U.S. Patent 8,880,350
`Declaration of Paul T. Spellman, Ph.D.
`
`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. 8,880,350
`
`____________________________________________
`
`Case IPR2019-00164
`____________________________________________
`
`DECLARATION OF PAUL T. SPELLMAN, PH.D.,
`ON BEHALF OF PETITIONER
`
`FMI 1002
`
`

`

`U.S. Patent 8,880,350
`Declaration of Paul T. Spellman, Ph.D.
`TABLE OF CONTENTS
`
`Page
`
`INTRODUCTION ........................................................................................... 1
`I.
`BACKGROUND AND QUALIFICATIONS ................................................. 1
`II.
`III. MATERIALS REVIEWED ............................................................................ 5
`IV. SUMMARY OF OPINION ............................................................................. 6
`V.
`RELEVANT LAW .......................................................................................... 6
`A.
`Scope of Opinion ................................................................................... 7
`B.
`Obviousness ........................................................................................... 7
`C.
`Claim Construction ............................................................................... 9
`VI. PRIORITY ..................................................................................................... 10
`VII. LEVEL OF ORDINARY SKILL IN THE ART ........................................... 10
`VIII. OVERVIEW OF THE TECHNOLOGY AS OF 2006 ................................. 11
`A.
`Personalized Medicine ........................................................................ 12
`B.
`Targeted Therapies .............................................................................. 16
`1.
`Gleevec® (Imatinib) ................................................................. 19
`2.
`Herceptin® (trastuzumab) ......................................................... 21
`3.
`Tarceva® (Erlotinib) and Iressa® (Gefitinib) .......................... 24
`4.
`Erbitux® (cetuximab) ............................................................... 26
`C.
`Genomic-Based Clinical Trials ........................................................... 28
`1.
`Non-Tissue Specific Molecular Target Treatments .................. 30
`D. Devices for Determining Molecular Profiles ...................................... 33
`1. Microarrays ............................................................................... 33
`2.
`Sequencing ................................................................................ 36
`Available Databases and Software ...................................................... 37
`E.
`1.
`Cancer Microarray Databases ................................................... 37
`2.
`Software Systems ...................................................................... 41
`3.
`Agents ....................................................................................... 42
`4.
`Integrated Systems .................................................................... 45
`IX. THE ’350 PATENT ....................................................................................... 46
`Claims .................................................................................................. 48
`A.
`Summary of the Specification ............................................................. 50
`B.
`File History .......................................................................................... 52
`C.
`
`Databases of Molecular Targets and Corresponding Therapeutic
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`

`U.S. Patent 8,880,350
`Declaration of Paul T. Spellman, Ph.D.
`
`[Ground 1] Claims 1-14 are Obvious under 35 U.S.C. § 103 over Lu
`
`The References Teach or Suggest All Claim Limitations of
`
`B.
`
`C.
`
`Obviousness .............................................................................. 52
`1.
`X. OVERVIEW OF THE PRIMARY PRIOR ART REFERENCES ................ 54
`Lu ......................................................................................................... 54
`A.
`Illumina ............................................................................................... 62
`B.
`C. Muraca ................................................................................................. 63
`D. McDoniels-Silvers ............................................................................... 65
`XI. GROUNDS FOR CHALLENGE .................................................................. 65
`A.
`and Illumina ......................................................................................... 66
`1. Motivation to Combine ............................................................. 66
`2.
`Claims 1-14 ............................................................................... 74
`3.
`Reasonable Expectation of Success ........................................ 117
`Lu, Illumina, and Muraca .................................................................. 120
`1. Motivation to Combine ........................................................... 121
`2.
`Claims 2 and 3 ......................................................................... 124
`3.
`Reasonable Expectation of Success ........................................ 129
`over Lu, Illumina, and McDoniels-Silvers ........................................ 130
`1. Motivation to Combine ........................................................... 130
`2.
`Claims 7 and 11-12 ................................................................. 134
`3.
`Reasonable Expectation of Success ........................................ 138
`XII. COMPENSATION; AVAILABILITY FOR CROSS EXAMINATION ... 139
`XIII. RIGHT TO SUPPLEMENT ........................................................................ 140
`XIV. JURAT ......................................................................................................... 140
`
`[Ground 2] Claims 2 and 3 Are Obvious under 35 U.S.C. § 103 over
`
`The References Teach or Suggest All Claim Limitations of
`
`[Ground 3] Claims 7 and 11-12 Are Obvious under 35 U.S.C. § 103
`
`The References Teach or Suggest All Claim Limitations of
`
`
`
`ii
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`

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`U.S. Patent 8,880,350
`Declaration of Paul T. Spellman, Ph.D.
`I, Paul T. Spellman, declare as follows:
`
`I.
`
`INTRODUCTION
`1.
`I have been retained as an expert in this proceeding by Petitioner
`
`Foundation Medicine, Inc. (“Foundation Medicine” or “Petitioner”).
`
`2.
`
`I understand that Patent Owner Caris MPI, Inc. (“Caris” or “Patent
`
`Owner”) has alleged that Foundation Medicine infringes U.S. Patent No. 8,880,350
`
`(the “’350 patent”).
`
`3.
`
`I have been asked to review the claims of the ’350 patent and to
`
`evaluate whether those claims would have been obvious to a person of ordinary
`
`skill in the art based on the prior art at the time of the invention.
`
`II. BACKGROUND AND QUALIFICATIONS
`4. My qualifications are reflected in my curriculum vitae, attached as
`
`Exhibit A, and the following comments.
`
`5.
`
`I am a Professor with tenure in the Department of Molecular and
`
`Medical Genetics at Oregon Health & Science University (“OHSU”), where I
`
`supervise my laboratory, a team of eight. I also serve as Co-Director of OHSU’s
`
`Cancer Early Detection Advanced Research (“CEDAR”) Center, which will grow
`
`to more than 100 members in 2019. I am also Interim Director of OHSU’s
`
`Program in Computational Biology, where I supervise eight faculty and a team of
`
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`U.S. Patent 8,880,350
`Declaration of Paul T. Spellman, Ph.D.
`more than 50. Finally, I am the Program leader for Quantitative Oncology in the
`
`Knight Cancer Institute, where I set programmatic goals for the Institute.
`
`6.
`
`My work at OHSU focuses on the intersection of computational
`
`biology, cancer biology, and genomics. As such, my lab develops technologies
`
`and approaches to understand the biology of cancer, to detect cancer, and to
`
`develop approaches to more effectively treat cancer. The approaches used to
`
`tackle this problem include genetic, genomic, and proteomic methods. My team
`
`and I participate in numerous collaborations to understand the effects of genetic
`
`and proteomic aberrations in cancer. These efforts include development of new
`
`methodologies for identifying changes in the cancer genome; systematic
`
`integration of multiple genomic data types (copy number, expression, and
`
`mutation) to better understand the process by which cancer develops; and the
`
`application of cell line systems as models for the genetic heterogeneity within
`
`cancers.
`
`7.
`
`CEDAR is a $314 million effort funded by a gift from Phil and Penny
`
`Knight to detect and treat early cancers. Among other activities, my work as Co-
`
`Director of CEDAR includes identifying populations at risk for developing cancer
`
`and understanding the early biology of breast cancers.
`
`8.
`
`I earned a Bachelor of Science degree in Biology from the
`
`Massachusetts Institute of Technology in 1995 and a Doctorate (Ph.D.) degree in
`
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`U.S. Patent 8,880,350
`Declaration of Paul T. Spellman, Ph.D.
`Genetics from Stanford University Medical School in 2000. My dissertation on
`
`using whole genome sequencing approaches to understand the eukaryotic cell
`
`cycle and for processing large-scale genomic data was titled “Generating and
`
`Analyzing Genome Scale Data.” My Ph.D. primary mentor was Dr. David
`
`Botstein and I was co-mentored by Dr. Patrick O. Brown, both members of the
`
`National Academy of Sciences.
`
`9.
`
`I have over 20 years of experience in the field of genomics and 15
`
`years of experience in cancer genomics and precision medicine. From 2000 to
`
`2003, I served as a postdoctoral Fellow at the University of California, Berkeley in
`
`the Department of Molecular and Cellular Biology with Dr. Gerald M. Rubin, a
`
`member of the National Academy of Sciences and Vice President of the Howard
`
`Hughes Medical Institute. I then worked in the Life Science Division at the
`
`Lawrence Berkeley National Laboratory, as a Scientist from 2003 to 2007, and as a
`
`Staff Scientist from 2007 to 2011. My work in the Lawrence Berkeley Laboratory
`
`focused on cancer genomics, cancer systems biology, and precision medicine
`
`applied to cancers.
`
`10.
`
`In 2011, I spent six months serving as Special Assistant to the Deputy
`
`Director of the National Cancer Institute (“NCI”) at the request of the NCI
`
`Director, Harold Varmus.
`
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`U.S. Patent 8,880,350
`Declaration of Paul T. Spellman, Ph.D.
`I have taught undergraduate and graduate level courses at OHSU in
`
`11.
`
`the area of cancer biology, computational analysis, and genetics. I have also
`
`supervised two completed Ph.D. theses since I joined the OHSU faculty in 2011.
`
`12.
`
`I have authored or co-authored more than 135 peer-reviewed
`
`publications in the areas of genomics, basic biology of eukaryotic cells, cancer
`
`evolution, and precision medicine. Together, these papers have been cited more
`
`than 42,000 times according to Scopus and 77,000 times by Google Scholar. In
`
`addition, I have presented over 80 invited lectures or conference presentations
`
`regarding these topics. My curriculum vitae includes a sample list of these
`
`publications and presentations.
`
`13.
`
`I have received approximately $16 million in federal grants for my
`
`research in the area of cancer genomics and cancer precision medicine. I am
`
`currently one of 30 principal investigators for the Genome Data Analysis Network,
`
`sponsored by NCI. The Genome Data Analysis Network is a consortium of
`
`computational researchers from across the United States focused on developing the
`
`framework for relating the genomics and outcomes of patients in cancer clinical
`
`trials.
`
`14.
`
`I am the holder of one issued patent (“Molecular predictors of
`
`therapeutic response to specific anti-cancer agents”, U.S. Patent No. 9,506,926). I
`
`have consulted for more than 20 years in the biotech industry. Much of my work
`
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`U.S. Patent 8,880,350
`Declaration of Paul T. Spellman, Ph.D.
`in the period 2005-2011 was supported by contracts from pharmaceutical
`
`companies (GSK primarily) focused on developing predictors of therapeutic
`
`response. I am a co-founder of a Convergent Genomics, which is focused on
`
`developing a sequencing-based assay to measure bladder cancer recurrence.
`
`15. As a postdoctoral scholar I was selected for the prestigious National
`
`Science Foundation Biocomputing Fellowship, which covered both my stipend and
`
`significant research costs. In 2017, I was named the inaugural holder of the Penny
`
`and Phil Knight Endowed Professorship for Cancer Research Innovation.
`
`III. MATERIALS REVIEWED
`16.
`I have reviewed the specification, claims, and file history of the ’350
`
`patent.
`
`17.
`
`I have also reviewed the following printed publications in preparing
`
`this declaration:
`
` PCT Publication No. WO 03/017038 to Lu et al., published on February 27,
`
`2003. (Ex. 1004 (“Lu”).)
`
` Illumina® Gene Expression Profiling, Technical Bulletin, RNA Profiling
`
`with the DASL® Assay, Pub. No. 470-2005-003, published in 2005. (Ex.
`
`1005 (“Illumina”).)
`
` U.S. Patent Publication No. 2002/0150966 to Muraca, published on October
`
`17, 2002. (Ex. 1006 (“Muraca”).)
`
`5
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`U.S. Patent 8,880,350
`Declaration of Paul T. Spellman, Ph.D.
` Amy L. McDoniels-Silvers, et al., Differential Expression of Critical
`
`Cellular Genes in Human Lung Adenocarcinomas and Squamous Cell
`
`Carcinomas in Comparison to Normal Lung Tissues, 4 Neoplasia 141
`
`(2002). (Ex. 1007 (“McDoniels-Silvers”).)
`
`18. A complete list of materials I relied upon in forming my opinions in
`
`preparing this declaration is included as Exhibit B.
`
`IV. SUMMARY OF OPINION
`19.
`I have reviewed the above-referenced printed publications and any
`
`other publication cited in this declaration. I have also relied on my scientific
`
`knowledge and experience as of May 18, 2006 when the earliest application to
`
`which the ’350 patent claims priority was filed.
`
`20.
`
`I have considered certain issues from the perspective of a person of
`
`ordinary skill in the art as described below at the time the provisional that led to
`
`the ’350 patent was filed. It is my opinion that every limitation described in claims
`
`1-14 (“the challenged claims”) of the ’350 patent is disclosed by the prior art, and
`
`that those claims are rendered obvious by the prior art.
`
`V. RELEVANT LAW
`21.
`I am not an attorney. For the purposes of this declaration, I have been
`
`informed about certain aspects of the law that are relevant to my opinions, as set
`
`forth below.
`
`6
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`

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`U.S. Patent 8,880,350
`Declaration of Paul T. Spellman, Ph.D.
`
`Scope of Opinion
`I have been informed and understand that the Petitioner in an inter
`
`A.
`22.
`
`partes review may request cancellation of claims as unpatentable only on grounds
`
`that such claims are anticipated or would have been obvious to a person of
`
`ordinary skill in the art at the time of the purported invention, and only on the basis
`
`of prior art consisting of patents or printed publications. My opinions in this
`
`matter address only such grounds.
`
`B. Obviousness
`23.
`I have been informed and understand that a patent claim can be
`
`considered to have been obvious to a person of ordinary skill in the art at the time
`
`of the invention. I further understand that, in order to invalidate a patent claim as
`
`obvious in the context of an inter partes review, it must be shown by a
`
`preponderance of the evidence that the claim would have been obvious to a person
`
`of ordinary skill in the art at the time the invention was made. This means that,
`
`even if all of the requirements of a claim are not found in a single prior art
`
`reference, the claim is not patentable if the differences between the subject matter
`
`in the prior art and the subject matter in the claim would have been obvious to a
`
`person of ordinary skill in the art at the time of the invention.
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`U.S. Patent 8,880,350
`Declaration of Paul T. Spellman, Ph.D.
`I have been informed and understand that a determination of whether
`
`24.
`
`a claim would have been obvious should be based upon several factors, including,
`
`among others:
`
` the level of ordinary skill in the art at the time of the invention;
`
` the scope and content of the prior art;
`
` what differences, if any, existed between the claimed invention and the prior
`
`art; and
`
` objective evidence, or secondary considerations.
`
`25.
`
`I have been informed and understand that obviousness can be
`
`established by combining or modifying the teachings of the prior art to produce the
`
`claimed invention where there is some teaching, suggestion, or motivation to do so,
`
`and a reasonable expectation of success that doing so would achieve the subject
`
`matter of the claimed invention. Further, I have been informed and understand that
`
`the teaching, suggestion, or motivation test is flexible and that explicit suggestion
`
`to combine the prior art is not necessary—the motivation to combine may be
`
`implicit and may be found in the knowledge of one of ordinary skill in the art, from
`
`the nature of the problem to be solved, market demand, or common sense.
`
`26.
`
`In determining whether a combination based on either a single
`
`reference or multiple references would have been obvious, I have been informed
`
`and understand that it is appropriate to consider, among other factors:
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`U.S. Patent 8,880,350
`Declaration of Paul T. Spellman, Ph.D.
` whether the teachings of the prior art references disclose known concepts
`
`combined in familiar ways, which, when combined, would yield predictable
`
`results;
`
` whether a person of ordinary skill in the art could implement a predictable
`
`variation, and would see the benefit of doing so;
`
` whether the claimed elements represent one of a limited number of known
`
`design choices;
`
` whether a person of ordinary skill would have recognized a reason to
`
`combine known elements in the manner described in the claim; and
`
` whether the alleged invention applies a known technique that had been used
`
`to improve a similar device or method in a similar way.
`
`27.
`
`I have been informed and understand that one of ordinary skill in the
`
`art has ordinary creativity.
`
`28.
`
`I have been informed and understand that in considering obviousness,
`
`it is important not to determine obviousness using the benefit of hindsight derived
`
`from the patent being considered.
`
`C. Claim Construction
`29.
`I have been informed and understand that claim construction is a
`
`matter of law and that the final claim construction will ultimately be determined by
`
`the Patent Trial and Appeal Board (“the Board”). For the purposes of my analysis
`
`9
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`

`U.S. Patent 8,880,350
`Declaration of Paul T. Spellman, Ph.D.
`in this proceeding and with respect to the prior art, I have been informed and
`
`understand that I should apply the broadest reasonable interpretation standard.
`
`30.
`
`I have been informed and understand that any claim term that lacks a
`
`definition in the specification is given its broadest reasonable interpretation as
`
`understood by one of ordinary skill in the art.
`
`VI. PRIORITY
`31.
`I understand that the ’350 patent was filed on January 31, 2014 and
`
`issued on November 4, 2014. I understand that the ’350 patent claims priority to
`
`U.S. Prov. App. No. 60/747,645, filed on May 18, 2006. I understand that, for
`
`purposes of determining whether a publication will qualify as prior art, the earliest
`
`date to which the ’350 patent could be entitled is May 18, 2006.
`
`VII. LEVEL OF ORDINARY SKILL IN THE ART
`32. A person of ordinary skill in the art as of the May 18, 2006 priority
`
`date of the ’350 patent would have had a Ph.D. in genetics, molecular biology,
`
`bioinformatics, or a related field, and at least five years of research experience in
`
`an academic or industry setting, including at least two to three years of research
`
`experience in the field of cancer genomics.
`
`33.
`
`I would have satisfied the criteria for a person of ordinary skill in the
`
`art as of the May 18, 2006 priority date of the ’350 patent.
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`U.S. Patent 8,880,350
`Declaration of Paul T. Spellman, Ph.D.
`VIII. OVERVIEW OF THE TECHNOLOGY AS OF 2006
`34. The term “cancer” describes a group of diseases caused by changes in
`
`an individual’s DNA and in the epigenomic context of individual cells that can
`
`alter cell behavior, causing uncontrolled growth and disease (i.e., malignancy).
`
`The genomic abnormalities can take many forms including, for example, DNA
`
`mutations, such as nucleotide changes, rearrangements, deletions, or
`
`amplifications. Epigenomic abnormalities include developmental state switches
`
`that change what cells are capable of doing. The product of these genomic and
`
`epigenomic abnormalities can be the overexpression or loss of certain proteins or
`
`the creation of misshapen proteins whose function is altered. An individual’s
`
`molecular profile reflects the genomic abnormalities in an individual’s DNA,
`
`which can be inherited from one’s parents (i.e., germline mutations) or acquired
`
`during an individual’s lifetime (i.e., somatic mutations). Somatic mutations occur
`
`more frequently and are the cause of more than 90% of cancer. The field of cancer
`
`genomics analyzes an individual’s tumor DNA and compares it to reference DNA
`
`(typically normal DNA from a reference sample). This comparison can help
`
`scientists identify the genomic differences that may be associated with an
`
`individual’s cancer.
`
`35. As of May 18, 2006, devices for determining molecular profiles were
`
`well known, and I will describe several such technologies including microarrays,
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`U.S. Patent 8,880,350
`Declaration of Paul T. Spellman, Ph.D.
`immunohistochemical analysis, and fluorescence in-situ hybridization. Public
`
`databases had been developed to host the vast information related to these
`
`associations and numerous peer-reviewed articles were published touting the uses
`
`of this information.
`
`36.
`
`In this Section, I will describe what personalized medicine is and what
`
`was known about personalized medicine as of May 18, 2006. By 2006, a number
`
`of targeted therapies had been developed for treating cancer based on associations
`
`of therapeutic agents with specific molecular targets, and I will discuss several
`
`such therapeutic agents identified in the specification, including the well-known
`
`examples of Gleevec, Herceptin, and Tarceva. I will also discuss the use of
`
`targeted therapies in multiple tumor types based on genomic associations with
`
`molecular markers.
`
`A.
`Personalized Medicine
`37. Personalized medicine is the application of genomic and molecular
`
`data to focus the delivery of health care and medical treatments, facilitate the
`
`discovery and clinical testing of new products, and help determine a patient’s
`
`predisposition to a particular disease or condition. Many commonly-used drugs
`
`are effective only in a portion of a patient population and other drugs may cause
`
`serious adverse reactions in patients; personalized medicine was developed as a
`
`means for identifying the drugs that are appropriate for individual patients.
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`U.S. Patent 8,880,350
`Declaration of Paul T. Spellman, Ph.D.
`38. By 1999, the promise of personalized medicine led pharmaceutical
`
`companies and “their gene-hunting partners in university labs” to invest enormous
`
`resources to discover information that would help them “create drugs specifically
`
`designed to target each person’s unique genetic profile.” See, e.g., Robert
`
`Langreth & Michael Waldholz, New Era of Personalized Medicine Targeting
`
`Drugs For Each Unique Genetic Profile, 4 The Oncologist 426, 426 (1999)
`
`(Ex. 1008). The completion of the Human Genome Project’s draft sequence in
`
`2000 contributed to a more sophisticated understanding of disease causation and
`
`advanced the practical application of personalized medicine.
`
`39. As of the early 2000’s, scientists were studying both pharmacology
`
`(the science of drugs) and genomics (the study of genes and their functions) to
`
`develop safe and effective medications and dosing regimens that would be tailored
`
`to an individual’s genomic makeup. The combined study of pharmacology and
`
`genomics, “pharmacogenomics,” refers to the study of how genes affect a person’s
`
`response to drugs, including whether a drug may be an effective treatment for a
`
`particular patient and whether a drug may cause side effects in a particular patient.
`
`As of the early 2000s, it was known that pharmacogenomics had the potential to
`
`dramatically increase the efficacy and safety of drugs, while reducing healthcare
`
`costs, through the practice of genome-based personalized medicine. The “progress
`
`in understanding the molecular changes that underlie cancer development offer[ed]
`
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`U.S. Patent 8,880,350
`Declaration of Paul T. Spellman, Ph.D.
`the prospect of specifically targeting malfunctioning molecules and pathways to
`
`achieve more effective and rational cancer therapy.” See Charles Sawyers,
`
`Targeted cancer therapy, 432 Nature 294, 294 (2004) (Ex. 1009).
`
`40. Several federal initiatives supporting the expansion of personalized
`
`medicine were launched in the 2000s.
`
`41. For example, the National Human Genome Research Institute
`
`(“NHGRI”) awarded tens of millions of dollars “in grants to spur the development
`
`of innovative technologies designed to dramatically reduce the cost of DNA
`
`sequencing, a move aimed at broadening the applications of genomic information
`
`in medical research and health care.” See NHGRI Seeks Next Generation of
`
`Sequencing Technologies (Oct. 14, 2004), https://www.genome.gov/12513210/
`
`(Ex. 1010). This research was designed to lower the cost of sequencing with the
`
`ultimate goal of cutting the cost of whole-genome sequencing to $1,000 or less to
`
`“enable the sequencing of individual genomes as part of medical care.” Id.
`
`NHGRI recognized that “[t]he ability to sequence each person’s genome cost-
`
`effectively could give rise to more individualized strategies for diagnosing, treating
`
`and preventing disease” and “[s]uch information could enable doctors to tailor
`
`therapies to each person’s unique genetic profile.” Id.
`
`42. The Cancer Genome Atlas Project (“TCGA”), a collaboration
`
`between the National Cancer Institute (“NCI”) and the National Human Genome
`
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`U.S. Patent 8,880,350
`Declaration of Paul T. Spellman, Ph.D.
`Research Institute (“NHGRI”), was initiated in 2005 to systematically catalog
`
`genomic mutations that cause cancer using genome sequencing, other genomic
`
`analysis, and bioinformatics. By understanding the cancer-causing changes in an
`
`individual’s DNA, scientists hoped to understand the molecular basis for cancer
`
`growth, metastasis (i.e., the spreading of cancer in an individual), and drug
`
`resistance. It was intended that this information would help scientists identify new
`
`ways to treat cancer.
`
`43.
`
`In 2006, Congress was also focused on providing additional funding
`
`for improved access to and development of genetic testing for the treatment of
`
`diseases like cancer. On August 3, 2006, the possibilities of personalized medicine
`
`led then Senator, later President, Obama to introduce the Genomics and
`
`Personalized Medicine Act “[t]o improve access to and appropriate utilization of
`
`valid, reliable and accurate molecular genetic tests by all populations thus helping
`
`to secure the promise of personalized medicine for all Americans.” See Genomics
`
`and Personalized Medicine Act of 2006, S. 3822, 109th Cong., at 1 (Ex. 1011).
`
`This was to be a systematic effort, ideally entailing the sequencing of every
`
`individual’s DNA sequence, thus cataloging in parallel possible inherited
`
`influences on disease.
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`U.S. Patent 8,880,350
`Declaration of Paul T. Spellman, Ph.D.
`
`Targeted Therapies
`In the early 2000s, scientists were studying the clinical management
`
`B.
`44.
`
`of tumors and the pharmaceutical development of new anti-cancer drugs based on
`
`the molecular and genomic characterization of tumors. See Charles Sawyers,
`
`Targeted cancer therapy, 432 Nature 294, 294 (2004) (Ex. 1009) (reviewing
`
`research related to the identification of targeted cancer therapies). Scientists were
`
`designing, identifying, and validating predictive biomarkers for treatment response
`
`and evaluating the susceptibility of individuals with different genomic
`
`constitutions to developing certain medical conditions. At this time, the use of
`
`targeted treatments (e.g., small molecules and biologics) was well-established.
`
`The term “targeted therapy” refers to cancer drugs “designed to interfere with a
`
`specific molecular target (typically a protein) that is believed to have a critical role
`
`in tumour growth or progression.” Id. “The identification of appropriate targets is
`
`based on a detailed understanding of the molecular changes underlying cancer.”
`
`Id. The targeted approach contrasted “with the conventional, more empirical
`
`approach used to develop cytotoxic chemotherapeutics — the mainstay of cancer
`
`drug development in past decades.” Id. A chart from a 2004 publication
`
`describing exemplary targeted agents and the status of their clinical testing is
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`provided below. Id. As this chart shows, as of 2004, it was common for
`
`researchers to investigate a particular therapeutic agent with respect to multiple
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`U.S. Patent 8,880,350
`Declaration of Paul T. Spellman, Ph.D.
`targets and multiple different cancers and this investigation was based on the
`
`presence of an appropriate target in each tumor.
`
`
`By 2005, there were “a number of outstanding examples of the successful
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`application of genetic and genomic data to guide cancer therapy” and a “growing
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`list of approved targeted therapies,” as depicted in the chart below. Phillip G.
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`Febbo & Geoffrey S. Ginsburg, Personalized diagnostic and therapeutic strategies
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`in oncology, 2 Personalized Medicine 97, 107 (2005) (Ex. 1059).
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`U.S. Patent 8,880,350
`Declaration of Paul T. Spellman, Ph.D.
`
`
`In many cases, targeted agents were designed to inhibit growth factor
`
`45.
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`signaling. A chart from an earlier 2000 review article providing a summary
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`description of growth factor inhibitor drugs and clinical candidates in development
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`is reproduced below. See Jackson B. Gibbs, Anticancer drug targets: growth
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`factors and growth factor signaling, 105 J. Clinical Investigation 9, 9-10 (2000)
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`(Ex. 1012) (providing a broad overview of a growth factor signal transduction
`
`18
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`U.S. Patent 8,880,350
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`system and a summary description of drugs or clinical candidates associated with
`
`growth factor signaling targets).
`
`
`46. Further, as mentioned above, the idea to apply targeted treatments in a
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`disease-agnostic manner, i.e., based on the identification of genomic or molecular
`
`profiles as opposed to the type of cancer, was also well-known by the mid-2000s.
`
`The targeted therapies discussed below exemplify this approach.
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`1. Gleevec® (Imatinib)
`47. Gleevec (imatinib) is a tyrosine kinase inhibitor that dramatically
`
`improved the treatment of chronic myeloid leukemia (“CML”) when it was
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`approved in 2001. See Nida Iqbal & Naveed Iqbal, Imatinib: A Breakthrough of
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`Targeted Therapy in Cancer, Chemotherapy Research & Practice 1 (2014) (Ex.
`
`19
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`U.S. Patent 8,880,350
`Declaration of Paul T. Spellman, Ph.D.
`1013) (“Iqbal”); NIH National Cancer Institute, How Imatinib Transformed
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`Leukemia Treatment and Cancer Research, (updated Apr. 11, 2018)
`
`https://www.cancer.gov/research/progress/discovery/gleevec (Ex. 1061); Claudia
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`Dreifus, Researcher Behind the Drug Gleevec, N.Y. Times (Nov. 2, 2009), at D4
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`(Ex. 1062); Dan L. Longo, Imatinib Changed Everything, 376 New England J.
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`Med. 982 (2017) (Ex. 1063) (explaining that “[t]he development of imatinib
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`fundamentally altered the field of oncology” and ushered in the era of personalized
`
`medicine focused on cancer biology and the search for molecular targets).
`
`48.
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`Imatinib was invented in the late 1990s by biochemists working for
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`Ciba-Geigy, and its use for the treatment of CML was developed by oncologists at
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`Oregon Health & Science University. See Iqbal at 1 (Ex. 1013). The first clinical
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`trial of imatinib took place in 1998 and the drug received FDA approval in May
`
`2001. See id. Scienti