sufficiently optically transparent for visual inspection, and steam sterilizable at temperatures up to 121xc2x0 C. The material should be capable of being subjected to significant strains without exhibiting strain whitening, which can indicate a physical and a cosmetic defect. A further objective is that the material be capable of assembly by the RF methods. Another objective is that the material be without low molecular weight leachable additives, and be capable of safe disposal by incineration without the generation of significant amounts of corrosive inorganic acids. Another objective is that the material be recyclable by standard thermoplastic processing methods after use. It is also desirable that the material incorporate reground scrap material recovered during the manufacturing process to save material costs. Finally, the material should serve as a cost effective alternative to various PVC formulations currently being used for medical devices.\nWhen more than one polymer is blended to form an alloying composition, it is difficult to achieve all of the above objectives simultaneously. For example, in most instances alloy composition scatter light; thus, they fail to meet the optical clarity objective. The light scattering intensity (measured by haze) depends on the domain size of components in the micrometer (xcexc) range, and the proximity of the refractive indices of the components. As a general rule, the selection of components that can be satisfactorily processed into very small domain sizes, and yet with a minimum of refractive index mismatches, is a difficult task.\nThe present invention is provided to solve these and other problems.\nIn accordance with the present invention certain thermoplastic polymer compositions have been developed which are substantial improvements to compositions and articles of which we are aware. These compositions may be fabricated into medical grade articles such as bags for storing medical solutions or tubings for conveying medical fluids or may be used to make other products or components of finished products such as connectors, adaptors, manifolds, valves, conduits, catheters, and etc.\nIt is an object of the present invention to prepare a composition having the following physical properties: (1) a mechanical modulus less than 40,000 psi and more preferably less than 25,000 when measured in accordance with ASTM D-882, (2) a greater than or equal to 70%, and more preferably greater than or equal to 75%, recovery in length after an initial deformation of 20%, (3) and optical haze of less than 30%, and more preferably less than 15%, when measured for a composition 9 mils thick and in accordance to ASTM D-1003, (4) the loss tangent measured at 1 Hz at processing temperatures is greater than 1.0, and more preferably greater than 2.0, (5) the content of elemental halogens is less than 0.1%, and more preferably less than 0.01%, (6) the low molecular weight water soluble fraction is less than 0.1%, and more preferably less than 0.005%, (7) the maximum dielectric loss between 1 and 60 MHz and between the temperature range of 25-250xc2x0 C. is greater than or equal to 0.05 and more preferably greater than or equal to 0.1, (8) autoclave resistance measured by sample creep at 121xc2x0 C. under 27 psi loading is less than or equal to 60% and more preferably less than or equal to 20%, and (9) there is no strain whitening after being strained at moderate speeds of about 20 inches (50 cm) per minute at about 100% elongation and the presence of strain whitening is noted or the lack thereof.\nThe polymer based compositions of the present invention that satisfy these physical properties comprise multiple component compositions. Three component compositions consists of a first component of a flexible polyolefin that confers heat resistance and flexibility, a second component of a RF susceptible polymer that renders the film RF sealable, and a third component that confers compatibility between the first two components. The RF susceptible polymers of the present invention, which will be set forth in detail below, should have a dielectric loss of greater than 0.05 at frequencies within the range of 1-60 MHz within a temperature range of ambient to 250xc2x0 C. The first component should constitute within a range of 40-90% by weight of the composition, the second component should constitute within the range of 5-50% by weight of the composition, and the third component should constitute 5-30% by weight of the composition.\nIn another embodiment of the three component composition, the first component confers high temperature resistance, the second component is an RF susceptible polymer that renders the composition RF sealable and confers flexibility to the film, and the third component serves as a compatabilizer between the first two components. The first component should constitute within the range of 30-60%, the second component 30-60%, and the third component 5-30% by weight of the composition.\nFour component compositions include a first propylene based polyolefin, which may include isotactic and syndiotactic stereo isomers, a second non-propylene based polyolefin, a third component of a RF susceptible polymer that renders the compositions RF sealable, and a compatibilizing polymer. Preferably the first polyolefin is polypropylene which constitutes approximately 30-60% by weight of the compositions, and most preferably 45%. The second polyolefin is preferably an ultra low density polyethylene or polybutene-1 which constitute approximately 25-50% by weight of the compositions, and most preferably 45%. The RF component is preferably a dimer fatty acid polyamide (which should be interpreted to include their hydrogenated derivatives as well), which constitutes approximately 3-40% by weight of the compositions, and most preferably 10%. The fourth component is a compatibilizing polymer that may be selected from various block copolymers of styrene with dienes or alpha olefins; the compatibilizing polymers may be modified with minor amounts of chemically active functionalities. For example, the compatibilizing polymer may be a styrene ethylene-butene styrene (xe2x80x9cSEBSxe2x80x9d) block copolymers. The fourth component should constitute between 5-40% by weight of the composition and most preferably 10%.\nThese three and four component compositions each may be compounded and extruded to form a thin film which is RF active so that it is RF sealable to itself. For example, films and tubings may be used to produce sterile fluid packages, containers for blood and blood components, intravenous and medical solutions, nutritional and respiratory therapy products, as well as dialysis solutions. The compositions may also be used to construct port tubes and access devices for containers. The compositions may also be used to form other products through injection molding, blow molding, thermoforming, or other known thermoplastically processing methods.\nThe compositions are compatible with medical applications because the components which constitute the film have a minimal extractability to the fluids and contents that the composition come in contact with. Further, the films are environmentally sound in that they do not generate harmful degradants upon incineration. Finally, the films provide a cost effective alternative to PVC.\nAdditional features and advantages of the present invention are described in, and will be apparent from the detailed description of the presently preferred embodiments.\nWhile this invention is susceptible of embodiments in many different forms, and will herein be described in detail, preferred embodiments of the invention are disclosed with the understanding that the present disclosure is to be considered as exemplifications of the principles of the invention and are not intended to limit the broad aspects of the invention to the embodiments illustrated.\nMore particularly, according to the present invention it is desirable to provide compositions which may be thermoplastically fabricated into articles, devices, and products, which meet the requirements set forth above.\nTo this end, as noted above, it has been found that material having these characteristics can be prepared from compositions having preferably three, four or more components. The three and four component compositions will be discussed separately below.\nIn a first embodiment of a three component system, the first component will confer heat resistance and flexibility to the composition. This component may be chosen from the group consisting of amorphously polyalpha olefins and preferably is a flexible polyolefin. These polyolefins should resist distortions to high temperatures up to 121xc2x0 C., having a peak melting point of greater than 130xc2x0 C. and be highly flexible, having a modulus of not more than 20,000 psi. Such a flexible polyolefin is sold under the product designation Rexene FPO 90007 which has a peak melting point of 145xc2x0 C. and a modulus of 11,000 psi. In addition, certain polypropylenes with high syndiotacticity also posses the properties of high melting point and low modulus. The first component-should constitute by weight within the range of 40-90% by weight of the composition.\nThe second component of the three component composition is an RF susceptible polymer which confers RF sealability to the composition and may be selected from either of two groups of polar polymers. The first group consists of ethylene copolymers having 50-85% ethylene content with comonomers selected from the group consisting of acrylic acid, methacrylic acid, ester derivatives of acrylic acid with alcohols having 1-10 carbons, ester derivatives of methacrylic acid with alcohols having 1-10 carbons, vinyl acetate, and vinyl alcohol. The-RF susceptible polymer may also be selected from a second group consisting of copolymers containing segments of polyurethane, polyester, polyurea, polyimide, polysulfones, and polyamides. These functionalities may constitute between 5-100% of the RF susceptible polymer. The RF susceptible polymer should constitute by weight within the range of 5-50% of the composition. Preferably, the RF component is copolymers of ethylene methyl acrylate with methyl acrylate within the range of 15-25% by weight of the polymer.\nThe final component of the three component compound ensures compatibility between-the first two components, and is selected from-an styrenic block copolymers and preferably is maleic anhydride functionalized. The third component should constitute by weight within the range of 5-30% of the composition.\nIn a second embodiment of the three component film, the first component confers RF sealability and flexibility over the desired temperature range. The first component confers high temperature resistance (xe2x80x9ctemperature resistant polymerxe2x80x9d) and is chosen from the group consisting of polyamides polyimides, polyurethanes, polypropylene and polymethylpentene. Preferably the first component constitutes by weight within the range of 30-60% of the composition, and preferably is polypropylene. The second component confers RF sealability and flexibility over the desired temperature range. The RF polymer is selected from the first and second groups identified above with the exception of ethylene vinyl alcohol. The second component should constitute by weight within the range of 30-60% of the composition.\nThe third component ensures compatibility between the first two components and is chosen from SEBS block copolymers and preferably is maleic anhydride functionalized. The third component should constitute within the range of 5-30% by weight of the composition.\nThe first component of the four component film is to confer heat resistance. This component may be chosen from polyolefins, most preferably polypropylenes, and more specifically the propylene alpha-olefin random copolymers (PPE). Preferably, the PPE\"\"s will have a narrow molecular weight range. The PPE\"\"s possess the required rigidity and the resistance to yielding at the autoclave temperatures of about 121xc2x0 C. However, by themselves, the PPE\"\"s are too rigid to meet the flexibility requirements. When combined by alloying with certain low modulus polymers, good flexibility can be achieved. Examples of acceptable PPE\"\"s include those sold under the product designations Soltex 4208, and Exxon Escorene PD9272.\nThese low modulus copolymers can include ethylene based copolymers such as ethylene-co-vinyl acetate (xe2x80x9cEVAxe2x80x9d), ethylene coalpha olefins, or the so-called ultra low density (typically less than 0.90 Kg\/L) polyethylenes (xe2x80x9cULDPExe2x80x9d). These ULDPE include those commercially available products sold under the trademarks TAFMER(copyright) (Mitsui Petrochemical Co.) under the product designation A485, Exact(copyright) (Exxon Chemical Company) under the product designations 4023-4024, and Insite (copyright) technology polymers (Dow Chemical Co.). In addition, poly butene-1 (xe2x80x9cPBxe2x80x9d), such as those sold by Shell Chemical Company under product designations PB-8010, PB-8310; thermoplastic elastomers based on SEBS block copolymers, (Shell Chemical Company), poly isobutene (xe2x80x9cPIBxe2x80x9d) under the product designations Vistanex L-80, L-100, L-120, L-140 (Exxon Chemical Company), ethylene alkyl acrylate, the methyl acrylate copolymers (xe2x80x9cEMAxe2x80x9d) such as those under the product designation EMAC 2707, and DS-1130 (Chevron), and n-butyl acrylates (xe2x80x9cENBAxe2x80x9d) (Quantum Chemical) were found to be acceptable copolymers. Ethylene copolymers such as the acrylic and methacrylic acid copolymers and their partially neutralized salts and ionomers, such as PRIMACOR(copyright) (Dow Chemical Company) and SURYLN(copyright) (E.I. DuPont de Nemours and Company) were also satisfactory. Typically, ethylene based copolymers have melting points of less than about 110xc2x0 C. are not suited for autoclaving applications. Further, as will be shown in certain of the below counter examples (eg., Example 8G), not all the alloying pairs are optically clear to qualify for the visual inspection requirement. Furthermore, only a limited range of proportions of each component allows the simultaneous fulfillment of the flexibility and autoclavability requirements.\nPreferably the-first component is chosen from the group of polypropylene homo and random copolymers with alpha olefins which constitute by weight approximately 30-60%, more preferably 35-45%, and most preferably 45%, of the composition. For example, random copolymers of propylene with ethylene where the ethylene content is in an amount within the range of 0-6%, and more preferably 2-4%, of the weight of the polymer is preferred as the first component.\nThe second component of the four component composition confers flexibility and low temperature ductility and is a second polyolefin different than that of the first component wherein it contains no propylene repeating units (xe2x80x9cnon propylene based polyolefinxe2x80x9d). Preferably it is ethylene copolymers including ULDPE, polybutene, butene ethylene copolymers, ethylene vinyl acetate, copolymers with vinyl acetate contents between approximately 18-50%, ethylene methyl acrylate copolymers with methyl acrylate contents being between approximately 20-40%, ethylene n-butyl acrylate copolymers with n-butyl acrylate content of between 20-40%, ethylene acrylic acid copolymers with the acrylic acid content of greater than approximately 15%. An example of these products are sold under such product designations as Tafmer A-4085 (Mitsui), EMAC DS-1130 (Chevron), Exact 4023, 4024 and 4028 (Exxon). More preferably, the second component is either ULDPE sold by Mitsui Petrochemical Company under the designation TAFMER A-4085, or polybutene-1, PB8010 and PB8310 (Shell Chemical Co.), and should constitute by weight approximately 25-50%, more preferably 35-45%, and most preferably 45%, of the composition.\nTo impart RF dielectric loss to the four component composition, certain known high dielectric loss ingredients (xe2x80x9cRF susceptible polymersxe2x80x9d) are included in the composition. These polymers may be selected from the group of RF polymers in the first and second group set forth above.\nOther RF active materials include PVC, vinylidine chlorides, and fluorides, copolymer of bis-phenol-A and epichlorohydrines known as PHENOXYS(copyright) (Union Carbide). However, significant contents of these chlorine and fluorine containing polymers would render the composition environmentally unsound as incineration of such a material would generate inorganic acids.\nThe polyamides of the RF susceptible polymer are preferably selected from aliphatic polyamides resulting from the condensation reaction of di-amines having a carbon number within a range of 2-13, aliphatic polyamides resulting from a condensation reaction of diacids having a carbon number within a range of 2-13, polyamides resulting from the condensation reaction of dimer fatty acids, and amides containing copolymers (random, block, and graft). Polyamides such as nylons are widely used in thin film material because they offer abrasion resistance to the film. However, rarely are the nylons found in the layer which contacts medical solutions as they typically contaminate the solution by leaching out into the solution. However, it has been found by the Applicants of the present invention that the most preferred RF susceptible polymer are a variety of dimer fatty acid polyamides sold by Henkel Corporation under the product designations MACROMELT and VERSAMID, which do not lead to such contamination. The RF susceptible polymer preferably should constitute by weight approximately 5-30%, more preferably between 7-13%, and most preferably 10%, of the composition.\nThe fourth component of the composition confers compatibility between the polar and nonpolar components of the composition (sometimes referred to as a xe2x80x9ccompatibilizing polymerxe2x80x9d) and preferably is styrenic block copolymers with hydrocarbon soft segments. More preferably, the fourth component was chosen from SEBS block copolymers that are modified by maleic anhydride, epoxy, or carboxylate functionalities, and preferably is an SEBS block copolymer that contains maleic anhydride functional groups (xe2x80x9cfunctionalizedxe2x80x9d). Such a product is sold by Shell Chemical,Company under the designation KRATON RP-6509. The compatibilizing polymer should constitute by weight approximately 5-40%, more preferably 7-13%, and most preferably 10% of the composition.\nIt may also desirable to add a fifth component of a nonfunctionalized SEBS block copolymer such as the ones sold by Shell Chemical Company under the product designations KRATON G-1652 and G-1657. The fifth component should constitute by weight approximately 5-40%, more preferably 7-13%, and most of the composition.\nFor each of the compositions set forth above, it may be desirable to add, in trace amounts, other additives such as slip agents, lubricants, waxes, and antiblocks as is needed and as is well known in the art as long as the final composition meets the physical requirements set forth above.\nThe above multiple component compositions may be processed to make a variety of porducts such as a film. Such film may be made using several techniques well known in the industry. For example, the above components may be blended in the dry form in a high intensity blender such as a Welex blender and fed into an extruder. The components may also be gravimetrically fed into a high intensity mixing extruder of the twin screw design, such as a Werner Pfleiderer, and the output may be quenched in multiple strands in a water bath, pelletized, and dried for use. The pelletizing step may be avoided in a third method by feeding the output of the compounding extruder directly into a film extruder. It is also possible to build into a film extruder a high intensity mixing section so that an alloy film may be produced using a single extruder. The alloy may be converted into other articles and shapes using other thermoplastic converting machines such as injection molding or injection blow molding machines. Of course there are many other known methods of processing alloys into film, and the present invention should not be limited to producing a film by these exemplary methods.\nCompositions having a various components and weight percentages set forth in the below examples were fabricated into films and tested using the following methods.\nAutoclave resistance is measured by sample creep, or the increase in the sample length, at 121xc2x0 C. under 27 psi loading for one hour. The autoclave resistance must be less than or equal to 60%.\n(A) Low Temperature Ductility\nIn an instrumented impact tester fitted with a low temperature environmental chamber cooled with liquid nitrogen, film samples about 7 by 7 inches (18 cm by 18 cm) are mounted onto circular sample holders about 6 inches (15 cm) in diameter. A semi-spherical impact head with stress sensors is driven at high velocities (typically about 3 m\/sec) into the preconditioned film loading it at the center. The stress-displacement curves are plotted, and the energy of impact is calculated by integration. The temperature at which the impact energy rises dramatically, and when the fractured specimen changes from brittle to ductile, high strain morphology is taken as a measure of the low temperature performance of the film (xe2x80x9cL.Tempxe2x80x9d).\n(B) Mechanical Modulus and Recovery:\nThe autoclaved film sample with a known geometry is mounted on a servohydraulically driven mechanical tester having cross heads to elongate the sample. At 10 inches (25 cm) per minute crosshead speed, the sample is elongated to about 20% elongation. At this point, the cross-heads travel and then reverse to travel in a direction opposite that originally used to stretch the sample. The stress strain behavior is recorded on a digital recorder. The elastic modulus (xe2x80x9cE(Kpsi)xe2x80x9d) is taken from the initial slope on the stress-strain curve, and the recovery taken from the excess sample dimension as a percentage of sample elongation.\nConnected to a Callanan 27.12 MHz, 2 KW Radio Frequency generator, is a rectangular brass die of about 0.25 (6.3 mm) by 4 inches (10 cm) opposing to a flat brass electrode, also connected to the generator. Upon closing the die with two sheets of the candidate material in between, RF power of different amplitudes and durations are applied. When the RF cycle is over, the die is opened and the resultant seal examined by manually pulling apart the two sheets. The strength of the seal (versus the film strength) and the mode of failure (peel, tear, or cohesive failures) are used to rate the RF responsiveness of the material.\nAlternatively, the candidate film is first sputter coated with gold or palladium to a thickness of 100 angstroms to render the surface conductive, cut into a circular geometry and mounted between the parallel electrodes in a dielectric capacitance measuring cell. Using a Hewlett Packard 4092 automatic RF bridge, the dielectric constant and the dielectric losses are measured at different frequencies up to 10 MHz and temperatures up to 150xc2x0 C. The dielectric loss allows the calculation of heat generation under an RF field. From calculations or correlations with RF seal experiments the minimum dielectric loss for performance is obtained.\nIf the RF seal performance is obtained from the Callanan sealer, the following ranking scale is adopted:\nPost autoclaved film samples are first cut into about 2 by 2 inches (5 by 5 cms) squares, mounted on a Hunter Colorimeter and their internal haze measured according to ASTM D-1003. Typically, internal haze level of less than 30% is required, preferably less than 20% for these thicknesses (xe2x80x9cHaze %xe2x80x9d).\nThe autoclaved film is strained at moderate speeds of about 20 inches (50 cm) per minute to about 100% elongation (twice the original length) and the presence (indicated by 1) of strain whitening or lack thereof (indicated by 0) is noted (xe2x80x9cS.Whiteningxe2x80x9d).\nThe environmental compatibility comprises three important properties: (a) the material is free of low molecular weight plasticizers which could leach into landfills upon disposal, (2) the material can be thermoplastically recycled into useful items upon fulfilling the primary purpose of medical delivery, and (3) when disposed of by energy reclaim by incineration, no significant inorganic acids are released to harm the environment. (xe2x80x9cEnvir.xe2x80x9d). The composition will also contain less than 0.1% halogens by weight. In order to facilitate recycling by melt processing, the resultant composition should have a loss tangent greater than 1.0 at 1 Hz measured at processing temperatures.\nBy solution compatibility we mean that a solution contained within the film is not contaminated by components which constitute the composition. (xe2x80x9cS.Comp.xe2x80x9d) The low molecular weight water soluble fraction of the composition will be less than 0.1%.\nThe following combinations were tested using the above test for three and four component co-positions. The examples demonstrate certain unexpected advantages obtained with these compositions.","meta":{"bibliographic_information":{"document_kind":"B1","document_number":"06399704","document_date":"20020604","publishing_country_or_organization":"US","title_of_invention":"Polymeric compositions for medical packaging and devices"},"source_file":"https:\/\/bulkdata.uspto.gov\/data\/patent\/grant\/redbook\/fulltext\/2002\/pg020604.zip","abstract":["Multiple component polymer compositions for fabrication into articles. In particular, polymeric compositions comprising a heat resistant polymer; a radio frequency (xe2x80x9cRFxe2x80x9d) susceptible polymer; and a compatibilizing polymer."],"citations":[{"DNUM":"2705223","DATE":"19550300","KIND":"A","CITING_PARTY":"other","US_PARTY_NAME":"Renfrew et al.","PNC":"260 18"},{"DNUM":"3255923","DATE":"19660600","KIND":"A","CITING_PARTY":"other","US_PARTY_NAME":"Soto","PNC":"222 80"},{"DNUM":"3375300","DATE":"19680300","KIND":"A","CITING_PARTY":"other","US_PARTY_NAME":"Ropp","PNC":"260857"},{"DNUM":"3772136","DATE":"19731100","KIND":"A","CITING_PARTY":"other","US_PARTY_NAME":"Workman","PNC":"161169"},{"DNUM":"3912843","DATE":"19751000","KIND":"A","CITING_PARTY":"other","US_PARTY_NAME":"Brazier","PNC":"428474"},{"DNUM":"3937758","DATE":"19760200","KIND":"A","CITING_PARTY":"other","US_PARTY_NAME":"Castagna","PNC":"260876"},{"DNUM":"3995084","DATE":"19761100","KIND":"A","CITING_PARTY":"other","US_PARTY_NAME":"Berger et al.","PNC":"428 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{"text":"This invention comprises manufacture of photovoltaic cells by deposition of thin film photovoltaic junctions on metal foil substrates. The photovoltaic junctions may be heat treated if appropriate following deposition in a continuous fashion without deterioration of the metal support structure. In a separate operation, an interconnection substrate structure is provided, optionally in a continuous fashion. Multiple photovoltaic cells are then laminated to the interconnection substrate structure and conductive joining methods are employed to complete the array. In this way the interconnection substrate structure can be uniquely formulated from polymer-based materials employing optimal processing unique to polymeric materials. Furthermore, the photovoltaic junction and its metal foil support can be produced in bulk without the need to use the expensive and intricate material removal operations currently taught in the art to achieve series interconnections.\n\nPhotovoltaic cells have developed according to two distinct methods. A first form produces cells employing a matrix of crystalline silicon appropriately doped to produce a planar p-n junction. An intrinsic electric field established at the p-n junction produces a voltage by directing solar photon produced holes and free electrons in opposite directions. Good conversion efficiencies and long-term reliability have been demonstrated for crystalline silicon cells. However, widespread energy collection using crystalline silicon cells is thwarted by the high cost of crystal silicon (especially single crystal silicon) material and interconnection processing.\nA second approach to produce photovoltaic cells is by depositing thin photovoltaic semiconductor films on a supporting substrate. Many various techniques have been proposed for deposition of semiconductor thin films. The deposition methods include vacuum vapor deposition, vacuum sputtering, electroplating, chemical vapor deposition and printing of nanoparticle inks. These structures have become know in the art as \"thin film\" devices. Material requirements are minimized and technologies can be proposed for mass production. Typical semiconductors used for thin film photovoltaic devices include cuprous sulfide, cadmium telluride (CdTe), copper-indium-gallium-diselenide (CIGS), amorphous silicon, printed silicon, and dye sensitized polymeric materials. The thin film structures can be designed according to doped homojunction technology or can employ heterojunction approaches such as those using CdTe or chalcopyrite materials.\nDespite significant improvements in individual cell conversion efficiencies for both single crystal and thin film approaches, photovoltaic energy collection has been generally restricted to applications having relatively low power requirements. One factor impeding development of bulk power systems is the problem of economically collecting the energy from an extensive collection surface. Photovoltaic cells can be described as high current, low voltage devices. Typically individual cell voltage is less than about two volts, and often less than 0.6 volt. The current component is a substantial characteristic of the power generated. Efficient energy collection from an expansive surface must minimize resistive losses associated with the high current characteristic. A way to minimize resistive losses is to reduce the size of individual cells and connect them in series. Thus, voltage is stepped through each cell while current and associated resistive losses are minimized.\nRegardless of whether the cells are crystalline silicon or thin film, making effective, durable series connections among multiple small cells can be laborious, difficult and expensive. In order to approach economical mass production of series connected arrays of individual cells, a number of factors must be considered in addition to the type of photovoltaic materials chosen. These include the substrate employed and the process envisioned. A first problem which has confronted production of expansive surface photovoltaic modules is that of collecting the photogenerated current from the top, light incident surface. Transparent conductive oxide (TCO) layers are normally employed to form a top surface. However, these TCO layers are relatively resistive compared to pure metals. Thus, efforts must be made to minimize resistive losses in transport of current through the TCO layer. One approach is simply to reduce the surface area of individual cells to a manageable amount. However, as cell widths decrease, the width of the area between individual cells (interconnect area) should also decrease so that the relative portion of inactive surface of the interconnect area does not become excessive. Typical cell widths of one centimeter or less are often taught in the art. These small cell widths demand very fine interconnect area widths, which dictate delicate and sensitive techniques to be used to electrically connect the top TCO surface of one cell to the bottom electrode of an adjacent series connected cell. Furthermore, achieving good stable ohmic contact to the TCO cell surface has proven difficult, especially when one employs those sensitive techniques available when using the TCO only as the top collector electrode.\nOne approach to expand the surface area of individual cells while avoiding excessive resistive losses in current collection is to form a current collector grid over the surface. This approach positions highly conductive material in contact with the surface of the TCO in a spaced arrangement such that the travel distance of current through the TCO is reduced. In the case of the classic single crystal silicon or polycrystal silicon cells, a common approach is to form a collector grid pattern of traces using a silver containing paste and then fuse the paste to sinter the silver particles into continuous conductive silver paths. These highly conductive traces normally lead to a collection buss such as a copper foil strip. One notes that this approach involves use of expensive silver and requires the photovoltaic semiconductors to tolerate the high fusion temperatures. The sintering temperatures involved are normally unsuitable for thin film photovoltaic structures. Another approach is to attach an array of fine copper wires to the surface of the TCO. The wires may also lead to a collection buss, or alternatively extend to an electrode of an adjacent cell. This wire approach requires positioning and fixing of multiple fine fragile wires which makes mass production difficult and expensive. Another approach commonly used for thin film photovoltaic cells is to print a collector grid array on the surface of the TCO using a conductive ink, usually one containing a heavy loading of fine particulate silver. The ink is simply dried or cured at mild temperatures to remove a solvent carrier. Compared to the high sintering temperatures associated with the silver pastes employed with crystal silicon cells, the milder curing temperatures for silver inks typically do not adversely affect thin film photovoltaic structures. However, the silver ink approaches require the use of relatively expensive inks because of the required high loading of finely divided silver. Furthermore, batch printing on the individual cells is laborious and expensive.\nIn addition to current collection from the top surface of cells, efficient photovoltaic power collection includes integration of multiple cells into arrays or modules to create a desired surface area. The multiple cells are typically electrically integrated in series arrangement such that the power is accumulated in voltage increments. Regarding crystalline silicon cells, the individual cells are normally initially discrete and comprise rigid wafers approximately 200 micrometers thick and approximately 230 square centimeters in area. A conventional way to harvest power from multiple such cells is to use a conventional \"string and tab\" arrangement. This technique involves first depositing fine conductive current collecting grid fingers over the light incident surface. As previously discussed, these fingers often are in the form of a fired silver paste or fine metal wires. Multiple grid fingers lead to a robust buss of substantial current carrying capacity. This buss material then extends and is electrically joined to the bottom electrode of an adjacent cell. Such methods for electrically integrating multiple discrete cells can be termed \"discrete integration\".\nA typical prior art \"string and tab\" arrangement for achieving series connections among crystalline silicon cells is embodied in FIGS. 1A through 1C. It is in seen in FIG. 1A that conductive grid fingers 82 are attached to the light incident (top) surface 83 of cells 84. These fingers 82 extend to buss material 85 positioned at opposite peripheral edges of cells 84. The buss material extends to the bottom electrode 86 of an adjacent cell, as is shown in the bottom view of FIG. 1B and side view of FIG. 1C. It is to be noted that the busses 85 in FIGS. 1A through 1C are depicted with section lines. This is done for contrast only and the views are not actually sectional views. While FIGS. 1A through 1C show the interconnection of two cells, in reality this connection is normally made among strings of many more cells (8 for example). This process is thus laborious, costly and subject to manufacturing error. Further, the strings of cells are physically turned over in order to access both top and bottom surfaces of the individual cells to accomplish the electrical connections. Such a process may lead to breaking of electrical connections and complicates efforts to achieve a continuous high volume production process for the integrated cells.\nThin film photovoltaic semiconductors can be deposited over expansive areas and often in a continuous roll-to-roll fashion. Thin film technologies may thus offer additional opportunities for mass production of interconnected arrays compared to inherently small, discrete single crystal silicon cells. For example, thin film photovoltaic cells may be subdivided and interconnected into arrays of multiple cells using a process generally referred to as \"monolithic integration\". Monolithic integration envisions initially depositing photovoltaic cell structure over an expanded surface of supporting substrate. The expansive photovoltaic structure is subsequently subdivided into smaller, isolated, individual cells which are then serially interconnected while maintaining the cells on the initial common substrate.\nA number of U.S. patents have issued proposing designs and processes to achieve such monolithic series integration among thin film photovoltaic cells. Examples of these proposed processes are presented in U.S. Pat. Nos. 4,443,651, 4,724,011, and 4,769,086 to Swartz, Turner et al. and Tanner et al. respectively which taught monolithic integration techniques for photovoltaic cells supported by glass substrates. The process comprises deposition of photovoltaic materials on glass substrates followed by scribing to form smaller area individual cells. Multiple steps then follow to electrically connect the individual cells in series array. While expanding the opportunities for mass production of interconnected cell arrays compared with single crystal silicon approaches, glass substrates must inherently be processed on an individual batch basis. Further, when multiple individual cells are formed monolithically on a common monolithic glass substrate, there is no way to check the quality of individual cells and remove deficient cell regions. Thus variations in cell quality over an expansive surface may jeopardize the entire module.\nMore recently, developers have explored depositing wide area films using continuous roll-to-roll processing. This technology generally involves depositing thin films of photovoltaic material onto a continuously moving sheetlike web of insulating plastic or metal foil. However, a challenge still remains regarding monolithically subdividing the expansive films into individual cells followed by interconnecting into a series connected array. For example, U.S. Pat. No. 4,965,655 to Grimmer et. al. and U.S. Pat. No. 4,697,041 to Okinawa teach processes employing insulating polymeric substrates requiring expensive laser scribing and interconnections achieved with laser heat staking. In addition, these two references teach a substrate of thin vacuum deposited metal on substrate films of relatively expensive polymers. The electrical resistance of thin vacuum metallized layers may significantly limit the active area of the individual interconnected cells. Finally, when multiple individual cells are formed on a common monolithic polymer support film it is difficult to check the quality of individual cells and remove deficient cell regions. Thus variations in cell quality over an expansive surface may jeopardize the entire module.\nIt has become well known in the art that the efficiencies of certain promising thin film photovoltaic junctions such as those based on copper-indium-gallium-diselenide or cadmium telluride can be substantially increased by high temperature treatments. These treatments involve temperatures at which even the most heat resistant and expensive plastics suffer rapid deterioration. Therefore, from a practical standpoint these thin film photovoltaic semiconductors are most often deposited on ceramic, glass, or metal substrates to support the thin film junctions. Use of a glass or ceramic substrates generally restricts one to batch processing and handling difficulty. Use of a metal foil, such as stainless steel, as a substrate allows continuous roll-to-roll manufacture of cell structure over an expansive surface. However, despite the fact that use of a metal foil allows high temperature processing in roll-to-roll fashion, the subsequent interconnection of individual cells effectively into an interconnected array has proven difficult, in part because the metal foil substrate is electrically conducting. For example, the monolithic integration techniques possible with insulating substrates are not possible using metal foil substrates, since the common substrate is a conducting metal and would not permit the required electrical isolation of individual cells prior to electrical series interconnection.\nMany manufacturers of thin film photovoltaic devices supported on metal foil substrates choose to subdivide the material into discrete cells prior to assembly into an interconnected array. Typical of these methods is that which replicates the \"string and tab\" legacy approaches used for module assembly of crystalline silicon cells. Here the expansive metal foil\/photovoltaic structure is subdivided into individual cells, typically of dimensions about 15 cm. by 15. cm, before subsequent assembly via the \"string and tab\" approach described above.\nSome attempts have been advanced to achieve the advantages of continuous production of interconnected modules using continuously produced cell structure supported on a metal foil substrate. U.S. Pat. No. 4,746,618 to Nath et al. teaches a design and process to achieve interconnected arrays using roll-to-roll processing of a metal web substrate such as stainless steel. U.S. Pat. No. 4,746,618 is hereby incorporated in its entirety by reference. The process includes multiple operations of cutting, selective deposition, material removal and riveting. These operations add considerably to the final interconnected array cost. U.S. Pat. No. 5,385,848 to Grimmer teaches roll-to-roll methods to achieve integrated series connections of adjacent thin film photovoltaic cells supported on an electrically conductive metal substrate. U.S. Pat. No. 5,385,848 is hereby incorporated in its entirety by reference. The process includes mechanical or chemical etch removal of a portion of the photovoltaic semiconductor and transparent top electrode to expose an upper surface portion of the electrically conductive metal substrate. The exposed metal serves as a contact area for interconnecting adjacent cells. These material removal techniques are troublesome for a number of reasons. First, many of the chemical elements involved in the best photovoltaic semiconductors are expensive and environmentally unfriendly. This removal subsequent to controlled deposition involves containment, dust and dirt collection and disposal, and possible cell contamination. This is not only wasteful but considerably adds to expense since a significant amount of the valuable photovoltaic semiconductor is lost to the removal process. Ultimate module efficiencies are further compromised in that the spacing between adjacent cells grows, thereby reducing the effective active collector area for a given module area.\nYet another approach to achieve current collection and series interconnections among multiple cells while maintaining the flexible characteristic of many thin film structures is represented by the teachings of Yoshida et al. in U.S. Pat. No. 5,421,908. U.S. Pat. No. 5,421,908 is hereby incorporated in its entirety by reference. An embodiment of the current collection teachings of Yoshida et al. is presented in FIGS. 2A through 2C. Yoshida et al. teach a process wherein a conductive rear \"1st\" electrode 94 is first deposited using vacuum processing onto a polymeric film 96 as shown in FIG. 2A. Through holes 92 are then formed through the laminate. As shown in FIG. 2B, an overlaying amorphous silicon photovoltaic film 97 and TCO \"2nd\" electrode layer 98 are deposited on the laminate and through the holes. As shown in FIG. 2C, electrical communication between a top surface TCO \"2nd\" electrode 98 and a backside \"3rd\" electrode 99 is made through the holes when the \"3rd\" electrode 99 is deposited on the rear of the structure, as shown in FIG. 2C. The rear \"3rd\" electrode 99 is deposited by vacuum processing which also may coat the side walls of the holes. As Yoshida et al. teach, the \"2nd\" and \"3rd\" electrode layers in the holes are insulated from the \"1St\" electrode 94 by the high resistance of the amorphous silicon semiconductor layer. One readily realizes that an appropriate insulating layer would have to coat the holes to separate these electrodes should a semiconductor of lower resistivity be employed. To complete a series connection to an adjacent cell, the \"3rd\" electrode 99 of a first cell is further electrically joined to rear \"1st\" electrode 94 of an adjacent cell through additional holes between scribe lines separating the adjoining cells.\nThe through holes taught by Yoshida represent means to transport current from the topside surface of a photovoltaic cell to a conductive material (\"3rd\" electrode) located remote from the top surface. Thus the through holes of Yoshida et al. are functionally equivalent to the silver grid lines and wire forms discussed above in relation to FIGS. 1A through 1C.\nA number of manufacturing and performance problems are intrinsic with the method and structure taught by Yoshida et al. First, both the \"1st\" rear cell electrode and the \"3rd\" backside electrode are relatively thin, being formed by vacuum sputtering. Vacuum processing is expensive and in practice yields relatively thin deposits. As taught by Yoshida et al. deposits of less than one half micrometer were employed. This relatively low practical thickness limits the current carrying ability of the deposited metal and thereby restricts the size of the individual cells. Moreover, absent additional conductive fill material in the holes, the connection between the backside \"3rd\" electrode and the rear \"1st\" electrode of adjacent cells is achieved only through a very restricted cross section. This is a result of the limited access to the \"1st\" electrode, since there is no access to the broad surface regions of the \"1st\" electrode, only its edge surface. The primary support for the Yoshida structure is the insulating polymeric film, which thus must be present during formation of the semiconductors. While perhaps acceptable when manufacturing amorphous silicon cells taught by Yoshida et al., it may be unlikely that the films taught would be suitable for the heat treatment requirements of other notable thin film semiconductors. The hole density taught by Yoshida et al. is quite large (15 mm centers) adding to complexity. However, even with the large hole density, the resistive losses expected in current transport to the holes would be quite large given the sheet resistance of a normal TCO. To address this issue, Yoshida et al. proposed a structure combining printed silver ink grid lines leading to a reduced number of through holes (see for example FIG. 28A of U.S. Pat. No. 5,421,908). Finally, many individual cells are formed on a common monolithic support film using the Yoshida et al. teaching. There is no way to check the quality of individual cells and remove deficient cell regions. Thus variations in cell quality over an expansive surface jeopardize the entire module.\nThus there remains a need for manufacturing processes and articles which allow facile production of photovoltaic semiconductor structures while also offering unique means to achieve effective integrated connections to result in final modular array.\nIn a somewhat removed segment of technology, a number of electrically conductive fillers have been used to produce electrically conductive polymeric materials. This technology generally involves mixing of a conductive filler such as silver particles with the polymer resin prior to fabrication of the material into its final shape. Many choices exist for the conductive filler, including those comprising metals such as silver, copper and nickel, those comprising conductive metal oxides such as indium-tin oxide and zinc oxide, intrinsically conductive polymers, graphite, carbon black and the like. Conductive fillers may have high aspect ratio structure such as metal fibers such as stainless steel fibers or metallized polymer fibers. Other high aspect ratio materials such as metal flakes or powder, or highly structured carbon blacks may be appropriate, with the choice based on a number of cost\/performance considerations. More recently, fine particles of intrinsically conductive polymers have been employed as conductive fillers within a resin binder. Electrically conductive polymers have been used as bulk thermoplastic compositions, or formulated into paints and inks. Their development has been spurred in large part by electromagnetic radiation shielding and static discharge requirements for plastic components used in the electronics industry. Other known applications include resistive heating fibers and battery components and production of conductive patterns and traces. The characterization \"electrically conductive polymer\" covers a very wide range of intrinsic resistivities depending on the filler, the filler loading and the methods of manufacture of the filler\/polymer blend. Resistivities for filled electrically conductive polymers may be as low as 0.00001 ohm-cm. for very heavily filled silver inks, yet may be as high as 10,000 ohm-cm or even more for lightly filled carbon black materials or other \"anti-static\" materials. \"Electrically conductive polymer\" has become a broad industry term to characterize all such materials. In addition, it has been reported that recently developed intrinsically conducting polymers (absent conductive filler) may exhibit resistivities comparable to conductive metals.\nIn yet another separate technological segment, coating plastic substrates with metal electrodeposits has been employed to achieve decorative effects on items such as knobs, cosmetic closures, faucets, and automotive trim. The normal conventional process actually combines two primary deposition technologies. The first is to deposit an adherent metal coating using chemical (electroless) deposition to first coat the nonconductive plastic and thereby render its surface highly conductive. This electroless step is then followed by conventional electroplating. ABS (acrylonitrile-butadiene-styrene) plastic dominates as the substrate of choice for most applications because of a blend of mechanical and process properties and ability to be uniformly etched. The overall plating process comprises many steps. First, the plastic substrate is chemically etched to microscopically roughen the surface. This is followed by depositing an initial metal layer by chemical reduction (typically referred to as \"electroless plating\"). This initial metal layer is normally copper or nickel of thickness typically one-half micrometer. The object is then electroplated with metals such as bright nickel and chromium to achieve the desired thickness and decorative effects. The process is very sensitive to processing variables used to fabricate the plastic substrate, limiting applications to carefully prepared parts and designs. In addition, the many steps employing harsh chemicals make the process intrinsically costly and environmentally difficult. Finally, the sensitivity of ABS plastic to liquid hydrocarbons has prevented certain applications. ABS and other such polymers have been referred to as \"electroplateable\" polymers or resins. This is a misnomer in the strict sense, since ABS (and other nonconductive polymers) are incapable of accepting an electrodeposit directly and must be first metallized by other means before being finally coated with an electrodeposit. The conventional technology for electroplating on plastic (etching, chemical reduction, electroplating) has been extensively documented and discussed in the public and commercial literature. See, for example, Saubestre, Transactions of the Institute of Metal Finishing, 1969, Vol. 47., or Arcilesi et al., Products Finishing, March 1984.\nMany attempts have been made to simplify the process of electroplating on plastic substrates. Some involve special techniques to produce an electrically conductive film on the surface. Typical examples of this approach are taught by U.S. Pat. No. 3,523,875 to Minklei, U.S. Pat. No. 3,682,786 to Brown et. al., and U.S. Pat. No. 3,619,382 to Lupinski. The electrically conductive film produced was then electroplated. None of these attempts at simplification have achieved any recognizable commercial application.\nA number of proposals have been made to make the plastic itself conductive enough to allow it to be electroplated directly thereby avoiding the \"electroless plating\" process. It is known that one way to produce electrically conductive polymers is to incorporate conductive or semiconductive fillers into a polymeric binder. Investigators have attempted to produce electrically conductive polymers capable of accepting an electrodeposited metal coating by loading polymers with relatively small conductive particulate fillers such as graphite, carbon black, silver or nickel powder or flake or small metal coated forms such as metal coated mica. When considering polymers rendered electrically conductive by loading with electrically conductive fillers, it may be important to distinguish between \"microscopic resistivity\" and \"bulk\" or macroscopic resistivity\". \"Microscopic resistivity\" refers to a characteristic of a polymer\/filler mix considered at a relatively small linear dimension of for example 1 micrometer or less. \"Bulk\" or \"macroscopic resistivity\" refers to a characteristic determined over larger linear dimensions. To illustrate the difference between \"microscopic\" and \"bulk, macroscopic\" resistivities, one can consider a polymer loaded with conductive fibers at a fiber loading of 10 weight percent. Such a material might show a low \"bulk, macroscopic\" resistivity when the measurement is made over a relatively large distance. However, because of fiber separation (holes) such a composite might not exhibit consistent \"microscopic\" resistivity. When producing an electrically conductive polymer intended to be electroplated, one should consider \"microscopic resistivity\" in order to achieve uniform, \"hole-free\" deposit coverage. Thus, it may be advantageous to consider conductive fillers comprising those that are relatively small, but with loadings sufficient to supply the required conductive contacting. Such fillers include metals such as silver in the form of powders or flake, metal coated particles such as mica or spheres, particles comprising conductive metal oxides such as indium-tin oxide and zinc oxide, fine particles of intrinsically conductive polymers, graphite powder and conductive carbon black and the like. Heavy loadings of such filler may be sufficient to reduce volume resistivity to a level where electroplating may be considered.\nHowever, attempts to make an acceptable electroplateable polymer using the small conductive fillers alone encounter a number of barriers. First, the most conductive fine metal containing fillers such as silver are relatively expensive. The loadings required to achieve the particle-to-particle proximity to achieve acceptable conductivity increases the cost of the polymer\/filler blend dramatically. The metal containing fillers are accompanied by further problems. They tend to cause deterioration of the mechanical properties and processing characteristics of many resins. This significantly limits options in resin selection. All polymer processing is best achieved by formulating resins with processing characteristics specifically tailored to the specific process (injection molding, extrusion, blow molding, printing etc.). A required heavy loading of metal filler severely restricts ability to manipulate processing properties in this way. A further problem is that metal fillers can be abrasive to processing machinery and may require specialized screws, barrels, and the like.\nAnother major obstacle involved in the electroplating of electrically conductive polymers is a consideration of adhesion between the electrodeposited metal and polymeric substrate (metal\/polymer adhesion). In most cases sufficient adhesion is required to prevent metal\/polymer separation during extended environmental and use cycles. Despite being electrically conductive, a simple metal-filled polymer offers no assured bonding mechanism to produce adhesion of an electrodeposit since the metal filler particles may be encapsulated by the resin binder or oxide, often resulting in a resin-rich or oxide \"skin\".\nA number of methods to enhance electrodeposit adhesion to electrically conductive polymers have been proposed. For example, etching of the surface prior to plating can be considered. Etching can be achieved by immersion in vigorous solutions such as chromic\/sulfuric acid. Alternatively, or in addition, an etchable species can be incorporated into the conductive polymeric compound. The etchable species at exposed surfaces is removed by immersion in an etchant prior to electroplating. Oxidizing surface treatments can also be considered to improve metal\/plastic adhesion. These include processes such as flame or plasma treatments or immersion in oxidizing acids.\nIn the case of conductive polymers containing finely divided metal, one can propose achieving direct metal-to-metal adhesion between electrodeposit and filler. However, here the metal particle surface may be shielded by an aforementioned resin or oxide \"skin\". To overcome this effect, one could propose methods to remove the \"skin\", exposing active metal filler to bond to subsequently electrodeposited metal. For the reasons described above, electrically conductive polymers employing metal fillers have not been widely used as bulk substrates for electroplateable articles. Nevertheless, revived efforts and advances have been made recently to accomplish electroplating onto printed conductive patterns formed by silver filled inks and pastes. In addition, such metal containing polymers have found considerable applications as inks or pastes in production of printed conductive traces for electrical circuitry, antennas etc.\nAnother approach to impart adhesion between conductive resin substrates and electrodeposits is incorporation of an \"adhesion promoter\" at the surface of the electrically conductive resin substrate. This approach was taught by Chien et al. in U.S. Pat. No. 4,278,510 where maleic anhydride modified propylene polymers were taught as an adhesion promoter. Luch, in U.S. Pat. No. 3,865,699 taught that certain sulfur bearing chemicals could function to improve adhesion of initially electrodeposited Group VIII metals.\nAn additional obstacle confronting practical electroplating onto electrically conductive polymers is the initial \"bridge\" of electrodeposit onto the surface of the electrically conductive polymer. In electrodeposition, the substrate to be plated is often made cathodic through a pressure contact to a highly conductive member under cathodic potential. However, if the contact resistance is excessive or the substrate is insufficiently conductive, the electrodeposit current favors the highly conductive member to the point where the electrodeposit will not bridge to the substrate.\nMoreover, a further problem is encountered even if specialized racking or cathodic contact successfully achieves electrodeposit bridging to the substrate. Many of the electrically conductive polymers have resistivities far higher than those of typical metal substrates. Also, many applications contemplate electroplating onto a thin printed conductive ink pattern of traces or \"fingers\". The dry conductive ink thickness is typically less than 25 micrometer and often less than 6 micrometer. The conductive polymeric pattern may be relatively limited in the amount of electrodeposition current which it alone can convey. Thus, the conductive polymeric substrate pattern does not cover almost instantly with electrodeposit as is typical with metallic substrates. Except for the most heavily loaded and highly conductive polymer substrates, a large portion of the electrodeposition current must pass back through the previously electrodeposited metal growing laterally over the surface of the conductive plastic substrate. In a fashion similar to the bridging problem discussed above, the electrodeposition current favors the electrodeposited metal and the lateral growth can be extremely slow and erratic. This restricts the size and \"growth length\" of the conductive ink pattern, increases plating costs, and can also result in large non-uniformities in electrodeposit integrity and thickness over the pattern.\nThis lateral growth is dependent on the ability of the substrate to convey current. Thus, the thickness and resistivity of a conductive polymeric ink pattern can be defining factors in the ability to achieve satisfactory electrodeposit coverage rates. When dealing with selectively electroplated patterns long thin metal traces are often desired, deposited on a relatively thin electrically conductive polymer substrate patterns. These factors of course often work against achieving the desired result.\nThis coverage rate problem likely can be characterized by a continuum, being dependent on many factors such as the nature of the initially electrodeposited metal, electroplating bath chemistry, the nature of the polymeric binder and the resistivity of the electrically conductive polymeric substrate. As a \"rule of thumb\", the instant inventor estimates that coverage rate issue would demand attention if the resistivity of a bulk conductive polymeric substrate rose above about 0.001 ohm-cm. Alternatively, as a \"rule of thumb\" appropriate for conductive thin film substrate patterns, coverage rate issues may require attention if the substrate pattern to be plated has a surface \"sheet\" resistance of greater than about 0.05 ohm per square.\nThe least expensive (and least conductive) of the readily available conductive fillers for plastics are carbon blacks. Attempts have been made to electroplate electrically conductive polymers using carbon black loadings. Examples of this approach are the teachings of U.S. Pat. Nos. 4,038,042, 3,865,699, and 4,278,510 to Adelman, Luch, and Chien et al. respectively.\nAdelman taught incorporation of conductive carbon black into a polymeric matrix to achieve electrical conductivity required for electroplating. The substrate was pre-etched in chromic\/sulfuric acid to achieve adhesion of the subsequently electroplated metal. A fundamental problem remaining unresolved by the Adelman teaching is the relatively high resistivity of carbon loaded polymers. The lowest \"microscopic resistivity\" generally achievable with carbon black loaded polymers is about 1 ohm-cm. This is about five to six orders of magnitude higher than typical electrodeposited metals such as copper or nickel. Thus, the electrodeposit bridging and coverage rate problems described above remained unresolved by the Adelman teachings.\nLuch in U.S. Pat. No. 3,865,699 and Chien et al. in U.S. Pat. No. 4,278,510 also chose carbon black as a filler to provide an electrically conductive surface for the polymeric compounds to be electroplated. The Luch U.S. Pat. No. 3,865,699 and the Chien U.S. Pat. No. 4,278,510 are hereby incorporated in their entirety by this reference. However, these inventors further taught inclusion of materials to increase the rate of electrodeposit coverage or the rate of metal deposition on the polymer. These materials can be described herein as \"electrodeposit growth rate accelerators\" or \"electrodeposit coverage rate accelerators\". An electrodeposit coverage rate accelerator is a material functioning to increase the electrodeposition coverage rate over the surface of an electrically conductive polymer independent of any incidental affect it may have on the conductivity of an electrically conductive polymer. In the embodiments, examples and teachings of U.S. Pat. Nos. 3,865,699 and 4,278,510, it was shown that certain sulfur bearing materials, including elemental sulfur, can function as electrodeposit coverage or growth rate accelerators to overcome problems in achieving electrodeposit coverage of electrically conductive polymeric surfaces having relatively high resistivity or thin electrically conductive polymeric substrates having limited current carrying capacity.\nIn addition to elemental sulfur, sulfur in the form of sulfur donors such as sulfur chloride, 2-mercapto-benzothiazole, N-cyclohexyle-2-benzothiaozole sulfonomide, dibutyl xanthogen disulfide, and tetramethyl thiuram disulfide or combinations of these and sulfur were identified. Those skilled in the art will recognize that these sulfur donors are the materials which have been used or have been proposed for use as vulcanizing agents or accelerators. Since the polymer-based compositions taught by Luch and Chien et al. could be electroplated directly they could be accurately defined as directly electroplateable resins (DER). These directly electroplateable resins (DER) can be generally described as electrically conductive polymers with the inclusion of a growth rate accelerator.\nSpecifically for the present invention, specification, and claims, directly electroplateable resins, (DER), are characterized by the following features:                (a) presence of an electrically conductive polymer;        (b) presence of an electrodeposit coverage rate accelerator;        (c) presence of the electrically conductive polymer and the electrodeposit coverage rate accelerator in the directly electroplateable composition in cooperative amounts required to achieve direct coverage of the composition with an electrodeposited metal or metal-based alloy.        \nIn his patents, Luch identified elastomers such as natural rubber, polychloroprene, butyl rubber, chlorinated butyl rubber, polybutadiene rubber, acrylonitrile-butadiene rubber, styrene-butadiene rubber etc. as suitable for the matrix polymer of a directly electroplateable resin. Other polymers identified by Luch as useful included polyvinyls, polyolefins, polystyrenes, polyamides, polyesters and polyurethanes.\nWhen used alone, the minimum workable level of carbon black required to achieve \"microscopic\" electrical resistivities of less than 1000 ohm-cm. for a polymer\/carbon black mix appears to be about 8 weight percent based on the combined weight of polymer plus carbon black. The \"microscopic\" material resistivity generally is not reduced below about 1 ohm-cm. by using conductive carbon black alone. This is several orders of magnitude larger than typical metal resistivities.\nIt is understood that in addition to carbon blacks, other well known, highly conductive fillers can be considered in DER compositions. Examples include but are not limited to metallic fillers such as silver powder or flake, metal coated forms such as metal coated mica or glass spheres, graphite powder and conductive metal oxides. In these cases the more highly conductive fillers can be used to augment or even replace the conductive carbon black. Furthermore, one may consider using intrinsically conductive polymers to supply the required conductivity. In this case, it may not be necessary to add conductive fillers to the polymer.\nThe \"bulk, macroscopic\" resistivity of fine conductive particle filled polymers can be further reduced by augmenting the filler with additional highly conductive, high aspect ratio forms such as metal containing fibers. This can be an important consideration in the success of certain applications. Furthermore, one should realize that incorporation of non-conductive fillers may increase the \"bulk, macroscopic\" resistivity of conductive polymers loaded with finely divided conductive fillers without significantly altering the \"microscopic resistivity\" of the conductive polymer \"matrix\" encapsulating the non-conductive filler particles.\nRegarding electrodeposit coverage rate accelerators, both Luch and Chien et al. in the above discussed U.S. patents demonstrated that sulfur and other sulfur bearing materials such as sulfur donors and vulcanization accelerators function as electrodeposit coverage rate accelerators when using an initial Group VIII metal electrodeposit \"strike\" layer. Thus, an electrodeposit coverage rate accelerator need not be electrically conductive, but may be a material that is normally characterized as a non-conductor. The coverage rate accelerator need not appreciably affect the conductivity of the polymeric substrate. As an aid in understanding the function of an electrodeposit coverage rate accelerator the following is offered:                a. A specific conductive polymeric structure is identified as having insufficient current carrying capacity to be directly electroplated in a practical manner.        b. A material is added to the conductive polymeric material forming said structure. Said material addition may have insignificant affect on the current carrying capacity of the structure (i.e. it does not appreciably reduce resistivity or increase thickness).        c. Nevertheless, inclusion of said material greatly increases the speed at which an electrodeposited metal laterally covers the electrically conductive surface.It is contemplated that a coverage rate accelerator may be present as an additive, as a species absorbed on a filler surface, or even as a functional group attached to a polymer chain. One or more growth rate accelerators may be present in a directly electroplateable resin (DER) to achieve combined often synergistic results.        \nA hypothetical example is an extended trace of conductive ink having a dry thickness of two micrometer. Such inks typically comprise a conductive filler such as silver, nickel, copper, conductive carbon etc. The limited thickness of the ink may reduce the current carrying capacity of this trace thus preventing direct electroplating in a practical manner. However, inclusion of an appropriate quantity of a coverage rate accelerator may allow the conductive trace to be directly electroplated in a practical manner.\nOne might expect that other Group 6A elements, such as oxygen, selenium and tellurium, could function in a way similar to sulfur. In addition, other combinations of electrodeposited metals, such as copper and appropriate coverage rate accelerators may be identified. It is important to recognize that such an electrodeposit coverage rate accelerator is important in order to achieve direct electrodeposition in a practical way onto polymeric substrates having low conductivity or very thin electrically conductive polymeric substrates having restricted current carrying ability.\nIt has also been found that the inclusion of an electrodeposit coverage rate accelerator promotes electrodeposit bridging from a discrete cathodic metal contact to a DER surface. This greatly reduces the bridging problems described above.\nDue to multiple performance problems associated with their intended end use, none of the attempts identified above to directly electroplate electrically conductive polymers or plastics has ever achieved any recognizable commercial success. Nevertheless, the current inventor has persisted in personal efforts to overcome certain performance deficiencies associated with the initial DER technology. Along with these efforts has come a recognition of unique and eminently suitable applications employing the DER technology. Some examples of these unique applications for electroplated articles include solar cell electrical current collection grids, electrodes, electrical circuits, electrical traces, circuit boards, antennas, capacitors, induction heaters, connectors, switches, resistors, inductors, batteries, fuel cells, coils, signal lines, power lines, radiation reflectors, coolers, diodes, transistors, piezoelectric elements, photovoltaic cells, emi shields, biosensors and sensors. One readily recognizes that the demand for such functional applications for electroplated articles is relatively recent and has been particularly explosive during the past decade.\nIt is important to recognize a number of important characteristics of directly electroplateable resins (DERs) which facilitate the current invention. One such characteristic of the DER technology is its ability to employ polymer resins and formulations generally chosen in recognition of the fabrication process envisioned and the intended end use requirements. A very wide choice of polymer resins and blends, additives and fillers is available with the directly electroplateable resin (DER) technology. Functional combinations of polymers and additives, such as curatives, stabilizers, and adhesion promoters can be widely chosen. In order to provide clarity, examples of some such fabrication processes are presented immediately below in subparagraphs 1 through 9.                (1) Should it be desired to electroplate an ink, paint, coating, or paste which may be printed or formed on a substrate, a good film forming polymer, for example a soluble resin such as an elastomer, can be chosen to fabricate a DER ink (paint, coating, paste etc.). For example, in some embodiments thermoplastic elastomers having an olefin base, a urethane base, a block copolymer base or a random copolymer base may be appropriate. In some embodiments the coating may comprise a water based latex. Other embodiments may employ more rigid film forming polymers. The DER ink composition can be tailored for a specific process such flexographic printing, rotary silk screening, gravure printing, flow coating, spraying etc. Furthermore, additives can be employed to improve the adhesion of the DER ink to various substrates. One example would be tackifiers.        (2) Very thin DER traces often associated with electrical traces such as current collector grid structures can be printed and then electroplated due to the inclusion of the electrodeposit growth rate accelerator.        (3) Should it be desired to cure the DER substrate to a 3 dimensional matrix, an unsaturated elastomer or other \"curable\" resin may be chosen.        (4) DER inks can be formulated to form electrical traces on a variety of flexible substrates. For example, should it be desired to form electrical structure on a laminating film, a DER ink adherent to the sealing surface of the laminating film can be effectively electroplated with metal and subsequently laminated to a separate surface.        (5) Should it be desired to electroplate a fabric, a DER ink can be used to coat all or a portion of the fabric intended to be electroplated. Furthermore, since DER's can be fabricated out of the thermoplastic materials commonly used to create fabrics, the fabric itself could completely or partially comprise a DER. This would eliminate the need to coat the fabric.        (6) Should one desire to electroplate a thermoformed article or structure, DER's would represent an eminently suitable material choice. DER's can be easily formulated using olefinic materials which are often a preferred material for the thermoforming process. Furthermore, DER's can be easily and inexpensively extruded into the sheetlike structure necessary for the thermoforming process.        (7) Should one desire to electroplate an extruded article or structure, for example a sheet or film, DER's can be formulated to possess the necessary melt strength advantageous for the extrusion process.        (8) Should one desire to injection mold an article or structure having thin walls, broad surface areas etc. a DER composition comprising a high flow polymer can be chosen.        (9) Should one desire to vary adhesion between an electrodeposited DER structure supported by a substrate the DER material can be formulated to supply the required adhesive characteristics to the substrate. For example, the polymer chosen to fabricate a DER ink can be chosen to cooperate with an \"ink adhesion promoting\" surface treatment such as a material primer or corona treatment.        \nAll polymer fabrication processes require specific resin processing characteristics for success. The ability to \"custom formulate\" DER's to comply with these changing processing and end use requirements while still allowing facile, quality electroplating is a significant factor in the teachings of the current invention.\nAnother important recognition regarding the suitability of DER's for the teachings of the current invention is the simplicity of the electroplating process. Unlike many conventional electroplated plastics, DER's do not require a significant number of process steps prior to actual electroplating. This allows for simplified manufacturing and improved process control. It also reduces the risk of cross contamination such as solution dragout from one process bath being transported to another process bath. The simplified manufacturing process will also result in reduced manufacturing costs.\nAnother important recognition regarding the suitability of DER's for the teachings of the current invention is the wide variety of metals and alloys capable of being electrodeposited. Deposits may be chosen for specific attributes. Examples may include copper or silver for conductivity and nickel or chromium for corrosion resistance, and tin or tin based alloys for solderability.\nYet another recognition of the benefit of DER's for the teachings of the current invention is the ability they offer to selectively electroplate an article or structure. The articles of the current invention often consist of metal patterns selectively positioned in conjunction with insulating materials. Such selective positioning of metals is often expensive and difficult. However, the attributes of the DER technology make the technology eminently suitable for the production of such selectively positioned metal structures. As will be shown in later embodiments, it is often desired to electroplate a polymer or polymer-based structure in a selective manner. DER's are eminently suitable for such selective electroplating.\nYet another recognition of the benefit of DER's for the teachings of the current invention is the ability they offer to continuously electroplate an article or structure. As will be shown in later embodiments, it is often desired to continuously electroplate articles. DER's are eminently suitable for such continuous electroplating. Furthermore, DER's allow for selective electroplating in a continuous manner.\nYet another recognition of the benefit of DER's for the teachings of the current invention is their ability to withstand the pre-treatments often required to prepare other materials for plating. For example, were a DER to be combined with a metal, the DER material would be resistant to many of the pre-treatments such as cleaning which may be necessary to electroplate the metal.\nYet another recognition of the benefit of DER's for the teachings of the current invention is that the desired plated structure often requires the plating of long and\/or broad surface areas. As discussed previously, the coverage rate accelerators included in DER formulations allow for such extended surfaces to be covered in a relatively rapid manner thus allowing one to consider the use of electroplating of conductive polymers.\nThese and other attributes of DER's may contribute to successful articles and processing of the instant invention. However, it is emphasized that the DER technology is but one of a number of alternative metal deposition or positioning processes suitable to produce many of the embodiments of the instant invention. Other approaches, such as printing of conductive resin formulations, metal spraying, etching metal foils, stamping metal foils, laminating metal foils, positioning and affixing metal patterns, electroless metal deposition, vacuum metal evaporation and sputtering, or electroplating onto various conductive ink patterns such as those comprising silver may be suitable alternatives. These choices will become clear in light of the teachings to follow in the remaining specification, accompanying figures and claims.\nIn order to eliminate ambiguity in terminology, for the present invention the following definitions are supplied:\nWhile not precisely definable, for the purposes of this specification, electrically insulating materials may generally be characterized as having electrical resistivities greater than 10,000 ohm-cm. Also, electrically conductive materials may generally be characterized as having electrical resistivities less than 10,000 ohm-cm. A subset of conductive materials, electrically resistive or semi-conductive materials may generally be characterized as having electrical resistivities in the range of 0.001 ohm-cm to 10,000 ohm-cm. The term \"electrically conductive polymer or resin\" as used in the art and in this specification and claims extends to materials of a very wide range of resitivities from about 0.00001 ohm-cm. to about 10,000 ohm-cm and higher.\nAn \"electroplateable material\" is a material having suitable attributes that allow it to be coated with a layer of electrodeposited material, either directly or following a preplating process.\nA \"metallizable material\" is a material suitable to be coated with a metal deposited by any one or more of the available metallizing process, including chemical deposition, vacuum metallizing, sputtering, metal spraying, sintering and electrodeposition.\n\"Metal-based\" refers to a material or structure having at least one metallic property and comprising one or more components at least one of which is a metal or metal-containing alloy.\n\"Alloy\" refers to a substance composed of two or more intimately mixed materials.\n\"Group VIII metal-based\" refers to a substance containing by weight 50% to 100% metal from Group VIII of the Periodic Table of Elements.\n\"metal-based foil\" refers to a thin structure of metal or metal-based material that may maintain its integrity absent a supporting structure. Generally, metal of thickness greater than about 2 micrometers may have this characteristic (i.e. 2 micrometers, 10 micrometers, 25 micrometers, 100 micrometers, 250 micrometers).\nA \"film\" refers to a thin material form that is not necessarily self supporting.\nIn this specification and claims, the terms \"monolithic\" or \"monolithic structure\" are used as is common in industry to describe an object that is seamless and made or formed into or from a single item.\nA \"continuous\" process is one wherein a continuous form of a material component is supplied to the process. The material feed can be continuous motion or repetitively intermittent, and the output is timed to remove product either by continuous motion or repetitively intermittent according to the rate of input.\nA \"roll-to-roll\" process is one wherein a material component is fed to the process from a roll of material and the output of the process is accumulated in a roll form.\nThe \"machine direction\" is that direction in which material is transported through a process step.\nThe term \"multiple\" is used herein to mean \"two or more\".\nA \"web\" is a thin, flexible sheetlike material form often characterized as continuous in a length direction.\n\"Sheetlike\" characterized a structure having surface dimensions far greater than the thickness dimension.\n\"Substantially planar\" characterizes a surface structure which may comprise minor variations in surface topography but from an overall and functional perspective can be considered flat.\nThe terms \"upper\" and \"top\" surfaces of structure refer to those surfaces of structure facing toward the light incident side of the structure and are thus depicted in the drawing embodiments as facing upward.\nThe terms \"lower\" or \"bottom\" surface refer to surfaces facing away from the light incident side of the structure.","meta":{"bibliographic_information":{"country":"US","doc-number":"12799885","kind":"B2","date":"20100503","disclaimer_text":"This patent is subject to a terminal disclaimer.","invention_title":"Substrate structures for integrated series connected photovoltaic arrays and process of manufacture of such arrays"},"source_file":"https:\/\/bulkdata.uspto.gov\/data\/patent\/grant\/redbook\/fulltext\/2011\/ipg110301.zip","abstract":["This invention comprises manufacture of photovoltaic cells by deposition of thin film photovoltaic junctions on metal foil substrates. The photovoltaic junctions may be heat treated if appropriate following deposition in a continuous fashion without deterioration of the metal support structure. In a separate operation, an interconnection substrate structure is provided, optionally in a continuous fashion. Multiple photovoltaic cells are then laminated to the interconnection substrate structure and conductive joining methods are employed to complete the array. In this way the interconnection substrate structure can be uniquely formulated from polymer-based materials employing optimal processing unique to polymeric materials. Furthermore, the photovoltaic junction and its metal foil support can be produced in bulk without the need to use the expensive and intricate material removal operations currently taught in the art to achieve series interconnections."],"citations":[{"country":"US","doc-number":"3094439","kind":"A","name":"Mann et al.","date":"19630600","category":"cited by other"},{"country":"US","doc-number":"3369939","kind":"A","name":"Meyer","date":"19680200","category":"cited by other"},{"country":"US","doc-number":"3376163","kind":"A","name":"Abrahamsohn","date":"19680400","category":"cited by other"},{"country":"US","doc-number":"3442007","kind":"A","name":"Griffin et al.","date":"19690500","category":"cited by other"},{"country":"US","doc-number":"3480473","kind":"A","name":"Tanos","date":"19691100","category":"cited by other"},{"country":"US","doc-number":"3483038","kind":"A","name":"Hui et al.","date":"19691200","category":"cited by 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other"}],"classifications":{"ipc-version-indicator\/date":"20060101","classification-level":"A","section":"H","class":"01","subclass":"L","main-group":"31","subgroup":"0224","symbol-position":"F","classification-value":"I","action-date\/date":"20110301","generating-office\/country":"US","classification-status":"B","classification-data-source":"H"},"dup_signals":{"dup_doc_count":152,"dup_dump_count":39,"dup_details":{"curated_sources":2,"2018-05":2,"2017-51":1,"2017-43":1,"2017-39":3,"2017-34":1,"2017-30":2,"2017-26":2,"2017-22":1,"2017-17":2,"2017-04":2,"2016-50":1,"2016-44":1,"2016-40":2,"2016-36":4,"2016-30":1,"2016-26":1,"2016-22":1,"2016-07":1,"2015-48":7,"2015-40":1,"2015-32":6,"2015-27":3,"2015-22":5,"2015-14":7,"2014-52":5,"2014-49":7,"2014-42":11,"2014-41":14,"2014-35":6,"2014-23":10,"2014-15":5,"2019-47":1,"2015-18":6,"2015-11":4,"2015-06":3,"2014-10":5,"2013-48":9,"2013-20":5,"2017-13":1}}},"subset":"uspto"}
{"text":"A new and distinct variety of peach Prunus persica, tree having the following unique combination of desirable featres:\n\nBotanical classification: Prunus persica. \nThe new peach tree (hereinafter referred to as the xe2x80x98P.F. 35-007xe2x80x99 peach tree) was originated by Paul Friday in the experimental orchard, which is maintained for the purposes of breeding peach trees, at Paul Friday Farms Inc., located in Coloma, Mich. Coloma is located in the southwest section of Michigan.\nIn an ongoing mass selection breeding program, superior seedlings of unrecorded parentage are maintained as seed sources for the production of seeds which are collected and planted in mass. The seed producing parent trees are maintained solely as proprietary trees for breeding purposes and have not been released from the experimental orchard, where such trees can be evaluated for their adaptability to local and regional growing conditions. Seeds resulting from open pollination of the trees in the experimental orchard are regularly planted in mass to produce new populations of seedlings which are cultured and monitored to maturity. Trees with superior attributes are retained for further observation and testing, and contribute seeds to advancing generations of new populations of seedlings.\nThe tree of this application, xe2x80x98P.F. 35-007xe2x80x99, was a single plant from one such a seedling population, and was based on the numerous superior genetic attributes of this tree which are described in the botanical description to follow. While not comprehensive, the details of the botanical description to follow are believed to be a reasonably complete botanical description of the tree of this disclosure.\nThe new and distinct variety of peach tree was asexually propagated by budding as performed in the experimental orchard of Paul Friday Farms Inc., located in Coloma, Mich. The asexual propagation demonstrated that such reproduction of the characteristics of the tree are consistent and are established and transmitted through suceeding propagation.\nThe new and distinct variety of peach tree is of average height and of upright growth and a regular and productive bearer of peaches. A distinct characteristic of the xe2x80x98P.F. 35-007xe2x80x99 peach tree is its medium vigor having growth of about twenty-four inches (24xe2x80x3) per year. The blossoms bloom in mid-season and are characterized by being contracted or partially spread to approximately xc2xe inch when in full bloom. At the same time the five petals of the blossoms are of lessor length than the length of petals of the normal showy blossom as exemplified by the xe2x80x98Loringxe2x80x99 (unpatented) peach blossom.\nThe blossoms of the present peach tree at full bloom may be characterized as being non-showy. More specifically, the blossoms of the present peach tree have radially projecting and angularly spaced five blossom petals to form a blossom having a diameter of about xc2xe inch measured across the blossoms.\nThe flesh of the fruit of the present peach tree is firm and is yellow.\nThe skin is smooth, having moderate to little down, and is of light red color overlying a yellow ground color. The yellow background covers approximately fifteen percent (15%) of its surface at maturity. At maturity, the peach is spherical having an average diameter of about 2\u215dxe2x80x3.\nThe fruit produced by this tree has firm, and non-melting flesh, and thereby has the attendant resistance to blemishes and soft spots in harvesting, shipping and handling due to bruising. The firmness of the fruit flesh is sufficient to allow the flesh to yield and be restored when bumped or dropped without the resulting soft spots as would be experienced in most late season peaches of this market class. Thus, fruit of this tree remains more attractive to the ultimate buyer, the consumer, and thereby will command premium prices for the late fresh desert market.\nThe fruit matures in the latter part of the peach growing season of southwestern Michigan. The fruit as mentioned heretofore is of light red color overlying a yellow which covers approximately fifteen percent (15%) of its surface and has a very attractive appearance.","meta":{"bibliographic_information":{"document_kind":"P3","document_number":"PP014368","document_date":"20031216","publishing_country_or_organization":"US","title_of_invention":"Peach tree named xe2x80x98P.F. 35-007xe2x80x99"},"source_file":"https:\/\/bulkdata.uspto.gov\/data\/patent\/grant\/redbook\/fulltext\/2003\/pg031216.zip","abstract":["A new and distinct variety of peach Prunus persica, tree having the following unique combination of desirable featres:","1. The new and distinct variety of peach tree is of average height and of upright growth and a regular and productive bearer of peaches.","2. Producing a very firm fruit having a resilient flesh texture.","3. Blossoms are non-showy when in full bloom.","4. A substantially oval spherical fruit with skin of dark red color overlying a yellow which covers approximately fifteen percent (15%) of its surface at maturity.","5. Late maturing fruit of good taste.","6. A late maturing fruit of good storage and shelf life."],"assignees":[{"assignee_parties":[{"city":"Coloma","state":"MI","first_name":"Paul J.","sir_name":"Friday"}],"assignee_type":"United States individual"}],"classifications":{"main_or_locrano_class":["A01H  500"],"ipc_edition":["7"],"domestic_main_classification":["PLT198"],"national_classifications":["PLT198"]},"inventors":[{"first_name":"Paul Jan","sir_name":"Friday","city":"Coloma","state":"MI"}],"dup_signals":{"dup_doc_count":566,"dup_dump_count":19,"dup_details":{"curated_sources":2,"2023-14":1,"2015-27":28,"2015-22":30,"2015-14":28,"2014-52":31,"2014-49":37,"2014-42":85,"2014-41":43,"2014-35":30,"2014-23":28,"2014-15":26,"2023-50":1,"2024-10":1,"2015-18":50,"2015-11":45,"2015-06":51,"2014-10":26,"2013-48":22,"2024-18":1}}},"subset":"uspto"}
{"text":"A digital camera is provided comprising a Bayer color filter array arranged to capture an input image as a non-linear Bayer image comprising RGB pixels arranged in Bayer format, and a processor arranged to linearize and planarize the input image and to map each color of the linearized, planarized input image from an input space to an output space. The coordinates of the input space are mapped by the processor to the coordinates of the output space by dividing the output space coordinates by the number of pixels in the output space per input space sample and adding a vector (k1, k2) where k1 and k2 are equal to either 0 or minus 0.5, depending on the color and the relative rotational orientation of the linearized, planarized input image in the input space.\n\nThe PCP 3 is specifically designed to connect to a 4-inch (10-cm) Memjet printhead 2. The printhead 2 is used as a page-width printer, producing a 4-inch wide printed image without having to be moved. Instead paper 20 is printed on as it moves past the printhead 2, as shown in FIG. 4.\nComposition of 4-Inch Printhead\nEach 4-inch printhead 2 consists of 8 segments, each segment \u00bd an inch in length. Each of the segments 21 prints bi-level cyan, magenta and yellow dots over a different part of the page to produce the final image. The positions of the segments are shown in FIG. 5.\nSince the printhead 2 prints dots at 1600 dpi, each dot is 22.5 \u03bcm in diameter, and spaced 15.875 \u03bcm apart. Thus each half-inch segment prints 800 dots, with the 8 segments corresponding to positions:\nTABLE 1Final Image Dots Addressed by Each SegmentSegmentFirst dotLast dot0079918001,59921,6002,39932,4003,19943,2003,99954,0004,79964,8005,59975,6006,399\nAlthough each segment 21 produces 800 dots of the final image, each dot is represented by a combination of bi-level cyan, magenta, and yellow ink. Because the printing is bi-level, the input image should be dithered or error-diffused for best results.\nEach segment 21 then contains 2400 nozzles: 800 each of cyan, magenta, and yellow. A four-inch printhead 2 contains 8 such segments 21 for a total of 19,200 nozzles.\n2.1.1 Grouping of Nozzles Within a Segment\nThe nozzles 22 within a single segment 21 are grouped for reasons of physical stability as well as minimization of power consumption during printing. In terms of physical stability, a total of 10 nozzles share the same ink reservoir. In terms of power consumption, groupings are made to enable a low-speed and a high-speed printing mode.\nThe printhead 2 supports two printing speeds to allow different speed\/power trade-offs to be made in different product configurations.\nIn the low-speed printing mode, 96 nozzles 22 are fired simultaneously from each 4-inch printhead 2. The fired nozzles should be maximally distant, so 12 nozzles 22 are fired from each segment. To fire all 19,200 nozzles, 200 different sets of 96 nozzles must be fired.\nIn the high-speed printing mode, 192 nozzles 22 are fired simultaneously from each 4-inch printhead 2. The fired nozzles 22 should be maximally distant, so 24 nozzles are fired from each segment. To fire all 19,200 nozzles, 100 different sets of 192 nozzles must be fired.\nThe power consumption in the low-speed mode is half that of the high-speed mode. Note however, that the energy consumed to print a line, and hence a page, is the same in both cases.\nIn a scenario such as a battery powered Printcam, the power consumption requirements dictate the use of low-speed printing.\n18.104.22.168 Nozzles Make a Pod\nA single pod 23 consists of 10 nozzles 22 sharing a common ink reservoir. 5 nozzles 22 are in one row, and 5 are in another. Each nozzle 22 produces dots approximately 22.5 \u03bcm in diameter spaced on a 15.875 \u03bcm grid. FIG. 6 shows the arrangement of a single pod, with the nozzles 22 numbered according to the order in which they must be fired.\nAlthough the nozzles 22 are fired in this order, the relationship of nozzles 22 and physical placement of dots on the printed page is different. The nozzles 22 from one row represent the even dots from one line on the page, and the nozzles on the other row represent the odd dots from the adjacent line on the page. FIG. 7 shows the same pod 23 with the nozzles 22 numbered according to the order in which they must be loaded.\nThe nozzles 22 within a pod 23 are therefore logically separated by the width of 1 dot. The exact distance between the nozzles 22 will depend on the properties of the Memjet firing mechanism. The printhead 2 is designed with staggered nozzles designed to match the flow of paper 20.\n188.8.131.52 Pods Make a Chromapod\nOne pod 23 of each color (cyan, magenta, and yellow) are grouped into a chromapod 24. A chromapod 24 represents different color components of the same horizontal set of 10 dots, on different lines. The exact distance between different color pods 23 depends on the Memjet operating parameters, and may vary from one Memjet design to another. The distance is considered to be a constant number of dot-widths, and must therefore be taken into account when printing: the dots printed by the cyan nozzles will be for different lines than those printed by the magenta or yellow nozzles. The printing algorithm must allow for a variable distance up to about 8 dot-widths between colors (see Table 3 for more details). FIG. 8 illustrates a single chromapod 24.\n18.104.22.168 Chromapods Make a Podgroup\n5 chromapods 24 are organized into a single podgroup 25. Since each chromapod contains 30 nozzles 22, each podgroup contains 150 nozzles 22: 50 cyan, 50 magenta, and 50 yellow nozzles. The arrangement is shown in FIG. 9, with chromapods numbered 0\u20134. Note that the distance between adjacent chromapods is exaggerated for clarity.\n18.104.22.168 Podgroups Make a Phasegroup\n2 podgroups 25 are organized into a single phasegroup 26. The phasegroup 26 is so named because groups of nozzles 23 within a phasegroup are fired simultaneously during a given firing phase (this is explained in more detail below). The formation of a phasegroup from 2 podgroups 25 is entirely for the purposes of low-speed and high-speed printing via 2 PodgroupEnable lines.\nDuring low-speed printing, only one of the two PodgroupEnable lines is set in a given firing pulse, so only one podgroup of the two fires nozzles. During high-speed printing, both PodgroupEnable lines are set, so both podgroups fire nozzles. Consequently a low-speed print takes twice as long as a high-speed print, since the high-speed print fires twice as many nozzles at once.\nFIG. 10 illustrates the composition of a phasegroup. The distance between adjacent podgroups is exaggerated for clarity.\n220.127.116.11 Phasegroups Make a Firegroup\nTwo phasegroups (PhasegroupA and PhasegroupB) are organized into a single firegroup 27, with 4 firegroups in each segment. Firegroups 27 are so named because they all fire the same nozzles 27 simultaneously. Two enable lines, AEnable and BEnable, allow the firing of PhasegroupA nozzles and PhasegroupB nozzles independently as different firing phases. The arrangement is shown in FIG. 11. The distance between adjacent groupings is exaggerated for clarity.\n220.127.116.11 Nozzle Grouping Summary\nTable 2 is a summary of the nozzle groupings in a printhead.\nTABLE 2Nozzle Groupings for a single 4-inch printheadName ofReplicationNozzleGroupingCompositionRatioCountNozzle 22Base unit1:11Pod 23Nozzles per pod10:1\u200210Chromapod 24Pods per CMY chromapod3:130Podgroup 25Chromapods per podgroup5:1150Phasegroup 26Podgroups per phasegroup2:1300Firegroup 27Phasegroups per firegroup2:1600Segment 21Firegroups per segment4:12,4004-inch printhead 2Segments per 4-inch printhead8:119,2002.2 Load and Print Cycles\nA single 4-inch printhead 2 contains a total of 19,200 nozzles 22. A Print Cycle involves the firing of up to all of these nozzles, dependent on the information to be printed. A Load Cycle involves the loading up of the printhead with the information to be printed during the subsequent Print Cycle.\nEach nozzle 22 has an associated NozzleEnable bit that determines whether or not the nozzle will fire during the Print Cycle. The NozzleEnable bits (one per nozzle) are loaded via a set of shift registers.\nLogically there are 3 shift registers per segment (one per color), each 800 long. As bits are shifted into the shift register for a given color they are directed to the lower and upper nozzles on alternate pulses. Internally, each 800-deep shift register is comprised-of two 400-deep shift registers: one for the upper nozzles, and one for the lower nozzles. Alternate bits are shifted into the alternate internal registers. As far as the external interface is concerned however, there is a single 800 deep shift register.\nOnce all the shift registers have been fully loaded (800 load pulses), all of the bits are transferred in parallel to the appropriate NozzleEnable bits. This equates to a single parallel transfer of 19,200 bits. Once the transfer has taken place, the Print Cycle can begin. The Print Cycle and the Load Cycle can occur simultaneously as long as the parallel load of all NozzleEnable bits occurs at the end of the Print Cycle.\n2.2.1 Load Cycle\nThe Load Cycle is concerned with loading the printhead's shift registers with the next Print Cycle's NozzleEnable bits.\nEach segment 21 has 3 inputs directly related to the cyan, magenta, and yellow shift registers. These inputs are called CDataln, MDataln and YDataln. Since there are 8 segments, there are a total of 24 color input lines per 4-inch printhead. A single pulse on the SRClock line (shared between all 8 segments) transfers the 24 bits into the appropriate shift registers. Alternate pulses transfer bits to the lower and upper nozzles respectively. Since there are 19,200 nozzles, a total of 800 pulses are required for the transfer. Once all 19,200 bits have been transferred, a single pulse on the shared PTransfer line causes the parallel transfer of data from the shift registers to the appropriate NozzleEnable bits.\nThe parallel transfer via a pulse on PTransfer must take place after the Print Cycle has finished. Otherwise the NozzleEnable bits for the line being printed will be incorrect.\nSince all 8 segments 21 are loaded with a single SRClock pulse, any printing process must produce the data in the correct sequence for the printhead. As an example, the first SRClock pulse will transfer the CMY bits for the next Print Cycle's dot 0, 800, 1600, 2400, 3200, 4000, 4800, and 5600. The second SRClock pulse will transfer the CMY bits for the next Print Cycle's dot 1, 801, 1601, 2401, 3201, 4001, 4801 and 5601. After 800 SRClock pulses, the PTransfer pulse can be given.\nIt is important to note that the odd and even CMY outputs, although printed during the same Print Cycle, do not appear on the same physical output line. The physical separation of odd and even nozzles within the printhead, as well as separation between nozzles of different colors ensures that they will produce dots on different lines of the page. This relative difference must be accounted for when loading the data into the printhead. The actual difference in lines depends on the characteristics of the inkjet mechanism used in the printhead. The differences can be defined by variables D1 and D2 where D1 is the distance between nozzles of different colors, and D2 is the distance between nozzles of the same color. Table 3 shows the dots transferred to segment n of a printhead on the first 4 pulses.\nTABLE 3Order of Dots Transferred to a 4-inch PrintheadPulseDotYellow LineMagenta LineCyan Line1800S1NN + D12N + 2D12800S + 1N + D23N + D1 + D2N + 2D1 + D23800S + 2NN + D1N + 2D14800S + 3N + D2N + D1 + D2N + 2D1 + D21S = segment number (0\u20137)2D1 = number of lines between the nozzles of one color and the next (likely = 4\u20138)3D2 = number of lines between two rows of nozzles of the same color (likely = 1)\nAnd so on for all 800 pulses.\nData can be clocked into the printhead at a maximum rate of 20 MHz, which will load the entire data for the next line in 40 \u03bcs.\n2.2.2 Print Cycle\nA 4-inch printhead 2 contains 19,200 nozzles 22. To fire them all at once would consume too much power and be problematic in terms of ink refill and nozzle interference. Consequently two firing modes are defined: a low-speed print mode and a high-speed print mode:    In the low-speed print mode, there are 200 phases, with each phase firing 96 nozzles. This equates to 12 nozzles per segment, or 3 per firegroup.    In the high-speed print mode, there are 100 phases, with each phase firing 192 nozzles. This equates to 24 nozzles per segment, or 6 per firegroup. The nozzles to be fired in a given firing pulse are determined by    3 bits ChromapodSelect (select 1 of 5 chromapods 24 from a firegroup 27)    4 bits NozzleSelect (select 1 of 10 nozzles 22 from a pod 23)    2 bits of PodgroupEnable lines (select 0, 1, or 2 podgroups 25 to fire)\nWhen one of the PodgroupEnable lines is set, only the specified Podgroup's 4 nozzles will fire as determined by ChromapodSelect and NozzleSelect. When both of the PodgroupEnable lines are set, both of the podgroups will fire their nozzles. For the low-speed mode, two fire pulses are required, with PodgroupEnable=10 and 01 respectively. For the high-speed mode, only one fire pulse is required, with PodgroupEnable=11.\nThe duration of the firing pulse is given by the AEnable and BEnable lines, which fire the PhasegroupA and PhasegroupB nozzles from all firegroups respectively. The typical duration of a firing pulse is 1.3\u20131.8 \u03bcs. The duration of a pulse depends on the viscosity of the ink (dependent on temperature and ink characteristics) and the amount of power available to the printhead. See Section 2.3 on page 18 for details on feedback from the printhead in order to compensate for temperature change.\nThe AEnable and BEnable are separate lines in order that the firing pulses can overlap. Thus the 200 phases of a low-speed Print Cycle consist of 100 A phases and 100 B phases, effectively giving 100 sets of Phase A and Phase B. Likewise, the 100 phases of a high-speed print cycle consist of 50 A phases and 50 B phases, effectively giving 50 phases of phase A and phase B.\nFIG. 12 shows the AEnable and BEnable lines during a typical Print Cycle. In a high-speed print there are 50 2 \u03bcs cycles, while in a low-speed print there are 100 2 \u03bcs cycles.\nFor the high-speed printing mode, the firing order is:    ChromapodSelect 0, NozzleSelect 0, PodgroupEnable 11 (Phases A and B)    ChromapodSelect 1, NozzleSelect 0, PodgroupEnable 11 (Phases A and B)    ChromapodSelect 2, NozzleSelect 0, PodgroupEnable 11 (Phases A and B)    ChromapodSelect 3, NozzleSelect 0, PodgroupEnable 11 (Phases A and B)    ChromapodSelect 4, NozzleSelect 0, PodgroupEnable 11 (Phases A and B)    ChromapodSelect 0, NozzleSelect 1, PodgroupEnable 11 (Phases A and B)    . . .    ChromapodSelect 3, NozzleSelect 9, PodgroupEnable 11 (Phases A and B)    ChromapodSelect 4, NozzleSelect 9, PodgroupEnable 11 (Phases A and B)\nFor the low-speed printing mode, the firing order is similar. For each phase of the high speed mode where PodgroupEnable was 11, two phases of PodgroupEnable=01 and 10 are substituted as follows:    ChromapodSelect 0, NozzleSelect 0, PodgroupEnable 01 (Phases A and B)    ChromapodSelect 0, NozzleSelect 0, PodgroupEnable 10 (Phases A and B)    ChromapodSelect 1, NozzleSelect 0, PodgroupEnable 01 (Phases A and B)    ChromapodSelect 1, NozzleSelect 0, PodgroupEnable 10 (Phases A and B)    . . .    ChromapodSelect 3, NozzleSelect 9, PodgroupEnable 01 (Phases A and B)    ChromapodSelect 3, NozzleSelect 9, PodgroupEnable 10 (Phases A and B)    ChromapodSelect 4, NozzleSelect 9, PodgroupEnable 01 (Phases A and B)    ChromapodSelect 4, NozzleSelect 9, PodgroupEnable 10 (Phases A and B)\nWhen a nozzle 22 fires, it takes approximately 100 \u03bcs to refill. The nozzle 22 cannot be fired before this refill time has elapsed. This limits the fastest printing speed to 100 \u03bcs per line. In the high-speed print mode, the time to print a line is 100 \u03bcs, so the time between firing a nozzle from one line to the next matches the refill time, making the high-speed print mode acceptable. The low-speed print mode is slower than this, so is also acceptable.\nThe firing of a nozzle 22 also causes acoustic perturbations for a limited time within the common ink reservoir of that nozzle's pod 23. The perturbations can interfere with the firing of another nozzle within the same pod 23. Consequently, the firing of nozzles within a pod should be offset from each other as long as possible. We therefore fire three nozzles from a chromapod 24 (one nozzle 22 per color) and then move onto the next chromapod 24 within the podgroup 25.    In the low-speed printing mode the podgroups 25 are fired separately. Thus the 5 chromapods 24 within both podgroups must all fire before the first chromapod fires again, totalling 10\u00d72 \u03bcs cycles. Consequently each pod 23 is fired once per 20 \u03bcs.    In the high-speed printing mode, the podgroups 25 are fired together. Thus the 5 chromapods 24 within a single podgroup must all fire before the first chromapod fires again, totalling 5\u00d72 \u03bcs cycles. Consequently each pod 23 is fired once per 10 \u03bcs.\nAs the ink channel is 300 \u03bcm long and the velocity of sound in the ink is around 1500 m\/s, the resonant frequency of the ink channel is 2.5 MHz, thus the low speed mode allows 50 resonant cycles for the acoustic pulse to dampen, and the high speed mode allows 25 resonant cycles. Thus any acoustic interference is minimal in both cases.\n2.2.3 Sample Timing\nAs an example, consider the timing of printing an 4\u2033\u00d76\u2033 photo in 2 seconds, as is required by Printcam. In order to print a photo in 2 seconds, the 4-inch printhead must print 9600 lines (6\u00d71600). Rounding up to 10,000 lines in 2 seconds yields a line time of 200 \u03bcs. A single Print Cycle and a single Load Cycle must both finish within this time. In addition, a physical process external to the printhead must move the paper an appropriate amount.\nFrom the printing point of view, the low-speed print mode allows a 4-inch printhead to print an entire line in 200 \u03bcs. In the low-speed print mode, 96 nozzles 22 fire per firing pulse, thereby enabling the printing of an entire line within the specified time.\nThe 800 SRClock pulses to the printhead 2 (each clock pulse transferring 24 bits) must also take place within the 200 \u03bcs line time. The length of an SRClock pulse cannot exceed 200 \u03bcs\/800=250 ns, indicating that the printhead must be clocked at 4 MHz. In addition, the average time to calculate each bit value (for each of the 19,200 nozzles) must not exceed 200 \u03bcs\/19,200=10 ns. This requires a dot generator running at one of the following speeds:    100 MHz generating 1 bit (dot) per cycle    50 MHz generating 2 bits (dots) per cycle    25 MHz generating 4 bits (dots) per cycle2.3 Feedback from the Printhead\nThe printhead 2 produces several lines of feedback (accumulated from the 8 segments). The feedback lines are used to adjust the timing of the firing pulses. Although each segment 21 produces the same feedback, the feedback from all segments share the same tri-state bus lines. Consequently only one segment 21 at a time can provide feedback.\nA pulse on the SenseSegSelect line ANDed with data on Cyan enables the sense lines for that segment. The feedback sense lines will come from the selected segment until the next SenseSegSelect pulse. The feedback sense lines are as follows:    Tsense informs the controller how hot the printhead is. This allows the controller to adjust timing of firing pulses, since temperature affects the viscosity of the ink.    Vsense informs the controller how much voltage is available to the actuator. This allows the controller to compensate for a flat battery or high voltage source by adjusting the pulse width.    Rsense informs the controller of the resistivity (Ohms per square) of the actuator heater. This allows the controller to adjust the pulse widths to maintain a constant energy irrespective of the heater resistivity.    Wsense informs the controller of the width of the critical part of the heater, which may vary up to \u00b15% due to lithographic and etching variations. This allows the controller to adjust the pulse width appropriately.2.4 Special Cycles2.4.1 Preheat Cycle\nThe printing process has a strong tendency to stay at the equilibrium temperature. To ensure that the first section of the printed photograph has a consistent dot size, the equilibrium temperature must be met before printing any dots. This is accomplished via a preheat cycle.\nThe Preheat cycle involves a single Load Cycle to all nozzles with 1s (i.e. setting all nozzles to fire), and a number of short firing pulses to each nozzle. The duration of the pulse must be insufficient to fire the drops, but enough to heat up the ink. Altogether about 200 pulses for each nozzle are required, cycling through in the same sequence as a standard Print Cycle.\nFeedback during the Preheat mode is provided by Tsense, and continues until equilibrium temperature is reached (about 30\u00b0 C. above ambient). The duration of the Preheat mode is around 50 milliseconds, and depends on the ink composition.\nPreheat is performed before each print job. This does not affect printer performance, as it is done while the page data is transferred to the printer.\n2.4.2 Cleaning Cycle\nIn order to reduce the chances of nozzles becoming clogged, a cleaning cycle can be undertaken before each print job. Each nozzle is be fired a number of times into an absorbent sponge.\nThe cleaning cycle involves a single Load Cycle to all nozzles with 1s (i.e. setting all nozzles to fire), and a number of firing pulses to each nozzle. The nozzles are cleaned via the same nozzle firing sequence as a standard Print Cycle. The number of times that each nozzle 22 is fired depends upon the ink composition and the time that the printer has been idle, as with preheat, the cleaning cycle has no effect on printer performance.\n2.5 Printhead Interface Summary\nA single 4-inch printhead 2 has the following connections:\nTABLE 4Four-Inch Printhead ConnectionsName#PinsDescriptionChromapodSelect3Select which chromapod will fire (0\u20134)NozzleSelect4Select which nozzle from the pod will fire(0\u20139)PodgroupEnable2Enable the podgroups to fire (choice of: 01,10, 11)AEnable1Firing pulse for phasegroup ABEnable1Firing pulse for phasegroup BCDataIn[0\u20137]8Cyan input to cyan shift register of segments0\u20137MDataIn[0\u20137]8Magenta input to magenta shift register ofsegments 0\u20137YDataIn[0\u20137]8Yellow input to yellow shift register ofsegments 0\u20137SRClock1A pulse on SRClock (ShiftRegisterClock) loadsthe current values from CDataIn[0\u20137],MDataIn[0\u20137] and YDataIn[0\u20137] into the 24shift registers.PTransfer1Parallel transfer of data from the shift registersto the internal NozzleEnable bits (one pernozzle).SenseSegSelect1A pulse on SenseSegSelect ANDed with dataon CDataIn[n] selects the sense lines forsegment n.Tsense1Temperature senseVsense1Voltage senseRsense1Resistivity senseWsense1Width senseLogic GND1Logic groundLogic PWR1Logic powerV\u2212BusActuator GroundV+barsActuator PowerTOTAL44\nInternal to the 4-inch printhead, each segment has the following connections to the bond pads:\nTABLE 5Four-Inch Printhead Internal Segment ConnectionsName#PinsDescriptionChromapodSelect3Select which chromapod will fire (0\u20134)NozzleSelect4Select which nozzle from the pod will fire(0\u20139)PodgroupEnable2Enable the podgroups to fire (choice of: 01,10, 11)AEnable1Firing pulse for phasegroup ABEnable1Firing pulse for phasegroup BCDataIn1Cyan input to cyan shift registerMDataIn1Magenta input to magenta shift registerYDataIn1Yellow input to yellow shift registerSRClock1A pulse on SRClock (ShiftRegisterClock) loadsthe current values from CDataIn, MDataIn andYDataIn into the 3 shift registers.PTransfer1Parallel transfer of data from the shift registersto the internal NozzleEnable bits (one pernozzle).SenseSegSelect1A pulse on SenseSegSelect ANDed with dataon CDataIn selects the sense lines for thissegment.Tsense1Temperature senseVsense1Voltage senseRsense1Resistivity senseWsense1Width senseLogic GND1Logic groundLogic PWR1Logic powerV\u221221Actuator GroundV+21Actuator PowerTOTAL65(65 \u00d7 8 segments = 520 for all segments)3 Image Processing Chains\nThe previous sections have dealt only with the highest level overview of the PCP functionality\u2014that of mapping CFA images to a variety of output print formats. In fact, there are a number of steps involved in taking an image from the image sensor, and producing a high quality output print. We can break the high level process into two image processing chains, each with a number of steps:    Image Capture Chain    Print Chain\nThe Image Capture Chain is concerned with capturing the image from the Image Sensor and storing it locally within the Printcam. The Print Chain is concerned with taking the stored image and printing it. These two chains map onto the basic Printcam functionality as follows:    Take&Print=Image Capture Chain followed by Print Chain    Reprint=Print Chain\nFor example, a user may print a thumbnail image (Take&Print), and if happy with the results, print several standard copies (Reprint).\nThis chapter describes an implementation independent image processing chain that meets the quality requirements of Printcam. At this stage, we are not considering exactly how the processing is performed in terms of hardware, but rather what must be done. These functions must be mapped onto the various units within the PCP.\nRegardless of the PCP implementation, there are a number of constraints:    The input image is a CFA based contone RGB image.    The output image is for a Memjet printhead (bi-level dots at 1600 dpi) in CMY color space, and is always the same output width (4 inches wide).3.0.1 Supported Print Formats\nThe PCP 3 supports a variety of output print formats, as shown in Table 6. In all cases, the width of the image is 4 inches (matching the printhead width). Only the length of the print out varies.\nTABLE 6Supported Image FormatsAspectOutput SizeOutput resolutionFormat NameRatio(inches)(at 1600 dpi)RotationStandard 302:34\u2033 \u00d7 6\u20336400 \u00d7 960090Passport 312:34\u2033 \u00d7 6\u20336400 \u00d7 960090Panoramic 334:64\u2033 \u00d7 12\u2033\u20026400 \u00d7 1920090Thumbnail 322:34\u2033 \u00d7 2.67\u20336400 \u00d7 42670\nThe image sensor does not provide orientation information. All input images are captured at the same resolution (1500\u00d71000), and may need to be rotated 90 degrees before printout. FIG. 13 illustrates the mapping between the captured CFA image and the various supported print formats. Note that although the image is shown rotated 90 degrees anti-clockwise, the image can be rotated clockwise or anti-clockwise.\n3.1 Image Capture Chain\nThe Image Capture Chain is responsible for taking an image from the Image Sensor and storing it locally within the Printcam. The Image Capture Chain involves a number of processes that only need to be performed during image capture. The Image Capture Chain is illustrated in FIG. 14, with subsequent sections detailing the sub-components.\n3.1.1 Image Sensor 1\nThe input image comes from an image sensor 1. Although a variety of image sensors are available, we only consider the Bayer color filter array (CFA). The Bayer CFA has a number of attributes which are defined here.\nThe image captured by the CMOS sensor 1 (via a taking lens) is assumed to have been sufficiently filtered so as to remove any aliasing artifacts. The sensor itself has an aspect ratio of 3:2, with a resolution of 1500\u00d71000 samples. The most likely pixel arrangement is the Bayer color filter array (CFA), with each 2\u00d72 pixel block arranged in a 2 G mosaic as shown in FIG. 15:\nEach contone sample of R, G, or B (corresponding to red, green, and blue respectively) is 10-bits. Note that each pixel of the mosaic contains information about only one of R, G, or B. Estimates of the missing color information must be made before the image can be printed out.\nThe CFA is considered to perform adequate fixed pattern noise (FPN) suppression.\n3.1.2 Linearize RGB 40\n    The image sensor 40 is unlikely to have a completely linear response. Therefore the 10-bit RGB samples from the CFA must be considered to be non-linear. These non-linear samples are translated into 8-bit linear samples by means of lookup tables (one table per color).\nPixels from the CFA lines 0, 2, 4 etc. index into the R and G tables, while pixels from the CFA lines 1, 3, 5 etc. index into the G and B tables. This is completely independent of the orientation of the camera. The process is shown in FIG. 16. The total amount of memory required for each lookup table is 210\u00d78-bits. The 3 lookup tables 45 therefore require a total of 3 KBytes (3\u00d7210 bytes).\n3.1.3 Planarize RGB 41\nThe pixels obtained from the CFA have their color planes interleaved due to the nature of the Bayer mosaic of pixels. By this we mean that on even horizontal lines, one red pixel is followed by a green pixel and then by another red pixel\u2014the different color planes are interleaved with each other. In some image processing systems, an interleaved format is highly useful. However in the Printcam processing system, the algorithms are more efficient if working on planar RGB.\nA planarized image is one that has been separated into its component colors. In the case of the CFA RGB image, there are 3 separate images: one image containing only the red pixels, one image containing only the blue pixels, and one image containing only the green pixels. Note that each plane only represents the pixels of that color which were actually sampled. No resampling is performed during the planarizing process. As a result, the R, G and B planes are not registered with each other, and the G plane is twice as large as either the R or B planes. The process is shown in FIG. 17.\nThe actual process is quite simple\u2014depending on the color of the pixels read in, the output pixels are sent to the next position in the appropriate color plane's image (therefore in the same orientation as the CFA).\nThe red 45 and blue 47 planar images are exactly one quarter of the size of the original CFA image. They are exactly half the resolution in each dimension. The red and blue images are therefore 750\u00d7500 pixels each, with the red image implicitly offset from the blue image by one pixel in CFA space (1500\u00d71000) in both the x and y dimensions.\nAlthough the green planar image 46 is half of the size of the original CFA image, it is not set out as straightforwardly as the red or blue planes. The reason is due to the checkerboard layout of green. On one line the green is every odd pixel, and on the next line the green is every even pixel. Thus alternate lines of the green plane represent odd and even pixels within the CFA image. Thus the green planar image is 750\u00d71000 pixels. This has ramifications for the resampling process (see \"Resample 64\" on page 28 below).\n3.1.4 Stored Image 42\nEach color plane of the linearized RGB image is written to memory for temporary storage. The memory should be Flash 11 so that the image is retained after the power has been shut off.\nThe total amount of memory required for the planarized linear RGB image is 1,500,000 bytes (approximately 1.5 MB) arranged as follows:    R: 750\u00d7500=375,000 bytes    B: 750\u00d7500=375,000 bytes    G: 750\u00d71000=750,000 bytes3.2 Print Chain\nThe Print Chain is concerned with taking an existing image from memory 42 and printing it to a Memjet printer 2. An image is typically printed as soon as it has been captured, although it can also be reprinted (i.e. without recapture).\nThere are a number of steps required in the image processing chain in order to produce high quality prints from CFA captured images. FIG. 18 illustrates the Print Chain. The chain is divided into 3 working resolutions. The first is the original image capture space 50 (the same space as the CFA), the second is an intermediate resolution 51 (lines of 1280 continuous tone pixels), and the final resolution is the printer resolution 52, with lines of 6400 bi-level dots.\n3.2.1 Input Image\nThe input image is a linearized RGB image 42 stored in planar form, as stored by the Image Capture Chain described in Section 3.1.4.\n3.2.2 Gather Statistics 60\nA number of statistics regarding the entire image need to be gathered before processes like white balance and range expansion can be performed. These statistics only need to be gathered once for all prints of a particular captured image 42, and can be gathered separately from the red, green, and blue planar images.\n184.108.40.206 Build Histogram\nThe first step is to build a histogram for each 8-bit value of the color plane. Each 1500\u00d71000 CFA image contains a total of:    375,000 red pixels (min 19-bit counter required)    375,000 blue pixels (min 19-bit counter required)    750,000 green pixels (min 20-bit counter required)\nTherefore a single 256\u00d720 bit table is required to hold the histogram.\nThe process of building the histogram is straightforward, as illustrated by the following pseudocode:\nFor I = 0 to 255\u2003Entry[I] = 0EndForFor Pixel = ImageStart to ImageEnd\u2003p = Image[Pixel]\u2003Entry[p] = Entry[p]+1EndFor126.96.36.199 Determine High and Low Thresholds\nOnce the histogram has been constructed for the color plane, it can be used to determine a high and low threshold. These thresholds can be used for automating later white balance and range expansion during the print process.\nBasing the thresholds on the number of pixels from the histogram, we consider the n % darkest pixels to be expendable and therefore equal. In the same way, we consider the n % lightest pixels to be expendable and therefore equal. The exact value for n is expected to be about 5%, but will depend on the CFA response characteristics.\nThe process of determining the n % darkest values is straightforward. It involves stepping through the color plane's histogram from the count for 0 upwards (i.e. 0, 1, 2, 3 etc.) until the n % total is reached or we have travelled further than a set amount from 0. The highest of these values is considered the low threshold of the color plane. Although there is a difference between these darkest values, the difference can be considered expendable for the purposes of range expansion and color balancing.\nThe process of determining the n % lightest values is similar. It involves stepping through the color plane's histogram from the count for 255 downwards (i.e. 255, 254, 253 etc.) until the n % total is reached or until we have travelled further than a set amount from 255. The lowest of these values is considered the high threshold of the color plane. Although there is a difference between these lightest values, the difference can be considered expendable for the purposes of range expansion and color balancing.\nThe reason for stopping after a set distance from 0 or 255 is to compensate for two types of images:    where the original dynamic range is low, or    where there is no white or black in an image\nIn these two cases, we don't want to consider the entire n % of upper and lower values to be expendable since we have a low range to begin with. We can safely set the high 73 and low 72 thresholds to be outside the range of pixel values actually sampled. The exact distance will depend on the CFA, but will be two constants.\nA sample color range for a color plane is shown in FIG. 19. Note that although the entire 0\u2013255 range is possible for an image color plane's pixels, this particular image has a smaller range. Note also that the same n % histogram range 70, 71 is represented by a larger range in the low end 70 than in the high end 71. This is because the histogram must contain more pixels with high values closer together compared to the low end.\nThe high 73 and low 72 thresholds must be determined for each color plane individually. This information will be used to calculate range scale and offset factors to be used in the later white balance and range expansion process.\nThe following pseudocode illustrates the process of determining either of the two thresholds (to find the low threshold, StartPosition=255, and Delta=1. To find the high threshold, StartPosition=0 and Delta=\u22121). The pseudocode assumes that Threshold is an 8-bit value that wraps during addition.\nThreshold = StartPositionTotal = 0TotalDelta = 0While ((TotalDelta < MaxDelta) AND (Total < MaxPixels))\u2003Threshold = Threshold + Delta\u2003Total = Total + Entry[Threshold]\u2003TotalDelta = TotalDelta + 1EndWhileReturn Threshold3.2.3 Rotate Image 61\nRotation of the image 61 is an optional step on both the Capture and Print and Reprint processes.\nDifferent print formats require the image to be rotated either 0 or 90 degrees relative to the CFA orientation, as shown in FIG. 13. The rotation amount depends on the currently selected print format. Although the direction of rotation is unimportant (it can be clockwise or counter-clockwise since the new orientation is only facilitating the printhead width), the rotation direction will affect the relative registration of the 3 color planes. Table 7 summarizes the rotation required for each print format from the original CFA orientation.\nTABLE 7Rotations from CFA orientation for Print FormatsPrint FormatRotationStandard 3090Passport 3190Panoramic 3390Thumbnail 320\nSince we are rotating only by 0 or 90 degrees, no information is lost during the rotation process. For a rotation of 0, the image can be read row by row, and for a rotation of 90, the image can be read column by column. Registration of the 3 color planes must take the rotation direction into account.\n3.2.4 White Balance 62 and Range Expansion 63\nA photograph is seldom taken in ideal lighting conditions. Even the very notion of \"perfect lighting conditions\" is fraught with subjectivity, both in terms of photographer and subject matter. However, in all cases, the subject matter of a photograph is illuminated by light either from a light source (such as the sun or indoor lighting), or its own light (such as a neon sign).\nIn most lighting conditions, what may appear to the photographer as \"white\" light, is usually far from white. Indoor lighting for example, typically has a yellow cast, and this yellow cast will appear on an uncorrected photograph. To most people, the yellow cast on the final uncorrected photograph is wrong. Although it may match the viewing conditions at the time the photograph was taken, it does not match the perceived color of the object. It is therefore crucial to perform white balance on a photograph before printing it out.\nIn the same way, an image can be perceived to be of higher quality when the dynamic range of the colors is expanded to match the full range in each color plane. This is particularly useful to do before an image is resampled to a higher resolution. If the dynamic range is higher, intermediate values can be used in interpolated pixel positions, avoiding a stepped or blocky image. Range expansion is designed to give the full 256 value range to those values actually sampled. In the best case, the lowest value is mapped to 0, and the highest value is mapped to 255. All the intermediate values are mapped to proportionally intermediate values between 0 and 255.\nMathematically, the operation performed is a translation of LowThreshold 72 to 0 followed by a scale. The formula is shown here:\n            Pixel      \u2032        =                  (                  Pixel          -          LowThreshold                )            \u00d7      RangeScaleFactor                  where      \u2062                          \u2062      RangeScaleFactor        =          256              (                  HighThreshold          -          LowThreshold                )            \nRangeScaleFactor should be limited to a maximum value to reduce the risk of expanding the range too far. For details on calculating LowThreshold, 72 see Section 3.2.2 \"Gather Statistics\". These values (LowThreshold and RangeScaleFactor) will be different for each color plane, and only need to be calculated once per image.\nBoth tasks can be undertaken simultaneously, as shown in FIG. 20:\nSince this step involves a scaling process, we can be left with some fractional component in the mapped value e.g. the value 12 may map to 5.25. Rather than discard the fractional component, we pass a 10 bit result (8 bits of integer, 2 of fraction) on to the next stage of the image processing chain. We cannot afford the memory to store the entire image at more than 8-bits, but we can make good use of the higher resolution in the resampling stage. Consequently the input image is 8-bits, and the output image has 10-bits per color component. The logical process is shown in FIG. 21.\nIt is important to have a floor of 0 during the subtraction so that all values below LowThreshold 72 to be mapped to 0. Likewise, the multiplication must have a ceiling of 255 for the integer portion of the result so that input values higher than HighThreshold 73 will be mapped to 255.\n3.2.5 Resample 64\nThe CFA only provides a single color component per pixel (x,y) coordinate. To produce the final printed image we need to have the other color component values at each pixel. Ultimately we need cyan, magenta, and yellow color components at each pixel, but to arrive at cyan, magenta, and yellow we need red, green and blue. With our one-color-per-pixel, we may have the red component for a particular position, but we need to estimate blue and green. Or we may have green, and need to estimate red and blue.\nEven if we did have the full red, green, and blue color components for each CFA resolution pixel, the CFA resolution image is not the final output resolution. In addition, although the output format varies, the physical width of the printed image is constant (4 inches at 1600 dpi). The constant width of the printhead is therefore 6400 dots.\nThere are two extreme cases to consider:    Interpolate to CFA resolution (minimal interpolation), and then perform sharpening, color conversion. Finally scale up to the print resolution. This has the advantage of a constant sharpening kernel and color conversion at the low resolution. However it has the disadvantage of requiring more than 8-bits per color component to be stored for the interpolated image or intermediate values will be incorrectly interpolated during the final scale-up to print resolution. It also has the disadvantage of requiring a scale-up unit that is capable of producing 1 print-res interpolated value per cycle.    Interpolate to the print resolution, then perform sharpening and color conversion. This has the advantage of only one resampling process, providing maximum accuracy. However it has the disadvantage of requiring a scale-up unit that is capable of producing 1 bi-cubic interpolated value per cycle as well as performing sharpening and color conversion, all on an average of a single cycle. The sharpening kernel must be large enough to apply the CFA-res kernel to the high-res image. Worse still, for sharpening, there must be at least 3 windows kept onto the output image (each containing a number of 6400 entry lines) since on a single print cycle, the cyan, magenta, and yellow dots represent dots from 6 different lines.\nNeither of these cases take into account the fact that the final print output is bilevel rather than contone. Consequently we can strike a middle ground with regards to resampling, and achieve the best from both methods.\nThe solution is to interpolate to an intermediate resolution. Sharpening and color conversion occur at the intermediate resolution, followed by a scale-up to print resolution. The intermediate resolution must be low enough to allow the advantages of small sharpening kernel size and color conversion timing. But the intermediate resolution must be high enough so that there is no loss of quality scaling up to the print resolution bi-level image. The effect must be the same as if there was a single interpolation to the print resolution (rather than two).\nSince the print image is printed as 1600 dpi dithered bi-level dots, it can be safely represented by a 320 dpi contone image. Consequently an intermediate resolution of 1280 contone pixels provides no perceived loss of quality over 6400 bi-level dots. The later scaling from 1280 to 6400 is therefore an exact scaling ratio of 1:5.\nTo decide how best to resample, it is best to consider each color plane in relation to the CFA resolution. This is shown in FIG. 22 for a rotation of 0.\n184.108.40.206 Red 45 and Blue 47\nLooking at the red 45 and blue 47 planes, the full CFA resolution version of the color plane can be created by scaling up the number of sampled pixels in each dimension by 2. The intermediate pixels can be generated by means of a reconstruction filter (such as a Lanczos or Exponential filter). Only one dimension in the kernel is required, since the kernel is symmetric. Since red and blue have different offsets in terms of their initial representation within the CFA sample space, the initial positions in the kernel will be different.\nThe mapping of output coordinates (in 1280 space) to input coordinates depends on the current rotation of the image, since the registration of pixels changes with rotation (either 0 or 90 degrees depending on print format). For red and blue then, the following relationship holds:\n                                                        x              \u2032                        =                                          (                                  x                  mps                                )                            +                              k                1                                                                                                    y              \u2032                        =                                          (                                  y                  mps                                )                            +                              k                2                                                          }    \u2003\nwhere\nx,y=coordinate in medium res space\nx\u2032y\u2032=coordinate in input space\nmps=medium res pixels per input space sample\nk1,2={0, \u22120.5} depending on rotation\nThis means that given a starting position in input space, we can generate a new line of medium resolution pixels by adding a \u0394x and \u0394y of 1\/mps and 0 respectively 1279 times. The fractional part of x and y in input space can be directly used for looking up the kernel coefficients for image reconstruction and resampling.\nNote that k1 and k2 are 0 and \u22120.5 depending on whether the image has been rotated by 0 or 90 degrees. Table 8 shows the values for k1 and k2 in the red and blue planes, assuming that the rotation of 90 degrees is anti-clockwise.\nTABLE 8Effect of Rotation on k1 and k2 (rotation is anti-clockwise)Rotation FromRedBlueFormatOriginal CFAk1k2k1k2Standard 30900\u22120.5\u22120.50Passport 31900\u22120.5\u22120.50Panoramic 33900\u22120.5\u22120.50Thumbnail 32000\u22120.5\u22120.5\nThe number of medium res pixels per sample, mps, depends on the print format. Given that the planarized RGB image has the following red and blue planar resolutions when unrotated: R: 750\u00d7500, B: 750\u00d7500, the scale factors for the different output formats (see FIG. 13 on page 17) are shown in Table 9. Note that with the Passport image format, the entire image is resampled into \u00bc of the output space.\nTABLE 9Red and Blue Scale Factors for Image FormatsFormatMappingmps1\/mpsStandard 30500   12802.560.390625Passport 31500   6401.280.78125Panoramic 33250   12805.120.1953125Thumbnail 32750   12801.710.5848\nAs can be seen in Table 9, the red and blue images are scaled up for all image formats. Consequently there will not be any aliasing artifacts introduced by the resampling process.\n22.214.171.124 Green 46\nThe green plane 46 cannot be simply scaled up in the same way as red or blue, since each line of the green plane represents different pixels\u2014either the odd or even pixels on alternate lines. Although in terms of the number of pixels it is representative to say the green image is 750\u00d71000, the image could equally be said to be 1500\u00d7500. This confusion arises because of the checkerboard nature of the green pixels, where the distance between pixels is not equal in x and y dimensions, and does not map well to image reconstruction or resampling. The number of interpolation methods used by other systems for green plane reconstruction is testimony to this\u2014from nearest neighbor replication to linear interpolation to bi-linear interpolation and heuristic reconstruction.\nThe mapping of output coordinates (in 1280 space) to input coordinates is conceptually the same for green as it is for red and blue. The mapping depends on the current rotation of the image, since the registration of pixels changes with rotation (either 0 or 90 degrees depending on print format). For the green plane the following relationship holds:\n                                                        x              \u2032                        =                                          (                                  x                  mps                                )                            +                              k                1                                                                                                    y              \u2032                        =                                          (                                  y                  mps                                )                            +                              k                2                                                          }    \u2003\nwhere\nx,y=coordinate in medium res space\nx\u2032y\u2032=coordinate in input space\nmps=medium res pixels per input space sample\nk1,2={0, \u22120.5} depending on rotation\nAs with the red 45 and blue 47 planes, the number of medium res pixels per sample, mps, depends on the print format. Given that the planarized RGB image has the following planar resolutions when unrotated: R: 750\u00d7500, B: 750\u00d7500, G: 750\u00d71000, the scale factors for the different output formats (see FIG. 13) are shown in Table 10. Note that with the Passport image format, the entire image is resampled into \u00bc of the output space.\nTABLE 10Green Plane Scale Factors for Image FormatsFormatMappingmps1\/mpsStandard 301000   12801.280.78125Passport 311000   6400.641.5625Panoramic 33\u2002500   12802.560.390625Thumbnail 321500   12800.851.17648\nThese scale factors allow the mapping of coordinates between CFA resolution input space and medium res space. However, once we have a coordinate in CFA resolution input space, we cannot perform image reconstruction and resampling on the samples in the same way as red or blue due to the checkerboard nature of the green plane 46.\nInstead, for the purposes of high quality image reconstruction and resampling, we can consider the green channel to be an image rotated by 45 degrees. When we look at the pixels in this light, as shown in FIG. 23, a high quality image reconstruction and resampling method becomes clear.\nLooking at FIG. 23, the distance between the sampled pixels in the X and Y directions is now equal. The actual distance between sampled pixels is \u221a{square root over (2)}, as illustrated in FIG. 24.\nThe solution for the green channel then, is to perform image reconstruction and resampling in rotated space. Although the same reconstruction filter is used as for resampling red and blue, the kernel should be different. This is because the relationship between the sampling rate for green and the highest frequency in the signal is different to the relationship for the red and blue planes. In addition, the kernel should be normalized so that the \u221a2 distance between samples becomes 1 as far as kernel coordinates go (the unnormalized distances between resampling coordinates must still be used to determine whether aliasing will occur however). Therefore we require two transformations:    The first is to map unrotated CFA space into rotated CFA space. This can be accomplished by multiplying each ordinate by 1\/\u221a2, since we are rotating by 45 degrees (cos 45=sin 45=1\/\u221a2).    The second is to scale the coordinates to match the normalized kernel, which can be accomplished by multiplying each ordinate by 1\/\u221a2.\nThese two transformations combine to create a multiplication factor of \u00bd. Consequently, as we advance in unrotated CFA space x by k, we increase by k\/2 in kernel x, and decrease by k\/2 in kernel y. Similarly, as we advance in y by k, we increase by k\/2 in kernel x and increase by k\/2 in kernel y.\nThe relationships between these different coordinate systems can be illustrated by considering what occurs as we generate a line of medium resolution pixels from a CFA space input image. Given a starting y ordinate in CFA input space, we begin at x=0, and advance 1280 times by 1\/mps, generating a new pixel at each new location. The movement in unrotated CFA space by 1\/mps can be decomposed into a movement in x and a movement in y in rotated CFA space. The process is shown in FIG. 25.\nSince cos 45=sin 45=1\/\u221a2, movement in unrotated CFA space by 1\/mps equates to equal movement in x and y by 1\/(mps\u221a2). This amount must now be scaled to match the normalized kernel. The scaling equates to another multiplication by 1\/\u221a2. Consequently, a movement of 1\/mps in unrotated CFA space equates to a movement of \u00bd mps in kernel x and kernel y. Table 11 lists the relationship between the three coordinate systems for the different formats:.\nTABLE 11Green Plane Kernel \u0394 Values for Image FormatsFormatScale Factor(mps)                                                        Unrotated                                                                          CFA                \u2062                                                                  \u2062                space                \u2062                                                                  \u2062                \u0394                                                                                  1          mps                      \u2003                                                        Rotated                                                                          CFA                \u2062                                                                  \u2062                space                \u2062                                                                  \u2062                \u0394                                                                                  1                      mps            \u2062                                                  \u2062                          2                                            \u2003                              Kernel          \u2062                                          \u2062          \u0394                                              1                      2            \u2062                                                  \u2062            mps                                \u2003Standard1.280.781250.5520.391Passport0.641.56251.1050.781Panoramic2.560.3910.2760.195Thumbnail0.851.176480.8320.601\nTable 11 shows that movement in kernel space is always by a number less than 1, but in rotated CFA space, only the Passport image has a \u0394 value of greater than 1. As a result, aliasing will occur for the Passport print format, but not for any of the others. However, given that the \u0394 is almost 1, and that each of the 4 images is only \u00bc size, aliasing will not be noticeable, especially since we assume ideal low pass filtering on the green during image capture.\n184.108.40.206 Reconstruction Filter for Red, Blue and Green\nThe exact reconstruction filter to be used will depend on a number of issues. There is always a trade off between the number of samples used in constructing the original signal, the time taken for signal reconstruction, and quality of the resampled image. A satisfactory trade-off in this case is 5 pixel samples from the dimension being reconstructed, centered around the estimated position X i.e. X\u22122, X\u22121, X, X+1, X+2. Due to the nature of reconstructing with 5 sample points, we only require 4 coefficients for the entry in the convolution kernel.\nWe create a kernel coefficient lookup table with n entries for each color component. Each entry has 4 coefficients. As we advance in output space, we map the changes in output space to changes in input space and kernel space. The most significant bits of the fractional component in the current kernel space are used to index into the kernel coefficients table. If there are 64 entries in the kernel table, the first 6 fraction bits are used to look up the coefficients. 64 entries is quite sufficient for the resampling in Printcam.\n3.2.6 Sharpen 65\nThe image captured by the CFA must be sharpened before being printed. Ideally, the sharpening filter should be applied in the CFA resolution domain. However, at the image capture resolution we do not have the full color information at each pixel. Instead we only have red, blue or green at a given pixel position. Sharpening each color plane independently gives rise to color shifts. Sharpening should instead be applied to the luminance channel of an image, so that the hue and saturation of a given pixel will be unchanged.\nSharpening then, involves the translation of an RGB image into a color space where the luminance is separated from the remainder of the color information (such as HLS or Lab) 80. The luminance channel 81 can then be sharpened 82 (by adding in a proportion of the high-pass-filtered version of the luminance). Finally, the entire image should be converted back to RGB 83 (or to CMY since we are going to print out in CMY). The process is shown in FIG. 26.\nHowever we can avoid much of the color conversion steps if we consider the effect of adding a high-passed-filtered L back into the image\u2014the effect is a change in the luminance of the image. A change in the luminance of a given pixel can be well-approximated by an equal change in linear R, G, and B. Therefore we simply generate L, high-pass-filter L, and apply a proportion of the result equally to R, G, and B.\n188.8.131.52 Convert RGB to L 80\nWe consider the CIE 1976 L*a*b* color space, where L is perceptually uniform. To convert from RGB to L (the luminance channel) we average the minimum and maximum of R, G, and B as follows:\n  L  =                    MIN        \u2061                  (                      R            ,            G            ,            B                    )                    +              MAX        \u2061                  (                      R            ,            G            ,            B                    )                      2  188.8.131.52 High Pass Filter L 84\nA high pass filter 84 can then be applied to the luminance information. Since we are filtering in med-res space rather than CFA resolution space, the size of the sharpening kernel can be scaled up or the high pass result can be scaled appropriately. The exact amount of sharpening will depend on the CFA, but a 3\u00d73 convolution kernel 85 will be sufficient to produce good results.\nIf we were to increase the size of the kernel, Table 12 shows the effective scaling 86 required for a 3\u00d73 convolution in CFA space as applied to 1280 resolution space, using the green channel as the basis for scaling the kernel. From this table it is clear that a 7\u00d77 sized kernel applied to the medium resolution space will be adequate for all sharpening.\nTABLE 12Scale Factors for Convolution FilterFormatScale3 \u00d7 3Kernel in Med-res (1280) SpaceStandard 301.283.843 \u00d7 3 or 5 \u00d7 5Passport 310.641.92none, or 3 \u00d7 3Panoramic 332.567.687 \u00d7 7Thumbnail 320.852.55none, or 3 \u00d7 3\nIf a 3\u00d73 filter 85 were applied on the med-res image, the result will be scaled 86 according to the scale factor used in the general image scale operation. Given the amounts in Table 12 (particularly the Standard print format), we can use a 3\u00d73 filter 85, and then scale the results. The process of producing a single filtered L pixel is shown in FIG. 27.\nThe actual kernel used can be any one of a set of standard highpass filter kernels. A basic but satisfactory highpass filter is shown in this implementation of the PCP in FIG. 49.\n220.127.116.11 Add Filtered L to RGB\nThe next thing to do is to add some proportion of the resultant high pass filtered luminance values back to the luminance channel. The image can then be converted back to RGB (or instead, to CMY). However, a change in luminance can be reasonably approximated by an equal change in R, G, and B (as long as the color space is linear). Consequently we can avoid the color conversions altogether by adding an equal proportion of the high pass filtered luminance value to R, G, and B. The exact proportion of the high-pass-filtered image can be defined by means of a scale factor.\nIf L is the high-pass-filtered luminance pixel, and k is the constant scale factor, we can define the transformation of sharpening R, G, and B as follows:\n                                                        R              \u2032                        =                          R              +              kL                                                                                      G              \u2032                        =                          G              +              kL                                                                                      B              \u2032                        =                          B              +              kL                                            }    \u2062          \u2062      (          limited      \u2062                          \u2062      to      \u2062                          \u2062      255      \u2062                          \u2062      each        )  \nOf course, the scale factor applied to L can be combined with the scale factor in the highpass filter process (see Section 18.104.22.168) for a single scale factor.\nOnce the sharpening has been applied to the RGB pixel, the image can be converted to CMY 83 in order to be printed out.\n3.2.7 Convert to CMY 83\nIn theoretical terms, the conversion from RGB to CMY is simply:C=1\u2212RM=1\u2212GY=1\u2212B\nHowever this conversion assumes that the CMY space has a linear response, which is definitely not true of pigmented inks, and only partially true for dye-based inks. The individual color profile of a particular device (input and output) can vary considerably. Consequently, to allow for accurate conversion, as well as to allow for future sensors, inks, and printers, a more accurate model is required for Printcam.\nThe transformations required are shown in FIG. 28. Lab is chosen because it is perceptually uniform (unlike XYZ). With regards to the mapping from the image sensor gamut to the printer gamut, the printer gamut is typically contained wholly within the sensor gamut.\nRather than perform these transformations exhaustively, excellent results can be obtained via a tri-linear conversion based on 3 sets of 3D lookup tables. The lookup tables contain the resultant transformations for the specific entry as indexed by RGB. Three tables are required: one table 90 mapping RGB to C, one table 91 mapping RGB to M, and one table 92 mapping RGB to Y. Tri-linear interpolation can be used to give the final result for those entries not included in the tables. The process is shown in FIG. 29.\nTri-linear interpolation requires reading 8 values from the lookup table, and performing 7 linear interpolations (4 in the first dimension, 2 in the second, and 1 in the third). High precision can be used for the intermediate values, although the output value is only 8 bits.\nThe size of the lookup table required depends on the linearity of the transformation. The recommended size for each table in this application is 17\u00d717\u00d7174, with each entry 8 bits. A 17\u00d717\u00d717 table is 4913 bytes (less than 5 KB). 4Although a 17 \u221e17 \u221e17 table will give excellent results, it may be possible to get by with only a 9 \u221e9 \u221e9 conversion table (729 bytes). The exact size can be determined by simulation. The 5K conservative-but-definite-results approach was chosen for the purposes of this document.\nTo index into the 17-per-dimension tables, the 8-bit input color components are treated as fixed-point numbers (4:4). The 4 bits of integer give the index, and the 4 bits of fraction are used for interpolation.\n3.2.8 Up Interpolate 67\nThe medium resolution (1280 wide) CMY image must now be up-interpolated to the final print resolution (6400 wide). The ratio is exactly 1:5 in both dimensions.\nAlthough it is certainly possible to bi-linearly interpolate the 25 values (1:5 in both X and Y dimensions), the resultant values will not be printed contone. The results will be dithered and printed bi-level. Given that the contone 1600 dpi results will be turned into dithered bi-level dots, the accuracy of bi-linear interpolation from 320 dpi to 1600 dpi will not be visible (the medium resolution was chosen for this very reason). Pixel replication will therefore produce good results.\nPixel replication simply involves taking a single pixel, and using it as the value for a larger area. In this case, we replicate a single pixel to 25 pixels (a 5\u00d75 block). If each pixel were contone, the result may appear blocky, but since the pixels are to be dithered, the effect is that the 25 resultant bi-level dots take on the contone value. The process is shown in FIG. 30.\n3.2.9 Halftone 68\nThe printhead 2 is only capable of printing dots in a bi-level fashion. We must therefore convert from the contone CMY to a dithered CMY image. More specifically, we produce a dispersed dot ordered dither using a stochastic dither cell, converting a contone CMY image into a dithered bi-level CMY image.\nThe 8-bit 1600 dpi contone value is compared to the current position in the dither cell 93. If the 80-bit contone value is greater than the dither cell value, an output bit of 1 is generated. Otherwise an output bit of 0 is generated. This output bit will eventually be sent to the printhead and control a single nozzle to produce a single C, M, or Y dot. The bit represents whether or not a particular nozzle will fire for a given color and position.\nThe same position in the dither cell 93 can be used for C, M, and Y. This is because the actual printhead 2 produces the C, M, and Y dots for different lines in the same print cycle. The staggering of the different colored dots effectively gives us staggering in the dither cell.\nThe half-toning process can be seen in FIG. 31.\nThe size of the dither cell 93 depends on the resolution of the output dots. Since we are producing 1600 dpi dots, the cell size should be larger than 32\u00d732. In addition, to allow the dot processing order to match the printhead segments, the size of the dither cell should ideally divide evenly into 800 (since there are 800 dots in each segment of the printhead).\nA dither cell size of 50\u00d750 is large enough to produce high quality results, and divides evenly into 800 (16 times). Each entry of the dither cell is 8 bits, for a total of 2500 bytes (approximately 1.5 KB).\n3.2.10 Reformat for Printer 69\nThe final process before being sent to the printer is for the dots to be formatted into the correct order for being sent to the printhead. The dots must be sent to the printhead in the correct order\u201424 dots at a time as defined in Section 2.2.1.\nIf the dots can be produced in the correct order for printing (i.e. the up-interpolate and dither functions generate their data in the correct order), then those dot values (each value is 1 bit) can simply be collected, and sent off in groups of 24. The process is shown in FIG. 32.\nThe 24 bit groups can then be sent to the printhead 2 by the Memjet Interface 15.\n4 CPU CORE AND MEMORY\n4.1 CPU Core 10\nThe PCP 3 incorporates a simple micro-controller CPU core 10 to synchronize the image capture and printing image processing chains and to perform Printcam's general operating system duties including the user-interface. A wide variety of CPU cores are suitable: it can be any processor core with sufficient processing power to perform the required calculations and control functions fast enough to met consumer expectations.\nSince all of the image processing is performed by dedicated hardware, the CPU does not have to process pixels. As a result, the CPU can be extremely simple. However it must be fast enough to run the stepper motor during a print (the stepper motor requires a 5 KHz process). An example of a suitable core is a Philips 8051 micro-controller running at about 1 MHz.\nThere is no need to maintain instruction set continuity between different Printcam models. Different PCP chip designs may be fabricated by different manufacturers, without requiring to license or port the CPU core. This device independence avoids the chip vendor lock-in such as has occurred in the PC market with Intel.\nAssociated with the CPU Core is a Program ROM 13 and a small Program Scratch RAM 14.\nThe CPU 10 communicates with the other units within the PCP 3 via memory-mapped I\/O. Particular address ranges map to particular units, and within each range, to particular registers within that particular unit. This includes the serial and parallel interfaces.\n4.2 Program Rom 13\nA small Program Flash ROM 13 is incorporated into the PCP 3. The ROM size depends on the CPU chosen, but should not be more than 16\u201332 KB.\n4.3 Program Ram 14\nLikewise, a small scratch RAM area 14 is incorporated into the PCP 3. Since the program code does not have to manipulate images, there is no need for a large scratch area. The RAM size depends on the CPU chosen (e.g. stack mechanisms, subroutine calling conventions, register sizes etc.), but should not be more than about 4 KB.\n4.4 CPU Memory Decoder 16\nThe CPU Memory Decoder 16 is a simple decoder for satisfying CPU data accesses. The Decoder translates data addresses into internal PCP register accesses over the internal low speed bus, and therefore allows for memory mapped I\/O of PCP registers.\n5 Communication Interfaces\n5.1 USB Serial Port Interface 17\nThis is a standard USB serial port, connected to the internal chip low-speed bus 18. The USB serial port is controlled by the CPU 10. The serial port allows the transfer of images to and from the Printcam, and allows DPOF (Digital Print Order Format) printing of transferred photos under external control.\n5.2 QA Chip Serial Interface 19\nThis is two standard low-speed serial ports, connected to the internal chip low-speed bus 18. The CPU-mediated protocol between the two is used to authenticate the print roll [1,2] and for the following functions:    Acquire ink characteristics    Acquire the recommended drop volume    Track the amount of paper printed and request new print roll when there is insufficient paper to print the requested print format.\nThe reason for having two ports is to connect to both the on-camera QA Chip 4 and to the print roll's QA Chip 5 using separate lines. The two QA chips are implemented as Authentication Chips [2]. If only a single line is used, a clone print roll manufacturer could usurp the authentication mechanism [1].\n5.2.1 Print Roll's QA Chip 5\nEach print roll consumable contains its own QA chip 5. The QA chip contains information required for maintaining the best possible print quality, and is implemented using an Authentication Chip[2]. The 256 bits of data are allocated as follows:\nTABLE 13Print roll's 256 bits (16M[n]AccessDescription0RO5Basic Header, Flags etc. (16 bits)1ROSerial number (16 bits)2ROBatch number (16 bits)3DO6Paper remaining in mm (16 bits)4ROCyan ink properties (32 bits)5RO6ROMagenta ink properties (32 bits)7RO8ROYellow ink properties (32 bits)9RO10\u201312ROFor future expansion = 0 (48 bits)13\u201315RORandom bits, different in each chip (48 bits)5Read Only6Decrement Only\nBefore each print, the amount of paper remaining is checked by the CPU to ensure that there is enough for the currently specified print format. After each print has started, the amount of paper remaining must be decremented in the print roll's QA chip by the CPU.\n5.3 Parallel Interface 6\nThe parallel interface 6 connects the PCP 3 to individual static electrical signals. The CPU is able to control each of these connections as memory-mapped I\/O via the low-speed bus. (See Section 4.4 for more details on memory-mapped I\/O).\nTable 14 shows the connections to the parallel interface.\nTABLE 14Connections to Parallel InterfaceConnectionDirectionPinsPaper transport stepper motorOut4Guillotine motorOut1Focus MotorOut1Capping solenoidOut1Flash triggerOut1Status LCD segment driversOut7Status LCD common driversOut4Paper pull sensorIn1ButtonsIn4TOTAL245.4 JTAG Interface 7\nA standard JTAG (Joint Test Action Group) Interface 7 is included in the PCP 3 for testing purposes. Due to the complexity of the chip, a variety of testing techniques are required, including BIST (Built In Self Test) and functional block isolation. An overhead of 10% in chip area is assumed for overall chip testing circuitry.\n6 Image RAM 11\nThe Image RAM 11 is used to store the captured image 42. The Image RAM is multi-level Flash (2-bits per cell) so that the image is retained after the power has been shut off.\nThe total amount of memory required for the planarized linear RGB image is 1,500,000 bytes (approximately 1.5 MB) arranged as follows:    R: 750\u00d7500=375,000 bytes    B: 750\u00d7500=375,000 bytes    G: 750\u00d71000=750,000 bytes\nThe image is written by the Image Capture Unit, and read by both the Image Histogram Unit 8 and the Print Generator Unit 99. The CPU 10 does not have direct random access to this image memory. It must access the image pixels via the Image Access Unit.\n7 Image Capture Unit 12\nThe Image Capture Unit contains all the functionality required by the Image Capture Chain, as described in Section 3.1. The Image Capture Unit accepts pixel data via the Image Sensor Interface 98, linearizes the RGB data via a lookup table 96, and finally writes the linearized RGB image out to RAM in planar format. The process is shown in FIG. 33.\n7.1 Image Sensor Interface 98\nThe Image Sensor Interface (ISI) 98 is a state machine that sends control information to the CMOS Image Sensor, including frame sync pulses and pixel clock pulses in order to read the image. Most of the ISI is likely to be a sourced cell from the image sensor manufacturer. The ISI is itself controlled by the Image Capture Unit State Machine 97.\n7.1.1 Image Sensor Format\nAlthough a variety of image sensors are available, we only consider the Bayer color filter array (CFA). The Bayer CFA has a number of attributes which are defined here.\nThe image captured by the CMOS sensor (via a taking lens) is assumed to have been sufficiently filtered so as to remove any aliasing artifacts. The sensor itself has an aspect ratio of 3:2, with a resolution of 1500\u00d71000 samples. The most likely pixel arrangement is the Bayer color filter array (CFA), with each 2\u00d72 pixel block arranged in a 2 G mosaic as shown in FIG. 15:\nEach contone sample of R, G, or B (corresponding to red, green, and blue respectively) is 10-bits. Note that each pixel of the mosaic contains information about only one of R, G, or B. Estimates of the missing color information must be made before the image can be printed out.\nThe CFA is considered to perform some amount of fixed pattern noise (FPN) suppression. Additional FPN suppression may required.\n7.2 Lookup Table 96\nThe lookup table 96 is a ROM mapping the sensor's RGB to a linear RGB. It matches the Linearize RGB process 40 described in Section 3.1.2. As such, the ROM is 3 KBytes (3\u00d71024\u00d78-bits). 10 bits of address come from the ISI, while the 2 bits of TableSelect are generated by the Image Capture Unit's State Machine 97.\n7.3 State Machine 97\nThe Image Capture Unit's State Machine 97 generates control signals for the Image Sensor Interface 1, and generates addresses for linearizing the RGB 40 and for planarizing the image data 41.\nThe control signals sent to the ISI 98 inform the ISI to start capturing pixels, stop capturing pixels etc.\nThe 2-bit address sent to the Lookup Table 96 matches the current line being read from the ISI. For even lines (0, 2, 4 etc.), the 2-bit address is Red, Green, Red, Green etc. For odd lines (1, 3, 5 etc.), the 2-bit address is Green, Blue, Green, Blue. This is true regardless of the orientation of the camera.\nThe 21-bit address sent to the Image RAM 11 is the write address for the image. Three registers hold the current address for each of the red, green, and blue planes. The addresses increment as pixels are written to each plane.\n7.3.1 Registers\nThe Image Capture Unit contains a number of registers:\nTABLE 15Registers in Image Capture UnitNameBitsDescriptionMaxPixels12Number of pixels each rowMaxRows12Number of rows of pixels in imageCurrentPixel12Pixel currently being fetchedCurrentRow12Row currently being processedNextR21The address in Image RAM to store the next Red pixel. Set to startaddress of red plane before image capture. After image capture, thisregister will point to the byte after the red plane.NextG21The address in Image RAM to store the next Green pixel. Set to startaddress of green plane before image capture. After image capture,this register will point to the byte after the green plane.NextB21The address in Image RAM to store the next Blue pixel. Set to startaddress of blue plane before image capture. After image capture,this register will point to the byte after the blue plane.EvenEven2Address to use for even rows\/even pixelsEvenOdd2Address to use for even rows\/odd pixelsOddEven2Address to use for odd rows\/even pixelsOddOdd2Address to use for odd rows\/odd pixelsGo1Writing a 1 here starts the capture. Writing a 0 here stops the imagecapture. A 0 is written here automatically by the state machine afterMaxRows of MaxPixels have been captured.\nIn addition, the Image Sensor Interface 98 contains a number of registers. The exact registers will depend on the Image Sensor 1 chosen.\n8 Image Access Unit 9\nThe Image Access Unit 9 produces the means for the CPU 10 to access the image in ImageRAM 11. The CPU 10 can read pixels from the image in ImageRAM 11 and write pixels back.\nPixels could be read for the purpose of image storage (e.g. via the USB) 17, or for simple image processing. Pixels could be written to ImageRAM 11 after the image processing, as a previously saved image (loaded via USB), or images for test pattern purposes. Test patterns could be synthetic images, specific test images (loaded via the USB) or could be 24-bit nozzle firing values to be directly loaded into the printhead via the test mode of the Print Generator Unit 99.\nThe Image Access Unit 9 is a straightforward access mechanism to ImageRAM 11, and operates quite simply in terms of 3 registers as shown in Table 16.\nTABLE 16IAU RegistersNameBitsDescriptionImageAddress21Address to read or write in ImageRAMMode30 = Read from ImageAddress into Value.1 = Write Value to ImageAddress.Value8Value stored at ImageAddress (if Mode = Read)Value to store at ImageAddress (if Mode = Write)\nThe structure of the Image Access Unit is very simple, as shown in FIG. 34.\nThe State Machine 101 simply performs the read\/write from\/to ImageRAM 11 whenever the CPU 10 writes to the Mode register.\n9 Image Histogram Unit 8\nThe Image Histogram Unit (IHU) 8 is designed to generate histograms of images as required by the Print Image Processing Chain described in Section 3.2.2. The IHU only generates histograms for planar format images with samples of 8 bits each.\nThe Image Histogram Unit 8 is typically used three times per print. Three different histograms are gathered, one per color plane. Each time a histogram is gathered, the results are analyzed in order to determine the low and high thresholds, scaling factors etc. for use in the remainder of the print process. For more information on how the histogram should be used, see Section 22.214.171.124 and Section 3.2.4.\n9.1 Histogram Ram 102\nThe histogram itself is stored in a 256-entry RAM 102, each entry being 20 bits. The histogram RAM is only accessed from within the IHU. Individual entries are read from and written to as 20-bit quantities.\n9.2 State Machine and Registers 103\nThe State Machine 103 follows the pseudocode described in Section 184.108.40.206. It is controlled by the registers shown in Table 17.\nTABLE 17Registers in Image Histogram UnitNameBitsDescriptionTotalPixels20The number of pixels to count (decrements until 0)StartAddress21Where to start counting fromPixelsRemaining20How many pixels remain to be countedPixelValue8A write to this register loads PixelCount with the PixelValueentry from the histogram.PixelCount20The number of PixelValue pixels counted in the currenthistogram. It is valid after a write to PixelValue.ClearCount1Determines whether the histogram count will be cleared atthe start of the histogram process. A 1 causes the counts tobe cleared, and a 0 causes the counts to remain untouched(i.e. the next histogram adds to the existing counts).Go1Writing a 1 here starts the histogram process. Writing a 0here stops the histogram process. A 0 is written hereautomatically by the state machine after TotalPixels hascounted down to 0.\nThe typical usage of the registers is to set up TotalPixels with the total number of pixels to include in the count (e.g. 375,000 for red), StartAddress with the address of the red plane, ClearCount with 1, and write a 1 to the Go register. Once the count has finished, the individual values in the histogram can be determined by writing 0\u2013255 to PixelValue and reading the corresponding PixelCount.\n10 Printhead Interface 105\nThe Printhead Interface (PHI) 105 is the means by which the PCP 3 loads the Memjet printhead 2 with the dots to be printed, and controls the actual dot printing process. The PHI is a logical wrapper for a number of units, namely:    a Memjet Interface (MJI) 15, which transfers data to the Memjet printhead, and controls the nozzle firing sequences during a print.    a Print Generator Unit (PGU) 99 is an implementation of most of the Print Chain described in Section 3.2 on page 24, as well as providing a means of producing test patterns. The PGU takes a planarized linear RGB obtained from a CFA format captured image from the ImageRAM 11, and produces a 1600 dpi dithered CMY image in real time as required by the Memjet Interface 15. In addition, the PGU has a Test Pattern mode, which enables the CPU 10 to specify precisely which nozzles are fired during a print.\nThe units within the PHI are controlled by a number of registers that are programmed by the CPU.\nThe internal structure of the Printhead Interface is shown in FIG. 36.\n10.1 Memjet Interface 15\nThe Memjet Interface (MJI) 15 connects the PCP to the external Memjet printhead, providing both data and appropriate signals to control the nozzle loading and firing sequences during a print.\nThe Memjet Interface 15 is simply a State Machine 106 (see FIG. 38) which follows the printhead loading and firing order described in Section 2.2, and includes the functionality of-the Preheat cycle and Cleaning cycle as described in Section 2.4.1 and Section 2.4.2.\nThe MJI 15 loads data into the printhead from a choice of 2 data sources:    All 1s. This means that all nozzles will fire during a subsequent Print cycle, and is the standard mechanism for loading the printhead for a Preheat or Cleaning cycle.    From the 24-bit input held in the Transfer register of the PGU 99. This is the standard means of printing an image, whether it be a captured photo or test pattern. The 24-bit value from the PGU is directly sent to the printhead and a 1-bit 'Advance' control pulse is sent to the PGU. At the end of each line, a 1-bit 'AdvanceLine' pulse is also sent to the PGU.\nThe MJI 15 must be started after the PGU 99 has already prepared the first 24-bit transfer value. This is so the 24-bit data input will be valid for the first transfer to the printhead.\nThe MJI 15 is therefore directly connected to the Print Generator Unit 99 and the external printhead 2. The basic structure is shown in FIG. 38.\n10.1.1 Connections to Printhead\nThe MJI 15 has the following connections to the printhead 2, with the sense of input and output with respect to the MJI 15. The names match the pin connections on the printhead (see Section 2).\nTABLE 18Printhead ConnectionsName#PinsI\/ODescriptionChromapodSelect4OSelect which chromapod will fire (0\u20139)NozzleSelect4OSelect which nozzle from the pod will fire (0\u20139)AEnable1OFiring pulse for phasegroup ABEnable1OFiring pulse for phasegroup BCDataIn[0\u20137]8OCyan output to cyan shift register of segments 0\u20137MDataIn[0\u20137]8OMagenta input to magenta shift register of segments 0\u20137YDataIn[0\u20137]8OYellow input to yellow shift register of segments 0\u20137SRClock1OA pulse on SRClock (ShiftRegisterClock) loads thecurrent values from CDataIn[0\u20137], MDataIn[0\u20137] andYDataIn[0\u20137] into the 24 shift registers of the printheadPTransfer1OParallel transfer of data from the shift registers to theprinthead's internal NozzleEnable bits (one per nozzle).SenseSegEnable1OA pulse on SenseSegEnable ANDed with data onCDataIn[n]selects the sense lines for segment n.Tsense1ITemperature senseVsense1IVoltage senseRsense1IResistivity senseWsense1IWidth senseTOTAL4110.1.2 Firing Pulse Duration\nThe duration of firing pulses on the AEnable and BEnable lines depend on the viscosity of the ink (which is dependent on temperature and ink characteristics) and the amount of power available to the printhead. The typical pulse duration range is 1.3 to 1.8 \u03bcs. The MJI therefore contains a programmable pulse duration table, indexed by feedback from the printhead. The table of pulse durations allows the use of a lower cost power supply, and aids in maintaining more accurate drop ejection.\nThe Pulse Duration table has 256 entries, and is indexed by the current Vsense and Tsense settings. The upper 4-bits of address come from Vsense, and the lower 4-bits of address come from Tsense. Each entry is 8 bits, and represents a fixed point value in the range of 0\u20134 \u03bcs. The process of generating the AEnable and BEnable lines is shown in FIG. 38.\nThe 256-byte table is written by the CPU 10 before printing the photo. Each 8-bit pulse duration entry in the table combines:    Brightness settings    Viscosity curve of ink (from the QA Chip) 5    Rsense    Wsense    Tsense    Vsense10.1.3 Dot Counts\nThe MJI 15 maintains a count of the number of dots of each color fired from the printhead 2. The dot count for each color is a 32-bit value, individually cleared under processor control. Each dot count can hold a maximum coverage dot count of 69 6-inch prints, although in typical usage, the dot count will be read and cleared after each print.\nWhile in the initial Printcam product, the consumable contains both paper and ink, it is conceivable that a different Printcam model has a replaceable ink-only consumable. The initial Printcam product can countdown the amount of millimeters remaining of paper (stored in the QA chip 5\u2014see Section 5.2) to know whether there is enough paper available to print the desired format. There is enough ink for full coverage of all supplied paper. In the alternative Printcam product, the dot counts can be used by the CPU 10 to update the QA chip 5 in order to predict when the ink cartridge runs out of ink. The processor knows the volume of ink in the cartridge for each of C, M, and Y from the QA chip 5. Counting the number of drops eliminates the need for ink sensors, and prevents the ink channels from running dry. An updated drop count is written to the QA chip 5 after each print. A new photo will not be printed unless there is enough ink left, and allows the user to change the ink without getting a dud photo which must be reprinted.\nThe layout of the dot counter for cyan is shown in FIG. 39. The remaining 2 dot counters (MDotCount and YDotCount, for magenta and yellow respectively) are identical in structure.\n10.1.4 Registers\nThe CPU 10 communicates with the MJI 15 via a register set. The registers allow the CPU to parameterize a print as well as receive feedback about print progress.\nThe following registers are contained in the MJI:\nTABLE 19Memjet Interface RegistersRegister NameDescriptionPrint ParametersNumTransfersThe number of transfers required to load the printhead (usually 800).This is the number of pulses on the SRClock and the number of 24-bitdata values to transfer for a given line.PulseDurationFixed point number to determine the duration of a single pulse on theColorEnable lines. Duration range = 0\u20136 \u03bcs.NumLinesThe number of Load\/Print cycles to perform.Monitoring the PrintStatusThe Memjet Interface's Status RegisterLinesRemainingThe number of lines remaining to be printed. Only valid while Go = 1.Starting value is NumLines.TransfersRemainingThe number of transfers remaining before the Printhead is consideredloaded for the current line. Only valid while Go = 1.SenseSegmentThe 8-bit value to place on the Cyan data lines during a subsequentfeedback SenseSegSelect pulse. Only 1 of the 8 bits should be set,corresponding to one of the 8 segments.SetAllNozzlesIf non-zero, the 24-bit value written to the printhead during the LoadDotsprocess is all 1s, so that all nozzles will be fired during the subsequentPrintDots process. This is used during the preheat and cleaning cycles.If 0, the 24-bit value written to the printhead comes from the PrintGenerator Unit. This is the case during the actual printing of the photoand any test images.ActionsResetA write to this register resets the MJI, stops any loading or printingprocesses, and loads all registers with 0.SenseSegSelectA write to this register with any value clears the Feedback bit of theStatus register, and sends a pulse on the SenseSegSelect line if theLoadingDots and PrintingDots status bits are all 0. If any of the statusbits are set, the Feedback bit is cleared and nothing more is done.Once the various sense lines have been tested, the values are placed inthe Tsense, Vsense, Rsense, and Wsense registers, and then theFeedback bit of the Status register is set. The feedback continues duringany subsequent print operations.GoA write of 1 to this bit starts the LoadDots\/PrintDots cycles. A total ofNumLines lines are printed, each containing NumTransfers 24-bittransfers. As each line is printed, LinesRemaining decrements, andTransfersRemaining is reloaded with NumTransfers again. The statusregister contains print status information. Upon completion of NumLines,the loading\/printing process stops and the Go bit is cleared. During thefinal print cycle, nothing is loaded into the printhead.A write of 0 to this bit stops the print process, but does not clear anyother registers.ClearCountsA write to this register clears the CDotCount, MDotCount, andYDotCount, registers if bits 0, 1, or 2 respectively are set. Consequentlya write of 0 has no effect.FeedbackTsenseRead only feedback of Tsense from the last SenseSegSelect pulse sentto segment SenseSegment. Is only valid if the FeedbackValid bit of theStatus register is set.VsenseRead only feedback of Vsense from the last SenseSegSelect pulse sentto segment SenseSegment. Is only valid if the FeedbackValid bit of theStatus register is set.RsenseRead only feedback of Rsense from the last SenseSegSelect pulse sentto segment SenseSegment. Is only valid if the FeedbackValid bit of theStatus register is set.WsenseRead only feedback of Wsense from the last SenseSegSelect pulse sentto segment SenseSegment. Is only valid if the FeedbackValid bit of theStatus register is set.CDotCountRead only 32-bit count of cyan dots sent to the printhead.MDotCountRead only 32-bit count of magenta dots sent to the printhead.YDotCountRead only 32-bit count of yellow dots sent to the printhead.\nThe MJl's Status Register is a 16-bit register with bit interpretations as follows:\nTABLE 20MJI Status RegisterNameBitsDescriptionLoadingDots1If set, the MJI is currently loading dots, with the number of dotsremaining to be transferred in TransfersRemaining.If clear, the MJI is not currently loading dotsPrintingDots1If set, the MJI is currently printing dots.If clear, the MJI is not currently printing dots.PrintingA1This bit is set while there is a pulse on the AEnable linePrintingB1This bit is set while there is a pulse on the BEnable lineFeedbackValid1This bit is set while the feedback values Tsense, Vsense, Rsense,and Wsense are valid.Reserved3\u2014PrintingChromapod4This holds the current chromapod being fired while the PrintingDotsstatus bit is set.PrintingNozzles4This holds the current nozzle being fired while the PrintingDotsstatus bit is set.10.1.5 Preheat and Cleaning Cycles\nThe Cleaning and Preheat cycles are simply accomplished by setting appropriate registers:    SetAllNozzles=1    Set the PulseDuration register to either a low duration (in the case of the preheat mode) or to an appropriate drop ejection duration for cleaning mode.    Set NumLines to be the number of times the nozzles should be fired    Set the Go bit and then wait for the Go bit to be cleared when the print cycles have completed.10.2 Print Generator Unit 99\nThe Print Generator Unit (PGU) 99 is an implementation of most of the Print Chain described in Section 3.2, as well as providing a means of producing test patterns.\nFrom the simplest point of view, the PGU provides the interface between the Image RAM 11 and the Memjet Interface 15, as shown in FIG. 41. The PGU takes a planarized linear RGB obtained from a CFA format captured image from the ImageRAM, and produces a 1600 dpi dithered CMY image in real time as required by the Memjet Interface. In addition, the PGU 99 has a Test Pattern mode, which enables the CPU 10 to specify precisely which nozzles are fired during a print. The MJI 15 provides the PGU 99 with an Advance pulse once the 24-bits have been used, and an AdvanceLine pulse at the end of the line.\nThe PGU 99 has 2 image processing chains. The first, the Test Pattern mode, simply reads data directly from Image RAM 11, and formats it in a buffer ready for output to the MJI. The second contains the majority of Print Chain functions (see Section 3.2). The Print Chain shown in FIG. 18 contains the functions:    Gather Statistics 60    Rotate Image 61    White Balance 62    Range Expansion 63    Resample 64    Sharpen 65    Convert to CMY 66    Up-Interpolate 67    Halftone 68    Reformat for Printer 69\nThe PGU 99 contains all of these functions with the exception of Gather Statistics 60. To perform the Gather Statistics step, the CPU 10 calls the Image Histogram Unit 8 three times (once per color channel), and applies some simple algorithms. The remainder of the functions are the domain of the PGU 99 for reasons of accuracy and speed: accuracy, because there would be too much memory required to hold the entire image at high accuracy, and speed, because a simple CPU 10 cannot keep up with the real-time high-speed demands of the Memjet printhead 2.\nThe PGU 99 takes as input a variety of parameters, including RGB to CMY conversion tables, constants for performing white balance and range expansion, scale factors for resampling, and image access parameters that allow for rotation.\nThe two process chains can be seen in FIG. 20. The most direct chain goes from the Image RAM 11 to Buffer 5 via the Test Pattern Access process 110. The other chain consists of 5 processes, all running in parallel. The first process 111 performs Image Rotation, White Balance and Range Expansion. The second process 112 performs Resampling. The third process 65 performs sharpening, the fourth process 66 performs color conversion. The final process 113 performs the up-interpolation, halftoning, and reformatting for the printer. The processes are connected via buffers, only a few bytes between some processes, and a few kilobytes for others.\nWe look at these processes and buffers in a primarily reverse order, since the timing for the printhead drives the entire process. Timings for particular processes and buffer size requirements are then more apparent. In summary however, the buffer sizes are shown in Table 21.\nTABLE 21Buffer sizes for Print Generator UnitSizeBuffer(bytes)Composition of BufferBuffer 1188Red Buffer = 6 lines of 6 entries@ 10-bits each = 45 bytesBlue Buffer = 6 lines of 6 entries@ 10-bits each = 45 bytesGreen Buffer = 13 lines of 6 entries@ 10-bits each = 97.5 bytesBuffer 2246 \u00d7 4 RAM3 lines of 4 entries of L @ 8-bits each = 12 bytes3 colors \u00d7 4 entries @ 8-bits each = 12 bytesBuffer 333 colors(RGB) @ 8-bits eachBuffer 423,0403 colors(CMY) \u00d7 6 lines \u00d7 1280 contonepixels @ 8-bits eachBuffer 593 \u00d7 24 bitsTOTAL23,264\nApart from a number of registers, some of the processes have significant lookup tables or memory components. These are summarized in Table 22.\nTABLE 22Memory requirements within PGU ProcessesSizeUnit(bytes)Composition of RequirementsRotate\/White Balance\/0Range ExpandResample\/Convert to L1,1523 kernels, each64 \u00d7 4 \u00d7 12-bitsSharpen0Convert to CMY14,7393 conversion tables, each17 \u00d7 17 \u00d7 17 \u00d7 8-bitsUpInterpolate\/Halftone\/2,500Dither Cell, 50 \u00d7 50 \u00d7 8-bitsReformatTest Pattern Access0TOTAL18,39110.2.1 Test Pattern Access\nThe Test Pattern Access process 110 is the means by which test patterns are produced. Under normal user circumstances, this process will not be used. It is primarily for diagnostic purposes.\nThe Test Pattern Access 110 reads the Image RAM 11 and passes the 8-bit values directly to Buffer 5 118 for output to the Memjet Interface. It does not modify the 8-bit values in any way. The data in the Image RAM 11 would be produced by the CPU 10 using the Image Access Unit 9.\nThe data read from Image RAM 11 is read in a very simple wraparound fashion. Two registers are used to describe the test data: the start address of the first byte, and the number of bytes. When the end of the data is reached, the data is read again from the beginning.\nThe structure of the Test Pattern Access Unit 110 is shown in FIG. 42.\nAs can be seen in FIG. 43, the Test Pattern Access Unit 110 is little more than an Address Generator 119. When started, and with every AdvanceLine signal, the generator reads 3 bytes, produces a TransferWriteEnable pulse, reads the next 3 bytes, and then waits for an Advance pulse. At the Advance pulse, the TransferWriteEnable pulse is given, the next 3 bytes are read, and the wait occurs again. This continues until the AdvanceLine pulse, whereupon the process begins again from the current address.\nIn terms of reading 3 bytes, the Address Generator 119 simply reads three 8-bit values from ImageRAM 11 and writes them to Buffer 5 118. The first 8-bit value is written to Buffer 5's 8-bit address 0, the next is written to Buffer 5's 8-bit address 1, and the third is written to Buffer 5's 8-bit address 2. The Address Generator 119 then waits for an Advance pulse before doing the same thing again.\nThe addresses generated for the Image RAM 11 are based on a start address and a byte count as shown in Table 23.\nTABLE 23Test Pattern Access RegistersRegister NameDescriptionTestModeEnabledIf 1, TestMode is enabled.If 0, TestMode is not enabled.DataStartStart Address of test data in Image RAMDataLengthNumber of 3 bytes in test data\nThe following pseudocode illustrates the address generation. The AdvanceLine and Advance pulses are not shown.\nDo Forever\u2003Adr = DataStart\u2003Remaining = DataLength\u2003Read Adr into Buffer 5 (0), Adr=Adr+1\u2003Read Adr into Buffer 5 (1), Adr=Adr+1\u2003Read Adr into Buffer 5 (2), Adr=Adr+1\u2003Remaining = Remaining\u22121\u2003if (Remaining = 0)\u2003\u2003Remaining = DataLengthEndDo\nIt is the responsibility of the CPU 10 to ensure that the data is meaningful for the printhead 2. Byte 0 is the nozzle-fire data for the 8 segments of cyan (bit 0=segment 0 etc.), Byte 1 is the same for magenta, and Byte 2 for yellow. Alternate sets of 24 bits are for odd\/even pixels separated by 1 horizontal dot line.\n10.2.2 Buffer 5 118\nBuffer 5 118 holds the generated dots from the entire Print Generation process. Buffer 5 consists of a 24-bit shift register to hold dots generated one at a time from the UHRU 113 (Uplnterpolate-Halftone and Reformat Unit), 3 8-bit registers to hold the data generated from the TPAU (Test Pattern AccessUnit), and a 24-bit register used as the buffer for data transfer to the MJI (Memjet Interface). The Advance pulse from the MJI loads the 24-bit Transfer register with all 24-bits, either from the 3 8-bit registers or the single 24-bit shift register.\nBuffer 5 therefore acts as a double buffering mechanism for the generated dots, and has a structure as shown in FIG. 43.\n10.2.3 Buffer 4 117\nBuffer 4 117 holds the calculated CMY intermediate resolution (1280-res) contone image. Buffer 4 is generated by the Color Conversion process 66, and accessed by the Up-interpolate, Halftone and Reformat process 113 in order to generate output dots for the printer.\nThe size of the Contone Buffer is dependent on the physical distance between the nozzles on the printhead. As dots for one color are being generated for one physical line, dots for a different color on a different line are being generated. The net effect is that 6 different physical lines are printed at the one time from the printer\u2014odd and even dots from different output lines, and different lines per color. This concept is explained and the distances are defined in Section 2.1.1.\nThe practical upshot is that there is a given distance in high-res dots from the even cyan dots through the magenta dots to the odd yellow dots. In order to minimize generation of RGB and hence CMY, the medium res contone pixels that generate those high-res dots are buffered in Buffer 4.\nSince the ratio of medium-res lines to high-res lines is 1:5, each medium res line is sampled 5 times in each dimension. For the purposes of buffer lines, we are only concerned with 1 dimension, so only consider 5 dot lines coming from a single pixel line. The distance between nozzles of different colors is 4\u20138 dots (depending on Memjet parameters). We therefore assume 8, which gives a separation distance of 16 dots, or 17 dots in inclusive distance. The worst case scenario is that the 17 dot lines includes the last dot line from a given pixel line. This implies 5 pixel lines, with dot lines generated as 1, 5, 5, 5, 1, and allows an increase of nozzle separation to 10.\nTo ensure that the contone generation process writing to the buffer does not interfere with the dot generation process reading from the buffer, we add an extra medium-res line per color, for a total of 6 lines per color.\nThe contone buffer is therefore 3 colors of 6 lines, each line containing 1280 8-bit contone values. The total memory required is 3\u00d76\u00d71280=23040 bytes (22.5 KBytes). The memory only requires a single 8-bit read per cycle, and a single 8-bit write every 25 cycles (each contone pixel is read 25 times). The structure of Buffer 4 is shown in FIG. 44.\nBuffer 4 can be implemented as single cycle double access (read and write) RAM running at the nominal speed of the printhead dot generation process, or can be implemented as RAM running 4% faster with only a single read or write access per cycle.\nBuffer 4 is set to white (all 0) before the start of the print process.\n10.2.4 Uplnterpolate, Halftone, and Reformat for Printer\nAlthough the Up-interpolate, Halftone, and Reformat For Printer tasks 113 are defined as separate tasks by Section 3.2.8, Section 3.2.9 and Section 3.2.10 respectively, they are implemented as a single process in the hardware implementation of the PCP 3.\nThe input to the Up-interpolate, Halftone and Reformat Unit (UHRU) 113 is the contone buffer (Buffer 4) 117 containing the pre-calculated CMY 1280-res (intermediate resolution) image. The output is a set of 24-bit values in the correct order to be sent to the Memjet Interface 15 for subsequent output to the printhead via Buffer 5 118. The 24 output bits are generated 1 bit at a time, and sent to the 24-bit shift register in Buffer 5 118.\nThe control of this process occurs from the Advance and AdvanceLine signals from the MJI 15. When the UHRU 113 starts up, and after each AdvanceLine pulse, 24 bits are produced, and are clocked into the 24-bit shift register of Buffer 5 by a ShiftWriteEnable signal. After the 24th bit has been clocked in, a TransferWriteEnable pulse is given, and the next 24 bits are generated. After this, the UHRU 113 waits for the Advance pulse from the MJI. When the Advance pulse arrives, the TransferWriteEnable pulse is given to Buffer 5 118, and the next 24 bits are calculated before waiting again. In practice, once the first Advance pulse is given, synchronization has occurred and future Advance pulses will occur every 24 cycles thereafter.\nThe Uplnterpolate, Halftone and Reformat process can be seen in FIG. 45.\nThe Halftone task is undertaken by the simple 8-bit unsigned comparator 120. The two inputs to the comparator come from the Staggered Dither Cell 121 and Buffer 4 117. The order that these values are presented to the Unsigned Comparator 120 is determined by the Address Generator State Machine 122, which ensures that the addresses into the 1280-res image match the segment-oriented order required for the printhead. The Address Generator State Machine 122 therefore undertakes the Up-Interpolation and Reformatting for Printer tasks. Rather than simply access an entire line at a time at high resolution, and then reformat the line according to the printer lookup requirements (as described in Section 3.2.10), the reformatting is achieved by the appropriate addressing of the contone buffer (Buffer 4) 117, and ensuring that the comparator 120 uses the correct lookup from the dither cell 121 to match the staggered addresses.\nThe Halftoning task is the same as described by Section 3.2.9. However, since the dot outputs are generated in the correct order for the printhead, the size of the Dither Cell 121 is chosen so that it divides evenly into 800. Consequently a given position in the dither cell for one segment will be the same for the remaining 7 segments. A 50\u00d750 dither cell provides a satisfactory result. As described in Section 3.2.9, the same position in the dither cell can be used for different colors due to the fact that different lines are being generated at the same time for each of the colors. The addressing for the dither cell is therefore quite simple. We start at a particular row in the Staggered Dither cell (e.g. row 0). The first dither cell entry used is Entry 0. We use that entry 24 times (24 cycles) to generate the 3 colors for all 8 segments, and then advance to Entry 1 of row 0. After Entry 49, we revert back to Entry 0. This continues for all 19,200 cycles in order to generate all 19,200 dots. The Halftone Unit then stops and waits for the AdvanceLine pulse which causes the address generator to advance to the next row in the dither cell.\nThe Staggered Dither cell 121 is so called because it differs from a regular dither cell by having the odd and even lines staggered. This is because we generate odd and even pixels (starting from pixel 0) on different lines, and saves the Address Generator 122 from having to advance to the next row and back again on alternative sets of 24 pixels. FIG. 25 shows a simple dither cell 93, and how to map it to a staggered dither cell 121 of the same size. Note that for determining the \"oddness\" of a given position, we number the pixels in a given row 0, 1, 2 etc.\nThe 8-bit value from Buffer 4 117 is compared (unsigned) to the 8-bit value from the Staggered Dither Cell 121. If the Buffer 4 pixel value is greater than or equal to the dither cell value, a \"1\" bit is output to the shift register of Buffer 5 118. Otherwise a \"0\" bit is output to the shift register of Buffer 5.\nIn order to halftone 19,200 contone pixels, 19,200 contone pixels must be read in. The Address Generator Unit 122 performs this task, generating the addresses into Buffer 4 117, effectively implementing the Uplnterpolate task. The address generation for reading Buffer 4 is slightly more complicated than the address generation for the dither cell, but not overly so.\nThe Address Generator for reading Buffer 4 only begins once the first row of Buffer 4 has been written. The remaining rows of Buffer 4 are 0, so they will effectively be white (no printed dots).\nEach of the 6 effective output lines has a register with an integer and fractional component. The integer portion of the register is used to select which Buffer line will be read to effectively upinterpolate the color for that particular colors odd and even pixels. 3 pixel counters are used to maintain the current position within segment 0, and a single temporary counter P_ADR (pixel address) is used to offset into the remaining 7 segments.\nIn summary then, address generation for reading Buffer 4 requires the following registers, as shown in Table 24.\nTABLE 24Registers Required for Reading Buffer 4Register NameSizeCyanEven\u20026 bits (3:3)CyanOdd\u20026 bits (3:3)MagentaEven\u20026 bits (3:3)MagentaOdd\u20026 bits (3:3)YellowEven\u20026 bits (3:3)YellowOdd\u20026 bits (3:3)Cyan_P_ADR14 bits (11:3Magenta_P_ADR14 bits (11:3Yellow_P_ADR14 bits (11:3P_ADR11 bits (only holds integer portion of X_P_ADR)\nThe initial values for the 6 buffer line registers is the physical dot distance between nozzles (remember that the fractional component is effectively a divide by 5). For example, if the odd and even output dots of a color are separated by a distance of 1 dot, and nozzles of one color are separated from the nozzles of the next by 8 dots, the initial values would be as shown in First Line column in Table 25. Once each set of 19,200 dots has been generated, each of these counters must increment by 1 fractional component, representing the fact that we are sampling each pixel 5 times in the vertical dimension. The resultant values will then be as shown in Second Line column in Table 25. Note that 5:4+1=0:0 since there are only 6 buffer lines.\nTABLE 25Example Inital Setup and Second Line Values for the 6 Buffer LineRegistersFirstSecondLineLineNameCalculationValueBuffValueBuffCyanEvenInitial Position0:000:10CyanOddCyanEven + 0:10:100:20MagentaEvenCyanOdd + 1:3 (8)1:412:02MagentaOddMagentaEven + 0:12:022:12YellowEvenMagentaOdd + 1:3 (8)3:333:43YellowOddYellowEven + 0:13:434:04\nThe 6 buffer line registers then, determine which of the buffer lines is to be read for a given color's odd or even pixels. To determine which of the 1280 medium res pixels are read from the specific line of Buffer 4, we use 3 Pixel Address counters, one for each color, and a single temporary counter (P_ADR) which is used to index into each segment. Each segment is separated from the next by 800 dots. In medium res pixels this distance is 160. Since 800 is divisible exactly by 5, we only need use the integer portion of the 3 Pixel Address counters. We generate the 8 addresses for the even cyan pixels, then the 8 addresses for the even magenta, and finally the 8 addresses for the even yellow. We then do the same for the odd cyan, magenta, and yellow pixels. This process of two sets of 24 bits\u201424 even then 24 odd, is performed 400 times. We can then reset the Pixel Address counters (X_P_ADR) to 0 and advance the 6 buffer line registers. Every 5 line advances, the next buffer line is now free and ready for updating (by the Convert to CMY process). Table 26 lists the steps in a simple form.\nTABLE 26Address Generation for Reading Buffer 4#AddressCalculationComment\u2014P_ADR =Generate address for even pixel inCyan_P_ADRCyan segment 0 and advance to nextCyan_P_ADR += 1pixel for cyan(mod5)\u20021CyanEven:P_ADRP_ADR += 160Advance to segment 1 (cyan)\u20022CyanEven:P_ADRP_ADR += 160Advance to segment 2 (cyan)\u20023CyanEven:P_ADRP_ADR += 160Advance to segment 3 (cyan)\u20024CyanEven:P_ADRP_ADR += 160Advance to segment 4 (cyan)\u20025CyanEven:P_ADRP_ADR += 160Advance to segment 5 (cyan)\u20026CyanEven:P_ADRP_ADR += 160Advance to segment 6 (cyan)\u20027CyanEven:P_ADRP_ADR += 160Advance to segment 7 (cyan)\u20028CyanEven:P_ADRP_ADR =Generate address for even pixel inMagenta_P_ADRMagenta segment 0 and advance toMagenta_P_ADR += 1next pixel for magenta(mod5)\u20029MagentaEven:P_ADRP_ADR += 160Advance to segment 1 (magenta)10MagentaEven:P_ADRP_ADR += 160Advance to segment 2 (magenta)11MagentaEven:P_ADRP_ADR += 160Advance to segment 3 (magenta)12MagentaEven:P_ADRP_ADR += 160Advance to segment 4 (magenta)13MagentaEven:P_ADRP_ADR += 160Advance to segment 5 (magenta)14MagentaEven:P_ADRP_ADR += 160Advance to segment 6 (magenta)15MagentaEven:P_ADRP_ADR += 160Advance to segment 7 (magenta)16MagentaEven:P_ADRP_ADR =Generate address for even pixel inYellow_P_ADRYellow segment 0 and advance toYellow_P_ADR += 1next pixel for yellow(mod 5)17YellowEven:P_ADRP_ADR += 160Advance to segment 1 (yellow)18YellowEven:P_ADRP_ADR += 160Advance to segment 2 (yellow)19YellowEven:P_ADRP_ADR += 160Advance to segment 3 (yellow)20YellowEven:P_ADRP_ADR += 160Advance to segment 4 (yellow)21YellowEven:P_ADRP_ADR += 160Advance to segment 5 (yellow)22YellowEven:P_ADRP_ADR += 160Advance to segment 6 (yellow)23YellowEven:P_ADRP_ADR += 160Advance to segment 7 (yellow)24YellowEven:P_ADRP_ADR =Generate address for even pixel inCyan_P_ADRCyan segment 0 and advance to nextCyan_P_ADR += 1pixel for cyan(mod5)25CyanOdd:P_ADRP_ADR += 160Advance to segment 1 (cyan)etc.\nThe pseudocode for generating the Buffer 4 117 addresses is shown here. Note that it is listed as a sequential set of steps. Table 26 shows a better view of the parallel nature of the operations during the address generation.\n% Calculate start positionsCyanEven = 0:0CyanOdd = CyanEven + 0:1MagentaEven = CyanOdd + 1:3MagentaOdd = MagentaEven + 0:1YellowEven = MagentaOdd + 1:3YellowOdd = YellowEven + 0:1Do N times (depends on print size)Cyan_P_ADR = 0Magenta_P_ADR = 0Yellow_P_ADR = 0Do 400 times\u2003% generate the even pixels for the first set of 24 bits\u2003P_ADR = Integer portion of Cyan_P_ADR\u2003Cyan_P_ADR += 0:1\u2003Do 8 times\u2003\u2003ReadBuffer4(line=CyanEven, pixel=P_ADR)\u2003\u2003P_ADR += 160\u2003EndDo\u2003P_ADR = Integer portion of Magenta_P_ADR\u2003Magenta_P_Adr += 0:1\u2003Do 8 times\u2003\u2003ReadBuffer4(line=MagentaEven, pixel=P_ADR)\u2003\u2003P_ADR += 160\u2003EndDo\u2003P_ADR = Integer portion of Yellow_P_ADR\u2003Yellow_P_Adr += 0:1\u2003Do 8 times\u2003\u2003ReadBuffer4(line=YellowEven, pixel=P_ADR)\u2003\u2003P_ADR += 160\u2003EndDo\u2003% generate the odd pixels for the first set of 24 bits\u2003P_ADR = Integer portion of Cyan_P_ADR\u2003Cyan_P_ADR += 0:1\u2003Do 8 times\u2003\u2003ReadBuffer4(line=CyanOdd, pixel=P_ADR)\u2003\u2003P_ADR += 160\u2003EndDo\u2003P_ADR = Integer portion of Magenta_P_ADR\u2003Magenta_P_Adr += 0:1\u2003Do 8 times\u2003\u2003ReadBuffer4(line=MagentaOdd, pixel=P_ADR)\u2003\u2003P_ADR += 160\u2003EndDo\u2003P_ADR = Integer portion of Yellow_P_ADR\u2003Yellow_P_Adr += 0:1\u2003Do 8 times\u2003\u2003\u2003ReadBuffer4(line=YellowOdd, pixel=P_ADR)\u2003\u2003\u2003P_ADR += 160\u2003\u2003EndDo\u2003\u2003% Now can advance to next \"line\"\u2003\u2003CyanEven += 0:1\u2003\u2003CyanOdd += 0:1\u2003\u2003MagentaEven += 0:1\u2003\u2003MagentaOdd += 0:1\u2003\u2003YellowEven += 0:1\u2003\u2003YellowOdd += 0:1\u2003EndDoEndDo10.2.5 Buffer 3 116\nBuffer 3 is a straightforward set of 8-bit R, G, B values. These RGB values are the sharpened medium res (1280-res) pixels generated by the Sharpen process 65, and read by the Convert to CMY process 66.\nIt is not necessary to double buffer Buffer 3 116. This is because the read (Convert to CMY) process 66 only requires the RGB values for the first 39 cycles, while the write (Sharpen) process 65 takes 49 cycles before being ready to actually update the RGB values.\n10.2.6 Convert to CMY 66\nThe conversion from RGB to CMY is performed in the medium resolution space (1280-res) as described in Section 3.2.7.\nThe conversion process 66 must produce the contone buffer pixels (Buffer 4) 117 at a rate fast enough to keep up with the Upinterpolate-Halftone-Reformat process 113. Since each contone value is used for 25 cycles (5 times in each of the x and y dimensions), the conversion process can take up to 25 cycles. This totals 75 cycles for all 3 color components.\nThe process as described here only requires 14 cycles per color component, with the input RGB values actually freed after 39 cycles. If the process is implemented with logic that requires access to the input RGB values for more than 49 cycles, then Buffer 3 116 will require double-buffering, since they are updated by the Sharpening process 65 after this time.\nThe conversion is performed as tri-linear interpolation. Three 17\u00d717\u00d717 lookup tables are used for the conversion process: RGB to Cyan 90, RGB to Magenta 91, and RGB to Yellow 92. However, since we have 25 cycles to perform each tri-linear interpolation, there is no need for a fast tri-linear interpolation unit. Instead, 8 calls to a linear interpolation process 130 is more than adequate.\nAddress generation for indexing into the lookup tables is straightforward. We use the 4 most significant bits of each 8-bit color component for address generation, and the 4 least significant bits of each 8-bit color component for interpolating between values retrieved from the conversion tables. The addressing into the lookup table requires an adder due to the fact that the lookup table has dimensions of 17 rather than 16. Fortunately, multiplying a 4-bit number X by 17 is an 8-bit number XX, and therefore does not require an adder or multiplier, and multiplying a 4 bit number by 172 (289) is only slightly more complicated, requiring a single add.\nAlthough the interpolation could be performed faster, we use a single adder to generate addresses and have a single cycle interpolation unit. Consequently we are able to calculate the interpolation for generating a single color component from RGB in 14 cycles, as shown in Table 27. The process must be repeated 3 times in order to generate cyan, magenta, and yellow. Faster methods are possible, but not necessary.\nTABLE 27Trilinear interpolation for color conversionCycleLoadEffective FetchAdjust ADR registerInterpolate1ADR = 289R2ADR = ADR + 17G3ADR = ADR + B4P1RGBADR = ADR + 15P2RGB + 1ADR = ADR + 166P1RG + 1BADR = ADR + 1P3 = P1 to P2 by B7P2RG + 1B + 1ADR = ADR + 2718P1R + 1GBADR = ADR + 1P4 = P1 to P2 by B9P2R + 1GB + 1ADR = ADR + 16P5 = P3 to P4 by G10P1R + 1G + 1BADR = ADR + 1P3 = P1 to P2 by B11P2R + 1G +1B + 112P4 = P1 to P2 by B13P6 = P3 to P4 by G14V = P5 to P6 by R\nAs shown in Table 27, a single ADR register and adder can be used for address generation into the lookup tables. 6 sets of 8-bit registers can be used to hold intermediate results\u20142 registers hold values loaded from the lookup tables, and 4 registers are used for the output from the interpolation unit. Note that the input to the linear interpolation unit is always a pair of 8-bit registers P1\/P2, P3\/P4, and P5\/P6. This is done deliberately to reduce register selection logic. In cycle 14, the \"V\" register 131 holds the 8-bit value finally calculated. The 8-bit result can be written to the appropriate location in Buffer 4 117 during the next cycle.\nA block diagram of the Convert to CMY process 66 can be seen in FIG. 47.\nAssuming the process is first run to generate cyan, the resultant cyan contone pixel is stored into the cyan 1280-res contone buffer. The process is then run again on the same RGB input to generate the magenta pixel. This magenta contone pixel is stored into the magenta 1280-res contone buffer. Finally, the yellow contone pixel is generated from the same RGB input, and the resultant yellow pixel is stored into the yellow 1280-res contone buffer).\nThe address generation for writing to the contone buffer (Buffer 4) 117 is straightforward. A single address (and accompanying ColorSelect bits) is used to write to each of the three color buffers. The Cyan buffer is written to on cycle 15, the Magenta on cycle 30, and Yellow on cycle 45. The pixel address is incremented by 1 every 75 cycles (after all 3 colors have been written). The line being written to increments with wrapping once every 5 AdvanceLine pulses. The order of lines being written to is simply 0-1-2-3-4-5-0-1-2-3 etc. . . . Thus the writes (25\u00d71280\u00d73) balance out with the reads (19200\u00d75).\n10.2.7 Buffer 2 115\nBuffer 2 accepts the output from the Resample-CreateLuminance process 112, where a complete RGB and L pixel is generated for a given pixel coordinate. The output from Buffer 2 115 goes to the Sharpen process 65, which requires a 3\u00d73 set of luminance values 135 centered on the pixel being sharpened.\nConsequently, during the sharpening process 65, there is need for access to the 3\u00d73 array of luminance values, as well as the corresponding RGB value 136 for the center luminance pixel. At the same time, the next 3 luminance values and the corresponding RGB center value must be calculated by the Resample-CreateLuminance process 112. The logical view of accesses to Buffer 2 115 is shown in FIG. 48.\nThe actual implementation of Buffer 2 115 is simply as a 4\u00d76 (24 entry) 8-bit RAM, with the addressing on read and write providing the effective shifting of values. A 2-bit column counter can be incremented with wrapping to provide a cyclical buffer, which effectively implements the equivalent of shifting the entire buffer's data by 1 column position. The fact that we don't require the fourth column of RGB data is not relevant, and merely uses 3 bytes at the saving of not having to implement complicated shift and read\/write logic. In a given cycle, the RAM can either be written to or read from. The read and write processes have 75 cycles in which to complete in order to keep up with the printhead.\n10.2.8 Sharpen\nThe Sharpen Unit 65 performs the sharpening task described in Section 3.2.6. Since the sharpened RGB pixels are stored into Buffer 3 116, the Sharpen Unit 65 must keep up with the Convert to CMY process 66, which implies a complete RGB pixel must be sharpened within 75 cycles.\nThe sharpening process involves a highpass filter of L (a generated channel from the RGB data and stored in Buffer 2) and adding the filtered L back into the RGB components, as described in Table 12 within Section 18.104.22.168 on page 35. The highpass filter used is a basic highpass filter using a 3\u00d73 convolution kernel, as shown in FIG. 49.\nThe high pass filter is calculated over 10 cycles. The first cycle loads the temporary register 140 with 8 times the center pixel value (the center pixel shifted left by 3 bits). The next 8 cycles subtract the remaining 8 pixel values, with a floor of 0. Thus the entire procedure can be accomplished by an adder. Cycle 10 involves the multiplication of the result by a constant 141. This constant is the representation of 1\/9, but is a register to allow the amount to altered by software by some scale factor.\nThe total amount is then added to the R, G, and B values (with a ceiling of 255) and written to Buffer 3 during cycles 72, 73, and 74. Calculating\/writing the sharpened RGB values during the last 3 cycles of the 75 cycle set removes the need for double buffering in Buffer 3.\nThe structure of the Sharpen unit can be seen in FIG. 50.\nThe adder unit 142 connected to Buffer 2 115 is a subtractor with a floor of 0. TMP 140 is loaded with 8\u00d7 the first L value during cycle 0 (of 75), and then the next 8 L values are subtracted from it. The result is not signed, since the subtraction has a floor of 0.\nDuring the 10th cycle (Cycle 9), the 11 bit total in TMP 140 is multiplied by a scale factor (typically 1\/9, but under software control so that the factor can be adjusted) and written back to TMP 140. Only 8 integer bits of the result are written to TMP (the fraction is truncated), so the limit from the multiply unit is 255. If a scale factor of 1\/9 is used, the maximum value written will be 226 (255\u00d7 8\/9). The scale factor is 8 bits of fraction, with the high bit representing \u215b. The variable scale factor can take account of the fact that different print formats are the result of scaling the CFA image by a different amount (and thus the 3\u00d73 convolution will produce correspondingly scaled results).\nThe sharpened values for red, green, and blue are calculated during Cycle 72, Cycle 73, and Cycle 74, and written to the R, G, and B registers of Buffer 3 116, one write per cycle. The calculation performed in these 3 cycles is simply the addition of TMP to Buffer 2's R, G, and B corresponding to the center pixel.\nAddress Generation is straightforward. Writing to Buffer 3 116 is simply R, G, and B in cycles 72, 73, and 74 respectively. Reading from Buffer 2 115 makes use of the cyclical nature of Buffer 2. The address consists of a 2-bit column component (representing which of the 4 columns should be read), and a 3-bit value representing L1, L2, L3, R, G, or B. The column number starts at 1 each line and increments (with wrapping) every 75 cycles. The order of reading Buffer 2 is shown in Table 28. The C register is the 2-bit column component of the address. All addition on C is modulo 4 (wraps within 2 bits).\nTABLE 28Read Access to Buffer 2 during75 Cycle setCycleAddressUpdate C0C, L2C = C \u2212 11C, L12C, L23C, L3C = C + 14C, L15C, L3C = C + 16C, L17C, L28C, L3C = C \u2212 19\u201371No access72\u2002C, R73\u2002C, G74\u2002C, BC = C \u2212 1\nAfter Cycle 74, the C register holds the column number for the next calculation set, thus making the fetch during the next Cycle 0 valid.\nSharpening can only begin when there have been sufficient L and RGB pixels written to Buffer 2 (so that the highpass filter is valid). The sharpen process must therefore stall until the Buffer 2 write process has advanced by 3 columns.\n10.2.9 Buffer 1 114\nBuffer 1 holds the white-balanced and range-expanded pixels at the original capture spatial resolution. Each pixel is stored with 10 bits of color resolution, compared to the image RAM image storage color resolution of 8 bits per pixel.\nBuffer 1 is arranged as 3 separately addressable buffers\u2014one for each color plane of red 145, green 146, and blue 147. A simple overview of the buffers is shown in FIG. 51.\nDuring the course of 75 cycles, 16 entries are read from each of the 3 buffers 3 times by the Resampling process 112, and up to 29 new values are written to the 3 buffers (the exact number depends on the scale factor and the current sub-pixel position during resampling).\nThe buffers must be wide enough so that the reading and writing can occur without interfering with one another. During the read process, 4 pixels are read from each of 6 rows. If the scale factor is very large (e.g. we are scaling up to Panoramic), the same input pixels can be read multiple times (using a different kernel position for resampling). Eventually, however, the next pixels will be required. If we are not scaling up so much, the new pixels may be required before the next pixel generation cycle (i.e. within 75 clock cycles).\nLooking at the scale factors in Table 9 and Table 11, the worst case for scaling is the Passport format 31:    The green plane has a \u0394 value for Passport of 1.5625, indicating that 4 locations can be contained within 6 CFA pixel positions. However, each row of green samples only holds every alternate pixel. This means that only 4 samples are required per row (worst case is 4, not 3, due to a worst case initial position). Movement in Y indicates the requirement of an additional sample column, making 5. Finally, an additional sample column is required for writing. This gives a total of 6 samples per row. 7 rows are required for a single sample. To generate the 3 sets of RGB pixels for each x position, the maximum movement in y will be 4 rows (3.125=2\u00d71.5625). Movement X adds one sample row above and below. Consequently a total of 13 rows are required. For more details see Section 10.2.10.    The red and blue planes have a \u0394 value for Passport of 0.78125, indicating that 4 locations can be contained within 4 samples. An additional sample is required for writing while the remaining 4 are being read. This gives a total of 5 samples per row, which is further increased to 6 samples to match the green plane (for startup purposes). 6 rows are required to cater for movement in y. For more details see Section 10.2.10.\nEach sub-buffer is implemented as a RAM with decoding to read or write a single 10-bit sample per cycle. The sub-buffers are summarized in Table 29, and consume less than 200 bytes.\nTABLE 29Sub-Buffer SummaryBufferCompositionBitsRed Buffer\u20026 rows \u00d7 6 samples \u00d7 10-bits360Blue Buffer\u20026 rows \u00d7 6 samples \u00d7 10-bits360Green Buffer13 rows \u00d7 6 samples \u00d7 10 bits780TOTAL150010.2.10 Resample and Create Luminance Channel\nThe Resample and Create Luminance Channel process 112 is responsible for generating the RGB pixel value in medium resolution space by appropriate resampling the white-balanced and range-expanded R, G, and B planar images, as described in Section 3.2.5 on page 28. In addition, the luminance values for the given RGB pixel, as well as the luminance values for the pixel above and below the RGB pixel must be generated for use in the later sharpening process.\nThe time allowed for producing the RGB value and 3 L values is 75 cycles. Given that L is simply the average of the minimum and maximum of R, G, and B for a given pixel location (see Section 220.127.116.11), we must effectively produce RGB values for 3 pixel coordinates\u2014the pixel in question, and the pixel above and below. Thus we have 75 cycles in which to calculate the 3 medium res RGB samples and their corresponding L values.\nBuffering L values (and hence RGB values) to save recalculation requires too much memory, and in any case, we have sufficient time to generate the RGB values. Buffer 4 117 contains medium res pixels, but cannot be used since it holds sharpened CMY pixels (instead of unsharpened RGB pixels).\n10.2.10.1 Resampling\nThe resampling process can be seen as 3 sets of RGB generation, each of which must be completed within 25 cycles (for a total maximum elapsed time of 75 cycles). The process of generating a single RGB value can in turn be seen as 3 processes performed in parallel: the calculation of R, the calculation of G, and the calculation of B, all for a given medium resolution pixel coordinate. The theory for generating each of these values can be found in Section 3.2.5, but the upshot is effectively running three image reconstruction filters, one on each channel of the image. In the case of the PCP, we perform image reconstruction with 5 sample points, requiring 4 coefficients in the convolution kernel (since one coefficient is always 0 and thus the sample point is not required).\nConsequently, calculation of the medium resolution R pixel is achieved by running an image reconstruction filter on the R data. Calculation of the medium resolution G pixel is achieved by running an image reconstruction filter on the G data, and calculation of the medium resolution B pixel is achieved by running an image reconstruction filter on the B data. Although the kernels are symmetric in x and y, they are not the same for each color plane. R and B are likely to be the same kernel due to their similar image characteristics, but the G plane, due to the rotation required for image reconstruction, must have a different kernel. The high level view of the process can be seen in FIG. 52. Address generation is not shown.\nThe resampling process can only begin when there are enough pixels in Buffer 1 for the current pixel line being generated. This will be the case once 4 columns of data have been written to each of the color planes in Buffer 1 114. The Resampling process 112 must stall until that time.\nTo calculate a given color plane's medium resolution pixel value, we have 25 cycles available. To apply the kernel to the 4\u00d74 sample area, we apply the 1D kernel (indexed by x) on each of the 4 rows of 4 input samples. We then apply the 1D kernel (indexed by y) on the resultant 4 pixel values. The final result is the output resampled pixel. Applying a single coefficient each cycle gives a total of 16 cycles to generate the 4 intermediate values, and 4 cycles to generate the final pixel value, for a total of 20 cycles.\nWith regards to precision, the input pixels are each 10 bits (8:2), and kernel coefficients are 12 bits. We keep 14 bits of precision during the 4 steps of each application of the kernel (8:6), but only save 10 bits for the result (8:2). Thus the same convolve engine can be used when convolving in x and y. The final output or R, G, or B is 8 bits.\nThe heart of the resampling process is the Convolve Unit 150, as shown in FIG. 53.\nThe process of resampling then, involves 20 cycles, as shown in Table 30. Note that the Row 1, Pixel 1 etc. refers to the input from Buffer 1 114, and is taken care of by the addressing mechanism (see below).\nTABLE 30The 20 Cycle ResampleCycleKernelApply Kernel to:Store Result in1X[1]Row 1, Pixel 1TMP2X[2]Row 1, Pixel 2TMP3X[3]Row 1, Pixel 3TMP4X[4]Row 1, Pixel 4TMP, V15X[1]Row 2, Pixel 1TMP6X[2]Row 2, Pixel 2TMP7X[3]Row 2, Pixel 3TMP8X[4]Row 2, Pixel 4TMP, V29X[1]Row 3, Pixel 1TMP10X[2]Row 3, Pixel 2TMP11X[3]Row 3, Pixel 3TMP12X[4]Row 3, Pixel 4TMP, V313X[1]Row 4, Pixel 1TMP14X[2]Row 4, Pixel 2TMP15X[3]Row 4, Pixel 3TMP16X[4]Row 4, Pixel 4TMP, V417Y[1]V1TMP18Y[2]V2TMP19Y[3]V3TMP20Y[4]V4TMP (for output)10.2.10.2 Generation of L 8- \nAs described in Section 188.8.131.52, we must convert 80 from RGB to L for the subsequent sharpening process. We consider the CIE 1976 L*a*b* color space, where L is perceptually uniform. To convert from RGB to L (the luminance channel) we average the minimum and maximum of R, G, and B\n  L  =                    MIN        \u2061                  (                      R            ,            G            ,            B                    )                    +              MAX        \u2061                  (                      R            ,            G            ,            B                    )                      2  as follows:\nThe generation of a given pixel's R, G, and B values is performed in parallel, taking 20 cycles. The total time for the generation of L as described here, is 4 cycles. This makes the total time of generating an RGBL pixel set 24 cycles, with 1 cycle to spare (since the process must be completed within 25 cycles).\nThe value for L can thus be safely written out to Buffer 2 115 in the 25th cycle. Address generation is described below.\nA single 8-bit comparator can produce 3 bits in 3 cycles, which can subsequently be used for selecting the 2 inputs to the adder, as shown in Table 31. The division by 2 can simply be incorporated in the adder.\nTABLE 31Selection of Min and Max based on 3comparisonsMINMAXR > GG > BR > BRB11x7RG101GR010GB011BR00x\u2002BG1007Don't care state\nSince the add merely adds the minimum to the maximum value, the order is unimportant. Consequently, of the 2 inputs to the adder, Input 1 can be a choice between R and G, while Input2 is a choice of G and B. The logic is a minimization of the appropriate bit patterns from Table 31.\n10.2.10.3 Address Generation for Buffer 2\nThe output from the Resampler is a single RGB pixel, and 3 luminance (L) pixels centered vertically on the RGB pixel. The 3 L values can be written to Buffer2, one each 25 cycles. The R, G, and B values must be written after cycle 45 and before cycle 50, since the second pixel generated is the center pixel whose RGB values must be kept. The Buffer2 address consists of a 2-bit column component (representing which of the 4 columns is to be written to), and a 3 bit value representing L1, L2, L3, R, G, or B. The column number starts at 0 each line, and increments (with wrapping) every 75 cycles (i.e. after writing out L3).\n10.2.10.4 Address Generation for Kernel Lookup\nThe method of calculating the kernel address is the same as described at the end of Section 3.2.5 on page 28. Each kernel is 1 dimensional, with 64 entries in the table. The 6 most significant bits (truncated) of the fractional component in the current kernel space are used to index into the kernel coefficients table. For the first 16 cycles, the X ordinate is used to index the kernel, while in the next 4 cycles, the Y ordinate is used. Since the kernel is symmetric, the same kernel can be used for both X and Y.\nFor each of the 1280 resampled values, we need to produce 3 pixels\u2014the pixel in question 161, and the pixels above 160 and below 162 that pixel. Rather than generate a center pixel and then move up and down from that center pixel, we generate a pixel 160 and generate the two pixels 161, 162 below it. The second pixel 161 generated is taken to be the center pixel. We then return to the original row and generate the next 3 pixels in the next output position. In this way, as shown in FIG. 54, we generate 3 pixels for each of the 1280 positions.\nThus we have a current position in kernel space. As we advance to the next pixel in X or Y in original input space, we add appropriate delta values to these kernel coordinates. Looking at FIG. 55, we see the two cases for rotated and unrotated input space.\nWe consider the movement in X and Y as \u0394X and \u0394Y, with their values dependent on the print format, and hence the value of mps (see Section 3.2.5). For the green channel, \u0394X=\u0394Y=\u00bd mps. For the red and blue channels, \u0394X=1\/mps and \u0394Y=0. See Table 9 and Table 11 for appropriate values of \u0394X and \u0394Y.\nWe can now apply the \u0394X and \u0394Y values to movement within the kernel. Consequently, when we advance in X, we add \u0394X to X and subtract \u0394Y from Y. In the unrotated case, this merely subtracts 0 from Y. Likewise, when we advance in Y, we add \u0394Y to X and \u0394X to Y. We can do this because movement in X and Y differs by 90 degrees.\nThe address generation for kernel lookup assumes a starting position set by software, and two deltas \u0394X an \u0394Y with respect to movement in Y in kernel space. The address generation logic is shown in the following pseudocode:\nColumnKernelY = StartKernelYColumnKernelX = StartKernelXDo NLines times (however many output lines there are to process)\u2003KernelX = ColumnKernelX\u2003KernelY = ColumnKernelY\u2003Do 1280 times\u2003\u2003GeneratePixel\u2003\u2003KernelX = KernelX + DeltaY (movement in Y)\u2003\u2003KernelY = KernelY + DeltaX (movement in Y)\u2003\u2003Generate Pixel\u2003\u2003KernelX = KernelX + DeltaY (movement in Y)\u2003\u2003KernelY = KernelY + DeltaX (movement in Y)\u2003\u2003GeneratePixel\u2003\u2003KernelX = ColumnKernelX + DeltaX (movement in X)\u2003\u2003KernelY = ColumnKernelY \u2212 DeltaY (movement in X)\u2003EndDo\u2003ColumnKernelY = ColumnKernelY + DeltaX (movement in Y)\u2003ColumnKernelX = ColumnKernelX + DeltaY (movement in Y)EndDo\nAs shown in the pseudocode, the generation of 3 pixels occurs 1280 times. Associated with the generation of each pixel is 2 additions, which can be performed during the course of the GeneratePixel 25 cycle task. Each GeneratePixel task is 25 cycles, consisting of 4 sets of 4 cycles indexing the kernel via KernelX (coefficients 0, 1, 2, 3), followed by 4 cycles indexing the kernel via KernelY (coefficients 0, 1, 2, 3), followed by 9 wait cycles.\nNote that all values are positive and fractional only. The two carry outs from the updating of the X and Y kernel values are output to the address generation of Buffer 1 (see Section 10.2.10.5 on page 71 below). These carry out flags simply indicate whether or not the particular ordinates for the kernel wrapped during the mathematical operation. Wrapping can be either above 1 or below 0, but the result is always positive.\nThe two carry out bits are also sent to the Rotate\/WhiteBalance\/RangeExpansion Unit for use in determining the relative input lines from the image.\n10.2.10.5 Address Generation for Buffer 1\nThe Resampler 112 reads from Buffer 1 114, which consists of 3 individually addressable buffers 145, 146 and 147\u2014one for each color plane. Each buffer can either be read from or written to during each cycle.\nThe reading process of 75 cycles is broken down into 3 sets of 25 cycles, one set of 25 cycles for the generation of each pixel. Each 25 cycle set involves 16 reads from Buffer 1 followed by 9 cycles with no access. Buffer 1 is written to during these 9 cycles. The 16 reads from Buffer 1 114 are effectively 4 sets of 4 reads, and coincide with 4 groups of 4 reads to the kernel for each color plane.\nThe address generation then, involves generating 16 addresses for calculating the first pixel (followed by 9 wait cycles), generating 16 addresses for calculating the second pixel (followed by 9 wait cycles), and finally generating the 16 addresses for the third pixel (followed by 9 wait cycles).\nEach color plane has its own starting Buffer 1 address parameters. As the 3 sets of 16 addresses are generated for each of the 1280 positions along the line, and as the sampler advances from one line of 1280 samples to the next, the two carry out bits from the Kernel Address Generation Unit are used to update these Buffer 1 address parameters.\n10.2.10.6 Green buffer 146\nAddress generation for the green sub-buffer 146 within Buffer 1 114 is more complicated than the red sub-buffer 145 and blue sub-buffer 147 for two main reasons:    the green channel represents a checkerboard pattern in the CFA. Alternate lines consist of odd or even pixels only. To resample the green channel, we must effectively rotate the channel by 45 degrees.    there are twice as many green pixels than red or blue pixels. Resampling means the reading of more samples in the same amount of time\u2014there are still 16 samples read to generate each pixel in medium res space, but there is a higher likelihood of advancing the buffer each time. The exact likelihood depends on the scale factor used.\nHowever, the same concept of using a RAM as a cyclical buffer is used for the green channel. The green sub-buffer is a 78 entry RAM with a logical arrangement of 13 rows, each containing 6 entries.\nThe relationship between RAM address and logical position is shown in FIG. 56.\nThe samples in Buffer 1 146 represent a checkerboard pattern in the CFA. Consequently, samples in one row (e.g. addresses 0, 13, 26, 39, 52, 65) may represent odd or even pixels, depending on the current line within the entire image, and whether or not the image had been rotated by 90 degrees or not. This is illustrated in FIG. 57.\nConsequently, when we map a 4\u00d74 sampling area onto the buffer, there are two possibilities for the interpretation of the samples. As a result there are two types of addressing, depending on whether the current line is represented by odd or even pixels. This means that even rows with image rotation 0 will have the same addressing as odd rows with image rotation 90 since they both hold odd pixels. Likewise, the odd rows with image rotation 0 will have the same addressing as even rows with image rotation 90 since they both hold even pixels. The decision is summarized in Table 32.\nTABLE 32Determining Sampling TypeRotationCurrent LinePixelsType0Even Line8OddType 20Odd Line8EvenType 190Even Line8EvenType 190Odd Line8OddType 2\nThe actual 4\u00d74 sampling window is the way we effectively rotate the buffer by 45 degrees. The 45 degree rotation is necessary for effective resampling, as described in Section 3.2.5.\nAssuming for the moment that we only need to generate a single resample, we consider the buffer addressing by examining the two types of 4\u00d74 sampling windows as shown in FIG. 58.\nAlthough the two 4\u00d74 sampling types look similar, the difference comes from the way in which the 4\u00d74 mapping is represented in the planar image. FIG. 59 illustrates the mapping of the Type 1 4\u00d74 sampling to the green sub-buffer. Only the top 7 rows and right-most 4 columns are shown since the 4\u00d74 sample area is contained wholly within this area.\nThe mapping of buffer pixels to sample rows for the Type 2 sampling process is very similar, and can be seen in FIG. 60.\nIn both Type 1 and Type 2 addressing of the 16 samples there are two ways of processing a row. Processing of Rows 1 and 3 of Type 1 addressing is the same (relatively speaking) as processing rows 2 and 3 of Type 2. Likewise, processing rows 2 and 4 of Type 1 is the same (relatively speaking) as processing rows 1 and 3 of Type 2. We will call these row addressing methods Type A 170 and Type B 171, as shown in FIG. 61.\nGiven a starting position for the 4\u00d74 window (WindowStartAdr) and a starting type (WindowStartType), we can generate the addresses for the 16 samples by means of an 8 entry table (for traversing the two sets of 4 samples). When we read the first sample value we add an offset from the table to arrive at the next sample position. The offset will depend on the type (A, B=0, 1). The offset from the fourth sample is the amount needed to arrive at the first sample point for the next line (and must take account of the number of sample columns). After generating each row of 4 samples, we swap between TypeA and TypeB. The logic for generating the addresses for a single set of 16 samples is shown in the following pseudocode. The addition modulo 78 caters for the cyclical buffer.\nAdr = WindowStartAdrTypeAB = WindowStartTypeDo 4 times\u2003For N = 0 to 4\u2003\u2003Fetch Adr\u2003\u2003Adr = (Adr + Table[TypeAB,N]) mod 78\u2003EndFor\u2003TypeAB = NOT TypeABEndDo\nThe lookup table consists of 8 entries\u20144 for Type A 170, and 4 for Type B 171 address offset generation. The offsets are all relative to the current sample position (Adr).\nTABLE 33Offset Values for 16-Sample Address GenerationTypeABNOffset00140110214033710111141211337\nAt the end of the 16 reads, the TypeAB bit will be the same as the original value (loaded from WindowStartType).\nReading a single set of 16 samples is not enough. Three sets of 16 samples must be read (representing 3 different positions in Y in unrotated input space). At the end of the first and second set of 16 samples, the kernel positions are updated by the kernel address generator. The carry bits from this update are used to set the window for the next set of 16 samples. The two carry bits index into a table containing an offset and a 1-bit flag. The offset is added to the WindowStartAdr, and the flag is used to determine whether or not to invert WindowStartType. The values for the table are shown in Table 34.\nTABLE 34Updating WindowStartAdr andWindowStartTypeKernelXKernelYCarryOutCarryOutOffset\u2032Type000No change011Invert1014Invert112No change\nAt the end of the third set of 16 samples, the kernel positions are updated to compensate for advancement in X in unrotated input space. This time, a different motion direction is produced, so a different Offset\/TypeAB modifying table is used. We cannot add these offsets to the current WindowStartAdr value, because that represents a position two movements in Y away from where we want to start the movement. Consequently we load WindowStartAdr and WindowStartType from another set of variables: TopStartAdr and TopStartAdr, representing the first entry in the current line of 1280. The two carry out flags from the Kernel address generator are used to lookup Table 35 to determine the offset to add to TopStartAdr and whether or not to invert TopStartType. As before, the addition is modulo 78 (the size of the green RAM). The results are copied to WindowStartAdr and WindowStartType for use in generating the next 3 sets of 16 samples.\nTABLE 35Updating TopStartAdr and TopStartTypeKernelXKernelYCarryOutCarryOutOffset\u2032Type000No change0112Invert1014Invert1113No change\nAfter processing the 1280 sets of 3 sets of 16 samples, the next line of 1280 begins. However the address of the first sample for position 0 within the next line must be determined. Since the samples are always loaded into the correct places in Buffer 1, we can always start from exactly the same position in Buffer 1 (i.e. TopStartAdr can be loaded from a constant Position0Adr). However, we must worry about which type we are dealing with, since the type depends on how much we advanced. Consequently we have an initial Position0Type which must be updated depending on the carry out flags from the kernel address generator. Since we are moving in unrotated Y input space, the logic used is the same as for updating WindowStartType, except that it is performed on Position0Type instead. The new value for Position0Type is copied into TopStartType, and WindowStartAdr to begin sampling of the first position of the new line.\nThe sampling process for a given 1280 position line cannot begin until there are enough entries in Buffer 1, placed there by the Rotate\/WhiteBalance\/RangeExpansion Unit. This will occur 128 cycles after the start of each new line (see Section 10.2.11).\n10.2.10.7 Red and Blue Buffers\nBuffer 1's red sub-buffer 145 and blue sub-buffer 147 are simply 2 RAMs accessed as cyclical buffers. Each buffer is 30 bytes, but has a logical arrangement of 6 rows, each containing 6 entries. The relationship between RAM address and logical position is shown in FIG. 62.\nFor red and blue, the first 16 samples to be read are always the top 4\u00d74 entries. The remaining two columns of samples are not accessed by the reading algorithm at this stage.\nThe address generation for these first 16 samples is simply a starting position (in this case 0) followed by 16 steps of addition modulo 36, as shown in the following pseudocode:\nADR = StartADRDo 4 times\u2003Do 4 times\u2003\u2003ADR = ADR + 6 MOD 36\u2003End Do\u2003ADR = ADR + 13 MOD 36End Do\nHowever, this address generation mechanism is different from the green channel. Rather than design two addressing mechanisms, it is possible to apply the green addressing scheme to the red and blue channels, and simply use different values in the tables. This reduces design complexity. The only difference then, becomes the addition modulo 36, instead of addition modulo 78. This can be catered for by a simple multiplexor.\nLooking at the various address generation tables for green, and considering them as applied to red and blue, it is apparent that there is no requirement for a Type, since both the red and the blue channels do not need to be rotated 45 degrees. So that we can safely ignore the Type value, the red\/blue equivalent of Table 33, shown in Table 36, has two sets of identical 4 entries.\nTABLE 36Offset Values for 16-Sample Address Generation(Red\/Blue)TypeABNOffset00601602603131061161261313\nAs with green address generation, we move twice in Y before advancing to the next entry of 1280. For red and blue there is no scaling between movement in kernel space and movement in the input space. There is also no rotation. As we move in Y, the \u0394Y of 0 is added to KernelX (see kernel address generation in Section 10.2.10.4 on page 69). As a result, the carry out from KernelX will never be set. Looking at Table 34, the only possible occurrences are KernelX\/KernelY values of 00 or 01. In the case of 00, the green solution is no change to either WindowStartAdr or WindowStartType, so this is correct for red and blue also. In the case of 01, we want to add 1 to WindowStartAdr, and don't care about WindowStartType. The green values can therefore be safely used for red and blue. The worst case is advancement by 1 in address both times, resulting in an overlapping worst case as shown in FIG. 64.\nAt the end of the third set of 16 samples, TopStartAdr and TopStartType must be updated. Since we are moving in X (and adding \u0394Y=0 to KernelY), the carry out from KernelY will always be 0. The red\/blue equivalent of Table 35 is shown here in Table 37. Note that there is no Type column, since Type is not important for Red or Blue.\nTABLE 37Updating TopStartAdr andTopStartType (Red\/Blue)KernelXKernelYCarryOutCarryOutOffset\u203200001\u201410611\u2014\nThe process of advancing from one line of 1280 sets of 3 pixels to the next is the same as for green. The Position0Adr will be the same for the first set of 16 samples for a given line (Position0Adr=0 for red and blue), and Type is irrelevant. Generation of the next line cannot begin until there are enough samples in Buffer 1. Red and blue generation must start at the same time as green generation, so cannot begin until 128 cycles after the start of a new line (see Section 10.2.11).\n10.2.11 Rotate, White Balance and Range Expansion 111\nThe actual task of loading Buffer 1 114 from the Image RAM 11 involves the steps of rotation, white balance, and range expansion 111, as described by Section 3.2.3 and Section 3.2.4. The pixels must be produced for Buffer 1 fast enough for their use by the Resampling process 112. This means that during a single group of 75 cycles, this unit must be able to read, process, and store 6 red pixels, 6 blue pixels, and 13 green pixels.\nThe optional rotation step is undertaken by reading pixels in the appropriate order. Once a given pixel has been read from the appropriate plane in the image store, it must be white balanced and its value adjusted according to the range expansion calculation defined in Section 3.2.4. The process simply involves a single subtraction (floor 0), and a multiply (255 ceiling), both against color specific constants. The structure of this unit is shown in FIG. 65.\nThe red, green and blue low thresholds 72, together with the red, green, and blue scale factors 173 are determined by the CPU 10 after generating the histograms for each color plane via the Image Histogram unit 8 (see Section 9).\nDepending on whether the current pixel being processed in the pipeline is red, green, or blue, the appropriate low threshold and scale factor is multiplexed into the subtract unit and multiply unit, with the output written to the appropriate color plane in Buffer 1.\nThe Subtract unit 172 subtracts the 8-bit low Threshold value from the 8-bit Image RAM pixel value, and has a floor of 0. The 8-bit result is passed on to the specialized 8\u00d78 multiply unit, which multiplies the 8-bit value by the 8-bit scale factor (8 bits of fraction, integer=1). Only the top 10 bits of the result are kept, and represent 8 bits of integer and 2 bits of fraction. The multiplier 174 has a result ceiling of 255, so if any bit higher than bit 7 would have been set as a result of the multiply, the entire 8-bit integer result is set to 1s, and the fractional part set to 0.\nApart from the subtraction unit 172 and multiply unit 174, the majority of work in this unit is performed by the Address Generator 175, which is effectively the state machine for the unit. The address generation is governed by two factors: on a given cycle, only one access can be made to the Image RAM 11, and on a given cycle, only one access can be made to Buffer 1 114. Of the 75 available cycles, 3 sets of 16 cycles are used for reading Buffer 1. The actual usage is 3 sets of 25 cycles, with 16 reads followed by 9 wait cycles. That gives a total of 27 available cycles for 25 writes (6 red, 6 blue, 6 green). This means the two constraints are satisfied if the timing of the writes to Buffer1 coincide with the wait cycles of the Resampler 112.\n10.2.11.1 Address Generation for Buffer1\nOnce the resampling process is running, we are only concerned with writing to Buffer1 during the period when the Resampler 112 is not reading from it. Since the Resampler has 3 sets of 16 reads each 75 cycle period, there are 27 cycles available for writing. When the resampler is not running, we want to load up Buffer1 as fast as possible, which means a write to Buffer1 114 each cycle. Address Generation for Buffer1 consequently runs off a state machine that takes these two cases into account. Whenever a value is loaded from ImageRAM 11, the adjusted value is written to the appropriate color in Buffer1 one cycle later.\nAddress Generation for Buffer1 therefore involves a single address counter for each of the red, blue and green sub-buffers. The initial address for RedAdr, BlueAdr and GreenAdr is 0 at the start of each line in each case, and after each write to Buffer1, the address increments by 1, with wrapping at 36 or 78, depending on whether the buffer being written to is red, green or blue. Not all colors are written each 75-cycle period. A column of green will typically require replenishing at twice the rate of red or blue, for example.\nThe logic is shown in the following pseudocode:\nIf the color to write is Red\u2003Write to Red Buffer1 at RedAdr\u2003RedAdr = RedAdr + 1 mod 36ElseIf the color to write is Blue\u2003Write to Blue Buffer1 at BlueAdr\u2003BlueAdr = BlueAdr + 1 mod 36ElseIf the color to write is Green\u2003Write to Green Buffer1 at GreenAdr\u2003GreenAdr = GreenAdr + 1 mod 78EndIf10.2.11.2 Address Generation for Image RAM\nEach plane can be read in one of two orientations\u2014rotated by 0 or 90 degrees (anti-clockwise). This translates effectively as row-wise or column-wise read access to the planar image. In addition, we allow edge pixel replication or constant color for reads outside image bounds, as well as image wrapping for such print formats as Passport 31.\nAt the start of each print line we must read the ImageRAM 11 to load up Buffer1 114 as fast as possible. This equates to a single access to a sample each cycle. Resampling can only occur once 5 columns have been loaded, which means 5 columns of 6, 6, and 13 samples, for a total of 125 cycles. Plus an extra cycle for the final value to be written out to Buffer1 114 after being loaded from ImageRAM 11. To make the counting easier, we round up to 128 cycles.\nAfter the first 128 cycles, the checking for the requirement to load the next column of samples for each of the 3 colors occurs each 75 cycles, with the appropriate samples loaded during the subsequent 75 cycles. However, the initial setting of whether to load during the first set of 75 cycles is always 1 for each color. This enables the final 6th column of each color within Buffer 1 to be filled.\nAt the end of each 75 cycle period, the KernelXCarryOut flag from each color plane of the Kernel Address Generator in the Resampler 112 is checked to determine if the next column of samples should be read. Similarly, an AdvanceLine pulse restarts the process on the following line if the KernelYCarryOut flag is set.\nSince each 'read' effectively becomes 6 or 13 reads to fill a column in Buffer1, we keep a starting position in order to advance to the next 'read'. We also keep a coordinate value to allow the generation of out-of-bounds coordinates to enable edge pixel replication, constant color, and image wrap.\nWe consider the active image 180 as being within a particular bounds, with certain actions to be taken when coordinates are outside the active area. The coordinates can either be before the image, inside the image, or after the image, both in terms of lines and pixels. This is shown in FIG. 66, although the space outside the active area has been exaggerated for clarity:\nNote that since we use (0, 0) as the start of coordinate generation, MaxPixel and MaxLine are also pixel and line counts. However, since address generation is run from kernel carry outs and AdvanceLine pulses from the MJI 15, these outer bounds are not required. Address generation for a line simply continues until the AdvanceLine pulse is received, and may involve edge replication, constant colors for out of bounds, or image pixel wrapping.\nIf we have an address, Adr, of the current sample, and want to move to the next sample, either on the next line or on the same line, the sample's coordinate will change as expected, but the way in which the address changes depends on whether we are wrapping around the active image, and must produce edge pixel replication when needed.\nWhen there is no wrapping of the image (i.e. all print formats except Passport 31), we perform the actions in Table 38 as we advance in line or pixel. To rotate an image by 90 degrees, the CPU 10 simply swaps the \u0394Line and \u0394Pixel values.\nLooking at Table 38, the only time that ADR changes is by \u0394Pixel when PixelSense is 0, and by \u0394Line when LineSense is 0. By following these simple rules Adr will be valid for edge pixel replication. Of course, if a constant color is desired for out of bounds coordinates, that value can be selected in instead of the value stored at the appropriate address.\nTABLE 38Actions to Perform when Advancing in Pixel or LineLine8Pixel9Pixel ChangeLine Change\u2212\u2212\u22120Adr = Adr + \u0394Pixel\u2212+0\u2212Adr = Adr + \u0394Line00Adr = Adr + \u0394PixelAdr = Adr + \u0394Line0+Adr = Adr + \u0394Line+\u2212+0Adr = Adr + \u0394Pixel++8We compare the current Line ordinate with ActiveStartLine and ActiveEndLine. If Line < ActiveStartLine, we call the value \"\u2212\". If ActiveStartLine \u00a3 \u039bine < ActiveEndLine, we call the value \"0\". If ActiveEndLine \u00a3 Line, we call the value \"+\".9We compare the current Pixel ordinate with ActiveStartPixel and ActiveEndPixel. If Pixel < ActiveStartPixel, we call the value \"\u2212\". If ActiveStartPixel \u00a3 \u039bine < ActiveEndPixel, we call the value \"0\". If ActiveEndPixel \u00a3 Pixel, we call the value \"+\".\nTo allow wrapping, we simply compare the previous sense (\u2212,0, +) for Line and Pixel with the new sense. When the sense is \"\u2212\" we use the advancement as described in Table 38, but when the ordinate becomes out of bounds (i.e. moving from 0 to +), we update the Adr with a new value not based on a delta. Assuming we keep the start address for the current line so that we can advance to the start of the next line once the current line has been generated, we can do the following:    If a change is in Pixel, and the pixel sense changes from 0 to + (indicating we have gone past the edge of the image), we replace Adr with the LineStartAdr and replace Pixel with ActiveStartPixel. Line remains the same.    If a change is in Line, and the line sense changes from 0 to + (indicating we have gone past the edge of the image), we subtract DeltaColumn from Adr and replace Line with ActiveStartLine. Pixel remains the same. DeltaColumn is the address offset for generating the address of (Pixel, ActiveStartLine) from (Pixel, ActiveEndLine-1).\nThe logic for loading the set number of samples (either 6 or 13, depending on color) is shown in the following pseudocode:\nline = FirstSampleLinepixel = FirstSamplePixeladr = FirstSampleAdrDo N times (6 or 13)\u2003\u2003oldPixelSense = PixelSense(pixel)\u2003\u2003oldLineSense = LineSense(gLine)\u2003\u2003inActive = ((oldLineSense == InActive) AND (oldPixelSense ==InActive))\u2003\u2003If ((NOT inActive) AND UseConstant)\u2003\u2003\u2003\u2003Sample = ConstantColor\u2003\u2003else\u2003\u2003\u2003\u2003Sample = Fetch(adr)\u2003\u2003EndIf\u2003\u2003line = line + 1\u2003\u2003If ((LineSense(line) == \"+\") AND wrapImage)\u2003\u2003\u2003\u2003adr = adr \u2212 DeltaColumn\u2003\u2003\u2003\u2003line = ActiveStartLine\u2003\u2003ElseIf ((LineSense(line) == \"0\") AND ((oldLineSense == \"0\"))\u2003\u2003\u2003\u2003adr = adr + DeltaLine\u2003\u2003EndIfEndDo\nThe setting for such variables as FirstSampleLine, FirstSamplePixel, and FirstSampleAdr is in the address generator section that responds to carry out flags from the Kernel Address Generator, as well as AdvanceLine pulses from the MJI. The logic for this part of the address generation is shown in the following pseudocode:\nFirstSamplePixel = 0FirstSampleLine = 0FirstSampleAdr = FirstLineSampleAdr = ActiveStartAddresscount = 0Do Forever\u2003\u2003If ((KernelXCarryOut) OR (AdvanceLine ANDKernelYCarryOut) OR (count < 5))\u2003\u2003\u2003\u2003Do N Samples for this color plane (see pseudocode above)\u2003\u2003EndIf\u2003\u2003oldPixelSense = PixelSense(FirstSamplePixel)\u2003\u2003oldLineSense = LineSense(FirstSampleLine)\u2003\u2003If (AdvanceLine AND KernelYCarryOut)\u2003\u2003\u2003\u2003count = 0\u2003\u2003\u2003\u2003FirstSampleLine = FirstSampleLine + 1\u2003\u2003\u2003\u2003FirstSamplePixel = 0\u2003\u2003\u2003\u2003If ((LineSense(FirstSampleLine) == \"+\") AND wrapImage)\u2003\u2003\u2003\u2003\u2003\u2003FirstLineSampleAdr = StartAddress\u2003\u2003\u2003\u2003\u2003\u2003FirstSampleLine = ActiveStartLine\u2003\u2003\u2003\u2003ElseIf ((LineSense(FirstSampleLine) == \"0\") AND(oldLineSense == \"0\"))\u2003\u2003\u2003\u2003\u2003\u2003FirstLineSampleAdr = FirstLineSampleAdr + DeltaLine\u2003\u2003\u2003\u2003EndIf\u2003\u2003\u2003\u2003FirstSampleAdr = FirstLineSampleAdr\u2003\u2003ElseIf (KernelXCarryOut OR (count < 5))\u2003\u2003\u2003\u2003FirstSamplePixel = FirstSamplePixel + 1\u2003\u2003\u2003\u2003count = count + 1\u2003\u2003\u2003\u2003If ((PixelSense(FirstSamplePixel) == \"+\") AND wrapImage)\u2003\u2003\u2003\u2003\u2003\u2003FirstSampleAdr = FirstLineSampleAdr\u2003\u2003\u2003\u2003\u2003\u2003FirstSamplePixel = ActiveStartPixel\u2003\u2003\u2003\u2003ElseIf ((PixelSense(FirstSamplePixel) == \"0\") AND(oldPixelSense == \"0\"))\u2003\u2003\u2003\u2003\u2003\u2003FirstSampleAdr = FirstSampleAdr + DeltaPixel\u2003\u2003\u2003\u2003EndIf\u2003\u2003EndIfEndDo10.2.11.3 Register Summary\nThere are a number of registers that must be set before printing an image. They are summarized here in Table 39. To rotate an image by 90 degrees, simply exchange the DeltaLine and DeltaPixel values, and provide a new DeltaColumn value.\nTABLE 39Registers Required to be set by Caller before PrintingRegister NameDescriptionImage Access ParametersWrapImageTile image reads to replicate image when out of image boundsUseConstantIf 0, image edge replication or wrapping occurs on reads out ofimage bounds.If 1, a constant color is returned.RedActiveStartAddressRThe address of red sample (ActiveStartPixel, ActiveStartLine) inImageRAMActiveStartLineRThe first valid line for the image in red space (in relation to line 0)ActiveEndLineRThe first line out of bounds for the image in red spaceActiveStartPixelRThe first valid pixel for the image in red space (in relation to pixel 0)ActiveEndPixelRThe first pixel out of bounds for the image in red spaceDeltaLineRThe amount to add to the current address to move from one line tothe next in red spaceDeltaPixelRThe amount to add to the current address to move from one pixel tothe next on the same line in red spaceDeltaColumnRThe amount to add to the current address to move from a pixel in thelast line of the Active image area to the same pixel on the first line ofthe Active image area in red space.ConstantColorRRed color value to use if address out of bounds and UseConstant = 1GreenActiveStartAddressGThe address of green sample (ActiveStartPixel, ActiveStartLine) inImageRAMActiveStartLineGThe first valid line for the image in green space (in relation to line 0)ActiveEndLineGThe first line out of bounds for the image in green spaceActiveStartPixelGThe first valid pixel for the image in green space (in relation to pixel0)ActiveEndPixelGThe first pixel out of bounds for the image in green spaceDeltaLineGThe amount to add to the current address to move from one line tothe next in green spaceDeltaPixelGThe amount to add to the current address to move from one pixel tothe next on the same line in green spaceDeltaColumnGThe amount to add to the current address to move from a pixel in thelast line of the Active image area to the same pixel on the first line ofthe Active image area in green space.ConstantColorGGreen color value to use if address out of bounds andUseConstant = 1BlueActiveStartAddressBThe address of blue sample (ActiveStartPixel, ActiveStartLine) inImageRAMActiveStartLineBThe first valid line for the image in blue space (in relation to line 0)ActiveEndLineBThe first line out of bounds for the image in blue spaceActiveStartPixelBThe first valid pixel for the image in blue space (in relation to pixel 0)ActiveEndPixelBThe first pixel out of bounds for the image in blue spaceDeltaLineBThe amount to add to the current address to move from one line tothe next in blue spaceDeltaPixelBThe amount to add to the current address to move from one pixel tothe next on the same line in blue spaceDeltaColumnBThe amount to add to the current address to move from a pixel in thelast line of the Active image area to the same pixel on the first line ofthe Active image area in blue space.ConstantColorBBlue color value to use if address out of bounds and UseConstant = 1White Balance and Range Expansion ParametersRedLowThreshold8-bit value subtracted from red input valuesGreenLowThreshold8-bit value subtracted from green input valuesBlueLowThreshold8-bit value subtracted from blue input valuesRedScaleFactor8-bit scale factor used for range expansion of red pixelsGreenScaleFactor8-bit scale factor used for range expansion of green pixelsBlueScaleFactor8-bit scale factor used for range expansion of blue pixels","meta":{"bibliographic_information":{"country":"US","doc-number":"11198233","kind":"B2","date":"20050808","disclaimer_text":"This patent is subject to a terminal disclaimer.","invention_title":"Camera for capturing and resampling non-linear Bayer image"},"source_file":"https:\/\/bulkdata.uspto.gov\/data\/patent\/grant\/redbook\/fulltext\/2007\/ipg070220.zip","abstract":["A digital camera is provided comprising a Bayer color filter array arranged to capture an input image as a non-linear Bayer image comprising RGB pixels arranged in Bayer format, and a processor arranged to linearize and planarize the input image and to map each color of the linearized, planarized input image from an input space to an output space. The coordinates of the input space are mapped by the processor to the coordinates of the output space by dividing the output space coordinates by the number of pixels in the output space per input space sample and adding a vector (k1, k2) where k1 and k2 are equal to either 0 or minus 0.5, depending on the color and the relative rotational orientation of the linearized, planarized input image in the input space."],"citations":[{"country":"US","doc-number":"6205245","kind":"B1","name":"Yuan et al.","date":"20010300","category":"cited by other"},{"country":"US","doc-number":"6466618","kind":"B1","name":"Messing et al.","date":"20021000","category":"cited by other"},{"country":"US","doc-number":"6573932","kind":"B1","name":"Adams et al.","date":"20030600","category":"cited by other"},{"country":"EP","doc-number":"709825","kind":"A","date":"19960500","category":"cited by other"}],"assignees":[{"city":"Balmain","country":"AU","addressbook\/orgname":"Silverbrook Research Pty Ltd","addressbook\/role":"03"}],"classifications":{"ipc-version-indicator\/date":"20060101","classification-level":"A","section":"G","class":"06","subclass":"K","main-group":"9","subgroup":"00","symbol-position":"F","classification-value":"I","action-date\/date":"20070220","generating-office\/country":"US","classification-status":"B","classification-data-source":"H"},"dup_signals":{"dup_doc_count":106,"dup_dump_count":35,"dup_details":{"curated_sources":2,"2018-26":2,"2018-13":2,"2017-51":3,"2017-34":1,"2017-30":3,"2017-26":1,"2017-22":1,"2016-50":1,"2016-44":2,"2016-40":2,"2016-36":2,"2016-30":1,"2016-26":1,"2016-22":1,"2016-18":1,"2016-07":1,"2015-48":1,"2015-40":1,"2015-35":2,"2015-32":5,"2015-27":1,"2015-22":3,"2015-14":3,"2014-52":4,"2014-49":1,"2014-42":2,"2014-41":7,"2014-35":7,"2014-23":12,"2015-18":6,"2015-11":4,"2015-06":4,"2014-10":12,"2013-48":2,"2013-20":2}}},"subset":"uspto"}
{"text":"A medical diagnosis and monitoring system having at least one sensor for detecting an electrical, physical, chemical, or biological property of a patient such as, but not limited to, EEG- and EKG-signals, respiration, oxygen saturation, temperature, perspiration, etc. A digital-to-analog converter coupled to the sensor and a digital transmitter and receiver for wireless digital two-way communication with an evaluator station.\n\nThe invention relates to a medical measured-data acquisition equipment for monitoring and diagnosis, in particular to EEG and EKG equipment, as well as to facilities for controlling the breathing, the O2 saturation content in the blood, the body temperature, and for recording electric potentials or electrodermal activities such as the SSR (sympathetic skin response). Such monitoring and diagnostic equipment is used mainly in intensive-care stations in hospitals, or in the examination of patients.\nMonitoring equipment is used also for monitoring infants at home, among other things. In the Federal Republic of Germany about 2000 infants die annually from the sudden infant death syndrome, a phenomenon, the causes of which have not yet been elucidated in spite of intensive research. However, everything speaks for the fact that the sudden infant death is to be attributed to a failure of the respiratory function (apnea), and possibly of the cardiac function. It exclusively occurs during sleeping. The only preventive measure for preventing the sudden infant death currently consists in the monitoring of the respiratory or cardiac function. Said procedure is useful in that by stimulating the infant immediately following failure of the respiratory function, the respiratory activity automatically starts again, with a few exceptions.\nEKG and EEG facilities assume a special position among monitoring and diagnostic devices because their high medical conclusiveness. An electrocardiogram (EKG) is the recording of the time curve of heart action potentials; an electroencephalogram (EEG) is the graphic record of the brain action potentials. The analysis of the EKG's and EEG's supplies important information about the heart or brain function of the patient.\nConventional monitoring and diagnostic equipment is structured in such a way that one or several electrode(s) is\/are mounted on the patient, which tap the respective signals (predominantly potential and impedance values) and transmit such signals via cables to amplifier units. Normally, separate electrodes are used for each measurement parameter.\nEspecially in EKG and EEG examinations, many cables are suspended on the patient, connecting the EKG\/EEG-electrodes with the evaluator units, which process and record the signals. Such cables obstruct the patient and highly limit his or her freedom of movement, and, therefore, are only conditionally suitable especially for carrying out examinations at stress (e.g. EKG's at stress). In addition, due to the stiffness of the cables and the lever forces connected therewith, the cables become easily detached particularly when the patient moves. Furthermore, in connection with infants, there is the risk that they may play with the cables and detach the glued-on electrodes.\nThe electrode cables are especially troublesome in connection with home or hospital monitoring of infants. The removal and reattachment of the electrodes is troublesome especially when garments are changed frequently (e.g. during the changing of diapers).\nFurthermore, in complicated examinations with a great number of measured quantities such as, for example, in the polysomnography in connection with infants, problems arise on account of the fact that many relatively large electrodes have to be attached to the patient. Moreover, it is necessary in this connection to take into account the psychic stress of the patient, who is connected to an electrical device via a great number of cables. Such psychic stress may have a bearing on both the physical stressability and the physiological characteristic lines.\nThe above-described methods are high in expenditure, user-unfriendly, and under certain circumstances may require certain medical expertise, for example as far as the arrangement of all sorts of different electrodes is concerned. They are consequently only conditionally suitable especially for use at home, for example for the long-term monitoring of infants. In addition, there is the increased risk of falsified data and alarm malfunction because due to the simple electrode structure, it is not possible to make a distinction between medical abnormalities and technical defects (e.g. detached electrodes).\nTherefore, there is need for a nonelectric connection between the electrodes connected to the patient and the equipment. Furthermore, due to the galvanic separation of the electrodes from the evaluation station, the safety of the patient is assured as well.\nTelemetry systems for biosignals, in connection with which the EKG- or EEG-data tapped on the patient are transmitted via electromagnetic waves (preferably in the infrared range), are described, for example in \"Biotelemetrie IX\" (publishers: H. P. Kimmich and M. R. Neumann, 1987, pp. 55\u201358). The data are transmitted in this connection in the one-way mode from the electrodes to the output unit, i.e., without (error) feedback from the receiver to the emitter. A particular drawback in this connection is that the measured values are transmitted as an analog signal, which means they are relatively susceptible to interference, for example with respect to the 50 Hz-ripple and its harmonics.\nA further development for telemetric EKG-measurements is described in laid-open patent specification WO 90\/08501, where for achieving a higher transmission rate and data safety, the recorded signals are digitalized, coded (preferably according to the Manchester code, or as FSK (frequency shift keying), and then transmitted electromagnetically or by light wave conductor.\nIn connection with said telemetric method, the signals of the individual electrodes attached to the body are transmitted via cable to an additional emitter unit, which is separately attached to the body, and transmitted from there by radio or light wave conductor to the evaluator station. However, the above-mentioned methods have the drawback that the emitter unit is supplied with current via batteries. The batteries have to assure not only the power supply for the data recording and data processing, but also for the data transmission via radio transmission. Therefore, the batteries have to be replaced frequently, which is connected with drawbacks especially in long-term monitoring. Since the emitter units are relatively large, said methods again limit the freedom of movement of the patient. No details are specified in the above-mentioned references with respect to the structure of the electrodes used for the signal acquisition.\nMeasuring probes with HF-energy supply are known, for example from the references DE-OS 32 19 558, U.S. Pat. No. 4,075,632, and WO 92\/07505. However, the fields of application of said measuring probes are almost exclusively aimed at the identification of objects, and are implanted for said purpose on the animal or human body. Furthermore, the structure of said device is not suitable for the medical signal acquisition as well as for transmitting such signals, in particular not in connection with a great number of data from one or a plurality of electrode(s), and from a number of patients, if need be. With said methods, the signal transmission takes place almost exclusively via passive telemetry, whereby the measured data are detected in that the measuring probe carries out a modulation absorption in the HF-field of the evaluator station (ES), such absorption acts back on the ES (indirect transmission of information by inductive coupling). Said procedure, however, is suitable only in connection with extremely small spacings between the emitter and the receiver of only a few centimeters (as it is the case especially in connection with implanted probes), and only in the absence of external interferences. Moreover, in connection with said measuring probes, no provision is made for two-way data transmission, i.e., information is transmitted only from the receiver to the transmitter, so that errors in the data transmission can not be compensated, or compensated only highly conditionally.\nThe invention is based on the problem of making available a reliable monitoring and diagnosis equipment with wireless electrodes, which is suitable for both the use at home and for operation in hospitals. In particular, a safe data transmission of the electrodes is to be assured also when a great number of electrodes are operated simultaneously.\nSaid problem is solved by the characterizing features of patent claim 1. Preferred embodiments and further developments are specified in the dependent claims.\nThe proposed bidirectional, digital data transmission results in the surprising effect that the data transmission safety is significantly increased. By transmitting redundant information in the data emitted by the electrodes, the evaluator station is capable of recognizing errors and request a renewed transmission of the data. In the presence of excessive transmission problems such as, for example transmission over excessively great distances, or due to obstacles absorbing the high-frequency radiation, the evaluator station is capable also of controlling the data transmission, or to manipulate on its own the data emitted by the electrodes. As control of the data transmission it is possible to consider, for example an adaptation of the transmitting power of the electrode, or a change of the transmission channel. If the signal transmitted by the electrode is too weak, the evaluator station will transmit to the electrode a command, which increases its transmitting power. However, if the signal transmitted by the electrode is superimposed by other sources of interference, the evaluator station, by changing the channel, is capable of attempting securing a flawless and interference-free transmission. Alternatively, the evaluator station can also cause the electrode to change the data format for the transmission, for example in order to increase the redundant information in the data flow. Due to the increased redundancy, transmission errors can be detected and corrected more easily. In this way, safe data transmissions are possible even with the poorest transmission qualities. Said measure opens in a surprisingly simple way the possibility of reducing the transmission power of the electrode to a considerable extent. This reduces the energy requirement of the electrodes, so that the latter can be used uninterruptedly over longer periods of time. Due to the reduced transmitting power it is possible also to exclude possible biological stresses caused by the electromagnetic waves. Another advantage of the bidirectional digital data transmission lies in the possibility of transmitting test codes in order to filter out external interferences such as, for example, refraction or scatter from the transmission current. In this way, it is possible also to reconstruct falsely transmitted data. Due to the safe data transmission between the electrodes and the evaluator station, the device according to the invention is particularly suitable for use at home such as, for example, far monitoring infants even though no technically trained personnel is available there, as a rule. When used in hospitals, for example for monitoring in intensive care, the device according to the invention offers the special advantage that very many electrodes can be operated at the same time without interferences in one and the same room. Mutual influencing of the electrodes is excluded a priori. In particular, it is possible to program standard electrodes with a great number of sensors via the evaluator station in such a way that such electrodes can be used for special applications, i.e., for special application cases.\nThe electrodes can be supplied with current by an evaluator station (ES) by means of high-frequency energy transmission (especially in the radio frequency (RF) range). The antennas or optic detectors (e.g. semiconductor diodes) of the electrodes absorb in this connection the high-frequency field (HF-Field) radiated by the evaluator station, the latter being arranged spaced from said electrodes. By means of the power supply unit arranged in the electrode, which unit converts (rectifies) the HF-radiation and stores it, if need be, then supply voltage is then generated for the electrodes.\nThe device according to the invention can be designed also in such a way that the power supply unit of the electrodes is realized by additional integrated, miniaturized accumulators. A replacement of weak or empty accumulators is not required in connection with the device of the invention because the accumulators are recharged by the high-frequency field radiated by the evaluator station. Charging of the accumulators can be carried out also only temporarily, for example at points in time at which the electrodes are not in use, i.e., outside of the recording of measured values. In this case, the energy for the charging can be transmitted via resonance coupling, for example by means of inductive coupling. Since the accumulators do not have to be replaced, they also can be encapsulated in the electrodes.\nFurthermore, it is possible particularly in connection with long-term monitoring to first supply the electrodes with current through the accumulator, and then later\u2014if necessary\u2014supply the electrodes, for example if the accumulators are weak, with current via the emitted HF-frequency field of the evaluator station. In this way, a possible biological stressing of the body by the high-frequency radiation acting on it can be excluded or minimized.\nFrequency generation units generate in the electrodes or in the evaluator station the required oscillator frequencies for the emitter units as well as receiving units. Preferably, the frequency generation unit comprises one or a plurality of PLL (phase-locked loop) or FLL (frequency-locked-loop) synthesizers, which generate the various frequencies. The transmission frequencies for the (data) transmission may basically extend from the 100 kHz range (long wave) to the 1015 Hz-range (optical frequencies). For small electrode dimensions, high bit transmission rates and short transmission distances, transmission frequencies in the UHF range, microwave range and above (>10) MHz, however, are particularly suitable.\nIt is advantageous for the device according to the invention if micro-structured sensors such as semiconductor sensors or thin-layer sensors are used for the signal detection or signal recording. Semiconductor sensors are characterized by their small size, their sensitivity, their high integration capability, and their low current consumption. Important are particularly sensors which are based on the (field effect) transistor (e.g. Si-MOS-FET), the diode or the capacitor principle. In this way, it is possible to realize a great number of sensors such as, for example, bio- or ion-sensitive sensors (ISFET), acceleration, pressure, voltage, impedance, current, temperature, as well as radiation sensors.\nBy using semiconductor components as sensors with integrated signal processing, transmitting\/receiving (transceiver) and, if need be, evaluator units, individual circuit arrangements with a number of sensors can be integrated in a chip with edge lengths of less than 10 mm and heights of under 0.5 mm. In this way, the number of electrodes can be reduced, on the one hand, and additional electric components\u2014which are attached to the body and which limit the freedom of movement\u2014can be omitted. Since the distance of transmission from the electrodes to the evaluator station normally amounts to only a few meters (order of magnitude: 1 to 10 m), the energy supply or transmitting power of the electrodes comes, in the ideal case, to only fractions of mW, which means it is completely harmless, medically speaking. The use of miniature batteries (e.g. button cells) is consequently suitable for the energy supply as well, especially for short transmission distances. For this purpose, the TDMA-process is particularly advantageous because the electrodes transmit only at certain time intervals, which means that energy can be saved.\nAnother feature of the device according to the invention lies in the arrangement of the antenna. The latter is preferably completely (or at least partly) arranged in the electrode covering or electrode diaphragm consisting of, for example flexible plastic. If the electrode is designed in the form of a bracelet, the bracelet can be used as the antenna as well. The antenna can be realized in all sort of ways, for example as a dipole, lagarithmic-periodic, dielectric, strip conduction or reflector antenna. Preferably, the antenna consists of one or a plurality of conductive wires or strips, which are arranged in a spiral form (spiral antenna or also helical antenna). In this way, the antenna can be designed with a relatively large surface area, which requires lower transmission outouts for the data transmission and HF-Supply. In particular, it is possible in the radio transmission to use frequency-selective antennas for separating the transmission and receiving band, and polarization-sensitive antennas in connection with directional transmission. Polarization-sensitive antennas consist of, for example thin metal strips arranged in parallel on an insulating carrier material. Such a structure is insensitive to or permeable to electromagnetic waves with vertical polarization, we es with parallel polarization are reflected of absorbed depending on the design, it is possible to obtain in this way, for example good cross polarization decoupling in connection with linear polarization.\nIt is possible, furthermore, to integrate the antenna, for example in the frame of the chip, whereby the antenna is preferably realized by means of the thin-layer technology.\nThe antenna of the electrodes serves both for transmitting the electrode data and for receiving the control data transmitted by the evaluator station, as well as for receiving, if need be, the high-frequency energy (for the energy supply), i.e., basically only one transmitting and receiving antenna is required.\nIn particular, directional couplers can be arranged on the transmitter outputs of the electrodes and\/or the evaluator station, which couplers measure the radiated or reflected (radio transmission) output. Any damage to the antenna (or also any faulty adaptation) thus can be registered, because it is expressed by increased reflection values.\nIt is possible to carry out the high-frequency energy supply and the data transmission on different frequencies (e.g. data transmission in the IR-range by means of transmitting and receiving semiconductor diodes in the electrodes and evaluator station; energy transmission in the microwave range via the antennas). In particular, it is possible also to transmit sensor data to be transmitted and also electrode control as well as control data from the evaluator station to the electrodes, in each case on different carrier frequencies or at different points in time.\nPreferably, the frequency modulation and\/or phase modulation is used for the data transmission in order to exclude excessively long zero series, as they may be present in connection with amplitude modulation. With pure HF-supply of the electrodes, (i.e., without the use of accumulators), transmission of the electrode control and transmission control data to the electrodes can take place, for example by modulating the HF-field.\nFurthermore, it has to be taken into account that the radio signal power of the transmitted data is subjected in the receiver to certain variations, as may be the supply voltage of the electrodes (for example if the electrodes are exclusively supplied with energy by the high-frequency field (HF) of the evaluator station). This is mainly the case when the patient moves or turns, thereby changing the spacing between the electrodes and the evaluator station. Also, a certain attenuation and scattering of the signals has to be taken into account, among other things, especially in long-term monitoring (for example in the monitoring of infants or patients in intensive care units), because these measurements are then frequently carried out on dressed patients and in the bed (under a blanket). Therefore, a further development of the invention consists in arranging in the evaluator station a control unit for the transmission output. With said control unit, the evaluator unit determines and controls the transmission output received from the individual electrodes, and, if need be, controls its own transmission output accordingly. If, in the evaluator station, the electrode field intensity falls short of a preset lower threshold value, the evaluator station controls the relevant electrode for increasing the transmission output. Preferably, the procedure followed is such that maximum values presentable for the electrode transmission output are not exceeded. For this purpose, the electrode transmits its transmission output to the evaluator station.\nFor controlling the transmission output of the evaluator station, the electrode contains a reference element for measuring the transmission output received. Said transmission output is then transmitted back to the evaluator station, which then controls its own-transmission output accordingly.\nIt is assured in this way that the transmission output of the electrodes and of the evaluator station (including, if necessary, the HF-energy supply) is adapted in each case in such a way that the signal level will not fall-short of or exceed certain lower and upper limits in the receiver and in the transmitter. The radiated transmission output is always adjusted by such control processes to the minimum required at the given time in order to receive data with adequate quality, or to optimally operate the electronic units of the electrodes. The transmission output can be adjusted step by step or continuously. This provides the evaluator station with the capability, among other things, to detect whether a signal change is caused by variations in the supply voltage, in the transmission output (with changes in distance), or by a change in the sensor output signal, which is important, for example in connection with amplitude modulation.\nAlternatively, instead of the transmission output, the control unit can also control the redundance in the data flow if the bit error rate exceeds a preset threshold value.\nA further development also consists in arranging in the electrodes a shutoff unit. When a preset maximum value for the required transmitting output of an electrode (and also of the evaluator unit, if need be) is exceeded, the respective electrode is temporarily automatically deactivated by means of the shutoff unit, the data transmission or recording of the measured values is temporarily interrupted in this way. The evaluator unit then adjusts itself only to the remaining electrodes and may emit an alarm signal depending on the adjustment. The required transmission outputs may be determined, for example by the control unit or by the reference elements in the respective electrodes. Said procedure can be particularly desirable when an infant, during monitoring, is turning, for example from the back to the belly and comes to rest on one or several electrodes. A possible biological stress due to HF-radiation is excluded in this way. The temporary shutoff of electrodes basically can be controlled also by integrated position and\/or inclination sensors.\nThe device according to the invention permits the patient to move freely during the recording of the measured values because such patient is no longer connected to an evaluator station via troublesome cables. When batteries or accumulators are used, such patient may even leave the room for a certain amount of time, especially if the individual electrodes have a data memory. Especially in hospitals, the mobility of the patient can be increased further if the evaluator station(s) comprise a plurality of global transmission or receiving antennas (arranged, for example, in different rooms and hallways). Advantages of the device according to the invention are seen also in the field of emergency medicine. A victim of an accident can be fitted with the electrodes already at the site of the accident, and their signals are then continuously transmitted to evaluator stations (ES), first to the ES in the ambulance and then to any desired ES in the hospital. The correct code for the electrodes or set-of electrodes can be transmitted to the evaluator station in the hospital, for example by means of chip cards or magnetic plug-in cards.\nBy equipping the evaluator station with an accumulator, infant monitoring can be carried out also \"on the road\", for example in the baby carriage or while driving in an automobile, especially if such station has a removable monitoring module.\nFor monitoring patients, it is particularly possible that only a limited number of electrodes connected to the patient receives sensor data and transmits same to the evaluator station. If irregularities or abnormalities occur, the evaluator station can then connect additional electrodes or sensors by deactivating the shutoff unit.\nFurthermore, the energy consumption of switched-off electrodes can be reduced in that such electrodes are capable of receiving (for an activation by the ES) and\/or measuring (for example for the integrated (position) sensors) only at certain time intervals.\nAn additional feature of the invention consists in that identification units can be arranged in the electrodes. By allocating certain identification codes patient code (for a set of electrodes) as well as electrode or sensor code\u2014the evaluator station is then capable of simultaneously supplying several patients in a room, such patients each having a great number of various electrodes, and to evaluate the data and to allocate electrodes or sensors to the respective patients. This is realized in a way such that the electrode for the identification unit has a control logic, as well as a memory for storing the identification codes. The identification unit of the electrodes is preferably programmed by high-frequency radio transmission of control characters and of the respective identification code from the programming unit of the evaluator station to the respective electrodes. A further development comprises the arrangement of (pressure) switches in the electrodes as programming lockouts, particularly for preventing unintentional reprogramming.\nA preferred further development of the device according to the invention particularly for long-term monitoring (for example for monitoring infants) is designed in such a way that the electrodes are already equipped with an evaluator unit (with memory). The data transmission can then take place from the electrodes to the evaluator station temporarily (for example by packets) and\/or already processed, if need be (following the reduction of redundant information), or, if necessary, only in the event of irregularities, or when medical abnormalities occur. Irregularities and abnormalities are detected, for example in that the signals are outside certain preset tolerance limits, or in that they deviate more strongly from the values of preceding measurements, which are stored in the (intermediate) memory. The tolerance limits are preferably transmitted by the evaluator station to the electrode and stored in the latter.\nThe evaluator station (and also the electrodes, if need be) preferably contain(s) a control unit for the various functional units. In the presence of malfunctions (for example: connection to the electrode is defective), the evaluator station can then emit a sound and\/or visual warning signal. In addition, it is possible to duplicate critical or important components of the evaluator station (and\/or of the electrodes), or to have them present as multiple units. Possible malfunctions can be reduced in this way. Furthermore, the evaluator station and\/or the electrodes can be provided with protective devices, for example for preventing antenna overvoltages.\nA preferred embodiment consists in the arrangement of control sensors in the electrodes for error detection. A possible error cause, for example, consists in that a sensor no longer receives any measuring signals, or falsified measuring signals because the electrode has become detached from the skin. Temperature, impedance (measurement of the transient resistance) or spacing sensors are suitable for the control. In this way, a malfunction of the electrodes can be distinguished from possible medical abnormalities or irregularities and thus assure a correct recording of the data, or prevent error alarms (especially in connection with home monitoring).\nBy means of a status unit in connection with the evaluator station it is possible to adjust which electrodes or sensors are to be used for the medical diagnosis or monitoring. In addition the status unit of the evaluator station can additionally assume control functions, for example by automatically detecting (for example by means of the control sensors arranged in the electrodes, or through the reference element, which measures the supply voltage) whether the electrodes are correctly connected to the body at the start of the medical diagnosis or monitoring. Alternatively or additionally, the electrodes can be equipped with an ON\/OFF switch for the activation.\nIdeally, all electronic components of the electrodes such as the sensor unit, the sensor control unit, the energy supply unit (except for the accumulator) etc. are designed as integrated circuits and realized on one single chip (electrode chip). In particular, the electrode chips can be realized as ASIC's application-specific integrated circuit), or in the form of ASIS's (application-specific intelligent sensor).\nASIC's include, among other things, microprocessors (with user programs in the program memory), circuits with programmable wiring (for example cutting through conducting paths by burning, or through application-specific manufacture of the last mask), and (gate, transistor) arrays. Array circuits represent chips manufactured in standardized ways, whose individual components (e.g. sensors, operation amplifiers, transistors, diodes, etc.) are not connected, and thus unwired. The individual elements are arranged in matrix-form in rows or columns, whereby intermediate spaces are left clear for the wiring. The connections of the individual elements in one or several metallization planes are produced according to the requirements. By using more modern C-MOS technologies (e.g. 0.1 \u03bcm technology), the structural dimensions can be highly reduced and the current consumption of the semiconductor components can be kept low. Particularly in connection with ASIS's on a wafer (preferably silicon or GaAs), the chips with the elementary sensors and suitable electronic circuit structures for the control electronics are manufactured with microelectric process steps (for example thermal oxidation, diffusion, ion implantation, metallization, passivation), as well as possibly processes of micromechanics, thin-layer, or thick-layer technology. The individual chips are subsequently finished in the metallization plane depending on the application. The electrode chips designed as type ASIS or ASICS thus offer the advantage of a rational semiconductor manufacture in spite of varied and different application specifications.\nPreferably, the electronic components of the electrodes and evaluator station are realized by means of digital circuit technology. The digital circuit technology satisfies in an ideal way the requirements with respect to integration capability, stability and programmability. Ideally, the evaluator unit of the evaluator station (ES) and\/or of the electrodes, as well as the sensor control and transmission control and frequency generation units are realized as microprocessors. However, for the determination of high transmission frequencies, it is necessary the design the receiving and transmitting units in part based on the analog technology.\nFor reducing the chip size further, preferably the two-side technology or the 3D-integration is used. With the two-side technology, the front and back sides of the chips are used for integrating the individual semiconductor components. It is possible, for example, to arrange the individual elementary sensors in the back side of the chips, and the signal processing and transmitting\/receiving units, as well as the evaluating and storing units, if necessary, in the front side of the chips. The electrode chip may be designed also based on the hybrid technology, among others. In connection with the latter, the component is divided in different units such as, for example in a sensor assembly, transceiver assembly, etc.\nPreferred embodiments of the (bio)sensors are discussed in the following in greater detail. For reducing the number of electrodes, preferably several sensors are arranged in one electrode.\nThe biophysical recording of measured values is carried out, on the one hand, by means of semiconductor sensors, which are based on the transistor (field effect or bipolar type), diode or capacitor principle. Examples of such sensors are:                The ISFET, which is structured similar to the MIS-field effect transistor; the metallic gate electrode (control electrode) is, with the ISFET, replaced by an ion-sensitive diaphragm. As diaphragm materials of a sensitive nature, use if made, for example of the following materials: SioxNy, Si3N4, Al2O3, Ta2O5, ZrO2, AgCl, AgBr, and various polymers, as well as biochemically active materials (enzymes).        The MOS gas sensor with (catalytic) metal gate electrode (e.g. palladium, platinum) reacts to hydrogen and, with geometrically structured gate electrodes, to other gases (transverse sensitivity). By using integrated (porous) filter layers it is possible to influence the cross sensitivity and thus the response behavior. With circuits of MOS gas sensors that are connected in parallel or in series it is possible to obtain distinct quality improvements and a superior response behavior.        The barrier-layer temperature sensor, in which the temperature dependency of p-n junctions in semiconductor components is used for measuring the temperature. Preferably, for this purpose, two identical transistors are operated in a differentiating network at the same temperature with different collector currents (measuring accuracy about 0.1\u00b0 C.).        Photodiodes, especially the p-i-n photodiode, as well as phototransistors.        \nOne alternative consists in realizing the sensors (and circuits) by means of thin-layer technology by applying thin inorganic or organic layers (films) to an insulating carrier material (substrate). The measuring principle of such sensors is based on the change in the electrical properties (e.g. electric resistance) of the thin layer under the influence of the external quantity to be measured. The application of this technology permits integrating a great number of elementary sensors with circuits on one chip, e.g. based on the hybrid technology. In connection with the thin-layer technology, vacuum processes are used for producing (by vapor deposition, application by atomization, or chemical deposition) thin metal, insulator or semiconductor layers on ceramic material, glass or plastic substrates, with layer thicknesses of less than 1 \u03bcm. As layer materials, preferably metal layers (e.g. aluminum, chromium) are used for conductors (conductor paths) and electrode pins, and for resistor layers preferably, for example, NiCr and tantalum, and for insulating layers preferably SiO2, Si3N4, AlAs (for the GaAs-technology), and Ta2O5. The following can be produced as sensors with application of the thin-layer technology:                Temperature-dependent resistor layers made, for example of platinum, gold, nickel, copper and iridium (resistance thermometer; and possibly thermoelements (Seebeck effect);        light-sensitive layers, for example made of CdS, PbSe, Si, etc.;        moisture-sensitive layers: the sensor contains electrodes engaging each other in a toothed way like a comb, such mating electrodes being protected against the moisture-sensitive layer\/layer sequence. For realizing the moisture- sensitive layer it is possible to use materials such as polymeric plastics, metal oxides, and porous ceramic materials;        gas-sensitive layers such as, for example, semiconducting metal oxide layers (SnO2, Fe2O3), particularly for detecting CO2;        magnetoresistive layers such as, for example Ni\u2014Fe-alloys, as well as        pressure-sensitive resistance layers such as strain gauges consisting of metallic film resistors (e.g. NiCr, CrSi and TaNi layers or foils, or of semiconductor layers. The pressure is measured in this connection through a change in the electric resistance; with metal strain gauges through a deformation; and with the more sensitive semiconductor-type strain gauges through the piezoresistive effect.        \nThe thin-layer sensors particularly include also the SSW-sensors (sound surface wave). SSW-sensors belong to the SSW-components whose function is based on the stimulation of mechanical vibrations on the surface of piezoelectric solids or layer structures when an electric voltage is applied to a metallic converter (IDC=interdigital converter) with mating finger structures. The SSW-sensor, when converting the sound wave into an electric signal, makes use of the electroresistive effect, which represents the reversal of the piezoelectric effect. The surface wave propagating between two IDC's is freely accessible and subjected to different biophysical quantities. Its propagation property (propagation rate and attenuation) is dependent upon, for example the gas concentration (by means of selectively absorbing layers), the moisture and the temperature of the surrounding medium directly on the surface of the substrate. With the help of these sensors it is possible, therefore to realize different biophysical sensors, particularly gas sensors, temperature sensors, and moisture sensors. The great advantage of the SSW-sensors is the direct conversion of the measured biophysical quantity into a frequency and the frequency-analogous interface connected therewith. This results in relatively good immunity to interference, high reliability, as well as simple digitalization, because a simple frequency counter can be used instead of an analog-to-digital converter.\nSince the substrate can be selected largely independently of the type of sensor layer used, the substrate and the sensor layer can be optimized independently of one another with respect to their specific properties, and a complex sensor system can be realized in this way. The thin-layer sensor technology and the semiconductor sensor technology are consequently fully process-compatible.\nBasically, the thick-layer technology can be used for the manufacture of the electrode chips or of the sensors as well, for example for realizing the structure of superset or hybrid-integrated circuits.\nFor monitoring the breathing, acceleration sensors or also motion sensors) consisting of one or a plurality of semiconductor components with inert mass are used, on the one hand, by measuring the up and down motion of the thoracic cage or of the abdomen. These sensors are considerably more sensitive and reliable than the conventional \"air cushion electrodes\", and, furthermore, integratable.\nThe breathing can be controlled\u2014also via a spacing sensor, which is integrated in an electrode arranged within the abdominal region. The spacing between the electrode and the evaluator station, which varies with the respiratory activity, can be determined in this connection, for example based on the difference in running time of the signals between the electrode and the evaluator station. The antenna of the evaluator station is, for this purpose, preferably mounted directly above the sleeping patient or the infant to be monitored. For control purposes it is possible to use additional spacing sensors, which are integrated in reference electrodes (mounted in sites that do not sensitively react to breathing motions such as, for example, on the head, arm, leg, etc.), or in other electrodes. It is possible in this way to distinguish movements of the entire body from breathing motions.\nAlternatives to monitoring of the breathing by means of acceleration or spacing sensors consist in the use of temperature, gas (CO2 or O2) or air humidity sensors, which are attached near the mouth and nose (preferably between the two).\nThe oxygen can be measured, for example by means of a Clark-cell. For this purpose, a micromechanical, spiral-shaped groove is etched, for example in an Si-chip or Si-wafer. A silver anode is produced by vapor deposition on the bottom of the groove, and a silver cathode between the grooves. The groove is filled with a polymer, which is impregnated with common salt solution, and finally covered with the diaphragm, the latter being permeable to oxygen. When a dc voltage (abt. 0.8 V) is applied to the electrodes, an electrolyse reaction occurs, which supplies a current proportional to the oxygen concentration.\nCO2 is detected, for example by means of an ISFET, whose ion-sensitive diaphragm contains a water-impregnated layer. In this connection, the CO2 diffusing into the water-impregnated layer leads to a chemical reaction with pH-shift.\nThe impedance or potential measurement, for example for the EKG or EEG signals, is carried out by means of measurement amplifiers consisting of difference operation amplifiers (with installed filters). Basically, also 3 and more tapping points (hereinafter referred to as electrode pins) can be arranged in one electrode. One electrode pin can be used in this connection for the reference value.\nFor measuring potential differences or impedances, a galvanic connection has to be present between the individual tapping points. Therefore, without a galvanic connection, it is possible only to determine the impedance values between the individual electrode pins in an electrode. Since the spacing between such electrode pins can be selected relatively small (up to about 1 cm; ideally 3 to 5 cm), it is possible in this way to monitor action voltages in small regions because the transmission takes place only over a small distance, which permits more sensitive measurements. In order to determine impedances or action potentials over greater distances, i.e., for example between two electrodes, such electrodes are galvanically connected with each other by means of a plug connection (for this purpose, the galvanically coupled electrodes have to be equipped only with the required electrode pins and, if need be, measurement amplifiers, but must not have their own transmitting, receiving, energy supply units, etc.).\nIntegrating two or more electrode pins in one electrode considerably simplifies the handling. In addition, the arrangement due to the integration of control sensors, permits a significantly better error diagnosis, for example in the event of incorrect mounting. Preferably, the sensor has an oblong shape (with two electrode pins) or the shape of a cloverleaf (with 3 or 4 electrode pins), which assures that with a small electrode surface, the spacing between the individual electrode pins or tapping points will not be too small, which would lead to measuring errors especially at high skin\/electrode transition resistance.\nThe transition from the ion conduction of the body to the electrode line of the (EKG\/EEG) lead connections takes place at the electric transition between the (EKG\/EEG) electrode pins and the skin of the patient. This generates a galvanoelectric dc voltage which, due to irregularities of the skin, can assume different values, and which effects a galvanoelectric dc voltage between two (EKG\/EEG) electrode pins. Said voltage has to be suppressed in the processing of the signal because it is significantly higher than the useful signal. Furthermore, as little current as possible should flow via the (EKG\/EEG) electrode pins because such flow changes the chemical composition of the skin and causes polarization voltages that may vary highly in terms of time. Therefore, the input currents have to be low and the input amplifier has to have a high input impedance. These conditions are ideally satisfied by operation amplifiers or measurement amplifiers based on the former.\nIt is notable in connection with impedance and potential measurements that conventional multiplexers are not capable of well-processing signals in the mV-range with a high dc voltage component. Therefore, for processing such signals, the dc voltage is suppressed by means of filters. Multiplexing of the sensor signals then takes place following the input amplification. Measuring the action potential by means of measurement amplifiers has the advantage that suppression of the dc voltage by filters (high-pass or bandpass filters) can be effected already directly in the measurement amplifier.\nFor temperature measurements, it is possible to use\u2014in addition to the aforementioned sensors\u2014also propagation resistance sensors, polysilicon temperature sensors (preferably based on the thin-layer technology), and basically also thermoelements. A contactless temperature measurement of the surface of the skin is basically possible as well; the temperature is detected, for example via the emitted heat radiation (infrared, remote infrared) of the body. With propagation resistance sensors, which have a high long-term stability, the specific resistance of semiconductors is measured according to the single-tip method. The propagation resistor preferably consists of a monocrystalline Si-crystal (e.g. with a lateral edge length 1 of about 0.5 mm and a thickness h of 0.2 mm) and has on the top side an etched contact hole with a diameter d (<<h, 1) of about 20 \u03bcm, from which a contact is produced by a strong doping (n+) and application of metallization layers. The resistance R between a rearward metal contact and the metallization contact then only is still dependent upon the temperature-dependent specific semiconductor resistance p of the (n-) doped silicon\n      (          R      =              P                  2          \u2062          d                      )    .\nPosition sensors for the determination of the (sleeping) position of the patient (for example belly, back or side position) are preferably realized by magnetic field sensors. Magnetic field sensors contain, for example a Hall element consisting of a (thin, long stretched-out) metal platelet, or a silicon or GaAs semiconductor platelet. For the determination of the position, a constant current is impressed into the Hall element, and the Hall voltage is evaluated as a function of the magnetic flow or the vertical component of the outer magnetic field of the earth. By arranging three Hall elements in the sensor or electrode, such elements being arranged vertically relative to each other, it is then possible to determine the exact position (belly, back or side position) of the patient.\nAn alternative in the use of inclination sensors, which is many cases operate according to the capacitive measuring principle. Capacitive inclination sensors consist of a microstructured measuring cell, which is filled with liquid an inert gas. In this connection, the two plates of a capacitor (or of a plurality of capacitors) are more or less covered by the liquid dielectric depending on the inclination. Turning of the sensor results in a change in capacity that is proportional to the angle. Basically, the position can be determined via micromechanical sensors as well.\nControl sensors are used especially for avoiding false alarms or falsified measured values. Such sensors can be realized, for example in the form of spacing sensors (ultrasound or radiation emitters and transmitters for determining the distance between the electrode and the skin), impedance sensors (measurement of the transition resistance between the electrode and the skin), temperature sensors (sensor measures the temperature of 36\u00b0 C. if the electrode is suitably attached), moisture sensors, or reference sensors.\nFor the determination of the value of oxygen saturation (O2) in the blood, transmission or reflection measurements are carried out. Preferably IR radiation emitters and receivers (diodes) are used for these measurements. IR emitters and receivers are arranged in this connection on the same or opposite sides of parts of the body (fingers, toes, palm or back of the hands) with high blood circulation (also on thin parts in connection with transition measurements).\nMoisture sensors are preferably realized in the form of impedance sensors (operation amplifiers) or ISFET's, which determine the sweat content or the pH (ion concentration of NaCl) on the skin.\nUsefully, the evaluator station contains a calibration unit (with memory) for the sensors, in particular for the temperatures, gas, ion-sensitive and Hall sensors. Basically, such a calibration unit can be arranged in the respective electrodes as well.\nThe radio transmission of the digitalized and coded sensor data is effected by the digital modulation (rekeying) of a sinusoidal carrier signal, in connection with which shifting takes place between discrete (e.g. two or four) wave shapes, or by means of discrete pulse modulation methods. The modulation or demodulation can take place directly in this connection (i.e. at the transmission frequency), or also indirectly (with an intermediate frequency), in which case, however, changing (via mixers) to the transmission frequency is necessary.\nIn connection with the digital carrier frequency technology, either the amplitude, preferably, however, the frequency (FSK=frequency shift keying), or the phase (PSK)\u2014as particularly with the GMSK=Gaussian minimum shift keying\u2014is varied (modulated), or a combination from the three methods is used.\nFor the discrete pulse modulation (basic band transmission), particularly the PCM-method (pulse code modulation) or the DM (delta modulation) method is considered. These methods are preferably used for the optical transmission of the data (e.g. in the IR-range by means of semiconductor diodes). In this connection, by scanning with quantized amplitudes, a change of analog (sensor) signals into coded digital signals takes place, namely mostly in sequences of binary pulses with the values 0 or 1. Possible are 8\u2014for example with compounding\u2014, but also 10 or higher-digit (linear) code words are possible with one or several parity bits. Coding is carried out, for example according to the Manchester-method.\nFor superior exploitation of the transmission channels, i.e., in order to be able to transmit the sensor data and the data of the evaluator station independently and simultaneously, the individual signals of the electrodes or sensors and of the evaluator station are preferably additionally processed prior to the transmission by a multiplexer (line transmission). Among the multiplex-methods, especially the TDMA (time division multiple access) process, the FDMA (frequency division MA) method, and the CDMA (code division MA) method are of interest.\nWith the TDMA-method, message signals are transmitted in blocks of data in a time-interleaved arrangement in a cyclic sequence. With the PCM, for example, this is possible because the pulses have a short duration, so that scanning samples of other input signals can be inserted in the intermediate spaces. With the FDMA method, the transmission medium is divided in N identically sized frequency bands (e.g. with N or N\/2 transmitters). By modulation with staggered carrier frequencies, the basic bands of the primary signals are shifted in this way to higher frequency positions, in a way such that they come to rest next to each other on the frequency scale.\nWith the CDMA-method, a distinction can be made in this connection between the \"frequency hogging\" and the \"direct-frequency\" coding. With the frequency hopping, several frequency (part) bands are available for the transmission. The message to be transmitted is divided in packets of the same length, which are transmitted one after the other on different part bands. In this way, a noise pulse generator cannot simultaneously interfere with all frequencies, so that only a few packets are disturbed by such a generator. Due to sufficiently high redundancy, the entire message will then reach the receiver with a good quality in spite of the interference. With direct sequence or also pseudo-noise coding, the message is highly stretched by bits in terms of time before it is transmitted, and modulated with a pseudo-random binary sequence. A receiver knowing the binary sequence can extract the useful signal again from the pseudo-noise. The separation of the signals is assured by the selection of orthogonal code sequences. This permits, on the one hand, a parallel transmission of different messages on one band; on the other hand, this method is relatively insensitive to wideband and narrowband interferences.\nThe space-division multiplex method offers another possibility for data transmission. In this case, the evaluator station is equipped with a plurality of transmitting\/receiving antennas, which each are directed at different patients to be monitored. Said method, furthermore, has the advantage that the antennas can be arranged relatively close to the patient (e.g. directly above the patient's bed), which permits reducing the transmission power. Especially in connection with directional antennas, the antenna can be equipped with an additional control unit and a driving motor, such unit and motor aligning or adjusting the antenna in such a way that the transmitting\/receiving adjustment is always optimal. This method basically can be used also in connection with a great number of electrodes attached to the patient. Especially with very large systems, for example in hospitals, several evaluator stations each having several antennas can be interlinked via cables or radio transmission. The individual sets of electrodes will always respond to the most suitable evaluator station or antenna (e.g. to the closest one), and when the patient is moving, will be handed-over to the next ES, if need be (hand-over). For reducing interferences, the individual evaluator stations are preferably operated on different frequency bands.\nDepending on the complexity of the data transmission methods, transmission control units are arranged in the electrodes. Preferably the evaluator station has a master transmission control unit and controls the transmission control units of the electrodes via signalizing data (synchronization). In this way, the evaluator station prevents collisions in the data transmission of different electrodes.\nSo that in the data transmission, the receiver is capable of scanning the received signals at the correct points in time in order to be capable of recognizing the individual bits correctly, a synchronous operation between the transmitter and the receiver is useful and necessary (synchronous data transmission). For this purpose, the evaluator station preferably contains a synchronizing unit which, as the reference cycle clock generator, controls the clock generators of all nodal points of the network, i.e., of the electrodes by means of synchronization characters and\/or via a reference timing frequency, for example according to the master slave method, and in this way assures the frequency, clock, base and\/or frame synchronization (TDMA). In particular, the high frequency (HF) for the energy supply can be used as the reference timing frequency. It is possible also to use the demodulated signal for the clock recovery, among other things.\nIt is basically possible also that the cycles of the individual electrodes do not correspond with the one of the evaluator station (ES)(asynchronous operation), or slightly deviate from the cycle of the ES within preset limit values (plesiochronous operation). If, for example, one electrode has a slightly higher clock pulse frequency than the evaluator station, the ES may occasionally be incapable to read a bit; reversely, the electrode will occasionally read a bit twice. This error can be compensated, for example through the use of padding methods, i.e., through the use of bits that do not carry any useful information. An alternative consists in that the system accepts an occasional slip. By using slip controls in the receivers it is particularly possible to prevent the system from losing its frame synchronization in spite of slip, for example in that a shift takes place by a whole frame, and not only by one bit width. Therefore, the requirements with respect to synchronization between the electrodes and the evaluator station can be low, comparatively speaking.\nSuitable for the transmission is particularly also the sub-division of the signals (to be transmitted) in packets, whereby each packet is provided with suitable addressing, code protection etc. (packet transmission). One packet comprises, for example start, stop, control and synchronization bits, the address of the transmitter and of the receiver, a test code, if necessary, as well as the useful information.\nIn the simplest case, the data are transmitted by the simplex method, i.e., from the electrodes to the evaluator station, and without acknowledgement and reception confirmation. However, the half-duplex (in both directions, but not simultaneously) or the full-duplex operation is preferably used for the data transmission. With both of said methods, the evaluator station may both confirm the reception of the data and also transmit command sequences to the individual electrodes.\nBasically random-oriented and also reservation methods are available for the channel access. The random-based methods include particularly the ALOHA-, CSMA-(carrier sense multiple access) and CSMA-CD-(CSMA with collision detection) methods, which are not discussed here in greater detail because they are of secondary importance to the device according to the invention. In connection with the reservation methods, the physical channel is divided by a time period (TDMA), a frequency (FDMA), or a code (CDMA). The channel access can take place also priority-oriented, i.e., according to a preset priority stage of the individual electrodes. The fixed allocation of transmission rights is possible only with knowledge of the number of electrodes or electrode sets that may transmit simultaneously.\nFor safeguarding the transmission quality it is advantageous, furthermore, to carry out the transmission according to the (code-independent) HDLC-method (high level data link control). In connection with said method, not each block is individually acknowledged after it has been transmitted, but several blocks are transmitted in one direction one after the other. The receiver (e.g. the evaluator station) can insert the acknowledgement in own data blocks, which are transmitted in the reverse direction (e.g. to the respective electrodes).\nFor reducing transmission errors, additional redundancy can be incorporated in the message sequence to be transmitted (channel coding). Deterministic codes (such as, for example, block codes, recurrent codes) and also stochastic codes can be used in this connection. An error correction unit in the evaluator station and\/or in the electrodes will then execute, for example a direct error correction at 1-bit transmission errors (FEC=forward error correction), so that a repeat request for repeating the data transmission can be omitted.\nThe data to be transmitted can be coded by a secret code for special applications. For this purpose, the signal processing units of the electrodes and of the evaluator station are equipped with coding and decoding units. Said units are preferably arranged in the encoders and decoders, respectively.\nFor increasing the reliability of the data transmission, training sequence units or equalizers may be arranged especially in the electrodes and\/or evaluator station. A training sequence unit in the electrode generates a test code (character sequence), which is specified between the transmitter and the receiver, and transmits said test code to the evaluator station at defined times. The test code also may consist of, for example the identification code of the individual electrodes, or contain said code. With the packet or time-slot operation, the test code is preferably arranged in the center of each packet or time-slot. The equalizer in the evaluator station compares the received test code with the specified one, and determines the algorithm for recovering the transmitted data. In the event of distortions or trouble such as due to multiple reflections, diffraction and interferences due to the absence of sight contact between the receiving antenna of the evaluator station and the electrodes (patient turned away, dressed or under the bed blanket), the receiver can then equalize the transmission. The equalizer and the training sequence unit also may be arranged in the electrodes or the evaluator station alternatively or additionally. The use of test codes is particularly useful if the transmission distances are greater or if the transmission frequencies or bit rates are very high.\nA preferred further development consists in the use of nesting\/denesting units. For this purpose, individual bits of a data block are time-interleaved (scrambling) and divided in a number of sub-blocks. Especially in connection with the TDMA-method, such sub-blocks can be divided in different data bursts. On the receiving side, burst errors lead to 1-bit errors of the unscrambled data and may be eliminated by the error correction unit, so that data transmission errors are thus reduced.\nFIG. 1 shows the basic schematic structure of the device according to the invention. The device contains as components an evaluator station (1), as well as one or a plurality of electrodes (2a to 2f), which are arranged on one (or a number of) patient(s). In the example explained here, the data are to be exchanged between the valuator station and the various electrodes according to the TDMA-method with PSK-modulation. Without limiting the general idea of the invention, the individual electrodes within a set of electrodes (i.e., for a certain patient), furthermore, are to have the same transmission frequencies, whereby the transmission is to take place in the doublex operation with two separate frequency bands in the 1 GH2-range (with less complex systems, e.g. for the home monitoring of infants, with a highly limited or specified number of electrodes, the frequency multiplex method can be used as well).\nWith multiple access in the time multiplex, the electrodes and the evaluator station periodically transmit pulse bundles (bursts). For synchronization, the bursts are combined in frames. The transmission times of the pulse bundles (e.g. data bursts) transmitted by the various electrodes are shifted against each other in terms of time in such a way that the busts are lined up at the input of the various receivers (e.g. of the evaluator station) with as few gaps as possible without, however, overlapping one another. This is achieved, for example in that each electrode transmits its burst in reference to a reference burst, which is transmitted by the evaluator station, and controls and corrects the transmission phase with the help of the reference bust. In particular, in the presence of greater distances, the running time of the signal s between the electrode and the evaluator station can be taken into account in connection with the transmission phase the electrode as well. In addition to the transmitted sensor or useful data, each data burst also contains a preamble consisting of the synchronizing header, the start of message identifier of the burst, if necessary sender addresses, and additional system-internal signalizing the, if need be. The synchronizing header is a preset code sequence permitting a rapid synchronization of the carrier, cycle and frame (additional synchronization can take place via separate synchronization bursts). The start identifiers of the bursts indicate at which point of the header the receiver has synchronized. Dummy bursts are used when no useful data are transmitted. The first access preferably takes place according to radomOoriented (e.g. ALOHA) or also according to priority-oriented methods.\nThe evaluator station (1) shown here is equipped with a receiving and transmitting antenna (4a), a receiving\/transmitting separating filter (antenna separating filter, frequency separating filter, bridge separating filter) (4), a control unit (4b)\u2014for determining\/controlling the transmission power\u2014, a receiving unit (5), a transmitting unit (6), as well as with a data processing or evaluating unit (7) with associated display (8a), printer (8b), storage (8c) and alarm (10) units. Additional components are the frequency generation unit (11) as well as the transmission control unit (7a) with the sequencing control (7b). The evaluator unit (7) contains a status unit (7c), which controls the selection of the patient, of the electrodes, as well as of the sensors contained in the latter. Based on such selection it is determined to which sensor a subsequent command is addressed. For detecting and minimizing transmission errors, provision is made in the evaluator station (7) for an error diagnosis and correction unit (7d). The latter uses redundant information in the transmission in order to be capable of eliminating errors. In order to permit a simple calibration of the sensors (40a . . . 49i) of the electrode (2), provision is made for a calibration unit (7e). The electrode is subjected to a fixed standard condition, from which the signals of the sensors (40a . . . 40i) to be expected are known. The calibration unit (7e) adjusts internal parameters of the electrode (2) such as, for example amplification factors or offsets, to such an extent that the sensors (40a . . . 40i) supply the expected signals. The receiving unit (5) or transmitting unit (6) substantially consists of a signal conversion unit (12\u201316, and 26\u201329, respectively), as well as of a signal processing unit (17\u201320 and 21\u201325, respectively) (this applies analogously to the electrodes).\nThe signal conversion unit for the receiving unit (5) contains a high-frequency amplifier (12) with synchronizable bandpass filters (for preselecting the transmission frequency of the individual electrodes), a mixer unit (13), a low-frequency (LF) amplifier with filters (14), as well as a demodulator (15). The mixer unit (13) may, in this connection, comprises a plurality of intermediate-frequency mixing stages (with the respective filter and amplifier stages), and, via one (or several) oscillator(s) in the frequency generator (11) (frequency synthesizer), converts the high frequency signals received (in the GHz-range) into the basic band (or an intermediate-frequency band). In the demodulator (15), which preferably is a quadraturE modulator, the signals are finally PSK-demodulated, as well as amplified again, if necessary (not shown). A connected equalizer (16) equalizes the signals. The demodulated signals are finally processed by the burst demultiplexer (17), which executes the TDMA-deframing, the deleaving unit (18), as well as the decoding unit (19), and the digital signals are further transmitted to the evaluator unit (7). The decoding unit (19) converts the signals received into binary signals, and executes an error correction. By means of the specific identification codes, which, for example, are stored in the evaluator unit (7) or in a separate identification unit, the individual data can be assigned to the respective patients, electrodes, or sensors. Subsequently, the different electrode data can be assigned to the respective evaluator sub-units by a demultiplexer (20).\nThe transmitting unit (6) comprises the digital multiplexer (21), the encoding unit (22), a training sequence unit (23), the interleaving unit (24), the burst multiplexer (25) for the TDMA-framing, the (PSK) modulator (26), a low-frequency amplifier (27), the mixer (28), as well as finally the HF-transmission amplifier (29) with built-in bandpasses.\nThe control unit (7a) serves for controlling the transmission between the evaluator station and the electrodes, as well as for controlling the frequency generation unit (11) and the sequencing control unit (7b). The frequency generation unit (11) especially comprises also a clock unit, which supplies the various system cycles especially for the evaluator processor (7) and the TDMA frame structure. Said unit particularly serves also for frequency and cycle synchronization of the electrodes with the evaluator station. For this purpose, the carrier frequencies and the system cycle are transmitted to the individual electrodes by the evaluator station via synchronization bursts (the high frequency field received for the energy supply can be used also directly, for example for transmitting the carrier frequency, among other things).\nThe frequency generation unit (11) comprises, for example one or a plurality of PLL (phase-locked loop) synthesizers, which generate(s) the various carrier frequencies within the range around 1 GHz. The frequency generation unit (11) particularly supplies the various oscillator frequencies (as well as the carrier frequencies) for the mixers and modulators, and also a reference frequency, from which the individual oscillator frequencies are generated. The reference frequency can be generated in this connection by means of (temperature-compensated) quartz oscillators or synchronizable oscillators.\nThe evaluator station is adapted to the burst operation via the sequence control (7b), which controls the burst (de)multiplexers (16, 22), the (de)modulators (15, 26), etc. For the TDMA (de)framing, the data are fed into intermediate memories (not shown) and read in and read out at the correct points in time at the system bite rate.\nFor the application of a plurality of electrode sets (with different carrier frequencies), for example for simultaneously monitoring a number of patients, several receiving units (5) and transmitting units (6) are required, or one receiving and transmitting unit with a great number of (de)multiplexers, (de)modulators, amplifiers, bandpasses, etc, for the individual carrier frequencies (not shown here in the drawing).\nFor other transmission methods such as, for example CDMA-transmission or TDMA with frequency hopping, additional synchronization stages as well as code generators and\/or frequency synthesizers for code or frequency rekeying have to be integrated in the receivers and transmitters, i.e., in the evaluator station and the electrodes.\nThe power supply of the evaluator station can take place in this connection via a mains transformer and\/or accumulators (9). Preferably, the evaluator station contains a removable, small portable module (1a) containing the important operational units such as the antenna unit (4a), the transmitting (6) and receiving unit (5), the evaluator (7), the transmission control unit (7a), the frequency generation (11), the accumulator (9), and alarm units (10) (the latter with sound and\/or visual warning signals). Thus the device can be used also outside of the home for monitoring infants, for example during automobile drives or while taking a walk.\nThe electrodes (2) each contain an energy supply unit (37), the receiving and transmitting antenna (36a), the latter having an antenna separating filter (36) for the transmitting and receiving operations, a transmitting unit (31), a receiving unit (30) (e.g. for synchronization, indication of the transmitting power, protocol transmission, error correction, programming and controlling), a sensor unit (34), as well as a frequency generation unit (35).\nThe frequency generation unit (35) particularly comprises also a clock unit for the various system cycles. The frequency generation unit (35) supplies the various oscillator frequencies (as well as the carrier frequencies) for the mixers and modulators, and also a reference frequency, from which the individual oscillator frequencies are generated. The reference frequency is preferably generated by means of a VCXO (voltage controlled crystal oscillator) reference generator, which can be returned in a highly precise way, in order to assure the required frequency accuracy with the evaluator station. For the voltage\/frequency conversion it is possible to use, for example a varactor.\nThe electric signals of the individual elementary sensors (40a\u2013i) are amplified and filtered by the preamplifiers. Preferably, the sensitive input amplifiers (41a\u2013i), for preventing over-driving, for example due to HF scatter, are equipped with protective devices, for example with a Zener diode circuit for signal limitation (not shown here). The amplified and filtered (equalized) signals are then applied to a high-speed analog multiplexes (42), which is controlled by the sensor control unit (33). The sensor control unit (33) receives the control commands from a storage unit (33a), or directly via radio transmission from the evaluator station (I). For detecting and correcting transmission errors, the electrode (2), too, has an error diagnosis and correction unit (33b), which operates in the same way as with the evaluator station (1). Then, the signals at the output of the analog multiplexer (42) are amplified again sensor-selectively by an amplifier (43), if necessary, and then applied to the analog-to-digital converter (44). By means of the identification unit (45a), the encoding unit (45) converts the analog signals into the electrode- or sensor-characteristic digital code. The coded electrode signals and the training sequence (test code) of the training sequence unit (46) are then applied to the interleaving unit (47) (the aforementioned equalizer (16) in the receiving unit (5) of the evaluator station (1) uses the training sequence for equalizing the data). The interleaved, coded sensor data are then adapted to the TDMA framing via the burst multiplexer (48), and, for modulation, fed into the (PSK) modulator unit (49). For amplification and change to the carrier frequency, the signals are applied to the mixer unit (51) via the low-frequency amplifier (50). The final HF amplifier (power amplifier) (52) with bandpasses amplifies the transmission signals and feeds the latter to the antenna (36a) by way of the transmission\/receiving separating filter (36). Preferably, the sequence control (34a) controls the HF amplifier (52) in order to adjust a suitable transmission output.\nThe receiving unit (30) for receiving the radio and control data of the evaluator station contains the HF amplifier (55) with synchronizable bandpasses, the mixer (56), the low-frequency amplifier (57), the demodulator (58) with the equalizer (59), the burst demultiplexer (60) (for the TDMA deframing), the delacing unit (61), as well as the decoder (62). The amplified digital signals are then transmitted further, for example to the storage unit (33a) or the sensor control unit (33). The sequence control (34a) in the transmission control unit (34) especially controls the interlacing\/delacing units (47; 61), the burst (de)multiplexers (48; 61), as well as the respective intermediate memories (not shown) for the TDMA-framing or TDMA-deframing.\nThe transmission control unit (34) is monitored by the evaluator station (1) and, when deviations from should-be values occur (e.g. of the transmitting power), receives correction instructions. The transmission control unit (34) is particularly responsible also for the frequency and cycle synchronization of the frequency generation unit (35). Preferably, the transmission control units (7a; 34) or the sequence control (7b; 34a), furthermore, contain synchronization stages (not shown in the drawing) which, on the one hand, determine the point of arrival of the bursts, and measure the channel distortion, on the other hand, in order to make the required information available to the equalizer. Said synchronization stages can be arranged also in the receiving units (5; 30). A frequency and cycle synchronization can take place particularly via the test code of the ES.\nThe HF-field emitted by the evaluator station is converted by the energy supply unit (37) of the electrodes into the supply voltage, and the energy supply unit stores the excess energy in an accumulator (38).\nThe receivers (5; 30) of the evaluator station (1) and the electrodes (2) may basically be designed in the form of straight-ahead and overlay receivers, and particularly as synchronous and quadratur receivers and Superhet's. The amplification, synchronization and selection means of the respective transmitting and receiving units, which are shown in FIG. 1 in only one box, particularly can be distributed to a number of units\/stages. The individual amplifier elements in the receiving units of the evaluator station (1) and\/or the electrodes (2) are controlled by an amplification control unit (AGC=automatic gain control) and monitored by the latter (not shown). The transmitting and receiving units are defined in the present specification in such a way that they contain the modulation and demodulation components.\nFor a digital design of the receiving units (5; 30), the signals received are converted into digital signals at intermediate frequencies (<<100 MHz), or in the basic band. For this purpose, digital-to-analog converters are integrated either in the mixing (13; 56) or in the demodulation units (15; 58). This applies analogously to the transmitting units (6 and 31) as well. The electrode units and the evaluator station are then controlled by digital microprocessors. Especially the homodyn receiver offers advantages for the monolithic integration of the entire receiver because the selection is shifted there to the basic band.\nFIG. 2a, FIGS. 2d and 2b, 2f show two typical exemplified embodiments for the design of the electrodes on a scale of about 2:1. Without limiting the basic idea of the invention, the individual electronic components of the electrodes, i.e., the elementary sensors and the sensor control, transmitting\/receiving and transmission control units etc. are integrated in one signal semiconductor chip.\nWith the electrodes, the antenna (36a) is designed as a spiral antenna arranged in the flexible electrode covering (71). On the underside, the antenna (36a) has a reflector (35b), by which the HF power radiated from the antenna (36a) in the direction of the patient is reflected upwardly. Preferably, the spiral antenna is realized with two or four arms; only one arm is shown here for the sake of better clarity. Since radiation in the direction of the body, i.e., radiation from both sides is undesirable, a plane reflector (not shown) is mounted between the antenna and the electrode covering facing the skin, preferably with a spacing 2\/4 (2=wavelength). This enhances the radiation in the desired direction of transmission; however, this is connected with a reduction of the bandwidth. Another possibility is the projection of the plane spiral antenna onto the surface of the electrode cone (conical spiral antenna).\nThe electrodes are fastened on the surface of the skin preferably by means of exchangeable adhesive tapes (coated with adhesive on both sides) or adhesive rings.\nSome electrode designs can be basically arranged also on materials resting closely to the skin such as, for example, bracelets, pieces of garment, or mattresses, if need be. Important is only that the sensors are in adequately close contact with the body.\nFIGS. 2a and 2d show a possible arrangement of the individual semiconductor elements such as the elementary sensors (40a to 40i), the sensor unit (32), an evaluator unit (74), the sensor control (33(, the transmission control (34), the frequency generation (35) units, as well as the transmitting\/receiving (31, 30) and the energy supply (37) units of the electrode chip (70).\nFIGS. 2b and 2e show an electrode (2) with which also EKG and EEG measurements can be carried out, among others. For discharging the action potentials, two electrode pins (76) (preferably coated with silver, gold or sintered material) are arranged in the electrode (2), said pins applying the action potentials to the input of a measuring amplifier (78)\u2014see FIG. 7 for more details\u2014by way of shielded cables (77). For establishing a good skin contact, the electrode pins are ideally fitted on the back side with mechanical, springs (79). In order to avoid moisture bridges on the skin contact side, the electrode pins are framed by a special insulating coating (89). In addition, a great number of additional sensors such as temperature (80), skin moisture (81), motion (82) and oxygen saturation (83) sensors, etc. are arranged in the electrode chip. The electrode chip (70) is realized in this connection by means of the two layer technology, i.e., the elementary sensors (40a to 40i) are arranged on the side of the chip facing the skin, and, for example the sensor control unit (33), the transmitting\/receiving (30, 31) and the frequency generation (35) units etc. are arranged on the back side. The accumulator (38) for energy storage) is, in the present embodiment, arranged above the electrode chip (70).\nFIGS. 2c and 2f show an electrode (2) having electrode pins (76) in the form of needles. Said electrode pins (76) penetrate the skin of the patient and lead to a reduction of the transition resistance, which permit more sensitive measurements. The antenna (36a) is integrated in the electrode chip (70) for reducing the size of the electrode (2) and for superior HF-transmission.\nVarious possibilities are available for the combination of sensors in one electrode; this is shown in FIG. 3 for various electrode arrangements.\nThe electrode(s) in the thoracic region (2a) comprise(s) EKG sensors with 2 to 4 tapping points for the action potentials (depending on the number of electrodes). The electrodes are shaped here, for example ovally or cloverleaf-like depending on the number of tapping points. One electrode is adequate for the monitoring of infants. Usefully, the electrode additionally comprises for control purposes an impedance sensor for measuring the transition resistance between the electrode and the skin. The transition resistance has an important bearing on the quality of the signals and should have values of lower than 5 to 10 kohm. In addition, the transition resistance between the individual electrode pins of an electrode is tested in order to exclude any possible short circuit (e.g. due to excessive moisture of the skin, or common salt bridge\u2014the resistance should not be significantly lower than about 500 ohm depending on the spacing of the electrode pins.) Preferably, the evaluator station tests continuously whether said measured control values fall short of or exceed the preset upper and lower limits, especially for the purpose of avoiding false alarms. In addition, preferably an acceleration sensor is arranged in the electrode, which can measure also the cardiac activity, on the one hand, and serve as a reference measurement for the breathing, on the other hand. Further useful possibilities include the integration of a position sensor, a temperature sensor, as well as a reference sensor for the moisture measurement.\nThe electrode on the abdomen (2b) contains a sensor for monitoring the breathing (for example an acceleration sensor). By comparison with the data of the reference sensors (arranged, for example at 2a, 2e and\/or 2f), it is possible to compensate or eliminate the influence of movements of the entire body, for example due to shocks in the carriage or during drives in the car.\nThe head electrode(s) (2c) contain(s) the EEG-sensors (shaped similar to the EKG-electrodes), which comprise 2 to 4 tapping points for the potential values as well. Due to the lower EEG signals (lower than the EKG signals by about a factor 1000), the head electrodes, too, comprise for control purposes impedance sensors for measuring the transition resistance. In addition, it is possible also to arrange, for example a moisture sensor between the individual electrode pins of the EEG discharge line, in order to detect in this way a short circuit or a data falsification due to excessive moisture. This procedure, of course, is possible with the EKG discharge as well.\nAnother possibility for the breathing control consists in the arrangement of an electrode in the facial region (2d), in particular between the mouth and the nose. With this electrode arrangement, the breathing can be measured by way of a temperature sensor. An alternative consists in monitoring the concentration of the exiting CO2-content (basically also of the O2 content) via a gas sensor. In addition, the respiratory activity can be monitored also by means of a moisture sensor by measuring the air humidity. With all three methods, a breathing activity is expressed by fluctuations in the ambient temperature, in the CO2-content and the air humidity within the immediate proximity of the nose and mouth.\nThe electrode in the palm of the hand (2e), which basically can be attached also to the sole of the foot, contains a potential sensor (preferably a measuring amplifier), a capacity sensor (capacity diode), or an electrocaloric sensor (the surface charge effects a change in temperature) for measuring the electrodermal activities or the SSR. It has been found recently that electric skin phenomena occur in infants in situations causing stress for the body, which phenomena can be detected in a simple way. Such phenomena are known from the lie detector technology. The measurement of said potentials opens new possibilities for a distinction of which events (for example breathing pauses, deceleration of the heart rate) are unimportant for the organism, and which ones have to be viewed as threatening. It has been found that these signals are particularly pronounced on the palms of the hands and the soles of the feet, so that they can be registered best in said sites. Furthermore, the electrode contains a moisture sensor for measuring the moisture of the skin (perspiration) because it has been found that parallel with the SSR, stress situations cause secretion of sweat on the palms of the hands and soles of the feet. In addition, a reference sensor can be arranged in the electrodes for the breathing.\nThe electrode (2f) is preferably design in the form of a finger clip (see FIG. 4a). Basically, such a clip can be attached also to toes of the foot or to the bridge of the nose. It contains a sensor for measuring the oxygen saturation in the blood (pulsoximetry). The pulsoximetry takes place in this connection either by means of transmission measurement or reflection measurement with optic wavelengths between 660 nm and 940 nm. The determination of the oxygen saturation in the blood is based on the spectral absorption of the specific wavelengths on the red light and remore infrared range of hemoglobin and oxhemoglobin when such radiation penetrates the skin, muscles and tissues. For these measurements, IR-light (88) or light is radiated by means of an emitting diode (e.g. Ga (Al, P) As and In (Ga)P-LED's), which penetrates the body parts with blood circulation, and which is then registered by a sensitive detector (e.g. GaAs-diode) (86). In connection with the more sensitive transmission measurements, the emitter and detector are arranged in separate units, which approximately oppose each other (as in the present exemplified embodiment). Pulsoximetry by means of reflection measurements can be carried out basically on all parts of the body (with suitable blood circulation), for example also in the thoracic region, whereby the emitter and the detector can be integrated in the same chip. Since pulsoximetric measurements react susceptibly to movements, an acceleration sensor (87) is preferably integrated in the finger clip. With the measurement of the oxygen saturation it is possible also to monitor the pulse, among other things. This is shown on the curve (K) in the cutout of FIG. 4, which represents the absorption (A) Versus time (T).\nThe electrode at (2g) is designed as an arm bracelet preferably made of elastic, flexible material. Especially for monitoring infants, this bracelet can be left permanently attached because it causes no inconvenience. With this bracelet it is possible to tap the pulse, for example by way of pressure sensors, and thus to monitor the cardiac activity. A combination especially with temperature and moisture sensors, or ISFET's (perspiration), as well as with acceleration sensors is suitable.\nThe electrode (2h), which is shown in greater detail in FIG. 5, serves for monitoring the transcutaneous oxygen (tcpO2) and carbon dioxide (tcpCO2) contents in the blood. These measurements, which are useful especially on infants, offer continuous information about the ability of the body to supply the tissue with oxygen, and to discharge carbon dioxide via the cardiopulmonary system. The transcutaneous pO2-value permits conclusions with respect to the arterial oxygen concentration and possible changes in the heart minute volume tcpO2- and tcpCO2-measurements are based on the fact that an increase in the skin temperature (preferably temperatures between 38\u00b0 C. and 45\u00b0 C.) effects an increase in the blood circulation of the skin and of the oxygen and carbon dioxide partial pressure, and makes the skin permeable to the gas diffusion.\nIn the present exemplified embodiment, the individual sensors, transmitting and receiving units etc. of the electrode are not integrated in one chip. For warming up certain parts of the skin, a heating element (e.g. a heating resistor) or preferably (for preventing burns in long-term applications) a heat radiator (90) (e.g. an IR-diode) is arranged on the side of the electrode facing the skin. A suitable temperature or radiation sensor (e.g. a pyroelectric sensor) (91) as well as a control unit (92) serve for the temperature control. An oxygen sensor (93) and a carbon dioxide sensor (94) then determine the gas concentrations (95) diffusing through the surface of the skin (96). The electrode (2h) is designed in such a way that the O2- and CO2-molecules flow directly past the gas sensors (93, 94). The electrode is preferably open at the top because the formation of moisture between the skin and the electrode can be more easily prevented in this way. For increasing the sensitivity and for protecting the sensors, the electrode can be closed at the top and\/or at the bottom by a membrane (not shown here) that is permeable to gas. Alternatively to the electrodes (2) shown in the foregoing, the electrode has a transmitting diode (98) and a receiving diode (97) for the optical transmission of the data and commands from and to the evaluator station (1).\nAnother monitoring of the breathing is offered by the electrode (2i), which is arranged near the bronchial tube. In this connection, the noise of the respiratory flow is recorded by way of a miniaturized microphone and the flow of air is monitored in this way. The microphone can be realized in many different ways, preferably in the form of a capacitor microphone or a piezoelectric microphone.\nSaid electrode (2i) is preferably combined with the electrode (2b) for monitoring the movement of the diaphragm. A distinction can be made in this way as to whether a central apnea (no movement of the diaphragm, no flow of air)\u2014which apnea originates from the breathing center in the brain stem\u2014is present, or an obstructive apnea (deglutition apnea; motion of the diaphragm, no flow of air).\nFor controlling and for avoiding false alarms, the individual electrodes may be equipped with additional control sensors, for example spacing sensors, which monitor the spacing between the electrode and the skin.\nFor infants, the fingerclip (2f) and the palm (2e) electrodes are ideally combined in one electrode. The measurement takes place in this connection preferably transversely across the palm of the hand, as shown in FIG. 6.\nFor measuring potential differences, it is basically possible to use one single operation amplifier. However, since the potentials to be measured have in the normal case a relatively high inner resistance, it is more useful to apply said potentials not directly to the input resistor of the subtracter. The use of impedance converters (potential sequencers) makes the operational mode of the subtracter independent of the inner resistances of the measuring potentials. FIG. 7a shows such an exemplified embodiment for an operation amplifier circuit (with a protective input circuit (99)) for difference formation, preamplification and filtering. Basically, it is possible also to arrange high-pass or bandpass filters upstream of the instrument or measuring amplifier (104) for suppressing the dc potential components.\nThe individual EEG or EKG signals of the electrode pins are, by way of the noninverting inputs of the operation amplifiers and impedance converters (100 and 101, respectively), supplied to the operation amplifier (102), and amplified. Higher inphase suppression is obtained through partial shifting of the potential amplification to the impedance converters. The advantage of this circuit is that the difference amplification can be adjusted by varying only one single resistor (103). With the electrometer amplifier (104), an operation amplification can be saved, if need be, if the symmetry of the circuit is dispensed with.\nFor dc potential separation and for the suppression of low-frequency noise (10 Hz, i.e., due to body movements), the amplified signals are then applied to the operation amplifier (105), which is wired as a high-pass filter of the first order with impedance conversion.\nThe component (106) represents an action low-pass filter with single positive feedback, by which the high-frequency redundant noise components of the measuring signal (e.g. caused by stray pick-up) are filtered out. The amplified and filtered potential finally can be tapped off between the potential points (120) and (121). The reference potential (121) is here applied to the battery\/accumulator mass (characterized by the \"\u2212\"-symbols), or the mass of the energy supply unit.\nWith electrode pins that are spaced far apart, or with galvanic connections between the electrodes, the highly resistive input leads (110, 111) are screened for preventing capacitive noise pick-up. The present exemplified embodiment contains for this purpose an operation amplifier (113) in an adding circuit (for forming the mean value of the tapped-off signals), to which the two outputs of the operation amplifiers (100 and 101) each are connected via a resistor. Since the formation of the sum on the operation amplifier (113) is inverting, an additional operation amplifier (114) is connected downstream, via which the averaged signals are supplied to the cable screening (112).\nWhen using 3 or more electrode pins in one electrode, additional impedance converters, operation amplifiers and high and low-pass filters are used. The connection (110), for example, can then be used as the reference point. An alternative is that an analog multiplexer (arranged, for example, between the individual impedance converters (100, 101, . . . ) and the difference operation amplifier (102) successively picks up the individual bio-potentials.\nThe module (104) shown can also be replaced by the circuit shown in FIG. 7b. As compared to the operation amplifiers\/subtracters, said circuit offers the advantage that the amount of inphase suppression is here not dependent upon the pairing tolerance of the individual potential dividers. For this reason, it is possible to produce the circuit as a completely monolithically integrated circuit, whereas otherwise it is necessary to realize the critical resistors separately, using the thin-layer technology. The symbols (+) and (\u2212) represent in this connection supply voltage (125) for a constant current source.","meta":{"bibliographic_information":{"country":"US","doc-number":"10396621","kind":"B2","date":"20030324","extension":"389","disclaimer_text":"This patent is subject to a terminal disclaimer.","invention_title":"Wireless medical diagnosis and monitoring equipment"},"source_file":"https:\/\/bulkdata.uspto.gov\/data\/patent\/grant\/redbook\/fulltext\/2007\/ipg070508.zip","abstract":["A medical diagnosis and monitoring system having at least one sensor for detecting an electrical, physical, chemical, or biological property of a patient such as, but not limited to, EEG- and EKG-signals, respiration, oxygen saturation, temperature, perspiration, etc. A digital-to-analog converter coupled to the sensor and a digital transmitter and receiver for wireless digital two-way communication with an evaluator station."],"citations":[{"country":"US","doc-number":"2864943","kind":"A","name":"Schultz","date":"19581200","category":"cited by other","classification_national_country":"US","classification_national_main-classification":"25015"},{"country":"US","doc-number":"2958781","kind":"A","name":"Marchal et al.","date":"19601100","category":"cited by other","classification_national_country":"US","classification_national_main-classification":"250833"},{"country":"US","doc-number":"3199508","kind":"A","name":"Roth","date":"19650800","category":"cited by other","classification_national_country":"US","classification_national_main-classification":"128206"},{"country":"US","doc-number":"3495584","kind":"A","name":"Schwalm","date":"19700200","category":"cited by other","classification_national_country":"US","classification_national_main-classification":"128206"},{"country":"US","doc-number":"3602215","kind":"A","name":"Parnell","date":"19710800","category":"cited by 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{"text":"Antisense compounds, compositions and methods are provided for modulating the expression of Inhibitor-kappa B Kinase-alpha. The compositions comprise antisense compounds, particularly antisense oligonucleotides, targeted to nucleic acids encoding Inhibitor-kappa B Kinase-alpha. Methods of using these compounds for modulation of Inhibitor-kappa B Kinase-alpha expression and for treatment of diseases associated with expression of Inhibitor-kappa B Kinase-alpha are provided.\n\nThe present invention provides compositions and methods for modulating the expression of Inhibitor-kappa B Kinase-alpha. In particular, this invention relates to antisense compounds, particularly oligonucleotides, specifically hybridizable with nucleic acids encoding human Inhibitor-kappa B Kinase-alpha. Such oligonucleotides have been shown to modulate the expression of Inhibitor-kappa B Kinase-alpha.\nInflammation is a localized protective response mounted by tissues in response to injury, infection, or tissue destruction resulting in the destruction of the infectious or injurious agent and isolation of the injured tissue. A typical inflammatory response proceeds as follows: recognition of an antigen as foreign or recognition of tissue damage, synthesis and release of soluble inflammatory mediators, recruitment of inflammatory cells to the site of infection or tissue damage, destruction and removal of the invading organism or damaged tissue, and deactivation of the system once the invading organism or damage has been resolved. In many human diseases with an inflammatory component, the normal, homeostatic mechanisms which attenuate the inflammatory responses are defective, resulting in damage and destruction of normal tissue. Consequently, much effort has been made to identify the molecular mechanisms underlying regulation of inflammatory responses.\nFor example, both TNF-alpha and IL-1 have been identified as important extracellular mediators that induce expression of a number of gene products involved in tissue inflammation (DiDonato et al., Nature, 1997, 388, 548-554). Although IL-1 and TNF-alpha bind to distinct cell surface receptors, it is currently believed that their intracellular signals ultimately converge to induce a similar spectrum of gene products through activation of the nuclear transcription factor NF-kappa-B (DiDonato et al., Nature, 1997, 388, 548-554). For several years, it has been known that NF-kappa-B normally exists in the cytoplasm bound to a family of inhibitor proteins known as IKB-alpha (Inhibitor-Kappa-B-alpha) and IKB-beta. Phosphorylation of the IKB\"\"s triggers them to be ubiquitinated and then degraded, thereby releasing NF-kappa-B, which is then free to translocate to the nucleus and activate expression of its downstream targets. Recently, two closely related kinases responsible for IKB phosphorylation (and hence NF-kappa-B activation) have been identified and are termed Inhibitor-Kappa B Kinase-alpha (IKK-l, for I-Kappa-B Kinase 1) and Inhibitor-Kappa B Kinase-beta (IKK-2, for I-Kappa-B Kinase 2) (DiDonato et al., Nature, 1997, 388, 548-554; Zandi et al., Science, 1998, 281, 1360-1363; Zandi et al., Cell, 1997, 91, 243-252). In these studies, Inhibitor-Kappa B Kinase-alpha and Inhibitor-Kappa B Kinase-beta were found to directly phosphorylate IKB-alpha and IKB-beta. Further, transfection of HeLa cells with an expression vector containing the Inhibitor-Kappa B Kinase-alpha gene in antisense orientation was found to inhibit induction of NF-kappa-B activity by TNF-alpha and interleukin-1.\nIt is currently believed that Inhibitor-Kappa B Kinase-alpha and\/or Inhibitor-Kappa B Kinase-beta may represent the point at which the signal transduction pathways activated by TNF-alpha and IL-1 converge to generate active NF-kappa-B (DiDonato et al., Nature, 1997, 388, 548-554). It has therefore been proposed that inhibition of Inhibitor-Kappa B Kinase-alpha or Inhibitor-Kappa B Kinase-beta may represent a method to uniformly inhibit the diverse range of molecular signals that lead to activation of the inflammatory response (Israel, Nature, 1997, 388, 519-521). Recently, activation of Inhibitor-Kappa B Kinase-alpha and Inhibitor-Kappa B Kinase-beta by the HTLV-1 protein Tax was demonstrated (Geleziunas et al., Mol. Cell. Biol., 1998, 18, 5157-5165). Since activation of NF-kappa-B in HTLV infected T-cells has been implicated in the development of T-cell leukemia, it has been proposed that activation of Inhibitor-Kappa B Kinase-alpha and\/or Inhibitor-Kappa B Kinase-beta through Tax may play a role in T-cell leukemia tumorigenesis as well (Geleziunas et al., Mol. Cell. Biol., 1998, 18, 5157-5165).\nAs a result of the role that Inhibitor-Kappa B Kinase-alpha activation is believed to play in the development of T-cell leukemia and in the activation of the inflammatory responses, there is a great desire to provide compositions of matter which can modulate the expression of Inhibitor-Kappa B Kinase-alpha.\nCurrently, there are no known therapeutic agents which effectively inhibit the synthesis of Inhibitor-Kappa B Kinase-alpha. Consequently, there is a long-felt need for agents capable of effectively inhibiting Inhibitor-Kappa B Kinase-alpha. It is anticipated that oligonucleotides capable of modulating the expression of Inhibitor-Kappa B Kinase-alpha may provide for a novel class of agents with activity towards a variety of inflammatory disorders or diseases with an inflammatory component such as asthma, juvenile diabetes mellitus, myasthenia gravis, Graves\"\" disease, rheumatoid arthritis, allograft rejection, inflammatory bowel disease, multiple sclerosis, psoriasis, lupus erythematosus, systemic lupus erythematosus, diabetes, multiple sclerosis, contact dermatitis, rhinitis and various allergies, or hyperproliferative disorders such as leukemias and other tumors. Antisense oligonucleotides against Inhibitor-Kappa B Kinase-alpha may therefore prove to be uniquely useful in a number of therapeutic, diagnostic, and research applications.\nThe present invention is directed to antisense compounds, particularly oligonucleotides, which are targeted to a nucleic acid encoding Inhibitor-kappa B Kinase-alpha, and which modulate the expression of Inhibitor-kappa B Kinase-alpha. Pharmaceutical and other compositions comprising the antisense compounds of the invention are also provided. Further provided are methods of modulating the expression of Inhibitor-kappa B Kinase-alpha in cells or tissues comprising contacting said cells or tissues with one or more of the antisense compounds or compositions of the invention. Further provided are methods of treating an animal, particularly a human, suspected of having or being prone to a disease or condition associated with expression of Inhibitor-kappa B Kinase-alpha by administering a therapeutically or prophylactically effective amount of one or more of the antisense compounds or compositions of the invention.\nThe present invention employs oligomeric antisense compounds, particularly oligonucleotides, for use in modulating the function of nucleic acid molecules encoding Inhibitor-kappa B Kinase-alpha, ultimately modulating the amount of Inhibitor-kappa B Kinase-alpha produced. This is accomplished by providing antisense compounds which specifically hybridize with one or more nucleic acids encoding Inhibitor-kappa B Kinase-alpha. As used herein, the terms xe2x80x9ctarget nucleic acidxe2x80x9d and xe2x80x9cnucleic acid encoding Inhibitor-kappa B Kinase-alphaxe2x80x9d encompass DNA encoding Inhibitor-kappa B Kinase-alpha, RNA (including pre-mRNA and mRNA) transcribed from such DNA, and also cDNA derived from such RNA. The specific hybridization of an oligomeric compound with its target nucleic acid interferes with the normal function of the nucleic acid. This modulation of function of a target nucleic acid by compounds which specifically hybridize to it is generally referred to as xe2x80x9cantisensexe2x80x9d. The functions of DNA to be interfered with include replication and transcription. The functions of RNA to be interfered with include all vital functions such as, for example, translocation of the RNA to the site of protein translation, translation of protein from the RNA, splicing of the RNA to yield one or more mRNA species, and catalytic activity which may be engaged in or facilitated by the RNA. The overall effect of such interference with target nucleic acid function is modulation of the expression of Inhibitor-kappa B Kinase-alpha. In the context of the present invention, xe2x80x9cmodulationxe2x80x9d means either an increase (stimulation) or a decrease (inhibition) in the expression of a gene. In the context of the present invention, inhibition is the preferred form of modulation of gene expression and mRNA is a preferred target.\nIt is preferred to target specific nucleic acids for antisense. xe2x80x9cTargetingxe2x80x9d an antisense compound to a particular nucleic acid, in the context of this invention, is a multistep process. The process usually begins with the identification of a nucleic acid sequence whose function is to be modulated. This may be, for example, a cellular gene (or mRNA transcribed from the gene) whose expression is associated with a particular disorder or disease state, or a nucleic acid molecule from an infectious agent. In the present invention, the target is a nucleic acid molecule encoding Inhibitor-kappa B Kinase-alpha. The targeting process also includes determination of a site or sites within this gene for the antisense interaction to occur such that the desired effect, e.g., detection or modulation of expression of the protein, will result. Within the context of the present invention, a preferred intragenic site is the region encompassing the translation initiation or termination codon of the open reading frame (ORF) of the gene. Since, as is known in the art, the translation initiation codon is typically 5xe2x80x2-AUG (in transcribed mRNA molecules; 5xe2x80x2-ATG in the corresponding DNA molecule), the translation initiation codon is also referred to as the xe2x80x9cAUG codon,xe2x80x9d the xe2x80x9cstart codonxe2x80x9d or the xe2x80x9cAUG start codonxe2x80x9d. A minority of genes have a translation initiation codon having the RNA sequence 5xe2x80x2-GUG, 5xe2x80x2-UUG or 5xe2x80x2-CUG, and 5xe2x80x2-AUA, 5xe2x80x2-ACG and 5xe2x80x2-CUG have been shown to function in vivo. Thus, the terms xe2x80x9ctranslation initiation codonxe2x80x9d and xe2x80x9cstart codonxe2x80x9d can encompass many codon sequences, even though the initiator amino acid in each instance is typically methionine (in eukaryotes) or formylmethionine (in prokaryotes). It is also known in the art that eukaryotic and prokaryotic genes may have two or more alternative start codons, any one of which may be preferentially utilized for translation initiation in a particular cell type or tissue, or under a particular set of conditions. In the context of the invention, xe2x80x9cstart codonxe2x80x9d and xe2x80x9ctranslation initiation codonxe2x80x9d refer to the codon or codons that are used in vivo to initiate translation of an mRNA molecule transcribed from a gene encoding Inhibitor-kappa B Kinase-alpha, regardless of the sequence(s) of such codons.\nIt is also known in the art that a translation termination codon (or xe2x80x9cstop codonxe2x80x9d) of a gene may have one of three sequences, i.e., 5xe2x80x2-UAA, 5xe2x80x2-UAG and 5xe2x80x2-UGA (the corresponding DNA sequences are 5xe2x80x2-TAA, 5xe2x80x2-TAG and 5xe2x80x2-TGA, respectively). The terms xe2x80x9cstart codon regionxe2x80x9d and xe2x80x9ctranslation initiation codon regionxe2x80x9d refer to a portion of such an mRNA or gene that encompasses from about 25 to about 50 contiguous nucleotides in either direction (i.e., 5xe2x80x2 or 3xe2x80x2) from a translation initiation codon. Similarly, the terms xe2x80x9cstop codon regionxe2x80x9d and xe2x80x9ctranslation termination codon regionxe2x80x9d refer to a portion of such an mRNA or gene that encompasses from about 25 to about 50 contiguous nucleotides in either direction (i.e., 5xe2x80x2 or 3xe2x80x2) from a translation termination codon.\nThe open reading frame (ORF) or xe2x80x9ccoding region,xe2x80x9d which is known in the art to refer to the region between the translation initiation codon and the translation termination codon, is also a region which may be targeted effectively. Other target regions include the 5xe2x80x2 untranslated region (5xe2x80x2UTR), known in the art to refer to the portion of an mRNA in the 5xe2x80x2 direction from the translation initiation codon, and thus including nucleotides between the 5xe2x80x2 cap site and the translation initiation codon of an mRNA or corresponding nucleotides on the gene, and the 3xe2x80x2 untranslated region (3xe2x80x2UTR), known in the art to refer to the portion of an mRNA in the 3xe2x80x2 direction from the translation termination codon, and thus including nucleotides between the translation termination codon and 3xe2x80x2 end of an mRNA or corresponding nucleotides on the gene. The 5xe2x80x2 cap of an mRNA comprises an N7-methylated guanosine residue joined to the 5xe2x80x2-most residue of the mRNA via a 5xe2x80x2-5xe2x80x2 triphosphate linkage. The 5xe2x80x2 cap region of an mRNA is considered to include the 5xe2x80x2 cap structure itself as well as the first 50 nucleotides adjacent to the cap. The 5xe2x80x2 cap region may also be a preferred target region.\nAlthough some eukaryotic mRNA transcripts are directly translated, many contain one or more regions, known as xe2x80x9cintrons,xe2x80x9d which are excised from a transcript before it is translated. The remaining (and therefore translated) regions are known as xe2x80x9cexonsxe2x80x9d and are spliced together to form a continuous mRNA sequence. mRNA splice sites, i.e., intron-exon junctions, may also be preferred target regions, and are particularly useful in situations where aberrant splicing is implicated in disease, or where an overproduction of a particular mRNA splice product is implicated in disease. Aberrant fusion junctions due to rearrangements or deletions are also preferred targets. It has also been found that introns can also be effective, and therefore preferred, target regions for antisense compounds targeted, for example, to DNA or pre-mRNA.\nOnce one or more target sites have been identified, oligonucleotides are chosen which are sufficiently complementary to the target, i.e., hybridize sufficiently well and with sufficient specificity, to give the desired effect.\nIn the context of this invention, xe2x80x9chybridizationxe2x80x9d means hydrogen bonding, which may be Watson-Crick, Hoogsteen or reversed Hoogsteen hydrogen bonding, between complementary nucleoside or nucleotide bases. For example, adenine and thymine are complementary nucleobases which pair through the formation of hydrogen bonds. xe2x80x9cComplementary,xe2x80x9d as used herein, refers to the capacity for precise pairing between two nucleotides. For example, if a nucleotide at a certain position of an oligonucleotide is capable of hydrogen bonding with a nucleotide at the same position of a DNA or RNA molecule, then the oligonucleotide and the DNA or RNA are considered to be complementary to each other at that position. The oligonucleotide and the DNA or RNA are complementary to each other when a sufficient number of corresponding positions in each molecule are occupied by nucleotides which can hydrogen bond with each other. Thus, xe2x80x9cspecifically hybridizablexe2x80x9d and xe2x80x9ccomplementaryxe2x80x9d are terms which are used to indicate a sufficient degree of complementarity or precise pairing such that stable and specific binding occurs between the oligonucleotide and the DNA or RNA target. It is understood in the art that the sequence of an antisense compound need not be 100% complementary to that of its target nucleic acid to be specifically hybridizable. An antisense compound is specifically hybridizable when binding of the compound to the target DNA or RNA molecule interferes with the normal function of the target DNA or RNA to cause a loss of utility, and there is a sufficient degree of complementarity to avoid non-specific binding of the antisense compound to non-target sequences under conditions in which specific binding is desired, i.e., under physiological conditions in the case of in vivo assays or therapeutic treatment, and in the case of in vitro assays, under conditions in which the assays are performed.\nAntisense compounds are commonly used as research reagents and diagnostics. For example, antisense oligonucleotides, which are able to inhibit gene expression with exquisite specificity, are often used by those of ordinary skill to elucidate the function of particular genes. Antisense compounds are also used, for example, to distinguish between functions of various members of a biological pathway. Antisense modulation has, therefore, been harnessed for research use.\nThe specificity and sensitivity of antisense is also harnessed by those of skill in the art for therapeutic uses. Antisense oligonucleotides have been employed as therapeutic moieties in the treatment of disease states in animals and man. Antisense oligonucleotides have been safely and effectively administered to humans and numerous clinical trials are presently underway. It is thus established that oligonucleotides can be useful therapeutic modalities that can be configured to be useful in treatment regimes for treatment of cells, tissues and animals, especially humans. In the context of this invention, the term xe2x80x9coligonucleotidexe2x80x9d refers to an oligomer or polymer of ribonucleic acid (RNA) or deoxyribonucleic acid (DNA) or mimetics thereof. This term includes oligonucleotides composed of naturally-occurring nucleobases, sugars and covalent internucleoside (backbone) linkages as well as oligonucleotides having non-naturally-occurring portions which function similarly. Such modified or substituted oligonucleotides are often preferred over native forms because of desirable properties such as, for example, enhanced cellular uptake, enhanced affinity for nucleic acid target and increased stability in the presence of nucleases.\nWhile antisense oligonucleotides are a preferred form of antisense compound, the present invention comprehends other oligomeric antisense compounds, including but not limited to oligonucleotide mimetics such as are described below. The antisense compounds in accordance with this invention preferably comprise from about 8 to about 30 nucleobases. Particularly preferred are antisense oligonucleotides comprising from about 8 to about 30 nucleobases (i.e. from about 8 to about 30 linked nucleosides). As is known in the art, a nucleoside is a base-sugar combination. The base portion of the nucleoside is normally a heterocyclic base. The two most common classes of such heterocyclic bases are the purines and the pyrimidines. Nucleotides are nucleosides that further include a phosphate group covalently linked to the sugar portion of the nucleoside. For those nucleosides that include a pentofuranosyl sugar, the phosphate group can be linked to either the 2xe2x80x2, 3xe2x80x2 or 5xe2x80x2 hydroxyl moiety of the sugar. In forming oligonucleotides, the phosphate groups covalently link adjacent nucleosides to one another to form a linear polymeric compound. In turn the respective ends of this linear polymeric structure can be further joined to form a circular structure, however, open linear structures are generally preferred. Within the oligonucleotide structure, the phosphate groups are commonly referred to as forming the internucleoside backbone of the oligonucleotide. The normal linkage or backbone of RNA and DNA is a 3xe2x80x2 to 5xe2x80x2 phosphodiester linkage.\nSpecific examples of preferred antisense compounds useful in this invention include oligonucleotides containing modified backbones or non-natural internucleoside linkages. As defined in this specification, oligonucleotides having modified backbones include those that retain a phosphorus atom in the backbone and those that do not have a phosphorus atom in the backbone. For the purposes of this specification, and as sometimes referenced in the art, modified oligonucleotides that do not have a phosphorus atom in their internucleoside backbone can also be considered to be oligonucleosides.\nPreferred modified oligonucleotide backbones include, for example, phosphorothioates, chiral phosphorothioates, phosphorodithioates, phosphotriesters, aminoalkylphosphotriesters, methyl and other alkyl phosphonates including 3xe2x80x2-alkylene phosphonates and chiral phosphonates, phosphinates, phosphoramidates including 3xe2x80x2-amino phosphoramidate and aminoalkylphosphoramidates, thionophosphoramidates, thionoalkylphosphonates, thionoalkylphosphotriesters, and boranophosphates having normal 3xe2x80x2-5xe2x80x2 linkages, 2xe2x80x2-5xe2x80x2 linked analogs of these, and those having inverted polarity wherein the adjacent pairs of nucleoside units are linked 3xe2x80x2-5xe2x80x2 to 5xe2x80x2-3xe2x80x2 or 2xe2x80x2-5xe2x80x2 to 5xe2x80x2-2xe2x80x2. Various salts, mixed salts and free acid forms are also included.\nRepresentative United States patents that teach the preparation of the above phosphorus-containing linkages include, but are not limited to, U.S. Pat. Nos. 3,687,808; 4,469,863; 4,476,301; 5,023,243; 5,177,196; 5,188,897; 5,264,423; 5,276,019; 5,278,302; 5,286,717; 5,321,131; 5,399,676; 5,405,939; 5,453,496; 5,455,233; 5,466,677; 5,476,925; 5,519,126; 5,536,821; 5,541,306; 5,550,111; 5,563,253; 5,571,799; 5,587,361; and 5,625,050, certain of which are commonly owned with this application, and each of which is herein incorporated by reference.\nPreferred modified oligonucleotide backbones that do not include a phosphorus atom therein have backbones that are formed by short chain alkyl or cycloalkyl internucleoside linkages, mixed heteroatom and alkyl or cycloalkyl internucleoside linkages, or one or more short chain heteroatomic or heterocyclic internucleoside linkages. These include those having morpholino linkages (formed in part from the sugar portion of a nucleoside); siloxane backbones; sulfide, sulfoxide and sulfone backbones; formacetyl and thioformacetyl backbones; methylene formacetyl and thioformacetyl backbones; alkene containing backbones; sulfamate backbones; methyleneimino and methylenehydrazino backbones; sulfonate and sulfonamide backbones; amide backbones; and others having mixed N, O, S and CH2 component parts.\nRepresentative United States patents that teach the preparation of the above oligonucleosides include, but are not limited to, U.S. Pat. Nos. 5,034,506; 5,166,315; 5,185,444; 5,214,134; 5,216,141; 5,235,033; 5,264,562; 5,264,564; 5,405,938; 5,434,257; 5,466,677; 5,470,967; 5,489,677; 5,541,307; 5,561,225; 5,596,086; 5,602,240; 5,610,289; 5,602,240; 5,608,046; 5,610,289; 5,618,704; 5,623,070; 5,663,312; 5,633,360; 5,677,437; and 5,677,439, certain of which are commonly owned with this application, and each of which is herein incorporated by reference.\nIn other preferred oligonucleotide mimetics, both the sugar and the internucleoside linkage, i.e., the backbone, of the nucleotide units are replaced with novel groups. The base units are maintained for hybridization with an appropriate nucleic acid target compound. One such oligomeric compound, an oligonucleotide mimetic that has been shown to have excellent hybridization properties, is referred to as a peptide nucleic acid (PNA). In PNA compounds, the sugar-backbone of an oligonucleotide is replaced with an amide containing backbone, in particular an aminoethylglycine backbone. The nucleobases are retained and are bound directly or indirectly to aza nitrogen atoms of the amide portion of the backbone. Representative United States patents that teach the preparation of PNA compounds include, but are not limited to, U.S. Pat. Nos. 5,539,082; 5,714,331; and 5,719,262, each of which is herein incorporated by reference. Further teaching of PNA compounds can be found in Nielsen et al., Science, 1991, 254, 1497-1500.\nMost preferred embodiments of the invention are oligonucleotides with phosphorothioate backbones and oligonucleosides with heteroatom backbones, and in particular xe2x80x94CH2xe2x80x94NHxe2x80x94Oxe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94N(CH3)xe2x80x94Oxe2x80x94CH2xe2x80x94 [known as a methylene (methylimino) or MMI backbone], xe2x80x94CH2xe2x80x94Oxe2x80x94N(CH3)xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94N(CH3)xe2x80x94N(CH3)xe2x80x94CH2xe2x80x94 and xe2x80x94Oxe2x80x94N(CH3)xe2x80x94CH2xe2x80x94CH2xe2x80x94 [wherein the native phosphodiester backbone is represented as xe2x80x94Oxe2x80x94Pxe2x80x94Oxe2x80x94CH2xe2x80x94] of the above referenced U.S. Pat. No. 5,489,677, and the amide backbones of the above referenced U.S. Pat. No. 5,602,240. Also preferred are oligonucleotides having morpholino backbone structures of the above-referenced U.S. Pat. No. 5,034,506.\nModified oligonucleotides may also contain one or more substituted sugar moieties. Preferred oligonucleotides comprise one of the following at the 2xe2x80x2 position: OH; F; O-, S-, or N-alkyl; O-, S-, or N-alkenyl; O-, S- or N-alkynyl; or O-alkyl-O-alkyl, wherein the alkyl, alkenyl and alkynyl may be substituted or unsubstituted C1 to C10 alkyl or C2 to C10 alkenyl and alkynyl. Particularly preferred are O[(CH2)nO]mCH3, O(CH2)nOCH3, O(CH2)nNH2, O(CH2)nCH3, O(CH2)nONH2, and O(CH2)nON[(CH2)nCH3)]2, where n and m are from 1 to about 10. Other preferred oligonucleotides comprise one of the following at the 2xe2x80x2 position: C1 to C10 lower alkyl, substituted lower alkyl, alkaryl, aralkyl, O-alkaryl or O-aralkyl, SH, SCH3, OCN, Cl, Br, CN, CF3, OCF3, SOCH3, SO2CH3, ONO2, NO2, N3, NH2, heterocycloalkyl, heterocycloalkaryl, aminoalkylamino, polyalkylamino, substituted silyl, an RNA cleaving group, a reporter group, an intercalator, a group for improving the pharmacokinetic properties of an oligonucleotide, or a group for improving the pharmacodynamic properties of an oligonucleotide, and other substituents having similar properties. A preferred modification includes 2xe2x80x2-methoxyethoxy (2xe2x80x2-Oxe2x80x94CH2CH2OCH3, also known as 2xe2x80x2-O-(2-methoxyethyl) or 2xe2x80x2-MOE) (Martin et al., Helv. Chim. Acta, 1995, 78, 486-504) i.e., an alkoxyalkoxy group. A further preferred modification includes 2xe2x80x2-dimethylaminooxyethoxy, i.e., a O(CH2)2ON(CH3)2 group, also known as 2xe2x80x2-DMAOE, as described in examples hereinbelow.\nOther preferred modifications include 2xe2x80x2-methoxy (2xe2x80x2-Oxe2x80x94CH3), 2xe2x80x2-aminopropoxy (2xe2x80x2-OCH2CH2CH2NH2) and 2xe2x80x2-fluoro (2xe2x80x2-F). Similar modifications may also be made at other positions on the oligonucleotide, particularly the 3xe2x80x2 position of the sugar on the 3xe2x80x2 terminal nucleotide or in 2xe2x80x2-5xe2x80x2 linked oligonucleotides and the 5xe2x80x2 position of 5xe2x80x2 terminal nucleotide. Oligonucleotides may also have sugar mimetics such as cyclobutyl moieties in place of the pentofuranosyl sugar. Representative United States patents that teach the preparation of such modified sugar structures include, but are not limited to, U.S. Pat. Nos. 4,981,957; 5,118,800; 5,319,080; 5,359,044; 5,393,878; 5,446,137; 5,466,786; 5,514,785; 5,519,134; 5,567,811; 5,576,427; 5,591,722; 5,597,909; 5,610,300; 5,627,053; 5,639,873; 5,646,265; 5,658,873; 5,670,633; and 5,700,920, certain of which are commonly owned with the instant application, and each of which is herein incorporated by reference in its entirety.\nOligonucleotides may also include nucleobase (often referred to in the art simply as xe2x80x9cbasexe2x80x9d) modifications or substitutions. As used herein, xe2x80x9cunmodifiedxe2x80x9d or xe2x80x9cnaturalxe2x80x9d nucleobases include the purine bases adenine (A) and guanine (G), and the pyrimidine bases thymine (T), cytosine (C) and uracil (U). Modified nucleobases include other synthetic and natural nucleobases such as 5-methylcytosine (5-me-C), 5-hydroxymethyl cytosine, xanthine, hypoxanthine, 2-aminoadenine, 6-methyl and other alkyl derivatives of adenine and guanine, 2-propyl and other alkyl derivatives of adenine and guanine, 2-thiouracil, 2-thiothymine and 2-thiocytosine, 5-halouracil and cytosine, 5-propynyl uracil and cytosine, 6-azo uracil, cytosine and thymine, 5-uracil (pseudouracil), 4-thiouracil, 8-halo, 8-amino, 8-thiol, 8-thioalkyl, 8-hydroxyl and other 8-substituted adenines and guanines, 5-halo particularly 5-bromo, 5-trifluoromethyl and other 5-substituted uracils and cytosines, 7-methylguanine and 7-methyladenine, 8-azaguanine and 8-azaadenine, 7-deazaguanine and 7-deazaadenine and 3-deazaguanine and 3-deazaadenine. Further nucleobases include those disclosed in U.S. Pat. No. 3,687,808, those disclosed in The Concise Encyclopedia Of Polymer Science And Engineering, pages 858-859, Kroschwitz, J. I., ed. John Wiley and Sons, 1990, those disclosed by Englisch et al., Angewandte Chemie, International Edition, 1991, 30, 613, and those disclosed by Sanghvi, Y. S., Chapter 15, Antisense Research and Applications, pages 289-302, Crooke, S. T. and Lebleu, B. , ed., CRC Press, 1993. Certain of these nucleobases are particularly useful for increasing the binding affinity of the oligomeric compounds of the invention. These include 5-substituted pyrimidines, 6-azapyrimidines and N-2, N-6 and O-6 substituted purines, including 2-aminopropyladenine, 5-propynyluracil and 5-propynylcytosine. 5-methylcytosine substitutions have been shown to increase nucleic acid duplex stability by 0.6-1.2xc2x0 C. (Sanghvi, Y. S., Crooke, S. T. and Lebleu, B., eds., Antisense Research and Applications, CRC Press, Boca Raton, 1993, pp. 276-278) and are presently preferred base substitutions, even more particularly when combined with 2xe2x80x2-O-methoxyethyl sugar modifications.\nRepresentative United States patents that teach the preparation of certain of the above noted modified nucleobases as well as other modified nucleobases include, but are not limited to, the above noted U.S. Pat. No. 3,687,808, as well as U.S. Pat. Nos. 4,845,205; 5,130,302; 5,134,066; 5,175,273; 5,367,066; 5,432,272; 5,457,187; 5,459,255; 5,484,908; 5,502,177; 5,525,711; 5,552,540; 5,587,469; 5,594,121, 5,596,091; 5,614,617; and 5,681,941, certain of which are commonly owned with the instant application, and each of which is herein incorporated by reference, and U.S. Pat. No. 5,750,692, which is commonly owned with the instant application and also herein incorporated by reference.\nAnother modification of the oligonucleotides of the invention involves chemically linking to the oligonucleotide one or more moieties or conjugates which enhance the activity, cellular distribution or cellular uptake of the oligonucleotide. Such moieties include but are not limited to lipid moieties such as a cholesterol moiety (Letsinger et al., Proc. Natl. Acad. Sci. USA, 1989, 86, 6553-6556), cholic acid (Manoharan et al., Bioorg. Med. Chem. Let., 1994, 4, 1053-1060), a thioether, e.g., hexyl-S-tritylthiol (Manoharan et al., Ann. N.Y. Acad. Sci., 1992, 660, 306-309; Manoharan et al., Bioorg. Med. Chem. Let., 1993, 3, 2765-2770), a thiocholesterol (Oberhauser et al., Nucl. Acids Res., 1992, 20, 533-538), an aliphatic chain, e.g., dodecandiol or undecyl residues (Saison-Behmoaras et al., EMBO J., 1991, 10, 1111-1118; Kabanov et al., FEBS Lett., 1990, 259, 327-330; Svinarchuk et al., Biochimie, 1993, 75, 49-54), a phospholipid, e.g., di-hexadecyl-rac-glycerol or triethylammonium 1,2-di-O-hexadecyl-rac-glycero-3-H-phosphonate (Manoharan et al., Tetrahedron Lett., 1995, 36, 3651-3654; Shea et al., Nucl. Acids Res., 1990, 18, 3777-3783), a polyamine or a polyethylene glycol chain (Manoharan et al., Nucleosides and Nucleotides, 1995, 14, 969-973), or adamantane acetic acid (Manoharan et al., Tetrahedron Lett., 1995, 36, 3651-3654), a palmityl moiety (Mishra et al., Biochim. Biophys. Acta, 1995, 1264, 229-237), or an octadecylamine or hexylamino-carbonyl-oxycholesterol moiety (Crooke et al., J. Pharmacol. Exp. Ther., 1996, 277, 923-937.\nRepresentative United States patents that teach the preparation of such oligonucleotide conjugates include, but are not limited to, U.S. Pat. Nos. 4,828,979; 4,948,882; 5,218,105; 5,525,465; 5,541,313; 5,545,730; 5,552,538; 5,578,717, 5,580,731; 5,580,731; 5,591,584; 5,109,124; 5,118,802; 5,138,045; 5,414,077; 5,486,603; 5,512,439; 5,578,718; 5,608,046; 4,587,044; 4,605,735; 4,667,025; 4,762,779; 4,789,737; 4,824,941; 4,835,263; 4,876,335; 4,904,582; 4,958,013; 5,082,830; 5,112,963; 5,214,136; 5,082,830; 5,112,963; 5,214,136; 5,245,022; 5,254,469; 5,258,506; 5,262,536; 5,272,250; 5,292,873; 5,317,098; 5,371,241, 5,391,723; 5,416,203, 5,451,463; 5,510,475; 5,512,667; 5,514,785; 5,565,552; 5,567,810; 5,574,142; 5,585,481; 5,587,371; 5,595,726; 5,597,696; 5,599,923; 5,599,928 and 5,688,941, certain of which are commonly owned with the instant application, and each of which is herein incorporated by reference.\nIt is not necessary for all positions in a given compound to be uniformly modified, and in fact more than one of the aforementioned modifications may be incorporated in a single compound or even at a single nucleoside within an oligonucleotide. The present invention also includes antisense compounds which are chimeric compounds. xe2x80x9cChimericxe2x80x9d antisense compounds or xe2x80x9cchimeras,xe2x80x9d in the context of this invention, are antisense compounds, particularly oligonucleotides, which contain two or more chemically distinct regions, each made up of at least one monomer unit, i.e., a nucleotide in the case of an oligonucleotide compound. These oligonucleotides typically contain at least one region wherein the oligonucleotide is modified so as to confer upon the oligonucleotide increased resistance to nuclease degradation, increased cellular uptake, and\/or increased binding affinity for the target nucleic acid. An additional region of the oligonucleotide may serve as a substrate for enzymes capable of cleaving RNA:DNA or RNA:RNA hybrids. By way of example, RNase H is a cellular endonuclease which cleaves the RNA strand of an RNA:DNA duplex. Activation of RNase H, therefore, results in cleavage of the RNA target, thereby greatly enhancing the efficiency of oligonucleotide inhibition of gene expression. Consequently, comparable results can often be obtained with shorter oligonucleotides when chimeric oligonucleotides are used, compared to phosphorothioate deoxyoligonucleotides hybridizing to the same target region. Cleavage of the RNA target can be routinely detected by gel electrophoresis and, if necessary, associated nucleic acid hybridization techniques known in the art.\nChimeric antisense compounds of the invention may be formed as composite structures of two or more oligonucleotides, modified oligonucleotides, oligonucleosides and\/or oligonucleotide mimetics as described above. Such compounds have also been referred to in the art as hybrids or gapmers. Representative United States patents that teach the preparation of such hybrid structures include, but are not limited to, U.S. Pat. Nos. 5,013,830; 5,149,797; 5,220,007; 5,256,775; 5,366,878; 5,403,711; 5,491,133; 5,565,350; 5,623,065; 5,652,355; 5,652,356; and 5,700,922, certain of which are commonly owned with the instant application, and each of which is herein incorporated by reference in its entirety.\nThe antisense compounds used in accordance with this invention may be conveniently and routinely made through the well-known technique of solid phase synthesis. Equipment for such synthesis is sold by several vendors including, for example, Applied Biosystems (Foster City, Calif.). Any other means for such synthesis known in the art may additionally or alternatively be employed. It is well known to use similar techniques to prepare oligonucleotides such as the phosphorothioates and alkylated derivatives.\nThe antisense compounds of the invention are synthesized in vitro and do not include antisense compositions of biological origin, or genetic vector constructs designed to direct the in vivo synthesis of antisense molecules. The compounds of the invention may also be admixed, encapsulated, conjugated or otherwise associated with other molecules, molecule structures or mixtures of compounds, as for example, liposomes, receptor targeted molecules, oral, rectal, topical or other formulations, for assisting in uptake, distribution and\/or absorption. Representative United States patents that teach the preparation of such uptake, distribution and\/or absorption assisting formulations include, but are not limited to, U.S. Pat. Nos. 5,108,921; 5,354,844; 5,416,016; 5,459,127; 5,521,291; 5,543,158; 5,547,932; 5,583,020; 5,591,721; 4,426,330; 4,534,899; 5,013,556; 5,108,921; 5,213,804; 5,227,170; 5,264,221; 5,356,633; 5,395,619; 5,416,016; 5,417,978; 5,462,854; 5,469,854; 5,512,295; 5,527,528; 5,534,259; 5,543,152; 5,556,948; 5,580,575; and 5,595,756, each of which is herein incorporated by reference.\nThe antisense compounds of the invention encompass any pharmaceutically acceptable salts, esters, or salts of such esters, or any other compound which, upon administration to an animal including a human, is capable of providing (directly or indirectly) the biologically active metabolite or residue thereof. Accordingly, for example, the disclosure is also drawn to prodrugs and pharmaceutically acceptable salts of the compounds of the invention, pharmaceutically acceptable salts of such prodrugs, and other bioequivalents.\nThe term xe2x80x9cprodrugxe2x80x9d indicates a therapeutic agent that is prepared in an inactive form that is converted to an active form (i.e., drug) within the body or cells thereof by the action of endogenous enzymes or other chemicals and\/or conditions. In particular, prodrug versions of the oligonucleotides of the invention are prepared as SATE [(S-acetyl-2-thioethyl) phosphate] derivatives according to the methods disclosed in WO 93\/24510 to Gosselin et al., published Dec. 9, 1993 or in WO 94\/26764 to Imbach et al.\nThe term xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d refers to physiologically and pharmaceutically acceptable salts of the compounds of the invention: i.e., salts that retain the desired biological activity of the parent compound and do not impart undesired toxicological effects thereto.\nPharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Examples of metals used as cations are sodium, potassium, magnesium, calcium, and the like. Examples of suitable amines are N,Nxe2x80x2-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, dicyclohexylamine, ethylenediamine, N-methylglucamine, and procaine (see, for example, Berge et al., xe2x80x9cPharmaceutical Salts,xe2x80x9d J. of Pharma Sci., 1977, 66, 1-19). The base addition salts of said acidic compounds are prepared by contacting the free acid form with a sufficient amount of the desired base to produce the salt in the conventional manner. The free acid form may be regenerated by contacting the salt form with an acid and isolating the free acid in the conventional manner. The free acid forms differ from their respective salt forms somewhat in certain physical properties such as solubility in polar solvents, but otherwise the salts are equivalent to their respective free acid for purposes of the present invention. As used herein, a xe2x80x9cpharmaceutical addition saltxe2x80x9d includes a pharmaceutically acceptable salt of an acid form of one of the components of the compositions of the invention. These include organic or inorganic acid salts of the amines. Preferred acid salts are the hydrochlorides, acetates, salicylates, nitrates and phosphates. Other suitable pharmaceutically acceptable salts are well known to those skilled in the art and include basic salts of a variety of inorganic and organic acids, such as, for example, with inorganic acids, such as for example hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid; with organic carboxylic, sulfonic, sulfo or phospho acids or N-substituted sulfamic acids, for example acetic acid, propionic acid, glycolic acid, succinic acid, maleic acid, hydroxymaleic acid, methylmaleic acid, fumaric acid, malic acid, tartaric acid, lactic acid, oxalic acid, gluconic acid, glucaric acid, glucuronic acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, salicylic acid, 4-aminosalicylic acid, 2-phenoxybenzoic acid, 2-acetoxybenzoic acid, embonic acid, nicotinic acid or isonicotinic acid; and with amino acids, such as the 20 alpha-amino acids involved in the synthesis of proteins in nature, for example glutamic acid or aspartic acid, and also with phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, ethane-1,2-disulfonic acid, benzenesulfonic acid, 4-methylbenzenesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, 2- or 3-phosphoglycerate, glucose-6-phosphate, N-cyclohexylsulfamic acid (with the formation of cyclamates), or with other acid organic compounds, such as ascorbic acid. Pharmaceutically acceptable salts of compounds may also be prepared with a pharmaceutically acceptable cation. Suitable pharmaceutically acceptable cations are well known to those skilled in the art and include alkaline, alkaline earth, ammonium and quaternary ammonium cations. Carbonates or hydrogen carbonates are also possible.\nFor oligonucleotides, preferred examples of pharmaceutically acceptable salts include but are not limited to (a) salts formed with cations such as sodium, potassium, ammonium, magnesium, calcium, polyamines such as spermine and spermidine, etc.; (b) acid addition salts formed with inorganic acids, for example hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid and the like; (c) salts formed with organic acids such as, for example, acetic acid, oxalic acid, tartaric acid, succinic acid, maleic acid, fumaric acid, gluconic acid, citric acid, malic acid, ascorbic acid, benzoic acid, tannic acid, palmitic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acid, polygalacturonic acid, and the like; and (d) salts formed from elemental anions such as chlorine, bromine, and iodine.\nThe antisense compounds of the present invention can be utilized for diagnostics, therapeutics, prophylaxis and as research reagents and kits. For therapeutics, an animal, preferably a human, suspected of having a disease or disorder which can be treated by modulating the expression of Inhibitor-kappa B Kinase-alpha is treated by administering antisense compounds in accordance with this invention. The compounds of the invention can be utilized in pharmaceutical compositions by adding an effective amount of an antisense compound to a suitable pharmaceutically acceptable diluent or carrier. Use of the antisense compounds and methods of the invention may also be useful prophylactically, e.g., to prevent or delay infection, inflammation or tumor formation, for example.\nThe antisense compounds of the invention are useful for research and diagnostics, because these compounds hybridize to nucleic acids encoding Inhibitor-kappa B Kinase-alpha, enabling sandwich and other assays to easily be constructed to exploit this fact. Hybridization of the antisense oligonucleotides of the invention with a nucleic acid encoding Inhibitor-kappa B Kinase-alpha can be detected by means known in the art. Such means may include conjugation of an enzyme to the oligonucleotide, radiolabelling of the oligonucleotide or any other suitable detection means. Kits using such detection means for detecting the level of Inhibitor-kappa B Kinase-alpha in a sample may also be prepared.\nThe present invention also includes pharmaceutical compositions and formulations which include the antisense compounds of the invention. The pharmaceutical compositions of the present invention may be administered in a number of ways depending upon whether local or systemic treatment is desired and upon the area to be treated. Administration may be topical (including ophthalmic and to mucous membranes including vaginal and rectal delivery), pulmonary, e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal, intranasal, epidermal and transdermal), oral or parenteral. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal or intramuscular injection or infusion; or intracranial, e.g., intrathecal or intraventricular, administration. Oligonucleotides with at least one 2xe2x80x2-O-methoxyethyl modification are believed to be particularly useful for oral administration.\nPharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable. Coated condoms, gloves and the like may also be useful.\nCompositions and formulations for oral administration include powders or granules, suspensions or solutions in water or non-aqueous media, capsules, sachets or tablets. Thickeners, flavoring agents, diluents, emulsifiers, dispersing aids or binders may be desirable.\nCompositions and formulations for parenteral, intrathecal or intraventricular administration may include sterile aqueous solutions which may also contain buffers, diluents and other suitable additives such as, but not limited to, penetration enhancers, carrier compounds and other pharmaceutically acceptable carriers or excipients.\nPharmaceutical compositions of the present invention include, but are not limited to, solutions, emulsions, and liposome-containing formulations. These compositions may be generated from a variety of components that include, but are not limited to, preformed liquids, self-emulsifying solids and self-emulsifying semisolids.\nThe pharmaceutical formulations of the present invention, which may conveniently be presented in unit dosage form, may be prepared according to conventional techniques well known in the pharmaceutical industry. Such techniques include the step of bringing into association the active ingredients with the pharmaceutical carrier(s) or excipient(s). In general the formulations are prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers. or finely divided solid carriers or both, and then, if necessary, shaping the product.\nThe compositions of the present invention may be formulated into any of many possible dosage forms such as, but not limited to, tablets, capsules, l-quid syrups, soft gels, suppositories, and enemas. The compositions of the present invention may also be formulated as suspensions in aqueous, non-aqueous or mixed media. Aqueous suspensions may further contain substances which increase the viscosity of the suspension including, for example, sodium carboxymethylcellulose, sorbitol and\/or dextran. The suspension may also contain stabilizers.\nIn one embodiment of the present invention the pharmaceutical compositions may be formulated and used as foams. Pharmaceutical foams include formulations such as, but not limited to, emulsions, microemulsions, creams, jellies and liposomes. While basically similar in nature these formulations vary in the components and the consistency of the final product. The preparation of such compositions and formulations is generally known to those skilled in the pharmaceutical and formulation arts and may be applied to the formulation of the compositions of the present invention.\nEmulsions\nThe compositions of the present invention may be prepared and formulated as emulsions. Emulsions are typically heterogenous systems of one liquid dispersed in another in the form of droplets usually exceeding 0.1 xcexcm in diameter. (Idson, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., volume 1, p. 199; Rosoff, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., Volume 1, p. 245; Block in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., volume 2, p. 335; Higuchi et al., in Remington\"\"s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa., 1985, p. 301). Emulsions are often biphasic systems comprising of two immiscible liquid phases intimately mixed and dispersed with each other. In general, emulsions may be either water in oil (w\/o) or of the oil in water (o\/w) variety. When an aqueous phase is finely divided into and dispersed as minute droplets into a bulk oily phase the resulting composition is called a water in oil (w\/o) emulsion. Alternatively, when an oily phase is finely divided into and dispersed as minute droplets into a bulk aqueous phase the resulting composition is called an oil in water (o\/w) emulsion. Emulsions may contain additional components in addition to the dispersed phases and the active drug which may be present as a solution in either the aqueous phase, oily phase or itself as a separate phase. Pharmaceutical excipients such as emulsifiers, stabilizers, dyes, and anti-oxidants may also be present in emulsions as needed. Pharmaceutical emulsions may also be multiple emulsions that are comprised of more than two phases such as, for example, in the case of oil in water in oil (o\/w\/o) and water in oil in water (w\/o\/w) emulsions. Such complex formulations often provide certain advantages that simple binary emulsions do not. Multiple emulsions in which individual oil droplets of an o\/w emulsion enclose small water droplets constitute a w\/o\/w emulsion. Likewise a system of oil droplets enclosed in globules of water stabilized in an oily continuous provides an o\/w\/o emulsion.\nEmulsions are characterized by little or no thermodynamic stability. Often, the dispersed or discontinuous phase of the emulsion is well dispersed into the external or continuous phase and maintained in this form through the means of emulsifiers or the viscosity of the formulation. Either of the phases of the emulsion may be a semisolid or a solid, as is the case of emulsion-style ointment bases and creams. Other means of stabilizing emulsions entail the use of emulsifiers that may be incorporated into either phase of the emulsion. Emulsifiers may broadly be classified into four categories: synthetic surfactants, naturally occurring emulsifiers, absorption bases, and finely dispersed solids (Idson, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., volume 1, p. 199).\nSynthetic surfactants, also known as surface active agents, have found wide applicability in the formulation of emulsions and have been reviewed in the literature (Rieger, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., volume 1, p. 285; Idson, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), Marcel Dekker, Inc., New York, N.Y., 1988, volume 1, p. 199). Surfactants are typically amphiphilic and comprise a hydrophilic and a hydrophobic portion. The ratio of the hydrophilic to the hydrophobic nature of the surfactant has been termed the hydrophile\/lipophile balance (HLB) and is a valuable tool in categorizing and selecting surfactants in the preparation of formulations. Surfactants may be classified into different classes based on the nature of the hydrophilic group: nonionic, anionic, cationic and amphoteric (Rieger, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., volume 1, p. 285).\nNaturally occurring emulsifiers used in emulsion formulations include lanolin, beeswax, phosphatides, lecithin and acacia. Absorption bases possess hydrophilic properties such that they can soak up water to form w\/o emulsions yet retain their semisolid consistencies, such as anhydrous lanolin and hydrophilic petrolatum. Finely divided solids have also been used as good emulsifiers especially in combination with surfactants and in viscous preparations. These include polar inorganic solids, such as heavy metal hydroxides, nonswelling clays such as bentonite, attapulgite, hectorite, kaolin, montmorillonite, colloidal aluminum silicate and colloidal magnesium aluminum silicate, pigments and nonpolar solids such as carbon or glyceryl tristearate.\nA large variety of non-emulsifying materials are also included in emulsion formulations and contribute to the properties of emulsions. These include fats, oils, waxes, fatty acids, fatty alcohols, fatty esters, humectants, hydrophilic colloids, preservatives and antioxidants (Block, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., volume 1, p. 335; Idson, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., volume 1, p. 199).\nHydrophilic colloids or hydrocolloids include naturally occurring gums and synthetic polymers such as polysaccharides (for example, acacia, agar, alginic acid, carrageenan, guar gum, karaya gum, and tragacanth), cellulose derivatives (for example, carboxymethylc cellulose and carboxypropyl cellulose), and synthetic polymers (for example, carbomers, cellulose ethers, and carboxyvinyl polymers). These disperse or swell in water to form colloidal solutions that stabilize emulsions by forming strong interfacial films around the dispersed-phase droplets and by increasing the viscosity of the external phase.\nSince emulsions often contain a number of ingredients such as carbohydrates, proteins, sterols and phosphatides that may readily support the growth of microbes, these formulations often incorporate preservatives. Commonly used preservatives included in emulsion formulations include methyl paraben, propyl paraben, quaternary ammonium salts, benzalkonium chloride, esters of p-hydroxybenzoic acid, and boric acid. Antioxidants are also commonly added to emulsion formulations to prevent deterioration of the formulation. Antioxidants used may be free radical scavengers such as tocopherols, alkyl gallates, butylated hydroxyanisole, butylated hydroxytoluene, or reducing agents such as ascorbic acid and sodium metabisulfite, and antioxidant synergists such as citric acid, tartaric acid, and lecithin.\nThe application of emulsion formulations via dermatological, oral and parenteral routes and methods for their manufacture have been reviewed in the literature (Idson, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., volume 1, p. 199). Emulsion formulations for oral delivery have been very widely used because of reasons of ease of formulation, efficacy from an absorption and bioavailability standpoint. (Rosoff, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., volume 1, p. 245; Idson, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., volume 1, p. 199). Mineral-oil base laxatives, oil-soluble vitamins and high fat nutritive preparations are among the materials that have commonly been administered orally as o\/w emulsions.\nIn one embodiment of the present invention, the compositions of oligonucleotides and nucleic acids are formulated as microemulsions. A microemulsion may be defined as a system of water, oil and amphiphile which is a single optically isotropic and thermodynamically stable liquid solution (Rosoff, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., volume 1, p. 245). Typically microemulsions are systems that are prepared by first dispersing an oil in an aqueous surfactant solution and then adding a sufficient amount of a fourth component, generally an intermediate chain-length alcohol to form a transparent system. Therefore, microemulsions have also been described as thermodynamically stable, isotropically clear dispersions of two immiscible liquids that are stabilized by interfacial films of surface-active molecules (Leung and Shah, in: Controlled Release of Drugs: Polymers and Aggregate Systems, Rosoff, M., Ed., 1989, VCH Publishers, New York, pages 185-215). Microemulsions commonly are prepared via a combination of three to five components that include oil, water, surfactant, cosurfactant and electrolyte. Whether the microemulsion is of the water-in-oil (w\/o) or an oil-in-water (o\/w) type is dependent on the properties of the oil and surfactant used and on the structure and geometric packing of the polar heads and hydrocarbon tails of the surfactant molecules (Schott, in Remington\"\"s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa., 1985, p. 271).\nThe phenomenological approach utilizing phase diagrams has been extensively studied and has yielded a comprehensive knowledge, to one skilled in the art, of how to formulate microemulsions (Rosoff, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., volume 1, p. 245; Block, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., volume 1, p. 335). Compared to conventional emulsions, microemulsions offer the advantage of solubilizing water-insoluble drugs in a formulation of thermodynamically stable droplets that are formed spontaneously.\nSurfactants used in the preparation of microemulsions include, but are not limited to, ionic surfactants, non-ionic surfactants, Brij 96, polyoxyethylene oleyl ethers, polyglycerol fatty acid esters, tetraglycerol monolaurate (ML310), tetraglycerol monooleate (MO310), hexaglycerol monooleate (PO310), hexaglycerol pentaoleate (PO500), decaglycerol monocaprate (MCA750), decaglycerol monooleate (MO750), decaglycerol sequioleate (SO750), decaglycerol decaoleate (DAO750), alone or in combination with cosurfactants. The cosurfactant, usually a short-chain alcohol such as ethanol, 1-propanol, and 1-butanol, serves to increase the interfacial fluidity by penetrating into the surfactant film and consequently creating a disordered film because of the void space generated among surfactant molecules. Microemulsions may, however, be prepared without the use of cosurfactants and alcohol-free self-emulsifying microemulsion systems are known in the art. The aqueous phase may typically be, but is not limited to, water, an aqueous solution of the drug, glycerol, PEG300, PEG400, polyglycerols, propylene glycols, and derivatives of ethylene glycol. The oil phase may include, but is not limited to, materials such as Captex 300, Captex 355, Capmul MCM, fatty acid esters, medium chain (C8-C12) mono, di, and tri-glycerides, polyoxyethylated glyceryl fatty acid esters, fatty alcohols, polyglycolized glycerides, saturated polyglycolized C8-C10 glycerides, vegetable oils and silicone oil.\nMicroemulsions are particularly of interest from the standpoint of drug solubilization and the enhanced absorption of drugs. Lipid based microemulsions (both o\/w and w\/o) have been proposed to enhance the oral bioavailability of drugs, including peptides (Constantinides et al., Pharmaceutical Research, 1994, 11, 1385-1390; Ritschel, Meth. Find. Exp. Clin. Pharmacol., 1993, 13, 205). Microemulsions afford advantages of improved drug solubilization, protection of drug from enzymatic hydrolysis, possible enhancement of drug absorption due to surfactant-induced alterations in membrane fluidity and permeability, ease of preparation, ease of oral administration over solid dosage forms, improved clinical potency, and decreased toxicity (Constantinides et al., Pharmaceutical Research, 1994, 11, 1385; Ho et al., J. Pharm. Sci., 1996, 85, 138-143). Often microemulsions may form spontaneously when their components are brought together at ambient temperature. This may be particularly advantageous when formulating thermolabile drugs, peptides or oligonucleotides. Microemulsions have also been effective in the transdermal delivery of active components in both cosmetic and pharmaceutical applications. It is expected that the microemulsion compositions and formulations of the present invention will facilitate the increased systemic absorption of oligonucleotides and nucleic acids from the gastrointestinal tract, as well as improve the local cellular uptake of oligonucleotides and nucleic acids within the gastrointestinal tract, vagina, buccal cavity and other areas of administration.\nMicroemulsions of the present invention may also contain additional components and additives such as sorbitan monostearate (Grill 3), Labrasol, and penetration enhancers to improve the properties of the formulation and to enhance the absorption of the oligonucleotides and nucleic acids of the present invention. Penetration enhancers used in the microemulsions of the present invention may be classified as belonging to one of five broad categoriesxe2x80x94surfactants, fatty acids, bile salts, chelating agents, and non-chelating non-surfactants (Lee et al., Critical Reviews in Therapeutic Drug Carrier Systems, 1991, p. 92). Each of these classes has been discussed above.\nLiposomes\nThere are many organized surfactant structures besides microemulsions that have been studied and used for the formulation of drugs. These include monolayers, micelles, bilayers and vesicles. Vesicles, such as liposomes, have attracted great interest because of their specificity and the duration of action they offer from the standpoint of drug delivery. As used in the present invention, the term xe2x80x9cliposomexe2x80x9d means a vesicle composed of amphiphilic lipids arranged in a spherical bilayer or bilayers.\nLiposomes are unilamellar or multilamellar vesicles which have a membrane formed from a lipophilic material and an aqueous interior. The aqueous portion contains the composition to be delivered. Cationic liposomes possess the advantage of being able to fuse to the cell wall. Non-cationic liposomes, although not able to fuse as efficiently with the cell wall, are taken up by macrophages in vivo.\nIn order to cross intact mammalian skin, lipid vesicles must pass through a series of fine pores, each with a diameter less than 50 nm, under the influence of a suitable transdermal gradient. Therefore, it is desirable to use a liposome which is highly deformable and able to pass through such fine pores.\nFurther advantages of liposomes include; liposomes obtained from natural phospholipids are biocompatible and biodegradable; liposomes can incorporate a wide range of water and lipid soluble drugs; liposomes can protect encapsulated drugs in their internal compartments from metabolism and degradation (Rosoff, in Pharmaceutical Dosage Forms, Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., volume 1, p. 245). Important considerations in the preparation of liposome formulations are the lipid surface charge, vesicle size and the aqueous volume of the liposomes.\nLiposomes are useful for the transfer and delivery of active ingredients to the site of action. Because the liposomal membrane is structurally similar to biological membranes, when liposomes are applied to a tissue, the liposomes start to merge with the cellular membranes. As the merging of the liposome and cell progresses, the liposomal contents are emptied into the cell where the active agent may act.\nLiposomal formulations have been the focus of extensive investigation as the mode of delivery for many drugs. There is growing evidence that for topical administration, liposomes present several advantages over other formulations. Such advantages include reduced side-effects related to high systemic absorption of the administered drug, increased accumulation of the administered drug at the desired target, and the ability to administer a wide variety of drugs, both hydrophilic and hydrophobic, into the skin.\nSeveral reports have detailed the ability of liposomes to deliver agents including high-molecular weight DNA into the skin. Compounds including analgesics, antibodies, hormones and high-molecular weight DNAs have been administered to the skin. The majority of applications resulted in the targeting of the upper epidermis.\nLiposomes fall into two broad classes. Cationic liposomes are positively charged liposomes which interact with the negatively charged DNA molecules to form a stable complex. The positively charged DNA\/liposome complex binds to the negatively charged cell surface and is internalized in an endosome. Due to the acidic pH within the endosome, the liposomes are ruptured, releasing their contents into the cell cytoplasm (Wang et al., Biochem. Biophys. Res. Commun., 1987, 147, 980-985).\nLiposomes which are pH-sensitive or negatively-charged, entrap DNA rather than complex with it. Since both the DNA and the lipid are similarly charged, repulsion rather than complex formation occurs. Nevertheless, some DNA is entrapped within the aqueous interior of these liposomes. pH-sensitive liposomes have been used to deliver DNA encoding the thymidine kinase gene to cell monolayers in culture. Expression of the exogenous gene was detected in the target cells (Zhou et al., Journal of Controlled Release, 1992, 19, 269-274).\nOne major type of liposomal composition includes phospholipids other than naturally-derived phosphatidylcholine. Neutral liposome compositions, for example, can be formed from dimyristoyl phosphatidylcholine (DMPC) or dipalmitoyl phosphatidylcholine (DPPC). Anionic liposome compositions generally are formed from dimyristoyl phosphatidylglycerol, while anionic fusogenic liposomes are formed primarily from dioleoyl phosphatidylethanolamine (DOPE). Another type of liposomal composition is formed from phosphatidylcholine (PC) such as, for example, soybean PC, and egg PC. Another type is formed from mixtures of phospholipid and\/or phosphatidylcholine and\/or cholesterol.\nSeveral studies have assessed the topical delivery of liposomal drug formulations to the skin. Application of liposomes containing interferon to guinea pig skin resulted in a reduction of skin herpes sores while delivery of interferon via other means (e.g. as a solution or as an emulsion) were ineffective (Weiner et al., Journal of Drug Targeting, 1992, 2, 405-410). Further, an additional study tested the efficacy of interferon administered as part of a liposomal formulation to the administration of interferon using an aqueous system, and concluded that the liposomal formulation was superior to aqueous administration (du Plessis et al., Antiviral Research, 1992, 18, 259-265).\nNon-ionic liposomal systems have also been examined to determine their utility in the delivery of drugs to the skin, in particular systems comprising non-ionic surfactant and cholesterol. Non-ionic liposomal formulations comprising Novasome(trademark) I (glyceryl dilaurate\/cholesterol\/polyoxyethylene-10-stearyl ether) and Novasome(trademark) II (glyceryl distearate\/cholesterol\/polyoxyethylene-10-stearyl ether) were used to deliver cyclosporin-A into the dermis of mouse skin. Results indicated that such non-ionic liposomal systems were effective in facilitating the deposition of cyclosporin-A into different layers of the skin.\nLiposomes also include xe2x80x9csterically stabilizedxe2x80x9d liposomes, a term which, as used herein, refers to liposomes comprising one or more specialized lipids that, when incorporated into liposomes, result in enhanced circulation lifetimes relative to liposomes lacking such specialized lipids. Examples of sterically stabilized liposomes are those in which part of the vesicle-forming lipid portion of the liposome (A) comprises one or more glycolipids, such as monosialoganglioside GM1, or (B) is derivatized with one or more hydrophilic polymers, such as a polyethylene glycol (PEG) moiety. While not wishing to be bound by any particular theory, it is thought in the art that, at least for sterically stabilized liposomes containing gangliosides, sphingomyelin, or PEG-derivatized lipids, the enhanced circulation half-life of these sterically stabilized liposomes derives from a reduced uptake into cells of the reticuloendothelial system (RES) (Allen et al., FEBS Letters, 1987, 223, 42; Wu et al., Cancer Research, 1993, 53, 3765). Various liposomes comprising one or more glycolipids are known in the art. Papahadjopoulos et al. (Ann. N.Y. Acad. Sci., 1987, 507, 64) reported the ability of monosialoganglioside GM1, galactocerebroside sulfate and phosphatidylinositol to improve blood half-lives of liposomes. These findings were expounded upon by Gabizon et al. (Proc. Natl. Acad. Sci. U.S.A., 1988, 85, 6949). U.S. Pat. No. 4,837,028 and WO 88\/04924, both to Allen et al., disclose liposomes comprising (1) sphingomyelin and (2) the ganglioside GM1 or a galactocerebroside sulfate ester. U.S. Pat. No. 5,543,152 (Webb et al.) discloses liposomes comprising sphingomyelin. Liposomes comprising 1,2-sn-dimyristoylphosphatidylcholine are disclosed in WO 97\/13499 (Lim et al.).\nMany liposomes comprising lipids derivatized with one or more hydrophilic polymers, and methods of preparation thereof, are known in the art. Sunamoto et al. (Bull. Chem. Soc. Jpn., 1980, 53, 2778) described liposomes comprising a nonionic detergent, 2C1215G, that contains a PEG moiety. Illum et al. (FEBS Lett., 1984, 167, 79) noted that hydrophilic coating of polystyrene particles with polymeric glycols results in significantly enhanced blood half-lives. Synthetic phospholipids modified by the attachment of carboxylic groups of polyalkylene glycols (e.g., PEG) are described by Sears (U.S. Pat. Nos. 4,426,330 and 4,534,899). Klibanov et al. (FEBS Lett., 1990, 268, 235) described experiments demonstrating that liposomes comprising phosphatidylethanolamine (PE) derivatized with PEG or PEG stearate have significant increases in blood circulation half-lives. Blume et al. (Biochimica et Biophysica Acta, 1990, 1029, 91) extended such observations to other PEG-derivatized phospholipids, e.g., DSPE-PEG, formed from the combination of distearoylphosphatidylethanolamine (DSPE) and PEG. Liposomes having covalently bound PEG moieties on their external surface are described in European Patent No. EP 0 445 131 B1 and WO 90\/04384 to Fisher. Liposome compositions containing 1-20 mole percent of PE derivatized with PEG, and methods of use thereof, are described by Woodle et al. (U.S. Pat. Nos. 5,013,556 and 5,356,633) and Martin et al. (U.S. Pat. No. 5,213,804 and European Patent No. EP 0 496 813 B1). Liposomes comprising a number of other lipid-polymer conjugates are disclosed in WO 91\/05545 and U.S. Pat. No. 5,225,212 (both to Martin et al.) and in WO 94\/20073 (Zalipsky et al.) Liposomes comprising PEG-modified ceramide lipids are described in WO 96\/10391 (Choi et al.) . U.S. Pat. No. 5,540,935 (Miyazaki et al.) and U.S. Pat. No. 5,556,948 (Tagawa et al.) describe PEG-containing liposomes that can be further derivatized with functional moieties on their surfaces.\nA limited number of liposomes comprising nucleic acids are known in the art. WO 96\/40062 to Thierry et al. discloses methods for encapsulating high molecular weight nucleic acids in liposomes. U.S. Pat. No. 5,264,221 to Tagawa et al. discloses protein-bonded liposomes and asserts that the contents of such liposomes may include an antisense RNA. U.S. Pat. No. 5,665,710 to Rahman et al. describes certain methods of encapsulating oligodeoxynucleotides in liposomes. WO 97\/04787 to Love et al. discloses liposomes comprising antisense oligonucleotides targeted to the raf gene.\nTransfersomes are yet another type of liposomes, and are highly deformable lipid aggregates which are attractive candidates for drug delivery vehicles. Transfersomes may be described as lipid droplets which are so highly deformable that they are easily able to penetrate through pores which are smaller than the droplet. Transfersomes are adaptable to the environment in which they are used, e.g. they are self-optimizing (adaptive to the shape of pores in the skin), self-repairing, frequently reach their targets without fragmenting, and often self-loading. To make transfersomes it is possible to add surface edge-activators, usually surfactants, to a standard liposomal composition. Transfersomes have been used to deliver serum albumin to the skin. The transfersome-mediated delivery of serum albumin has been shown to be as effective as subcutaneous injection of a solution containing serum albumin.\nSurfactants find wide application in formulations such as emulsions (including microemulsions) and liposomes. The most common way of classifying and ranking the properties of the many different types of surfactants, both natural and synthetic, is by the use of the hydrophile\/lipophile balance (HLB). The nature of the hydrophilic group (also known as the xe2x80x9cheadxe2x80x9d) provides the most useful means for categorizing the different surfactants used in formulations (Rieger, in Pharmaceutical Dosage Forms, Marcel Dekker, Inc., New York, N.Y., 1988, p. 285).\nIf the surfactant molecule is not ionized, it is classified as a nonionic surfactant. Nonionic surfactants find wide application in pharmaceutical and cosmetic products and are usable over a wide range of pH values. In general their HLB values range from 2 to about 18 depending on their structure. Nonionic surfactants include nonionic esters such as ethylene glycol esters, propylene glycol esters, glyceryl esters, polyglyceryl esters, sorbitan esters, sucrose esters, and ethoxylated esters. Nonionic alkanolamides and ethers such as fatty alcohol ethoxylates, propoxylated alcohols, and ethoxylated\/propoxylated block polymers are also included in this class. The polyoxyethylene surfactants are the most popular members of the nonionic surfactant class.\nIf the surfactant molecule carries a negative charge when it is dissolved or dispersed in water, the surfactant is classified as anionic. Anionic surfactants include carboxylates such as soaps, acyl lactylates, acyl amides of amino acids, esters of sulfuric acid such as alkyl sulfates and ethoxylated alkyl sulfates, sulfonates such as alkyl benzene sulfonates, acyl isethionates, acyl taurates and sulfosuccinates, and phosphates. The most important members of the anionic surfactant class are the alkyl sulfates and the soaps.\nIf the surfactant molecule carries a positive charge when it is dissolved or dispersed in water, the surfactant is classified as cationic. Cationic surfactants include quaternary ammonium salts and ethoxylated amines. The quaternary ammonium salts are the most used members of this class.\nIf the surfactant molecule has the ability to carry either a positive or negative charge, the surfactant is classified as amphoteric. Amphoteric surfactants include acrylic acid derivatives, substituted alkylamides, N-alkylbetaines and phosphatides.\nThe use of surfactants in drug products, formulations and in emulsions has been reviewed (Rieger, in Pharmaceutical Dosage Forms, Marcel Dekker, Inc., New York, N.Y., 1988, p. 285).\nPenetration Enhancers\nIn one embodiment, the present invention employs various penetration enhancers to effect the efficient delivery of nucleic acids, particularly oligonucleotides, to the skin of animals. Most drugs are present in solution in both ionized and nonionized forms. However, usually only lipid soluble or lipophilic drugs readily cross cell membranes. It has been discovered that even non-lipophilic drugs may cross cell membranes if the membrane to be crossed is treated with a penetration enhancer. In addition to aiding the diffusion of non-lipophilic drugs across cell membranes, penetration enhancers also enhance the permeability of lipophilic drugs.\nPenetration enhancers may be classified as belonging to one of five broad categories, i.e., surfactants, fatty acids, bile salts, chelating agents, and non-chelating non-surfactants (Lee et al., Crit. Rev. Ther. Drug Carrier Systems, 1991, p.92). Each of the above mentioned classes of penetration enhancers are described below in greater detail.\nSurfactants: In connection with the present invention, surfactants (or xe2x80x9csurface-active agentsxe2x80x9d) are chemical entities which, when dissolved in an aqueous solution, reduce the surface tension of the solution or the interfacial tension between the aqueous solution and another liquid, with the result that absorption of oligonucleotides through the mucosa is enhanced. In addition to bile salts and fatty acids, these penetration enhancers include, for example, sodium lauryl sulfate, polyoxyethylene-9-lauryl ether and polyoxyethylene-20-cetyl ether) (Lee et al., Crit. Rev. Ther. Drug Carrier Systems, 1991, p.92); and perfluorochemical emulsions, such as FC-43. Takahashi et al., J. Pharm. Pharmacol., 1988, 40, 252).\nFatty acids: Various fatty acids and their derivatives which act as penetration enhancers include, for example, oleic acid, lauric acid, capric acid (n-decanoic acid), myristic acid, palmitic acid, stearic acid, linoleic acid, linolenic acid, dicaprate, tricaprate, monoolein (1-monooleoyl-rac-glycerol), dilaurin, caprylic acid, arachidonic acid, glycerol 1-monocaprate, 1-dodecylazacycloheptan-2-one, acylcarnitines, acylcholines, C1-10 alkyl esters thereof (e.g., methyl, isopropyl and t-butyl), and mono- and di-glycerides thereof (i.e., oleate, laurate, caprate, myristate, palmitate, stearate, linoleate, etc.) (Lee et al., Crit. Rev. Ther. Drug Carrier Systems, 1991, p.92; Muranishi, Crit. Rev. Ther. Drug Carrier Systems, 1990, 7, 1-33; El Hariri et al., J. Pharm. Pharmacol., 1992, 44, 651-654).\nBile salts: The physiological role of bile includes the facilitation of dispersion and absorption of lipids and fat-soluble vitamins (Brunton, Chapter 38 in: Goodman and Gilman\"\"s The Pharmacological Basis of Therapeutics, 9th Ed., Hardman et al. Eds., McGraw-Hill, New York, 1996, pp. 934-935). VarIous natural bile salts, and their synthetic derivatives, act as penetration enhancers. Thus the term xe2x80x9cbile saltsxe2x80x9d includes any of the naturally occurring components of bile as well as any of their synthetic derivatives. The bile salts of the invention include, for example, cholic acid (or its pharmaceutically acceptable sodium salt, sodium cholate), dehydrocholic acid (sodium dehydrocholate), deoxycholic acid (sodium deoxycholate), glucholic acid (sodium glucholate), glycholic acid (sodium glycocholate), glycodeoxycholic acid (sodium glycodeoxycholate), taurocholic acid (sodium taurocholate), taurodeoxycholic acid (sodium taurodeoxycholate), chenodeoxycholic acid (sodium chenodeoxycholate), ursodeoxycholic acid (UDCA), sodium tauro-24,25-dihydro-fusidate (STDHF), sodium glycodihydrofusidate and polyoxyethylene-9-lauryl ether (POE) (Lee et al., Critical Reviews in Therapeutic Drug Carrier Systems, 1991, page 92; Swinyard, Chapter 39 In: Remington\"\"s Pharmaceutical Sciences, 18th Ed., Gennaro, ed., Mack Publishing Co., Easton, Pa., 1990, pages 782-783; Muranishi, Critical Reviews in Therapeutic Drug Carrier Systems, 1990, 7, 1-33; Yamamoto et al., J. Pharm. Exp. Ther., 1992, 263, 25; Yamashita et al., J. Pharm. Sci., 1990, 79, 579-583).\nChelating Agents: Chelating agents, as used in connection with the present invention, can be defined as compounds that remove metallic ions from solution by forming complexes therewith, with the result that absorption of oligonucleotides through the mucosa is enhanced. With regards to their use as penetration enhancers in the present invention, chelating agents have the added advantage of also serving as DNase inhibitors, as most characterized DNA nucleases require a divalent metal ion for catalysis and are thus inhibited by chelating agents (Jarrett, J. Chromatogr., 1993, 618, 315-339). Chelating agents of the invention include but are not limited to disodium ethylenediaminetetraacetate (EDTA), citric acid, salicylates (e.g., sodium salicylate, 5-methoxysalicylate and homovanilate), N-acyl derivatives of collagen, laureth-9 and N-amino acyl derivatives of beta-diketones (enamines)(Lee et al., Critical Reviews in Therapeutic Drug Carrier Systems, 1991, page 92; Muranishi, Critical Reviews in Therapeutic Drug Carrier Systems, 1990, 7, 1-33; Buur et al., J. Control Rel., 1990, 14, 43-51).\nNon-chelating non-surfactants: As used herein, non-chelating non-surfactant penetration enhancing compounds can be defined as compounds that demonstrate insignificant activity as chelating agents or as surfactants but that nonetheless enhance absorption of oligonucleotides through the alimentary mucosa (Muranishi, Critical Reviews in Therapeutic Drug Carrier Systems, 1990, 7, 1-33). This class of penetration enhancers include, for example, unsaturated cyclic ureas, 1-alkyl- and 1-alkenylazacycloalkanone derivatives (Lee et al., Critical Reviews in Therapeutic Drug Carrier Systems, 1991, page 92); and non-steroidal anti-inflammatory agents such as diclofenac sodium, indomethacin and phenylbutazone (Yamashita et al., J. Pharm. Pharmacol., 1987, 39, 621-626).\nAgents that enhance uptake of oligonucleotides at the cellular level may also be added to the pharmaceutical and other compositions of the present invention. For example, cationic lipids, such as lipofectin (Junichi et al, U.S. Pat. No. 5,705,188), cationic glycerol derivatives, and polycationic molecules, such as polylysine (Lollo et al., PCT Application WO 97\/30731), are also known to enhance the cellular uptake of oligonucleotides.\nOther agents may be utilized to enhance the penetration of the administered nucleic acids, including glycols such as ethylene glycol and propylene glycol, pyrrols such as 2-pyrrol, azones, and terpenes such as limonene and menthone.\nCarriers\nCertain compositions of the present invention also incorporate carrier compounds in the formulation. As used herein, xe2x80x9ccarrier compoundxe2x80x9d or xe2x80x9ccarrierxe2x80x9d can refer to a nucleic acid, or analog thereof, which is inert (i.e., does not possess biological activity per se) but is recognized as a nucleic acid by in vivo processes that reduce the bioavailability of a nucleic acid having biological activity by, for example, degrading the biologically active nucleic acid or promoting its removal from circulation. The coadministration of a nucleic acid and a carrier compound, typically with an excess of the latter substance, can result in a substantial reduction of the amount of nucleic acid recovered in the liver, kidney or other extracirculatory reservoirs, presumably due to competition between the carrier compound and the nucleic acid for a common receptor. For example, the recovery of a partially phosphorothioate oligonucleotide in hepatic tissue can be reduced when it is coadministered with polyinosinic acid, dextran sulfate, polycytidic acid or 4-acetamido-4xe2x80x2isothiocyano-stilbene-2,2xe2x80x2-disulfonic acid (Miyao et al., Antisense Res. Dev., 1995, 5, 115-121; Takakura et al., Antisense and Nucl. Acid Drug Dev., 1996, 6, 177-183).\nExcipients\nIn contrast to a carrier compound, a xe2x80x9cpharmaceutical carrierxe2x80x9d or xe2x80x9cexcipientxe2x80x9d is a pharmaceutically acceptable solvent, suspending agent or any other pharmacologically inert vehicle for delivering one or more nucleic acids to an animal. The excipient may be liquid or solid and is selected, with the planned manner of administration in mind, so as to provide for the desired bulk, consistency, etc., when combined with a nucleic acid and the other components of a given pharmaceutical composition. Typical pharmaceutical carriers include, but are not limited to, binding agents (e.g., pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose, etc.); fillers (e.g., lactose and other sugars, microcrystalline cellulose, pectin, gelatin, calcium sulfate, ethyl cellulose, polyacrylates or calcium hydrogen phosphate, etc.); lubricants (e.g., magnesium stearate, talc, silica, colloidal silicon dioxide, stearic acid, metallic stearates, hydrogenated vegetable oils, corn starch, polyethylene glycols, sodium benzoate, sodium acetate, etc.); disintegrants (e.g., starch, sodium starch glycolate, etc.); and wetting agents (e.g., sodium lauryl sulphate, etc.).\nPharmaceutically acceptable organic or inorganic excipient suitable for non-parenteral administration which do not deleteriously react with nucleic acids can also be used to formulate the compositions of the present invention. Suitable pharmaceutically acceptable carriers include, but are not limited to, water, salt solutions, alcohols, polyethylene glycols, gelatin, lactose, amylose, magnesium stearate, talc, silicic acid, viscous paraffin, hydroxymethylcellulose, polyvinylpyrrolidone and the like.\nFormulations for topical administration of nucleic acids may include sterile and non-sterile aqueous solutions, non-aqueous solutions in common solvents such as alcohols, or solutions of the nucleic acids in liquid or solid oil bases. The solutions may also contain buffers, diluents and other suitable additives. Pharmaceutically acceptable organic or inorganic excipients suitable for non-parenteral administration which do not deleteriously react with nucleic acids can be used.\nSuitable pharmaceutically acceptable excipients include, but are not limited to, water, salt solutions, alcohol, polyethylene glycols, gelatin, lactose, amylose, magnesium stearate, talc, silicic acid, viscous paraffin, hydroxymethylcellulose, polyvinylpyrrolidone and the like.\nOther Components\nThe compositions of the present invention may additionally contain other adjunct components conventionally found in pharmaceutical compositions, at their art-established usage levels. Thus, for example, the compositions may contain additional, compatible, pharmaceutically-active materials such as, for example, antipruritics, astringents, local anesthetics or anti-inflammatory agents, or may contain additional materials useful in physically formulating various dosage forms of the compositions of the present invention, such as dyes, flavoring agents, preservatives, antioxidants, opacifiers, thickening agents and stabilizers. However, such materials, when added, should not unduly interfere with the biological activities of the components of the compositions of the present invention. The formulations can be sterilized and, if desired, mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorings, flavorings and\/or aromatic substances and the like which do not deleteriously interact with the nucleic acid(s) of the formulation.\nAqueous suspensions may contain substances which increase the viscosity of the suspension including, for example, sodium carboxymethylcellulose, sorbitol and\/or dextran. The suspension may also contain stabilizers.\nCertain embodiments of the invention provide pharmaceutical compositions containing (a) one or more antisense compounds and (b) one or more other chemotherapeutic agents which function by a non-antisense mechanism. Examples of such chemotherapeutic agents include, but are not limited to, anticancer drugs such as daunorubicin, dactinomycin, doxorubicin, bleomycin, mitomycin, nitrogen mustard, chlorambucil, melphalan, cyclophosphamide, 6-mercaptopurine, 6-thioguanine, cytarabine (CA), 5-flucrouracil (5-FU), floxuridine (5-FUdR), methotrexate (MTX), colchicine, vincristine, vinblastine, etoposide, teniposide, cisplatin and diethylstilbestrol (DES). See, generally, The Merck Manual of Diagnosis and Therapy, 15th Ed., Berkow et al., eds., 1987, Rahway, N.J., pages 1206-1228). Anti-inflammatory drugs, including but not limited to nonsteroidal anti-inflammatory drugs and corticosteroids, and antiviral drugs, including but not limited to ribivirin, vidarabine, acyclovir and ganciclovir, may also be combined in compositions of the invention. See, generally, The Merck Manual of Diagnosis and Therapy, 15th Ed., Berkow et al., eds., 1987, Rahway, N.J., pages 2499-2506 and 46-49, respectively). Other non-antisense chemotherapeutic agents are also within the scope of this invention. Two or more combined compounds may be used together or sequentially.\nIn another related embodiment, compositions of the invention may contain one or more antisense compounds, particularly oligonucleotides, targeted to a first nucleic acid and one or more additional antisense compounds targeted to a second nucleic acid target. Numerous examples of antisense compounds are known in the art. Two or more combined compounds may be used together or sequentially.\nThe formulation of therapeutic compositions and their subsequent administration is believed to be within the skill of those in the art. Dosing is dependent on severity and responsiveness of the disease state to be treated, with the course of treatment lasting from several days to several months, or until a cure is effected or a diminution of the disease state is achieved. Optimal dosing schedules can be calculated from measurements of drug accumulation in the body of the patient. Persons of ordinary skill can easily determine optimum dosages, dosing methodologies and repetition rates. Optimum dosages may vary depending on the relative potency of individual oligonucleotides, and can generally be estimated based on EC50s found to be effective in in vitro and in vivo animal models. In general, dosage is from 0.01 ug to 100 g per kg of body weight, and may be given once or more daily, weekly, monthly or yearly, or even once every 2 to 20 years. Persons of ordinary skill in the art can easily estimate repetition rates for dosing based on measured residence times and concentrations of the drug in bodily fluids or tissues. Following successful treatment, it may be desirable to have the patient undergo maintenance therapy to prevent the recurrence of the disease state, wherein the oligonucleotide is administered in maintenance doses, ranging from 0.01 ug to 100 g per kg of body weight, once or more daily, to once every 20 years.\nWhile the present invention has been described with specificity in accordance with certain of its preferred embodiments, the following examples serve only to illustrate the invention and are not intended to limit the same.","meta":{"bibliographic_information":{"document_kind":"B1","document_number":"06395545","document_date":"20020528","publishing_country_or_organization":"US","title_of_invention":"Antisense modulation of inhibitor-kappa B kinase-alpha expression"},"source_file":"https:\/\/bulkdata.uspto.gov\/data\/patent\/grant\/redbook\/fulltext\/2002\/pg020528.zip","abstract":["Antisense compounds, compositions and methods are provided for modulating the expression of Inhibitor-kappa B Kinase-alpha. The compositions comprise antisense compounds, particularly antisense oligonucleotides, targeted to nucleic acids encoding Inhibitor-kappa B Kinase-alpha. Methods of using these compounds for modulation of Inhibitor-kappa B Kinase-alpha expression and for treatment of diseases associated with expression of Inhibitor-kappa B Kinase-alpha are provided."],"citations":[{"DNUM":"5962673","DATE":"19991000","KIND":"A","CITING_PARTY":"examiner","US_PARTY_NAME":"Monia et al."}],"assignees":[{"assignee_parties":[{"organization_name":"Isis Pharmaceuticals, Inc.","city":"Carlsbad","state":"CA"}],"assignee_type":"United States company or corporation"}],"classifications":{"main_or_locrano_class":["C07H 2104"],"further_ipc_classification":["C07H 2102","C12Q  1168","C12N 1585","A61K 4800"],"ipc_edition":["7"],"domestic_main_classification":["435375"],"domestic_further_classification":["435  6","435455","536 231","536 243","536 2431","536 2433","536 245"],"national_classifications":["536 245","536 231","536 243","536 2431","536 241","536 221","536 2433","435  6","435325","435375","435455","514 44"]},"inventors":[{"first_name":"Brett P.","sir_name":"Monia","city":"La Costa","state":"CA"},{"first_name":"Lex M.","sir_name":"Cowsert","city":"San Mateo","state":"CA"}],"dup_signals":{"dup_doc_count":178,"dup_dump_count":50,"dup_details":{"curated_sources":2,"2023-06":2,"2021-43":1,"2020-45":8,"2020-40":1,"2019-47":1,"2019-30":1,"2019-09":1,"2018-39":1,"2018-26":2,"2018-13":3,"2017-51":2,"2017-43":3,"2017-34":4,"2017-30":1,"2017-26":3,"2017-22":1,"2017-17":3,"2017-09":1,"2017-04":1,"2016-50":3,"2016-44":1,"2016-40":1,"2016-36":3,"2016-30":1,"2016-26":1,"2016-22":3,"2016-18":3,"2016-07":5,"2015-48":4,"2015-40":2,"2015-35":9,"2015-32":5,"2015-27":7,"2015-22":6,"2015-14":6,"2014-52":2,"2014-49":4,"2014-42":5,"2014-41":7,"2014-35":5,"2014-23":15,"2014-15":4,"2023-23":1,"2015-18":8,"2015-11":1,"2015-06":6,"2014-10":11,"2013-48":5,"2013-20":1,"2017-13":1}}},"subset":"uspto"}