System and method for determining an individualized medical intervention for a disease state

Abstract

To provide systems and methods for determining individualized medical intervention for a disease state based on molecular profiling independent of disease lineage diagnosis used to target specific genes and / or gene expressed proteins with specific drugs or agents.SOLUTION: The present invention provides for the application of molecular profiling to provide systems and methods for determining medical interventions for particular disease states. The systems and methods can be performed at any stage of the disease. In particular, the invention provides systems and methods for determining a medical intervention for a critically ill patient, e.g., a patient with cancer who is on at least two chemotherapeutic or hormonal regimens.SELECTED DRAWING: None

Description

[Technical Field]

[0001] FIELD OF THE INVENTION The present invention generally relates to the application of molecular profiling, which provides a system and method for determining medical intervention for a specific disease state. The system and method can be performed at any stage of the disease. In particular, the present invention relates to a system and method for determining medical intervention for a patient suffering from a serious disease, for example, a patient with cancer who is undergoing at least two chemotherapy or hormonal regimens, which comprises: molecular profiling a biological sample from the patient; determining whether any molecular findings, including one or more genes, gene expression proteins, molecular mechanisms, and / or combinations of these molecular findings, show altered expression compared to a normal reference; and identifying a drug therapy that can interact with the genes, gene expression proteins, molecular mechanisms, or combinations of these molecular findings that show altered expression. [Background technology]

[0002] BACKGROUND OF THE INVENTION A patient's disease state is typically treated with a treatment regimen or therapy that is selected based on underlying clinical criteria; that is, a treatment regimen or therapy is selected for a patient based on a determination that the patient has been diagnosed with a particular disease (the diagnosis being made from conventional diagnostic assays). While the molecular mechanisms behind various disease states have been the subject of research for many years, the specific application of an affected individual's molecular profile in determining treatment regimens and therapies for that individual is disease-specific and has not been widely pursued.

[0003] Some treatment regimens have been determined using molecular profiling in combination with a patient's clinical characteristics (e.g., findings made by a physician (e.g., International Classification of Diseases code and the date such code was determined)), laboratory test results, X-rays, biopsy results, patient explanations, and any other medical information that physicians generally rely on to diagnose a particular disease. However, because some treatment regimens, although associated with the treatment of a particular type of disease state, may also be effective for a variety of disease states, using a combination of selection factors based on molecular profiling and clinical characteristics (e.g., a diagnosis of a particular type of cancer) to determine a treatment regimen or treatment carries the risk that an effective treatment regimen for a particular individual may be overlooked.

[0004] Patients with metastatic cancer are of particular interest to treating physicians. The majority of patients with metastatic cancer eventually exhaust treatment options for their tumors. After progressing through standard first- and second-line (and occasionally third-line and beyond) therapies for their tumors, these patients have very limited options. These patients can participate in Phase I and Phase II clinical trials for novel anticancer agents, but they typically must meet very strict eligibility criteria to participate. When patients participate in these types of trials, studies have shown that the novel anticancer agents can result in response rates ranging from an average of 5% to 10% in Phase I to 12% in Phase II. These patients also have the option of receiving the best supportive care to treat their symptoms.

[0005] In recent years, there has been a surge in interest in developing new anti-cancer drugs that target cell surface receptors or upregulated or amplified gene products. This approach has achieved some success (e.g., Herceptin for HER2 / neu in breast cancer cells, rituximab for CD20 in lymphoma cells, bevacizumab for VEGF, cetuximab for EGFR, etc.). However, patients' tumors still ultimately progress to these therapies. When multiple targets or molecular findings (e.g., molecular mechanisms, genes, gene expression proteins, and / or combinations thereof) are measured in patients' tumors, additional targets or molecular findings can be found that can be utilized by using specific therapeutic agents. Identifying multiple drugs that can treat multiple targets or underlying mechanisms can provide metastatic cancer patients with viable alternative treatments to existing treatment regimens. Summary of the Invention [Problem to be solved by the invention]

[0006] Therefore, there is a need for systems and methods for determining individualized medical interventions for disease states based on molecular profiling independent of disease lineage diagnosis that is used to target specific genes and / or gene expression proteins with specific drugs or agents. [Means for solving the problem]

[0007] (Summary of the Invention) The present invention relates to a system and method for determining a medical intervention tailored to an individual for a particular disease state. One exemplary method of the present invention for determining a medical intervention for a disease state includes testing genes and / or gene-expressed proteins from a biological sample of an affected individual, determining which genes and / or gene-expressed proteins show altered expression compared to a reference, and identifying a drug therapy that is not limited to a single disease and that is used to interact with the genes and / or gene-expressed proteins that show altered expression. In one aspect of this exemplary embodiment of the present invention, identifying a drug therapy that is used to interact with the genes and / or gene-expressed proteins that show altered expression can include identifying a drug therapy from an automated review of data obtained from a large literature database and / or clinical trials.

[0008] In another aspect of the above exemplary embodiment of the present invention, the step of testing for genes and / or testing for gene-expressed proteins may include performing immunohistochemical (IHC) analysis and / or microarray analysis.Furthermore, the step of performing microarray analysis may include performing analysis using expression microarrays, comparative genomic hybridization (CGH) microarrays, single nucleotide polymorphism (SNP) microarrays, fluorescent in situ hybridization (ISH), in situ hybridization (ISH) and proteomics arrays.Furthermore, the step of performing IHC analysis may include performing IHC analysis for gene-expressed proteins including at least one of Her2 / Neu, ER, PR, c-kit, EGFR, MLH1, MSH2, CD20, p53, cyclin D1, bcl2, COX-2, androgen receptor, CD52, PDGFR, AR, CD25 and VEGF.

[0009] In another aspect of the present invention, the step of performing microarray analysis in the above exemplary method for determining medical intervention for a disease state includes the step of analyzing a gene encoding a gene encoding a gene encoding a gene for a disease state, the gene encoding a gene for a disease state, a ... 2, POLA, CES2, EGFR, OGFR, ASNS, NFKB2, RARA, MS4A1, DCK, DNMT3A, EREG, epiregulin, FOLR1, GNRH1, GNRHR1, FSHB, FSHR, FSHPRH1, folate receptor, HGF, HIG1, IL13RA1, LTB, ODC1, PPARG, PPARGC1, VHL, lymphotoxin β receptor, Myc, TOP2B topoisomerase II, TOPO2B, TXN, VEGFC, ACE2, ADH1C, ADH4, AGT, AREG, CA2, CDK2, caveolin, and NFKB1.

[0010] In yet another aspect of the above exemplary method of the present invention, testing for genes and / or testing for gene-expressed proteins from a biological sample from the diseased individual may include performing immunohistochemical analysis on the tumor, and determining which genes and / or gene-expressed proteins show altered expression compared to the reference may include determining whether 30% or more tumor cells stain +2 or higher for a particular gene-expressed protein. In yet another aspect of the above exemplary method of the present invention, testing for genes and / or testing for gene-expressed proteins from a biological sample from the diseased individual may include performing microarray analysis on the tumor, and determining which genes and / or gene-expressed proteins show altered expression compared to the reference may include identifying which genes are up-regulated or down-regulated by determining whether the overall change in expression for a particular gene compared to the reference normal tissue of origin is significant at p<0.001. Additionally, the above-described exemplary methods of the present invention for determining medical intervention for a disease state may also include providing a patient profile report identifying altered expression for genes and / or gene-expressed proteins along with potential drug therapies for interactions with each of the genes and / or gene-expressed proteins that exhibit altered expression.

[0011] Another exemplary embodiment of the present invention relates to a method for identifying a drug therapy that can interact with a molecular target, the method comprising the steps of: identifying a molecular target in a plurality of diseased individuals that exhibits altered expression when compared to a normal reference; administering a drug therapy to the diseased individuals that exhibits altered expression of the molecular target; and measuring any changes in the molecular target in the diseased individuals after the drug therapy. Furthermore, in one aspect of this exemplary embodiment of the method for identifying a drug therapy that can interact with a molecular target, identifying a molecular target in a plurality of diseased individuals that exhibits altered expression when compared to a normal reference can include performing a test for a gene and / or a test for gene-expressed proteins from biological samples from the diseased individuals, wherein the test comprises immunohistochemical (IHC) analysis and / or microarray analysis.

[0012] In yet another exemplary embodiment of the present invention, a system for determining a personalized medical intervention for a disease state is provided, the system comprising: a host server; a user interface for accessing the host server to access and input data; a processor for processing the input data; a memory connected to the processor for storing the processed data and instructions for: (a) accessing a molecular profile obtained from a patient's biological specimen; (b) determining whether at least one of genes, gene expression proteins, molecular mechanisms, and other molecular findings obtained from the molecular profile exhibits altered expression compared to a normal reference; and (c) accessing a medication database to identify one or more medications that interact with the genes, gene expression proteins, molecular mechanisms, and / or other molecular findings that exhibit altered expression; and a display means for displaying the genes, gene expression proteins, molecular mechanisms, and other molecular findings that exhibit altered expression and the medications that interact therewith. Regarding the exemplary embodiment of the present invention relating to the system for determining a personalized medical intervention for a disease state, the molecular profile obtained from the biological specimen may include the same immunohistochemical (IHC) analysis and microarray analysis described above with reference to the first exemplary embodiment of the present invention. Furthermore, the genes analyzed using these analyses as well as the various types of these analyses may be the same as those described above with reference to the first exemplary embodiment of the present invention relating to a method for determining a medical intervention for a disease state.

[0013] Yet another exemplary embodiment of the present invention relates to a method for determining a medical intervention for a disease state, the method comprising: performing at least one molecular test on at least one target from a biological sample of an affected individual; determining whether the target exhibits altered expression compared to a reference; and identifying at least one non-disease-specific agent that interacts with the target exhibiting altered expression. Identifying at least one non-disease-specific agent that interacts with the target may include identifying a drug therapy from an automated review of a large literature base and / or an automated review of data obtained from clinical trials. Furthermore, an exemplary embodiment of the present invention relating to a method for determining a medical intervention for a disease state may also include providing a patient profile report including the patient's test results for various targets and any suggested treatments based on those results.

[0014] In exemplary embodiments of the present invention relating to methods for determining medical intervention for a disease state, the step of performing at least one molecular test on at least one target from a biological sample of an affected individual may include all of the analyses described above with respect to immunohistochemical (IHC) analysis and microarray analysis and the genes analyzed using those analyses. Therefore, the present invention provides, for example, the following items. (Item 1) 1. A method for determining a medical intervention for a disease state, comprising: conducting at least one of testing for the gene and testing for the gene expressed protein from a biological sample from the affected individual; Determining which genes and / or gene-expressed proteins show altered expression compared to the reference; and The method includes identifying a drug therapy that is not limited to a single disease and that is used to interact with at least one of the genes and / or gene-expressed proteins that exhibit altered expression. (Item 2) 2. The method of claim 1, wherein identifying a drug therapy used to interact with at least one of the genes and / or gene-expressed proteins that exhibited altered expression comprises identifying the drug therapy from at least one of automated review of large literature databases and data obtained from clinical trials. (Item 3) Item 10. The method of item 1, wherein the step of performing at least one of testing for genes and testing for gene-expressed proteins comprises performing at least one of immunohistochemical (IHC) analysis and microarray analysis. (Item 4) Item 4. The method according to item 3, wherein the step of performing microarray analysis comprises performing analysis using at least one of an expression microarray, a comparative genomic hybridization (CGH) microarray, a single nucleotide polymorphism (SNP) microarray, fluorescent in situ hybridization (FISH), in situ hybridization (ISH), and a proteomics array. (Item 5) 4. The method according to Item 3, wherein the step of performing IHC analysis comprises the step of performing IHC analysis for gene expression proteins including at least one of Her2 / Neu, ER, PR, c-kit, EGFR, MLH1, MSH2, CD20, p53, cyclin D1, bcl2, COX-2, androgen receptor, CD52, PDGFR, AR, CD25, and VEGF. (Item 6) The step of performing microarray analysis may include the steps of: BCL2, HIF1A, AR, ESR1, PDGFRA, KIT, PDGFRB, CDW52, ZAP70, PGR, SPARC, GART, GSTP1, NFKBIA, MSH2, TXNRD1, HDAC1, PDGFC, PTEN, CD33, TYMS, RXRB, ADA, TNF, ERCC3, RAF1, VEGF, TOP1, TOP2A, BRCA2, TK1, FOLR2, TOP2B, MLH1, IL2RA, DNMT1, HSPCA, ERBR2, ERBB2, SSTR1, VHL, VDR, PTGS2, POLA, CES2, EGFR, OGFR, ASNS, 4. The method of Item 3, comprising a step of performing microarray analysis for genes including at least one of NFKB2, RARA, MS4A1, DCK, DNMT3A, EREG, epiregulin, FOLR1, GNRH1, GNRHR1, FSHB, FSHR, FSHPRH1, folate receptor, HGF, HIG1, IL13RA1, LTB, ODC1, PPARG, PPARGC1, VHL, lymphotoxin β receptor, Myc, TOP2B topoisomerase II, TOPO2B, TXN, VEGFC, ACE2, ADH1C, ADH4, AGT, AREG, CA2, CDK2, caveolin, and NFKB1. (Item 7) 4. The method of claim 3, wherein the step of conducting at least one of testing for genes and testing for gene-expressed proteins from a biological sample of the affected individual comprises performing immunohistochemistry on the tumor, and the step of determining which genes and / or gene-expressed proteins show altered expression compared to a reference comprises determining whether 30% or more of the tumor cells stain +2 or higher for a particular gene-expressed protein. (Item 8) 4. The method of item 3, wherein the step of conducting at least one of testing genes and testing gene-expressed proteins from a biological sample of the affected individual comprises performing microarray analysis on the tumor, and the step of determining which genes and / or gene-expressed proteins show altered expression compared to the reference comprises identifying which genes are up-regulated or down-regulated by determining what fold change in expression for a particular gene compared to normal tissue of reference origin is significant at p<0.001. (Item 9) 2. The method of claim 1, further comprising providing a patient profile report identifying altered expression for the genes and / or gene-expressed proteins, along with potential drug therapies for interactions with each of the genes and / or gene-expressed proteins that show altered expression. (Item 10) 1. A method for identifying a drug therapy capable of interacting with a molecular target, comprising: identifying molecular targets in a plurality of affected individuals that exhibit altered expression when compared to a normal reference; administering a drug therapy to said affected individual exhibiting altered expression of said molecular target; and measuring any changes in said molecular target in said affected individual following said drug therapy. A method comprising: (Item 11) 11. The method of claim 10, wherein the step of identifying molecular targets in a plurality of diseased individuals that exhibit altered expression when compared to a normal reference comprises performing at least one of testing for genes and testing for gene-expressed proteins from biological samples of the diseased individuals, wherein the testing comprises at least one of immunohistochemical (IHC) analysis and microarray analysis. (Item 12) 1. A system for determining personalized medical intervention for a disease state, comprising: Host server and; a user interface for accessing the host server to access and input data; a processor for processing the input data; the processed data, and i) an order to access molecular profiles obtained from patients' biological specimens; ii) instructions for determining whether at least one or more of the genes, gene expression proteins, molecular mechanisms, and other molecular findings obtained from the molecular profile exhibit altered expression compared to a normal reference; and iii) instructions for accessing a medication database to identify one or more medications that interact with the at least one gene that exhibits altered expression, gene expression proteins, molecular mechanisms, and other molecular findings; a memory coupled to the processor for storing: display means for displaying said at least one gene exhibiting altered expression, gene expressed proteins, molecular mechanisms and other molecular findings, and said drug therapy interacting therewith; A system comprising: (Item 13) Item 13. The system of item 12, wherein the molecular profile comprises at least one of immunohistochemical (IHC) analysis and microarray analysis. (Item 14) Item 14. The system of item 13, wherein the microarray analysis comprises at least one of an expression microarray, a comparative genomic hybridization (CGH) microarray, a single nucleotide polymorphism (SNP) microarray, a fluorescent in situ hybridization (FISH), an in situ hybridization (ISH), and a proteomics array. (Item 15) 14. The system of Item 13, wherein the IHC analysis comprises IHC analysis of gene expression proteins including at least one of Her2 / Neu, ER, PR, c-kit, EGFR, MLH1, MSH2, CD20, p53, cyclin D1, bcl2, COX-2, androgen receptor, CD52, PDGFR, AR, CD25, and VEGF. (Item 16) The above microarray analysis shows BCL2, HIF1A, AR, ESR1, PDGFRA, KIT, PDGFRB, CDW52, ZAP70, PGR, SPARC, GART, GSTP1, NFKBIA, MSH2, TXNRD1, HDAC1, PDGFC, PTEN, CD33, TYMS, RXRB, AD A, TNF, ERCC3, RAF1, VEGF, TOP1, TOP2A, BRCA2, TK1, FOLR2, TOP2B, MLH1, IL2RA, DNMT1, HSPCA, ERBR2, ERBB2, SSTR1, VHL, VDR, PTGS2, POLA, CES2, EGFR, OGFR, ASNS, NF 14. The system of item 13, comprising microarray analysis of genes including at least one of KB2, RARA, MS4A1, DCK, DNMT3A, EREG, epiregulin, FOLR1, GNRH1, GNRHR1, FSHB, FSHR, FSHPRH1, folate receptor, HGF, HIG1, IL13RA1, LTB, ODC1, PPARG, PPARGC1, VHL, lymphotoxin beta receptor, Myc, TOP2B topoisomerase II, TOPO2B, TXN, VEGFC, ACE2, ADH1C, ADH4, AGT, AREG, CA2, CDK2, caveolin, and NFKB1. (Item 17) 14. The system of claim 13, wherein the molecular profile comprises immunohistochemical analysis of the tumor, and the instructions for determining whether at least one or more of genes, gene expression proteins, molecular mechanisms, and other molecular findings obtained from the molecular profile show altered expression compared to a reference comprise instructions for determining whether 30% or more of the tumor cells stain +2 or higher for a particular gene expression protein. (Item 18) Item 14. The system of item 13, wherein the molecular profile comprises a microarray analysis of the tumor, and the instructions for determining whether at least one or more of the genes, gene-expressed proteins, molecular mechanisms, and other molecular findings obtained from the molecular profile show altered expression compared to a normal reference comprise instructions for identifying which genes are up-regulated or down-regulated by determining what fold change in expression for a particular gene compared to the normal tissue of reference origin is significant at p<0.001. (Item 19) Item 13. The system of item 12, wherein the display means includes a printed patient profile report. (Item 20) 13. The method of claim 12, wherein the instructions for accessing a medication database to identify one or more medications that interact with the at least one gene, gene expression protein, molecular mechanism, and other molecular findings that exhibit altered expression comprise instructions for performing an automated review of a large literature database containing literature correlating genes and / or gene expression proteins with medication interactions. (Item 21) 1. A method for determining a medical intervention for a disease state, comprising: conducting at least one molecular test on at least one target from a biological sample of the diseased individual; determining whether the at least one target exhibits altered expression relative to a reference; and identifying at least one non-disease specific agent that interacts with said at least one target that exhibits altered expression. A method comprising: (Item 22) 22. The method of claim 21, wherein identifying at least one non-disease specific agent that interacts with the at least one target comprises identifying drug therapies from at least one of automated review of large literature databases and data obtained from clinical trials. (Item 23) 22. The method of claim 21, wherein the step of performing at least one molecular test on at least one target comprises performing at least one of immunohistochemical (IHC) analysis and microarray analysis. (Item 24) 24. The method of claim 23, wherein the step of performing microarray analysis comprises performing analysis using at least one of an expression microarray, a comparative genomic hybridization (CGH) microarray, a single nucleotide polymorphism (SNP) microarray, fluorescent in situ hybridization (FISH) and in situ hybridization (ISH), and a proteomics array. (Item 25) 24. The method of item 23, wherein the step of performing at least one IHC analysis comprises performing IHC analysis for gene expression proteins including at least one of Her2 / Neu, ER, PR, c-kit, EGFR, MLH1, MSH2, CD20, p53, cyclin D1, bcl2, COX-2, androgen receptor, CD52, PDGFR, AR, CD25, and VEGF. (Item 26) The step of performing at least one microarray analysis is preferably carried out using at least one of BCL2, HIF1A, AR, ESR1, PDGFRA, KIT, PDGFRB, CDW52, ZAP70, PGR, SPARC, GART, GSTP1, NFKBIA, MSH2, TXNRD1, HDAC1, PDGFC, PTEN, CD33, TYMS, RXRB, ADA, TNF, ERCC3, RAF1, VEGF, TOP1, TOP2A, BRCA2, TK1, FOLR2, TOP2B, MLH1, IL2RA, DNMT1, HSPCA, ERBR2, ERBB2, SSTR1, VHL, VDR, PTGS2, POLA, CES2, EGFR, OGFR, AS 24. The method of Item 23, comprising the step of performing microarray analysis for genes including at least one of NS, NFKB2, RARA, MS4A1, DCK, DNMT3A, EREG, epiregulin, FOLR1, GNRH1, GNRHR1, FSHB, FSHR, FSHPRH1, folate receptor, HGF, HIG1, IL13RA1, LTB, ODC1, PPARG, PPARGC1, VHL, lymphotoxin β receptor, Myc, TOP2B topoisomerase II, TOPO2B, TXN, VEGFC, ACE2, ADH1C, ADH4, AGT, AREG, CA2, CDK2, caveolin, and NFKB1. (Item 27) 24. The method of claim 23, wherein performing at least one molecular test on at least one target from a biological sample of the diseased individual comprises performing immunohistochemical analysis on the tumor, and determining whether the at least one target exhibits altered expression compared to a reference comprises determining whether 30% or more of the tumor cells stain +2 or higher for a particular gene expression protein. (Item 28) 24. The method of claim 23, wherein performing at least one molecular test on at least one target from a biological sample of the diseased individual comprises performing microarray analysis on the tumor, and determining whether the at least one target exhibits altered expression compared to a reference comprises identifying which genes are up-regulated or down-regulated by determining what fold change in expression for a particular gene compared to normal tissue of reference origin is significant at p<0.001. (Item 29) 22. The method of claim 21, further comprising providing a patient profile report including the patient's test results for various targets and any suggested treatments based on those results. [Brief explanation of the drawings]

[0015] [Figure 1] FIG. 1 shows a block diagram of an exemplary embodiment of a system for determining personalized medical interventions for specific disease states that utilizes non-disease specific molecular profiling of a patient's biological specimen. [Figure 2] FIG. 2 is a flow chart of an exemplary embodiment of a method for determining personalized medical interventions for a particular disease state that utilizes non-disease specific molecular profiling of a patient's biological specimen. [Figure 3A] 3A-3D show exemplary patient profile reports according to step 80 of FIG. [Figure 3B] 3A-3D show exemplary patient profile reports according to step 80 of FIG. [Figure 3C] 3A-3D show exemplary patient profile reports according to step 80 of FIG. [Figure 3D] 3A-3D show exemplary patient profile reports according to step 80 of FIG. [Figure 4]FIG. 4 is a flow chart of an exemplary embodiment of a method for identifying medications / drugs capable of interacting with a target. [Figure 5] 5-14 are flow charts and diagrams illustrating various portions of the informed personalized drug discovery system and method of the present invention. [Figure 6] 5-14 are flow charts and diagrams illustrating various portions of the informed personalized drug discovery system and method of the present invention. [Figure 7] 5-14 are flow charts and diagrams illustrating various portions of the informed personalized drug discovery system and method of the present invention. [Figure 8] 5-14 are flow charts and diagrams illustrating various portions of the informed personalized drug discovery system and method of the present invention. [Figure 9] 5-14 are flow charts and diagrams illustrating various portions of the informed personalized drug discovery system and method of the present invention. [Figure 10] 5-14 are flow charts and diagrams illustrating various portions of the informed personalized drug discovery system and method of the present invention. [Figure 11] 5-14 are flow charts and diagrams illustrating various portions of the informed personalized drug discovery system and method of the present invention. [Figure 12] 5-14 are flow charts and diagrams illustrating various portions of the informed personalized drug discovery system and method of the present invention. [Figure 13] 5-14 are flow charts and diagrams illustrating various portions of the informed personalized drug discovery system and method of the present invention. [Figure 14] 5-14 are flow charts and diagrams illustrating various portions of the informed personalized drug discovery system and method of the present invention. [Figure 15]15-25 are computer screen printouts relating to various portions of the personalized drug discovery system and method based on the information shown in FIGS. 5-14. [Figure 16] 15-25 are computer screen printouts relating to various portions of the personalized drug discovery system and method based on the information shown in FIGS. 5-14. [Figure 17] 15-25 are computer screen printouts relating to various portions of the personalized drug discovery system and method based on the information shown in FIGS. 5-14. [Figure 18] 15-25 are computer screen printouts relating to various portions of the personalized drug discovery system and method based on the information shown in FIGS. 5-14. [Figure 19] 15-25 are computer screen printouts relating to various portions of the personalized drug discovery system and method based on the information shown in FIGS. 5-14. [Figure 20] 15-25 are computer screen printouts relating to various portions of the personalized drug discovery system and method based on the information shown in FIGS. 5-14. [Figure 21] 15-25 are computer screen printouts relating to various portions of the personalized drug discovery system and method based on the information shown in FIGS. 5-14. [Figure 22] 15-25 are computer screen printouts relating to various portions of the personalized drug discovery system and method based on the information shown in FIGS. 5-14. [Figure 23] 15-25 are computer screen printouts relating to various portions of the personalized drug discovery system and method based on the information shown in FIGS. 5-14. [Figure 24] 15-25 are computer screen printouts relating to various portions of the personalized drug discovery system and method based on the information shown in FIGS. 5-14. [Figure 25] 15-25 are computer screen printouts relating to various portions of the personalized drug discovery system and method based on the information shown in FIGS. 5-14. DETAILED DESCRIPTION OF THE INVENTION

[0016] (Detailed explanation) The detailed description of exemplary embodiments herein refers to the accompanying drawings and images, which for illustrative purposes show exemplary embodiments and their best modes. These exemplary embodiments have been described in sufficient detail to enable those skilled in the art to practice the invention, but it should be understood that other embodiments may be realized and that logical and mechanical changes may be made without departing from the spirit and scope of the invention. Accordingly, the detailed descriptions herein are for purposes of illustration only, and not limitation. For example, the steps recited in any method or process description may be performed in any order and are not limited to the order shown. Furthermore, any of the functions or steps may be outsourced to or performed by one or more third parties. Furthermore, any reference to the singular includes plural embodiments, and any reference to more than one component may include a single embodiment. For the sake of brevity, conventional data networking, application development, and other functional aspects of the system (and the components of the individual operating components of the system) may not be described in detail herein. Furthermore, the connecting lines shown in the various figures contained herein are intended to represent example functional relationships and / or physical couplings between the various elements. It should be noted that many alternative or additional functional relationships or physical couplings may exist in an actual system.

[0017] The various system components described herein may comprise one or more of the following: a host server or other computing system (including a processor for processing digital data; memory coupled to the processor for storing digital data; an input digitizer coupled to the processor for inputting digital data; an application program stored in the memory and accessible to the processor for directing the processing of the digital data by the processor; and a display device coupled to the processor and memory for displaying information derived from the digital data processed by the processor) and a plurality of databases. As used herein, the various databases may include patient data (e.g., family history, demographic, and environmental data), biological sample data, pretreatment and protocol data, patient clinical data, molecular profiling data of biological samples, data on therapeutic and / or investigational drugs, gene libraries, disease libraries, drug libraries, patient tracking data, file management data, financial management data, billing data, and / or similar data useful in the operation of the system. As one skilled in the art will appreciate, the user computer may include an operating system (e.g., Windows NT, 95 / 98 / 2000, OS2, UNIX, Linux, Solaris, MacOS, etc.) and various conventional support software and drivers typically associated with a computer. The computer may include any suitable personal computer, network computer, workstation, minicomputer, mainframe, etc. The user computer may be located in a home or medical / business environment with network access. In an exemplary embodiment, access is via a network or via the Internet via a commercially available web browser software package.

[0018] As used herein, the term "network" shall include any electronic communication means incorporating both hardware and software components thereof. Communication between parties may be achieved by any suitable communication channel (e.g., telephone network, extranet, intranet, Internet, point of interaction device, personal digital assistant (e.g., Palm Pilot®, Blackberry®), mobile phone, kiosk, etc.), online communication, satellite communication, offline communication, wireless communication, transponder communication, local area network (LAN), wide area network (WAN), network-connected or associated devices, keyboard, mouse, and / or any suitable communication or data entry modality. Furthermore, although the system is often described herein as running on the TCP / IP communication protocol, the system may also be run using IPX, Appletalk, IP-6, NetBIOS, OSI, or any number of existing or future protocols. If the network falls within the scope of an inherently public network such as the Internet, it may be beneficial to presume that the network is not secure and open to eavesdroppers. The specific information relating to the above protocols, standards, and application software utilized in connection with the Internet is generally known to those skilled in the art and need not be detailed herein. See, for example, DLIP NAIK, INTERNET STANDARDS AND PROTOCOLS (1998); JAVA 2 COMPLETE, various authors, (Sybex) 1999); DEBORAH RAY AND ERIC RAY, MASTERING HTML 4.0 (1997); and LOSHIN, TCP / IP CLEARLY EXPLAINED (1997) and DAVID GOURLEY AND BRIAN TOTTY, HTTP, THE DEFINITIVE GUIDE (2002), the contents of which are incorporated herein by reference.

[0019] The various system components may be suitably coupled, independently, separately, or collectively, to a network via data links, including, for example, a connection to an Internet Service Provider (ISP) via a local loop, as commonly used in connection with standard modem communications, cable modem, Dish Network, ISDN, digital subscriber line (DSL), or various wireless communication methods. See, e.g., Gilbert Held, Understanding Data Communications (1996), which is incorporated herein by reference. Note that the network may be implemented as other types of networks, such as an interactive television (ITV) network. Furthermore, the system contemplates the use, sale, or distribution of any goods, services, or information over any network having similar functionality as described herein.

[0020] As used herein, "transmitting" may include sending electronic data from one system component to another over a network connection. Additionally, as used herein, "data" may include generic information such as commands, queries, files, data for storage, etc., in digital or any other format.

[0021] The system is contemplated for use in connection with web services, utility computing, pervasive and personalized computing, security and identity solutions, autonomous computing, commodity computing, mobility and wireless solutions, open source, biometrics, grid computing and / or mesh computing.

[0022] Any database described herein may include a relational, hierarchical, graphical, or object-oriented structure and / or any other database configuration. Typical database products that may be used to implement the database include DB2 from IBM (White Plains, NY), various database products available from Oracle Corporation (Redwood Shores, CA), Microsoft Access or Microsoft SQL Server from Microsoft Corporation (Redmond, Washington), or any other suitable database product. Furthermore, a database may be organized in any suitable manner, such as a data table or lookup table. Each record may be a single file, a series of files, a series of associated data fields, or any other data structure. Association of certain data may be achieved via any desired data association technique (e.g., one known or practiced in the art). For example, the association may be achieved either manually or automatically. Auto-association techniques may include, for example, database lookup, database merge, GREP, AGREP, SQL, using key fields in tables to speed up searches, sequentially searching through all tables and files, sorting records in files according to known instructions to simplify searches, and / or the like. The association process may be accomplished by a database merge function, for example, using "key fields" in pre-selected databases or data sectors.

[0023] More specifically, a "key field" divides the database according to the high-level class of objects defined by the key field. For example, a particular type of data may be designated as a key field in multiple related data tables, and the data tables may then be related based on the type of data in the key field. The data corresponding to the key field in each of the related data tables is preferably identical or of the same type. However, data tables with similar but non-identical data in the key field may also be related, for example, by using AGREP. According to one embodiment, any suitable data storage technology may be utilized to store data without a standard format. Datasets may be stored using any suitable technique, including, for example, storing separate files using the ISO / IEC 7816-4 file structure; implementing a domain where a dedicated file publishes one or more base files containing one or more datasets; using datasets stored in separate files using a hierarchical filing system; datasets stored as records within a single file (including compressed, SQL usable, hashed via one or more keys, numeric, alphabetic, etc., with a first tuple); binary large object (BLOB); storage as ungrouped data elements encoded using ISO / IEC 7816-6 data elements; storage as ungrouped data elements encoded using ISO / IEC Abstract Syntax Notation (ASN.1) such as in ISO / IEC 8824 and 8825; and / or other proprietary techniques (which may include fractal compression, image compression).

[0024] In one exemplary embodiment, the ability to store a wide variety of information in various formats is facilitated by storing information as BLOBs. Thus, any binary information can be stored in the storage space associated with a dataset. The BLOB method may store datasets as ungrouped data elements formatted as blocks of binary data across fixed memory offsets using either fixed storage allocation, circular queue techniques, or best-of-breed memory management (e.g., least recently used page memory, etc.). Using the BLOB method, the ability to store various datasets with different formats facilitates the storage of data by multiple and unrelated owners of the datasets. For example, a first dataset that can be stored can be provided by a first party, a second dataset that can be stored can be provided by an unrelated second party, and a third dataset that can be stored can be provided by a third party unrelated to the first and second parties. Each of these three exemplary datasets can contain different information stored using various data storage formats and / or techniques. Furthermore, each dataset can contain a subset of data that can differ from the other subsets.

[0025] As noted above, in various embodiments, data may be stored without regard to conventional format. However, in one exemplary embodiment, when a dataset (e.g., a blob) is provided for manipulating data, the dataset may be annotated in a standard manner. The annotations may include short headers, trailers, or other appropriate indicators for each dataset that are designed to convey information useful for managing various datasets. For example, annotations may be referred to herein as “conditional headers,” “headers,” “trailers,” or “status,” and may include an indication of the status of the dataset or may include an identifier correlating to a particular publisher or owner of the data. Subsequent bytes of data may be used to indicate, for example, the identity of the publisher or owner of the data, a user, a transaction / membership account identifier, or the like. Each of these conditional annotations is described further herein.

[0026] Dataset annotations may also be used for other types of status information and various other purposes. For example, a dataset annotation may include security information establishing access levels. The access level may be set to allow only one specific entity, such as an employee, company, or other entity, to access a dataset, or to allow a data issuer or owner, user, or other entity to access a particular dataset based on a transaction. Furthermore, security information may restrict or allow only certain actions (e.g., accessing, modifying, and / or deleting a dataset). In one example, a dataset annotation may indicate that only the dataset owner or user is authorized to delete the dataset, that various identified users may be authorized to access the dataset for reading, and that others may be excluded from accessing the dataset altogether. However, other access restriction parameters may also be used to allow various entities, at various permission levels, as appropriate. Data including a header or trailer may be received by a standalone interaction device configured to add, delete, modify, or augment data according to the header or trailer.

[0027] Those skilled in the art will also recognize that for security reasons, any database, system, device, server, or other component of a system may consist of any combination thereof in a single location or multiple locations, where each database or system is equipped with any of a variety of appropriate security features (e.g., firewalls, access codes, encryption, decryption, compression, decompression, etc.).

[0028] The web client computing device may further comprise an internet browser connected to the internet or an intranet using standard dial-up, cable, DSL, or any other internet protocol known in the art. Transactions from the web client may pass through a firewall to prevent unauthorized access by users of other networks. Additionally, additional firewalls may be deployed between various components of the CMS to further enhance security.

[0029] A firewall may include any hardware and / or software appropriately configured to protect the CMS components and / or enterprise computing resources from users of other networks. Additionally, a firewall may be configured to limit or restrict access to various systems and components beyond the firewall for web clients connecting through the web server. Firewalls may exist in a variety of configurations, including stateful inspection, proxy-based, and packet filtering, among others. A firewall may be integrated within the web server or any other CMS component, or may exist as a separate entity.

[0030] The computers described herein may provide a suitable website or other Internet-based graphical user interface accessible by a user. In one embodiment, Microsoft Internet Information Server (IIS), Microsoft Transaction Server (MTS), and Microsoft SQL Server are used in conjunction with the Microsoft operating system, Microsoft NT web server software, the Microsoft SQL Server database system, and Microsoft Commerce Server. Additionally, an Active Data Object (ADO)-compliant database management system may be provided using components such as Access or Microsoft SQL Server, Oracle, Sybase, Informix MySQL, Interbase, and the like.

[0031] Any of the communication, input, storage, database, or display described herein can be facilitated through a website having a web page. The term "web page," as used herein, is not meant to limit the types of documents and applications that can be used to interact with a user. For example, a typical website may include, in addition to standard HTML documents, various forms, Java applets, JavaScript, Active Server Pages (ASP), Common Gateway Interface Script (CGI), Extensible Markup Language (XML), Dynamic HTML, Cascading Style Sheets (CSS), helper applications, plug-ins, and the like. A server may include a web service that receives requests from a web server, including a URL (http: / / yahoo.com / stockquotes / ge) and an IP address (123.56.789.234). The web server retrieves the appropriate web page and transmits the data or application for that web page to the IP address. A web service is an application that can interact with other applications through a communications medium such as the Internet. Web services are typically based on standards or protocols such as XML, XSLT, SOAP, WSDL, and UDDI. Web service methods are well known in the art and are covered in many standard textbooks. See, for example, Alex Nghiem, IT WEB SERVICES: A ROADMAP FOR THE ENTERPRISE (2003), which is hereby incorporated by reference.

[0032] The web-based clinical database for the systems and methods of the present invention preferably has the ability to upload and store clinical data files in native format and is searchable for any clinical parameter. The database is also extensible, utilizing the EAV data model (metadata) to input clinical annotations from any study for easy integration with other studies. Furthermore, the web-based clinical database is adaptable, being XML and XSLT capable of dynamically adding user-customized queries. The database also has exportability to CDISC ODM.

[0033] Those skilled in the art will also recognize that there are many ways to display data in a browser-based document. Data may be displayed as standard text or may be displayed in fixed lists, scrollable lists, drop-down lists, editable text fields, fixed text fields, pop-up windows, etc. Similarly, there are many ways available to modify data in a web page (e.g., free text entry using a keyboard, selecting menu items, check boxes, option boxes, etc.).

[0034] The systems and methods may be described herein in terms of functional block components, screenshots, option selections, and various process steps. It should be appreciated that such functional blocks may be realized by a number of hardware and / or software components configured to perform specific functions. For example, the systems may use various integrated circuit components, such as memory elements, processing elements, logic elements, look-up tables, etc., which may perform various functions under the control of one or more microprocessors or other control devices. Similarly, the software elements of the systems may be implemented in any programming or scripting language (e.g., C, C++, Macromedia Cold Fusion, Microsoft Active Server Pages, Java, COBOL, Assembler, PERL, Visual Basic, SQL). Stored Procedures may be implemented using Extensible Markup Language (XML), and various algorithms may be implemented using any combination of data structures, objects, processes, routines, or other programming elements. Furthermore, it should be noted that the system may use several conventional techniques for data transmission, signaling, data processing, network control, etc. Still further, the system may be used to detect or avoid security issues using client-side scripting languages ​​(e.g., JavaScript, VBScript, etc.). For a basic introduction to cryptography and network security, see any of the following references: (1) "Applied Cryptography: Protocols, Algorithms, and Source Code In C" by Bruce Schneier, published by John Wiley & Sons (2nd ed., 1995); (2) "Java Cryptography" by Jonathan Knudson, published by O'Reilly & Associates (1998); (3) "Cryptography & Network Security: Principles & Practice" by William Stallings, published by Prentice Hall; all of which are hereby incorporated by reference.

[0035] As used herein, the terms "end user," "consumer," "customer," "client," "treating physician," "hospital," or "business" may be used interchangeably, and each shall mean any person, entity, machine, hardware, software, or business. Each participant is equipped with a computing device to exchange information with the system and to facilitate online data access and entry. Customers have computing units in the form of personal computers, although other types of computing units may be used, including laptops, notebooks, handheld computers, set-top boxes, cellular phones, touch-tone phones, and the like. Owners / operators of the systems and methods of the present invention have computing units implemented in the form of computer servers, although other implementations by systems including computing centers depicted as mainframe computers, minicomputers, PC servers, networks of computers co-located in different geographic locations, and the like, are also contemplated. Furthermore, the present system contemplates the use, sale, or distribution of any goods, services, or information through any network having similar functionality as described herein.

[0036] In one exemplary embodiment, each client customer may be given an "account" or "account number." As used herein, an account or account number may include any device, code, number, letter, symbol, digital certificate, smart chip, digital signal, analog signal, biometric, or other identifier / indicia (e.g., one or more of an authorization / access code, personal identification number (PIN), internet code, other identification code, etc.) that is suitably configured to allow the consumer to access, interact with, or communicate with the system. The account number may be associated with a charge card, credit card, debit card, prepaid card, embossed card, or other card, as appropriate. The information may be located on or tied to a card, smart card, magnetic stripe card, bar code card, transponder, radio frequency card, or associated account. The system may comprise or interface with any of the foregoing cards or devices or fobs having transponders and RFID readers in RF communication with the fob. While the system may comprise a fob embodiment, the invention is not so limited. Indeed, the system may comprise any device having a transponder configured to communicate with an RFID reader via RF communication. Exemplary devices may include, for example, a key ring, tag, card, cell phone, watch, or any such form of device capable of displaying for interrogation. Additionally, the systems, computing units, or devices described herein may comprise "pervasive computing devices," which may comprise previously non-computerized devices with attached computing units. The account number may be distributed and stored in any form of plastic, electronic, magnetic, radio frequency, wireless, audio and / or optical device that is capable of transmitting or downloading data from itself to a second device.

[0037] As will be appreciated by those skilled in the art, the system may be embodied as a customization of an existing system, an add-on product, upgraded software, a standalone system, a distributed system, a method, a data processing system, a device for data processing, and / or a computer program product. Accordingly, the system may take the form of an entirely software embodiment, an entirely hardware embodiment, or an embodiment combining both software and hardware aspects. Furthermore, the system may take the form of a computer program product on a computer-readable recording medium having computer-readable program code means embodied in the recording medium. Any suitable computer-readable recording medium may be utilized, including hard disks, CD-ROMs, optical storage devices, magnetic storage devices, and the like.

[0038] The present systems and methods are described herein with reference to screenshots, block diagrams, and flowchart illustrations of methods, apparatus (e.g., systems), and computer program products according to various embodiments. It will be understood that each functional block of the block diagrams and flowchart illustrations, and combinations of functional blocks in each block diagram and flowchart illustration, can be implemented by computer program instructions.

[0039] Referring now to Figures 2-25, the illustrated process flows and screenshots are merely exemplary and are not intended to limit the scope of the invention as described herein. For example, the steps listed in either the method or process descriptions may be performed in any order and are not limited to the order shown. It will be appreciated that the following description will make appropriate reference to the steps and user interface elements shown in Figures 2-25 as well as various system components as described above with reference to Figure 1.

[0040] These computer program instructions can be loaded into a general purpose computer, special purpose computer, or other programmable data processing apparatus to produce a machine, where the instructions executing on the computer or other programmable data processing apparatus create means for performing the functions identified in the flowchart blocks. These computer program instructions can also be stored in a computer-readable memory that can direct the computer or other programmable data processing apparatus to function in a particular manner, where the instructions stored in the computer-readable memory produce a product comprising instruction means for performing the functions identified in the flowchart blocks. The computer program instructions can also be loaded into a computer or other programmable data processing apparatus to cause a series of operational steps to be performed on the computer or other programmable apparatus, resulting in a computer-implemented process, where the instructions executing on the computer or other programmable apparatus provide the steps for performing the functions identified in the flowchart blocks.

[0041] Accordingly, the functional blocks in the block diagrams and flowchart diagrams represent combinations of means for performing a particular function, combinations of steps for performing a particular function, and program instruction means for performing a particular function. It will also be understood that each functional block of the block diagrams and flowchart diagrams, and combinations of functional blocks in the block diagrams and flowchart diagrams, can be implemented either by a special-purpose hardware-based computer system that performs the particular function or step, or by an appropriate combination of special-purpose hardware and computer instructions. Furthermore, the process flow diagrams and descriptions thereof may refer to user windows, web pages, websites, web forms, prompts, and the like. Those skilled in the art will recognize that the illustrated steps described herein can be included in several configurations, including the use of windows, web pages, web forms, pop-up windows, prompts, and the like. It should further be appreciated that multiple steps as illustrated and described may be combined into a single web page and / or window, but have been expanded for simplicity. In other cases, steps illustrated and described as a single process step may be divided into multiple web pages and / or windows, but have been combined for simplicity.

[0042] Advantages, other benefits, and solutions to problems are described herein with respect to specific embodiments. However, the advantages, benefits, solutions to the problems, and any elements that may provide or make more apparent any resulting advantages, benefits, or solutions, should not be construed as critical, necessary, or essential features or elements of any or all of the claims of the present invention. Accordingly, the scope of the present invention should not be limited by anything other than the appended claims, and in the claims, any reference to an element in the singular is intended to mean "one and only one," but "one or more," unless expressly stated as "one and only one." All structural, chemical, and functional equivalents to the elements of the above exemplary embodiments that are known to those skilled in the art are expressly incorporated herein by reference and are intended to be encompassed by the claims of the present invention. Furthermore, it is not necessary for a device or method to address each and every problem the present invention seeks to solve. Furthermore, no element, component, or method step in this disclosure is intended to be made available to the public regardless of whether that element, component, or method step is expressly recited in a claim. No element in a claim herein is intended to be available under U.S. Patent Law (35 U.S.C. 1995 / 010029) unless that element is expressly recited using the phrase "means for." The present invention is not to be construed pursuant to the provisions of Section 112, sixth paragraph of the present application. As used herein, the terms "comprises," "comprising," or any other variation thereof, are intended to be non-exclusive inclusions, and a process, method, article, or apparatus that includes a list of elements does not include only those elements, but may include other elements not expressly listed or that are not inherent in such process, method, article, or apparatus. Furthermore, no element described herein is necessary for the practice of the invention unless expressly described as "essential" or "critical."

[0043] 1 is a block diagram of an exemplary embodiment of a system 10 for determining individualized medical interventions for specific disease states using molecular profiling of patient biological samples. System 10 includes a user interface 12, a host server 14 with a processor 16 for processing data, memory 18 coupled to the processor, an application program 20 stored within memory 18 and accessible to processor 16 for directing the processing of data by processor 16, a number of internal databases 22 and external databases 24, and an interface 26 to a wired or wireless communication network (e.g., the Internet). System 10 may also include an input digitizer 28 coupled to processor 16 for inputting digital data from data received from user interface 12.

[0044] The user interface 12 includes an input device 30 for inputting data into the system 10 and a display 32 for displaying information derived from the data processed by the processor 16. The user interface 12 may also include a printer 34 for printing information derived from the data processed by the processor 16 (e.g., a patient report that may include test results for a target and suggested medications based on the test results).

[0045] Internal databases 22 may include, but are not limited to, patient biological sample information / specimen information and tracking, clinical data, patient data, patient tracking, file management, research protocols, patient molecular profiling test results, and billing information and tracking. External databases 24 may include, but are not limited to, drug libraries, gene libraries, disease libraries, and public and private databases (e.g., UniGene, OMIM, GO, TIGR, GenBank, KEGG, and Biocarta).

[0046] Various methods may be used in accordance with system 10. FIG. 2 shows a flowchart of an exemplary embodiment of a method 50 for utilizing molecular profiling of a patient's biological specimen to determine a non-disease-specific, personalized medical intervention for a particular disease state. To determine a medical intervention for a particular disease state using molecular profiling independent of disease series diagnosis (i.e., not limited to a single disease), at least one test is performed on at least one target from an affected patient's biological sample in step 52. A target is defined as any molecular finding that can be obtained from a molecular test. For example, a target may include one or more genes, one or more gene expression proteins, one or more molecular mechanisms, and / or combinations thereof. Tests for detecting such targets may include, but are not limited to, immunohistochemical (IHC) analysis, microarray analysis (e.g., comparative genomic hybridization (CGH) microarrays, single nucleotide polymorphism (SNP) microarrays, fluorescent in situ hybridization (FISH), in situ hybridization (ISH), and proteomics arrays), and other molecular tests known to those skilled in the art. Thus, one or more of the following may be performed: IHC analysis in step 54, microanalysis in step 56, and other molecular tests known to those skilled in the art in step 58.

[0047] Biological samples are obtained from affected patients by taking a tumor biopsy, or by performing minimally invasive surgery, or if no recent tumor is available, by obtaining a patient's blood sample or a sample of any other biological fluid (such as a cellular extract, nuclear extract, cell lysate, or biological product or substance of biological origin (e.g., excreta, blood, serum, plasma, urine, sputum, tears, stool, saliva, membrane extract, etc.)).

[0048] In step 60, a determination is made as to whether one or more of the targets tested in step 52 exhibit altered expression compared to a normal reference for the particular target. In one exemplary method of the present invention, IHC analysis can be performed in step 54, and a determination is made in step 64 as to whether any targets from the IHC analysis exhibit altered expression by determining whether 30% or more of the biological sample cells stain +2 or higher for the particular target. Because staining results can vary depending on the technician performing the test and the type of target being tested, those skilled in the art will understand that staining +1 or higher may indicate an altered expression. In another exemplary embodiment of the present invention, microarray analysis can be performed in step 56, and a determination is made in step 66 as to whether any targets from the microarray analysis exhibit altered expression by identifying which targets are up-regulated or down-regulated by determining what fold change in expression for the particular target compared to the normal tissue of reference origin is significant at p<0.001. Altered expression can also be evidenced by the absence of one or more genes, gene expression proteins, molecular mechanisms, or other molecular findings.

[0049] After determining which targets show altered expression in step 60, at least one non-disease specific agent that interacts with each altered expression target is identified in step 70. The agent can be any drug or compound that has a therapeutic effect. A non-disease specific agent is a therapeutic drug or compound that can interact with a target from a patient's biological sample that showed altered expression and that has not previously been associated with the treatment of the disease for which the patient was diagnosed. Some non-disease specific agents that have been found to interact with specific targets found in various cancer patients are listed in Table 1 below.

[0050] [Table 1] Finally, in step 80, a patient profile report may be provided that includes the patient's test results for various targets and any suggested treatments based on those results. An exemplary patient profile report 100 is shown in Figures 3A-3D. The patient profile report 100 shown in Figure 3A identifies the targets tested 102, those tested targets 104 that showed significant changes in expression, and non-disease-specific drugs 106 proposed to interact with those targets. The patient profile report 100 shown in Figure 3B identifies the results of immunohistochemical analysis 108 for a particular gene expression protein 110 and whether the gene expression protein is a molecular target 112 by determining whether 30% or more of the tumor cells stained +2 or higher. The report 100 also identifies immunohistochemical tests 114 that were not performed. The patient profile report 100 shown in Figure 3C identifies the genes analyzed using microarray analysis 116 and whether the genes were under- or overexpressed compared to a reference 118. Finally, the patient profile report 100 shown in FIG. 3D identifies the patient's medical history 120 and specimens 122 submitted by the patient.

[0051] 4 shows a flowchart of an exemplary embodiment of a method 200 for identifying a drug therapy / drug capable of interacting with a target. In step 202, a molecular target that shows altered expression in a number of affected individuals is identified. Next, in step 204, the drug therapy / drug is administered to the affected individuals. In step 206, any changes in the molecular target identified in step 202 are identified after administration of the drug therapy / drug to determine whether the drug therapy / drug administered in step 204 interacts with the molecular target identified in step 202. If it is determined that the drug therapy / drug administered in step 204 interacts with the molecular target identified in step 202, the drug therapy / drug may be approved for treating patients who show altered expression of the identified molecular target instead of approving the drug therapy / drug for a specific disease.

[0052] Figures 5-14 are flowcharts and diagrams illustrating various parts of the information-based personalized medicine discovery system and method of the present invention. Figure 5 is a diagram illustrating an exemplary clinical decision support system of the information-based personalized medicine discovery system and method of the present invention. Data obtained through clinical research and clinical care (e.g., clinical trial data, biomedical data / molecular imaging data, genomics / proteomics / chemical libraries / literature / expert curation, biospecimen tracking / LIMS, family history / environmental records, and clinical data) are collected and stored as databases and data marts in a data warehouse. Figure 6 is a diagram illustrating the flow of information through the clinical decision support system of the information-based personalized medicine discovery system and method of the present invention using web services. Users interact with the system by entering data into the system via form-based entry / uploading of datasets, formulating queries, running data analysis jobs, and retrieving and evaluating the display of output data. The data warehouse in a web-based system is where data is extracted, transformed, and loaded from various database systems. The data warehouse is also where common formats, mappings and transformations reside. The web-based system also includes data marts that are created based on the desired view of the data.

[0053] A flowchart of an exemplary clinical decision support system of the information-based personalized medicine discovery system and method of the present invention is shown in Figure 7. The clinical information management system includes a laboratory information management system, and the medical information contained in the data warehouse and database includes a medical information library (e.g., a drug library, a gene library, and a disease library) in addition to literature text mining. Both the information management system for a specific patient and the medical information database and medical information data warehouse are integrated in a data junction center where diagnostic information and therapeutic options can be obtained. A financial management system can also be integrated into the clinical decision support system of the information-based personalized medicine discovery system and method of the present invention.

[0054] Figure 8 shows an exemplary biospecimen tracking and management system that can be utilized as part of the information-based personalized drug discovery system and method of the present invention. Figure 8 shows two host medical centers that send specimens to tissue / blood banks. The specimens may undergo laboratory analysis before shipping. Research may be performed on the samples via microarray, genotyping, and proteomic analysis. This information may be redistributed to the tissue / blood banks. Figure 9 shows a flowchart of an exemplary biospecimen tracking and management system that can be utilized with the information-based personalized drug discovery system and method of the present invention. The host hospital obtains samples from patients and then ships the patient samples to a molecular profiling laboratory that may also perform RNA and DNA isolation and analysis.

[0055] A diagram illustrating a method for maintaining a clinical standardized vocabulary for use with the information-based personalized medicine discovery system and method of the present invention is shown in Figure 10. Figure 10 illustrates how physician findings and patient information related to one physician's patient can be made accessible to other physicians so that they can utilize the data in making diagnostic and therapeutic decisions for that patient.

[0056] Figure 11 shows a schematic diagram of an exemplary microarray gene expression database that can be used as part of the personalized drug discovery system and method based on the information of the present invention. The microarray gene expression database includes both external and internal databases accessible via a web-based system. External databases may include, but are not limited to, UniGene, GO, TIGR, GenBank, and KEGG. Internal databases may include, but are not limited to, tissue tracking, LIMS, clinical data, and patient tracking. Figure 12 shows a diagram of an exemplary microarray gene expression database data warehouse that can be used as part of the personalized drug discovery system and method based on the information of the present invention. Laboratory data, clinical data, and patient data can all be stored within the microarray gene expression database data warehouse, which can then be accessed via public / private release and utilized by data analysis tools.

[0057] Another schematic diagram showing the flow of information through the information-based personalized medicine discovery system and method of the present invention is shown in Figure 13. Similar to Figure 7, this schematic diagram includes clinical information management, medical and literature information management, and financial management of the information-based personalized medicine discovery system and method of the present invention. Figure 14 is a schematic diagram showing an exemplary network of the information-based personalized medicine discovery system and method of the present invention. Patients, medical practitioners, host hospitals, and research institutes all share and exchange various information in order to provide patients with suggested treatments or drugs based on the various targets identified.

[0058] Figures 15-25 are computer screen printouts related to various portions of the personalized medicine discovery system and method based on the information shown in Figures 5-14. Figures 15 and 16 show computer screens where physician and insurance company information is entered on behalf of a client. Figures 17-19 show computer screens where information for ordering analyses and tests on patient samples can be entered.

[0059] Figure 20 is a computer screen showing the results of a microarray analysis of specific genes tested using a patient sample. This information and computer screen is similar to the information detailed in the patient profile report shown in Figure 3C. Figure 22 is a computer screen showing the immunohistochemistry test results for a specific patient for various genes. This information is similar to the information contained in the patient profile report shown in Figure 3B.

[0060] FIG. 21 is a computer screen showing options for locating a particular patient, ordering tests and / or publishing patient reports on test results, and tracking current cases / patients.

[0061] Figure 23 is a computer screen outlining some of the steps for generating a patient profile report such as that shown in Figures 3A through 3D. Figure 24 shows a computer screen for ordering immunohistochemistry testing on patient samples, and Figure 25 shows a computer screen for entering information regarding primary tumor site for microarray analysis. It will be understood by those skilled in the art that any number and type of computer screen can be used to enter the information necessary to utilize the information-based personalized drug discovery system and method of the present invention, and to obtain the information generated by utilizing the information-based personalized drug discovery system and method of the present invention.

[0062] It will also be understood that the foregoing description is of preferred exemplary embodiments of the present invention, and that the present invention is not limited to the specific forms shown or described herein. Various modifications can be made in the design, arrangement, and types of elements disclosed herein and in the process of utilizing the present invention without departing from the scope of the present invention as set forth in the appended claims.

Claims

1. 1. A method for determining a medical intervention for a disease state, comprising: conducting at least one of testing for the gene and testing for the gene expressed protein from a biological sample from the affected individual; Determining which genes and / or gene-expressed proteins show altered expression compared to the reference; and The method includes identifying a drug therapy that is not limited to a single disease and that is used to interact with at least one of the genes and / or gene-expressed proteins that exhibit altered expression.

2. 2. The method of claim 1, wherein the step of identifying drug therapies used to interact with at least one of the genes and / or gene-expressed proteins that exhibited altered expression comprises identifying drug therapies from at least one of automated review of large literature databases and data obtained from clinical trials.

3. 2. The method of claim 1, wherein the step of performing at least one of testing for genes and testing for gene-expressed proteins comprises performing at least one of immunohistochemical (IHC) analysis and microarray analysis.

4. 4. The method of claim 3, wherein the step of performing microarray analysis comprises performing the analysis using at least one of an expression microarray, a comparative genomic hybridization (CGH) microarray, a single nucleotide polymorphism (SNP) microarray, fluorescent in situ hybridization (FISH), in situ hybridization (ISH), and a proteomics array.

5. 4. The method of claim 3, wherein the step of performing IHC analysis comprises performing IHC analysis for gene expression proteins including at least one of Her2 / Neu, ER, PR, c-kit, EGFR, MLH1, MSH2, CD20, p53, cyclin D1, bcl2, COX-2, androgen receptor, CD52, PDGFR, AR, CD25, and VEGF.

6. The step of performing microarray analysis includes the steps of: BCL2, HIF1A, AR, ESR1, PDGFRA, KIT, PDGFRB, CDW52, ZAP70, PGR, SPARC, GART, GSTP1, NFKBIA, MSH2, TXNRD1, HDAC1, PDGFC, PTEN, CD33, TYMS, RXRB , ADA, TNF, ERCC3, RAF1, VEGF, TOP1, TOP2A, BRCA2, TK1, FOLR2, TOP2B, MLH1, IL2RA, DNMT1, HSPCA, ERBR2, ERBB2, SSTR1, VHL, VDR, PTGS2, POLA, CES2, EGFR, OGFR, ASNS, N 4. The method of claim 3, comprising a step of performing microarray analysis for genes including at least one of FKB2, RARA, MS4A1, DCK, DNMT3A, EREG, epiregulin, FOLR1, GNRH1, GNRHR1, FSHB, FSHR, FSHPRH1, folate receptor, HGF, HIG1, IL13RA1, LTB, ODC1, PPARG, PPARGC1, VHL, lymphotoxin beta receptor, Myc, TOP2B topoisomerase II, TOPO2B, TXN, VEGFC, ACE2, ADH1C, ADH4, AGT, AREG, CA2, CDK2, caveolin, and NFKB1.

7. The method of claim 3, wherein the step of performing at least one of testing for genes and testing for gene-expressed proteins from a biological sample of the diseased individual comprises performing immunohistochemical analysis on the tumor, and the step of determining which genes and / or gene-expressed proteins show altered expression compared to a reference comprises determining whether 30% or more of the tumor cells stain +2 or higher for a particular gene-expressed protein.

8. 4. The method of claim 3, wherein the step of performing at least one of testing genes and testing gene-expressed proteins from a biological sample of the diseased individual comprises performing microarray analysis on the tumor, and determining which genes and / or gene-expressed proteins show altered expression compared to the reference comprises identifying which genes are up-regulated or down-regulated by determining what fold change in expression for a particular gene compared to normal tissue of reference origin is significant at p<0.

001.

9. 10. The method of claim 1, further comprising providing a patient profile report identifying altered expression for the genes and / or gene-expressed proteins, along with potential drug therapies for interactions with each of the genes and / or gene-expressed proteins that show altered expression.

10. 1. A method for identifying a drug therapy capable of interacting with a molecular target, comprising: identifying molecular targets in a plurality of affected individuals that exhibit altered expression when compared to a normal reference; administering drug therapy to said affected individual exhibiting altered expression of said molecular target; and measuring any changes in said molecular target in said affected individual following said drug therapy. A method comprising:

11. 11. The method of claim 10, wherein the step of identifying molecular targets in a plurality of diseased individuals that exhibit altered expression when compared to a normal reference comprises performing at least one of testing for genes and testing for gene-expressed proteins from biological samples of the diseased individuals, wherein the testing comprises at least one of immunohistochemical (IHC) analysis and microarray analysis.

12. 1. A system for determining personalized medical intervention for a disease state, comprising: a host server; a user interface for accessing the host server to access and input data; a processor for processing the input data; the processed data, and i) instructions to access molecular profiles obtained from the patient's biological specimen; ii) instructions for determining whether at least one or more of the genes, gene expression proteins, molecular mechanisms, and other molecular findings obtained from the molecular profile exhibit altered expression compared to a normal reference; and iii) instructions for accessing a medication database to identify one or more medications that interact with the at least one gene that exhibits altered expression, gene expression proteins, molecular mechanisms, and other molecular findings; a memory coupled to the processor for storing: display means for displaying said at least one gene exhibiting altered expression, gene expressed proteins, molecular mechanisms and other molecular findings, and said drug therapy interacting therewith; A system comprising:

13. The system of claim 12 , wherein the molecular profile comprises at least one of an immunohistochemical (IHC) analysis and a microarray analysis.

14. 14. The system of claim 13, wherein the microarray analysis comprises at least one of an expression microarray, a comparative genomic hybridization (CGH) microarray, a single nucleotide polymorphism (SNP) microarray, a fluorescent in situ hybridization (FISH), a fluorescent in situ hybridization (ISH), and a proteomics array.

15. 14. The system of claim 13, wherein the IHC analysis comprises IHC analysis for gene expression proteins including at least one of Her2 / Neu, ER, PR, c-kit, EGFR, MLH1, MSH2, CD20, p53, cyclin D1, bcl2, COX-2, androgen receptor, CD52, PDGFR, AR, CD25, and VEGF.

16. The microarray analysis revealed that BCL2, HIF1A, AR, ESR1, PDGFRA, KIT, PDGFRB, CDW52, ZAP70, PGR, SPARC, GART, GSTP1, NFKBIA, MSH2, TXNRD1, HDAC1, PDGFC, PTEN, CD33, TYMS, RXRB, AD A, TNF, ERCC3, RAF1, VEGF, TOP1, TOP2A, BRCA2, TK1, FOLR2, TOP2B, MLH1, IL2RA, DN MT1, HSPCA, ERBR2, ERBB2, SSTR1, VHL, VDR, PTGS2, POLA, CES2, EGFR, OGFR, ASNS, NF KB2, RARA, MS4A1, DCK, DNMT3A, EREG, epiregulin, FOLR1, GNRH1, GNRHR1, FSHB, FSHR, FSHPRH1, folate receptor, HGF, HIG1, IL13RA1, LTB, ODC1, PPARG, PPARGC1, VHL, lymphotoxin beta receptor, Myc, TOP2B topoisomerase II, TOPO2B, TXN, VEGFC, ACE2, ADH1C, ADH4, AGT, AREG, CA2, CDK2, caveolin, and NFKB1.

17. 14. The system of claim 13, wherein the molecular profile comprises immunohistochemical analysis of the tumor, and wherein the instructions for determining whether at least one of genes, gene expression proteins, molecular mechanisms, and other molecular findings obtained from the molecular profile exhibit altered expression compared to a reference comprise instructions for determining whether 30% or more of the tumor cells stain +2 or higher for a particular gene expression protein.

18. 14. The system of claim 13, wherein the molecular profile comprises a microarray analysis of the tumor, and wherein the instructions for determining whether at least one or more of the genes, gene-expressed proteins, molecular mechanisms, and other molecular findings obtained from the molecular profile show altered expression compared to a normal reference comprise instructions for identifying which genes are up-regulated or down-regulated by determining what fold change in expression for a particular gene compared to the normal tissue of reference origin is significant at p<0.

001.

19. 13. The system of claim 12, wherein the display means includes a printed patient profile report.

20. 13. The method of claim 12, wherein the instructions for accessing a medication database to identify one or more medications that interact with the at least one gene, gene expression protein, molecular mechanism, and other molecular findings that exhibited altered expression comprise instructions for performing an automated review of a large literature database containing literature correlating genes and / or gene expression proteins with medication interactions.

21. 1. A method for determining a medical intervention for a disease state, comprising: conducting at least one molecular test on at least one target from a biological sample of the diseased individual; determining whether the at least one target exhibits altered expression compared to a reference; and identifying at least one non-disease specific agent that interacts with said at least one target that exhibits altered expression. A method comprising:

22. 22. The method of claim 21 , wherein identifying at least one non-disease specific agent that interacts with the at least one target comprises identifying drug therapies from at least one of automated review of large literature databases and data obtained from clinical trials.

23. 22. The method of claim 21, wherein said step of performing at least one molecular test on at least one target comprises performing at least one of immunohistochemical (IHC) analysis and microarray analysis.

24. 24. The method of claim 23, wherein the step of performing microarray analysis comprises performing the analysis using at least one of an expression microarray, a comparative genomic hybridization (CGH) microarray, a single nucleotide polymorphism (SNP) microarray, fluorescent in situ hybridization (FISH) and fluorescent in situ hybridization (ISH), and a proteomics array.

25. 24. The method of claim 23, wherein said step of performing at least one IHC analysis comprises performing IHC analysis for gene expressed proteins comprising at least one of Her2 / Neu, ER, PR, c-kit, EGFR, MLH1, MSH2, CD20, p53, cyclin D1, bcl2, COX-2, androgen receptor, CD52, PDGFR, AR, CD25, and VEGF.

26. The step of performing at least one microarray analysis includes the step of analyzing at least one of BCL2, HIF1A, AR, ESR1, PDGFRA, KIT, PDGFRB, CDW52, ZAP70, PGR, SPARC, GART, GSTP1, NFKBIA, MSH2, TXNRD1, HDAC1, PDGFC, PTEN, CD33, TYM S, RXRB, ADA, TNF, ERCC3, RAF1, VEGF, TOP1, TOP2A, BRCA2, TK1, FOLR2, TOP2B, MLH1, I L2RA, DNMT1, HSPCA, ERBR2, ERBB2, SSTR1, VHL, VDR, PTGS2, POLA, CES2, EGFR, OGFR, AS 24. The method of claim 23, comprising performing microarray analysis for genes including at least one of NS, NFKB2, RARA, MS4A1, DCK, DNMT3A, EREG, epiregulin, FOLR1, GNRH1, GNRHR1, FSHB, FSHR, FSHPRH1, folate receptor, HGF, HIG1, IL13RA1, LTB, ODC1, PPARG, PPARGC1, VHL, lymphotoxin beta receptor, Myc, TOP2B topoisomerase II, TOPO2B, TXN, VEGFC, ACE2, ADH1C, ADH4, AGT, AREG, CA2, CDK2, caveolin, and NFKB1.

27. 24. The method of claim 23, wherein the step of performing at least one molecular test on at least one target from a biological sample of the diseased individual comprises performing immunohistochemical analysis on the tumor, and the step of determining whether the at least one target exhibits altered expression compared to a reference comprises determining whether 30% or more of the tumor cells stain +2 or higher for a particular gene expression protein.

28. 24. The method of claim 23, wherein the step of performing at least one molecular test on at least one target from a biological sample of the diseased individual comprises performing microarray analysis on the tumor, and the step of determining whether the at least one target exhibits altered expression compared to a reference comprises identifying which genes are up-regulated or down-regulated by determining what fold change in expression for a particular gene compared to normal tissue of reference origin is significant at p<0.

001.

29. 22. The method of claim 21, further comprising providing a patient profile report including the patient's test results for various targets and any suggested treatments based on those results.

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