U.S. Patent No. 9,372,193
`IPR Petition
`
`Filed on behalf of Foundation Medicine, Inc.
`
`By: David L. Cavanaugh, Reg. No. 36,476 (Lead Counsel)
`Wilmer Cutler Pickering Hale and Dorr LLP
`1875 Pennsylvania Avenue, NW
`Washington, DC 20006
`Tel: (202) 663-6000
`Email: David.Cavanaugh@wilmerhale.com
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________________________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________________________________________
`
`Foundation Medicine, Inc.
`Petitioner
`
`v.
`
`Caris MPI, Inc.
`Patent Owner
`
`U.S. Patent No. 9,372,193
`
`Case IPR2019-00170
`____________________________________________
`
`PETITION FOR INTER PARTES REVIEW
`OF U.S. PATENT NO. 9,372,193
`
`
`
`

`

`U.S. Patent No. 9,372,193
`IPR Petition
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`Page
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`TABLE OF CONTENTS
`
`Introduction ...................................................................................................... 1
`I.
`II. Mandatory Notices ........................................................................................... 1
`A.
`Real Party-in-Interest ............................................................................ 1
`B.
`Related Matters ...................................................................................... 2
`C.
`Counsel .................................................................................................. 2
`D.
`Service Information ............................................................................... 2
`III. Certification of Grounds for Standing ............................................................. 3
`IV. Overview of Challenge and Relief Requested ................................................. 3
`A. Grounds of Challenge ............................................................................ 3
`B.
`Relief Requested .................................................................................... 4
`V. Overview of the Technology ........................................................................... 4
`A.
`Personalized Medicine .......................................................................... 5
`B.
`Targeted Therapies ................................................................................ 5
`C.
`Devices for Determining Molecular Profiles ........................................ 6
`D.
`Exemplary Databases and Software ...................................................... 7
`1.
`Cancer Microarray Databases ..................................................... 7
`2.
`Software Systems ........................................................................ 8
`3.
`Agents ......................................................................................... 9
`VI. The ’193 Patent ................................................................................................ 9
`Claims .................................................................................................. 10
`A.
`Summary of the Specification ............................................................. 12
`B.
`Summary of the File History ............................................................... 13
`C.
`VII. Level of Ordinary Skill in the Art ................................................................. 15
`VIII. Claim Construction ........................................................................................ 16
`IX. Overview of the Primary Prior Art References ............................................. 16
`A.
`Lu ......................................................................................................... 16
`B.
`Illumina ............................................................................................... 20
`C. Muraca ................................................................................................. 21
`
`Databases of Molecular Targets and Corresponding Therapeutic
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`i
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`U.S. Patent No. 9,372,193
`IPR Petition
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`Ground 2: Claims 2 and 3 Are Obvious over Lu, Illumina, and Muraca
`
`Ground 3: Claims 7 and 11 Are Obvious over Lu, Illumina, and
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`D. McDoniels-Silvers ............................................................................... 22
`X. Detailed Grounds for Challenge .................................................................... 23
`A. Ground 1: Claims 1-14 Are Obvious Over Lu in View of Illumina ... 23
`1.
`Claim 1 ...................................................................................... 23
`2.
`Claims 2-14 ............................................................................... 37
`3. Motivation to Combine ............................................................. 47
`4.
`Reasonable Expectation of Success .......................................... 54
` ............................................................................................................. 57
`1.
`Claims 2 and 3 ........................................................................... 57
`2. Motivation to Combine ............................................................. 60
`3.
`Reasonable Expectation of Success .......................................... 62
`McDoniels-Silvers ............................................................................... 63
`1.
`Claims 7 and 11 ......................................................................... 63
`2. Motivation to Combine ............................................................. 64
`3.
`Reasonable Expectation of Success .......................................... 66
`D.
`Secondary Considerations ................................................................... 67
`XI. Conclusion ..................................................................................................... 67
`
`B.
`
`C.
`
`
`
`ii
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`

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`I.
`
`INTRODUCTION
`Pursuant to 35 U.S.C. § 311 and 37 C.F.R. Part 42, Foundation Medicine,
`
`U.S. Patent No. 9,372,193
`IPR Petition
`
`Inc. (“Petitioner”) requests inter partes review of claims 1-14 of U.S. Patent No.
`
`9,372,193 (“the ’193 patent”) (Ex. 1001), which is assigned to Caris MPI, Inc.
`
`(“Patent Owner”). This Petition demonstrates by a preponderance of the evidence
`
`that it is more likely than not that claims 1-14 of the ’193 patent are unpatentable
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`over the prior art. Accordingly, IPR should be instituted, and the challenged
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`claims found unpatentable and canceled.
`
`The ’193 patent is directed to a system for generating a report that identifies
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`potential cancer therapeutics that could be effective based on an individual’s
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`molecular profile. Ex. 1001, ’193 patent, claim 1. The ’193 patent recites nothing
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`more than a generic approach for using known molecular profiling technologies to
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`match individuals possessing changes to certain genes or proteins known to be
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`associated with cancer, with existing therapies that were known in the prior art to
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`be effective against these targets. As discussed in detail below, a person of
`
`ordinary skill in the art (“POSA”) would have found the claims of the ’193 patent
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`obvious in view of the state of the art as of the applicable priority date.
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`II. MANDATORY NOTICES
`A. Real Party-in-Interest
`Petitioner Foundation Medicine, Inc. and Roche Holdings, Inc., Roche
`
`Finance Ltd., and Roche Holding Ltd. are real parties-in-interest.
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`1
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`

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`B. Related Matters
`Patent Owner has asserted the ’193 patent against Petitioner in the U.S.
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`U.S. Patent No. 9,372,193
`IPR Petition
`
`District Court for the District of Massachusetts, Civil Action No. 1:17-cv-12194-
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`MLW. Petitioner filed a motion to dismiss, which remains pending. No initial
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`scheduling conference has been held and the parties have not served any discovery.
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`Additionally, Petitioner is filing IPR petitions on U.S. Patent Nos.
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`8,880,350; 9,383,365; 9,092,392; and 9,292,660, all of which have also been
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`asserted by Patent Owner in the same litigation. Petitioner respectfully requests
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`that the same Panel be assigned to each of Petitioner’s IPR petitions.
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`C. Counsel
`
`Petitioner designates the following counsel:
`
`Lead Counsel:
`
`David Cavanaugh (Reg. No. 36,476)
`
`Back-up Counsel:
`
`William Kim (Reg. No. 53,127)
`
`Kevin Yurkerwich (Reg. No. 71,195)
`
`D.
`
`Service Information
`
`Email:
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`david.cavanaugh@wilmerhale.com;
`
`william.kim@wilmerhale.com;
`
`kevin.yurkerwich@wilmerhale.com
`
`2
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`Post and Hand Delivery: Wilmer Cutler Pickering Hale and Dorr LLP
`
`U.S. Patent No. 9,372,193
`IPR Petition
`
`1875 Pennsylvania Ave. NW, Washington, DC 20006
`
`Tel: (202) 663-6000; Facsimile: (202) 663-6363
`
`Petitioner consents to email service.
`
`III. CERTIFICATION OF GROUNDS FOR STANDING
`Petitioner certifies pursuant to Rule 42.104(a) that the ’193 patent is
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`available for IPR and that Petitioner is not barred or estopped from requesting an
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`IPR challenging the patent claims on the grounds identified in this Petition.
`
`IV. OVERVIEW OF CHALLENGE AND RELIEF REQUESTED
`A. Grounds of Challenge
`Pursuant to Rules 42.22(a)(1) and 42.104(b)(1)-(2), Petitioner challenges
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`claims 1-14 (“challenged claims”) of the ’193 patent and requests that each
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`challenged claim be canceled based on the following grounds.
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`Ground
`
`Claims
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`Basis
`
`1
`
`2
`
`3
`
`1-14
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`2-3
`
`7, 11
`
`Obvious under § 103 over Lu in view of
`Illumina
`
`Obvious under § 103 over Lu, Illumina, and
`Muraca
`
`Obvious under § 103 over Lu, Illumina, and
`McDoniels-Silvers
`
`
`The ’193 patent claims priority to U.S. Provisional Application No. 60/747,645,
`
`filed on May 18, 2006. For purposes of determining whether a publication will
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`U.S. Patent No. 9,372,193
`IPR Petition
`qualify as prior art, the earliest date to which the ’193 patent could be entitled is
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`May 18, 2006.
`
`B. Relief Requested
`Petitioner requests that the Board cancel the challenged claims because they
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`are unpatentable under pre-AIA § 103. This conclusion is further supported by the
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`Declaration of Paul Spellman, Ph.D. (“Spellman Decl.,” Ex. 1002).
`
`V. OVERVIEW OF THE TECHNOLOGY
`The term “cancer” describes a group of diseases caused by changes in an
`
`individual’s DNA and genome that can alter cell behavior, causing uncontrolled
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`growth and disease. These genomic abnormalities can take many forms—
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`including, for example, DNA mutations including nucleotide changes,
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`rearrangements, deletions, or amplifications. The product of these abnormalities
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`can be the overexpression or loss of certain genes and proteins, or altered protein
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`functionality. Ex. 1002, Spellman Decl. ¶¶ 34-36.
`
`The field of cancer genomics analyzes an individual’s tumor DNA and
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`compares it to reference DNA—typically, normal DNA. This comparison helps
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`scientists identify genomic differences that may be associated with an individual’s
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`cancer. Id. ¶¶ 37-43.
`
`By 2006, oncologists and cancer researchers routinely sought to obtain
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`molecular profiles of individuals’ cancer, and devices for doing so were
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`U.S. Patent No. 9,372,193
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`well-known. Public databases hosted information regarding associations between
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`genomic alterations and cancers, and numerous peer-reviewed articles were
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`published discussing uses of this information. Moreover, targeted therapies for
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`treating cancer—including Gleevec, Herceptin, and Tarceva—had been developed
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`based on associations of therapeutic agents with specific molecular targets. Id.
`
`¶¶ 44-63.
`
`A.
`Personalized Medicine
`Personalized medicine is the application of genomic and molecular data to,
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`among other things, focus the delivery of healthcare and medical treatments.
`
`Personalized medicine has been a goal of scientists since long before 2006. Id.
`
`¶¶ 37-43.
`
`Several federal initiatives supporting the expansion of personalized medicine
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`were launched in the 2000s. For example, the Cancer Genome Atlas Project was
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`initiated in 2005 to systematically catalog genomic mutations that cause cancer
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`using genome sequencing, other genomic analysis, and bioinformatics to help
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`scientists identify new ways to treat cancer. Id. ¶¶ 41-43.
`
`B.
`Targeted Therapies
`The term “targeted therapy” refers to cancer drugs “designed to interfere
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`with a specific molecular target (typically a protein) that is believed to have a
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`critical role in tumour growth or progression.” Ex. 1009 at 294. “The
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`U.S. Patent No. 9,372,193
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`identification of appropriate targets is based on a detailed understanding of the
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`molecular changes underlying cancer.” Id.
`
`In the early 2000s, scientists were studying the clinical management of
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`tumors and the pharmaceutical development of new anti-cancer drugs based on the
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`molecular and genomic characterization of tumors. Ex. 1002, Spellman Decl. ¶¶
`
`44-46. In the late 1990s and early 2000s, for example, the association of the
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`overexpression of certain genes with cancer—including EGFR, VEGF, and Her2
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`receptor—drove target-specific research into antibodies and small-molecule drugs
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`designed to inhibit the overproduced gene-expressed proteins unrestricted to any
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`particular cancer. Id. ¶¶ 61-63. By 2006, for many biomarkers, including the
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`genes listed in the ’193 patent, drugs targeting those specific genes were already
`
`being tested in pre-clinical and clinical trials as therapy in multiple diseases. Id.
`
`(describing exemplary clinical studies). Thus, as of 2006, the use of targeted
`
`treatments for cancer was well-established. Id. ¶¶ 44-46. For many cancer drugs,
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`including those listed in the ’193 patent, it was already known that those drugs
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`targeted certain genes. Id. ¶¶ 47-60.
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`C. Devices for Determining Molecular Profiles
`By the early 2000s, microarrays were widely-used in genomics-based
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`research to predict drug response based on gene expression profiles. Id. ¶¶ 64-66
`
`(citing Ex. 1026).
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`U.S. Patent No. 9,372,193
`IPR Petition
`Commercial microarrays with many thousands of genes on a single device
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`were widely-available as of the early 2000s. Id. (citing Ex. 1028). Daly observed
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`that “adoption of this technology is probably most advanced in the field of
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`oncology, in which molecular profiling of tumors can potentially provide better
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`characterization of tumor types, leading to better prediction of prognosis and more
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`accurate selection of therapy.” Id. (quoting Ex. 1028 at 404). The ability to screen
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`hundreds to thousands of potential targets in a single experiment allowed scientists
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`to identify new genetic and molecular profiles or signatures not previously
`
`associated with a particular disease, tissue, or cell-type. Id.
`
`D. Exemplary Databases and Software
`Cancer Microarray Databases
`1.
`By 2006, DNA microarray technology had “led to an explosion of
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`oncogenomic analyses, generating a wealth of data and uncovering the complex
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`gene expression patterns of cancer.” Id. ¶¶ 68-74 (quoting Ex. 1030 at 1). In 2004,
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`Daniel Rhodes and colleagues introduced ONCOMINE, “a cancer microarray
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`database and web-based data-mining platform,” containing “65 gene expression
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`datasets comprising nearly 48 million gene expression measurements from over
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`4700 microarray experiments” and “[d]ifferential expression analyses comparing
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`most major types of cancer with respective normal tissues.” Ex. 1030 at 1.
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`U.S. Patent No. 9,372,193
`IPR Petition
`“Based on the hypothesis that therapeutic agents are most effective in cancer
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`types in which their targets are highly expressed,” Rhodes and colleagues
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`published the ONCOMINE platform that same year “to explore the expression of
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`all known therapeutic targets in cancer, even those that are targeted in diseases
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`other than cancer.” Id. at 3; Ex. 1031. Rhodes and colleagues “hypothesized that
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`this platform may lead to novel drug target-cancer type associations, suggesting
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`novel applications of therapeutic agents currently in use” and “compiled a set of
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`148 known drug targets and their respective drugs.” Ex. 1030 at 3.
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`Other exemplary microarray databases publicly available by 2006 included
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`Oncomine 3.0 (which contained “1000+ gene expression signatures”) (Ex. 1032),
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`ArrayExpress (Ex. 1033), and The Stanford Microarray Database (Ex. 1034).
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`Ex. 1002, Spellman Decl. ¶¶ 68-74.
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`Software Systems
`2.
`By 2005, there were dozens of software systems designed for microarray
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`gene expression data analysis, including sixteen software systems specifically
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`described in a 2005 publication by Alexander Statnikov. Ex. 1002, Spellman Decl.
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`¶ 75 (citing Ex. 1035 (identifying software systems)).
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`U.S. Patent No. 9,372,193
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`Databases of Molecular Targets and Corresponding
`Therapeutic Agents
`In the early 2000s, it was known that certain proteins and nucleic acids “play
`
`3.
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`key roles in disease processes” and were therefore “explored as therapeutic targets
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`for drug development.” Id. ¶¶ 76-80 (quoting Ex. 1036 at 2236)).
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`In 2002, the Therapeutic Target Database (“TTD”) was released to provide a
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`“publicly accessible database that provides comprehensive information” about
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`targets to relevant communities interested in biomedical and pharmaceutical
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`research. Id. ¶ 78 (quoting Ex. 1037 at 412).
`
`In 2004, bioinformatic scientists published a database of known
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`therapeutically relevant multiple pathways (“TRMPs”) “[t]o facilitate mechanistic
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`study of drug actions and a more comprehensive understanding [of] the
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`relationship between different targets of the same disease.” Id. ¶ 79 (quoting
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`Ex. 1036 at 2236).
`
`VI. THE ’193 PATENT
`The ’193 patent is directed to a system for generating a report that identifies
`
`potential cancer therapeutics that could be effective based on an individual’s
`
`molecular profile. Ex. 1001, ’193 patent, claim 1.
`
`The ’193 patent does not disclose a new or improved method for performing
`
`molecular profiling to identify genomic alterations that may be associated with
`
`particular cancers, nor does it identify or disclose any new correlation between a
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`U.S. Patent No. 9,372,193
`IPR Petition
`specific cancer, gene, or drug. The ’193 patent also does not disclose any new
`
`technology relating to computers, software, or databases. Further, the ’193 patent
`
`does not provide any actual working examples. Instead, the ’193 patent purports to
`
`claim a generic approach for matching individuals possessing changes to certain
`
`genes or proteins associated with cancer to existing therapies that are known in the
`
`prior art to be effective against cancers exhibiting these changes. This is
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`confirmed in the claims, specification, and file history of the ’193 patent. Ex.
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`1002, Spellman Decl. ¶ 84.
`
`A. Claims
`The ’193 patent has one independent claim and thirteen dependent claims.
`
`Independent claim 1 (recited in full in Dr. Spellman’s declaration) relates to a
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`system for generating a report that identifies potential cancer therapeutics that
`
`could be effective based on an individual’s molecular profile comprising: (1) a
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`device to analyze an individual’s molecular profile with respect to a plurality of
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`targets that includes at least (i.e., comprises) AR, EGFR, HER2, KIT, MLH1,
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`PTEN, and PDGFRA—all molecular targets known in the art to be associated with
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`cancer; (2) a database that contains information about what the standard (i.e.,
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`“reference value”) is for each target along with information about available
`
`therapies associated with each of those targets; (3) software for comparing the
`
`individual’s molecular profile with the reference to determine if a molecular
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`U.S. Patent No. 9,372,193
`IPR Petition
`aberration (e.g., a change in gene expression) is present; (4) software to match the
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`individual with known therapies where the aforementioned comparison indicates a
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`likely benefit from the therapy; and (5) software to generate a report identifying
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`any such molecular aberration and the associated therapy. Ex. 1002, Spellman
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`Decl. ¶¶ 86-87.
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`In parallel litigation, Patent Owner has asserted that the novelty of the
`
`claimed invention is the creation of a molecular profile based on a set of targets,
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`the combination of which was not traditionally associated with a particular type of
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`cancer, and use of that profile to identify treatment options independent of cancer
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`type. Ex. 1065, Complaint for Patent Infringement, ¶ 12. However, although the
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`specification of the ’193 patent mentions the determination of “a medical
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`intervention … using molecular profiling that is independent of disease lineage
`
`diagnosis (i.e. not single disease restricted),” none of the claims include this
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`requirement. Ex. 1002, Spellman Decl. ¶ 85 (comparing Ex. 1001, ‘350 patent,
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`13:15-18, with id., 17:1-33).1
`
`
`1 In contrast, claim 1 of the provisional application to which the ’193 patent claims
`
`priority expressly included a requirement that the “drug therapy … is not single
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`disease restricted.” Ex. 1002, Spellman Decl at n.2 (quoting Ex. 1041 at 1041-25,
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`U.S. Provisional Patent Application No. 60/747,645, claim 1).
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`11
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`B.
`Summary of the Specification
`The specification of the ’193 patent acknowledges that using an individual’s
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`U.S. Patent No. 9,372,193
`IPR Petition
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`molecular profile to identify potential therapies was known long before the ’193
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`patent. Indeed, the specification states that “the molecular mechanisms behind
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`various disease states have been the subject of studies for years,” and notes that
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`“treatment regimens have been determined using molecular profiling in
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`combination with clinical characterization” of a patient. Ex. 1001, ’193 patent,
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`1:45-52; Ex. 1002, Spellman Decl. ¶ 89.
`
`The specification further acknowledges that targeted anticancer agents
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`designed to interact with specific receptors or gene products had been developed
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`by the priority filing date, including “Herceptin against HER2/neu,” “rituximab
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`against CD20,” “bevacizamab against VEGF,” and “Cetuximab against EGFR,
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`etc.” Ex. 1001, ’193 patent, 2:16-19. Moreover, Table 1 of the specification
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`describes several additional “non-disease specific agents that have been found to
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`interact with specific targets found in different cancer patients” (id., 14:10-24), all
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`of which were already provided by the prior art. Ex. 1002, Spellman Decl. ¶¶ 90-
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`91.
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`Further, although the specification refers to the goal of using “molecular
`
`profiling that is used to target specific genes and/or gene expressed proteins with
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`specific drugs or agents that is independent of disease lineage diagnosis”
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`U.S. Patent No. 9,372,193
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`(Ex. 1001, ’193 patent, 2:32-35), the specification contains no description of a
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`specific panel of the seven genes recited in the claims at all. To the contrary, the
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`specification contains multiple lengthy lists that include approximately 100 genes.
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`The specification does not disclose or suggest that any subset of these genes would
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`be useful as a panel, or explain the relationship or significance of any particular
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`subset of genes. Nor does it explain how to select individual genes to include on a
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`panel. Ex. 1002, Spellman Decl. ¶ 92.
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`Finally, although the specification provides information regarding a handful
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`of targets that are correlated with specific therapeutic agents, the specification fails
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`to disclose any such correlation for several of the genes listed in the claimed panel,
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`including KIT, MLH1, PTEN, and PDGFRA. And there is no suggestion—nor
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`could there be—that the inventors discovered or “invented” any of the listed
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`correlations. Ex. 1002, Spellman Decl. ¶ 93.
`
`C.
`Summary of the File History
`The Examiner rejected the claims as obvious over U.S. Patent Publication
`
`No. 2007/0172844 (“Lancaster”) in view of U.S. Patent Publication No.
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`2006/0019256 (“Clarke”). Ex. 1003 at 1003-220. The Examiner found that
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`Lancaster discloses a general method of using markers to predict a cancer patient’s
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`response to therapeutic treatments. Id. at 1003-226. The Examiner relied upon
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`Clarke for the disclosure of EGFR, HER2, KIT, MLH1, PTEN, and PDGFRA as
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`U.S. Patent No. 9,372,193
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`markers for cancer, and also pointed out that this reference teaches the markers are
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`assessed by protein testing, nucleic acid testing, or sequencing. Id. at 1003-221.
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`The Examiner concluded that “one of ordinary skill in the art would have used the
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`markers of Clarke [] in the method of Lancaster [] to determine if a cancer patient
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`would respond to a particular therapy.” Id. at 1003-222.
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`In response, Applicants argued that the combined teaching of Lancaster and
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`Clarke would not lead to “the precise molecular profile provided by Applicants’
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`claimed invention.” Id. at 1003-99. Applicants pointed to Clarke’s gene list,
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`which contains all the claimed genes and more, and argued that there are no
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`“guideposts” to lead “one of skill to [select] the specific subset of markers recited
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`by the claimed invention.” Id. Applicants further argued lack of motivation to
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`pick out the claimed markers from Clarke’s gene list because Clarke does not
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`suggest that the claimed markers are relevant for therapeutic efficacy. Id.
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`Thereafter, the Examiner allowed the application. Id. at 1003-29; id. at
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`1003-74. The Examiner’s statement of reasons for allowance was: “The prior art
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`does not does not teach the recited panel of biomarkers.” Id. at 1003-29. As
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`discussed above, however, the ’193 patent claims are not limited in any way to a
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`panel of only the seven genes specifically recited, but rather claim a “plurality of
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`molecular targets, wherein the plurality of molecular targets comprises” the recited
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`genes. Indeed, the ’193 patent itself lacks any “guideposts” for the specific set of
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`U.S. Patent No. 9,372,193
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`genes recited in the claims. Further, the molecular targets recited in claim 1 were
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`well-known in the prior art as being associated with cancer, and it was common at
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`the time of the invention to assay a comprehensive panel of targets and, based on
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`the results of such assay, determine which genes might be targets for potential
`
`therapeutics. Thus, there is nothing inventive about the selection of seven genes
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`recited in the ’193 patent claims, and the claims cannot survive challenge on the
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`basis of that selection.
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`This Petition explains how Lu and Illumina disclose the same claim feature
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`that the Examiner identified as missing from the references considered during
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`prosecution. Accordingly, these new references present new art and a new
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`combination that the Examiner never had a chance to consider and these new
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`references address the deficiencies of the prior art of record identified by the
`
`examiner in the reasons for allowance. Ex. 1002, Spellman Decl. ¶ 97.
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`VII. LEVEL OF ORDINARY SKILL IN THE ART
`Petitioner’s technical expert, Dr. Paul Spellman, is a tenured professor in the
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`Department of Molecular and Medical Genetics at Oregon Health & Science
`
`University. Dr. Spellman explains that a person of ordinary skill in the art as of the
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`2006 priority date of the ’193 patent would have had a Ph.D. in genetics, molecular
`
`biology, bioinformatics, or a related field, and at least five years of research
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`experience in an academic or industry setting, including at least two to three years
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`U.S. Patent No. 9,372,193
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`of research experience in the field of cancer genomics. Ex. 1002, Spellman Decl.
`
`¶ 32.
`
`VIII. CLAIM CONSTRUCTION
`A claim in IPR is given the “broadest reasonable construction in light of the
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`specification.” 37 C.F.R. § 42.100(b); Cuozzo Speed Techs. LLC v. Lee, 136 S. Ct.
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`2131, 2142 (2016).2 Should Patent Owner, seeking to avoid the prior art, contend
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`that the claims warrant a narrower construction, the appropriate course is for Patent
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`Owner to seek to amend the claims to correspond expressly to its contentions in
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`this proceeding. See 77 Fed. Reg. 48764, Aug. 14, 2012. Petitioner reserves the
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`right to advance alternative constructions in other forums.
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`IX. OVERVIEW OF THE PRIMARY PRIOR ART REFERENCES
`A. Lu
`PCT Publication WO 03/017038 by Lu titled “A Molecular Diagnostic and
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`Computerized Decision Support System for Selecting the Optimum Treatment for
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`Human Cancer” (“Lu”) (Ex. 1004), was filed August 9, 2002 and published
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`February 27, 2003. Ex. 1002, Spellman Decl. ¶ 98. Therefore, Lu is prior art
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`2 Pursuant to § 42.100, the Board will be replacing the broadest reasonable
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`interpretation (“BRI”) standard. Given the filing date, however, this Petition is
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`subject to BRI. Petitioner’s arguments set forth herein apply under either standard.
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`U.S. Patent No. 9,372,193
`IPR Petition
`under § 102(b). Lu was not considered by the Patent Office during prosecution.
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`Ex. 1001, ’193 patent, References Cited (56).
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`Lu describes a system of screening a sample from a patient to identify drugs
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`that are “optimum for treating the patient’s cancer.” Lu, Abstract (Ex. 1004). The
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`system includes (1) analyzing a sample from a patient to detect genes, expression
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`levels, and cancer-associated mutations to provide a patient’s molecular profile;
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`and (2) making treatment recommendations using that information. Id. ¶ [0038].
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`Lu’s system further compares the patient’s molecular profile to a database of
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`known mutations, expression levels, and anti-cancer drug outcomes, and, based on
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`those comparisons, generates a report reciting recommended drug therapies. Id.
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`Abstract, ¶ [0018]. Ex. 1002, Spellman Decl. ¶ 99.
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`Lu’s system includes the components of sample preparation, nucleic acid
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`assays, and at least one device to analyze resulting data. E.g., Lu, Figure 2
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`(Ex. 1004). The raw outputs of these molecular assays are provided to a detector
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`for patient profiling. Analysis of the raw data generates a patient’s molecular
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`profile, including the genes’ presence or absence, expression levels (i.e., whether
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`the gene is “up-regulated” or “down-regulated” compared to some reference
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`value), and mutations specific to the patient’s sample. Id. ¶¶ [0034]-[0037]; id. ¶¶
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`[0051]-[0053]; Ex. 1002, Spellman Decl. ¶101. Lu discloses that exemplary genes
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`U.S. Patent No. 9,372,193
`IPR Petition
`targeted by this approach may include ER Alpha, EGFR, HER23, BRCA1,
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`BRCA2, and DPD. Lu ¶¶ [0022], [0048], [0051], [0053]-[0054] (Ex. 1004).
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`Ex. 1002, Spellman Decl. ¶¶ 100-101.
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`Lu then uses the resulting molecular profile defined by the expression levels
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`or mutation data to select one or more suitable drugs to treat the patient’s
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`cancerous condition. Lu ¶¶ [0001], [0018], [0038] (Ex. 1004). As depicted in
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`Figure 4, the detector is connected to a computer that runs a bioinformatics
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`program to further analyze the patient’s molecular profile. Id. ¶¶ [0041]-[0042].
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`The bioinformatics program compares and correlates the molecular data from the
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`detector with a “gene and drug database.” Id. ¶ [0044]. The gene and drug
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`database contains statistical associations between cancer drug outcomes and
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`patient’s profiles. Id. ¶ [0044]. The associations of the gene and drug database are
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`based on clinical studies, public domain research, and private studies. Id. Thus,
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`3 ERBB1 and ERBB2 are alternate names for EGFR and HER2, respectively. See
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`HUGO Gene Nomenclature Committee Symbol Report: EGFR, available at
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`https://www.genenames.org/cgi-bin/gene_symbol_report?hgnc_id=HGNC:3236
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`(Ex. 1044); HUGO Gene Nomenclature Committee Symbol Report: EGFR,
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`available at https://www.genenames.org/cgi-
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`bin/gene_symbol_report?hgnc_id=HGNC:3236 (Ex. 1045).
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`U.S. Patent No. 9,372,193
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`the bioinformatics program “automatically correlates the output of the detector to a
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`database comprising the results of clinical studies testing the efficacy and toxicity
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`of various drugs in treating patients” with particular molecular profiles. Id. ¶
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`[0023]. Ex. 1002, Spellman Decl. ¶ 103. Lu teaches that its system can be applied
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`to various cancers such as breast, liver, and ovarian cancers. Lu ¶¶ [0015], [0036],
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`[0056] (Ex. 1004). Lu explicitly teaches its system may be used “to predict or
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`identify the optimum drug for treating cancers other th[a]n breast cancer[, and] can
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`be used to identify an optimum drug for treating virtually any disease for which
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`there exists an established correlation between a patient genotype and the efficacy
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`and toxicity of each of a group of drugs developed to treat the general condition.”