`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`___________________
`
`
`
`
`Foresight Diagnostics Inc.,
`Petitioner,
`
`v.
`
`Personalis, Inc.,
`Patent Owner.
`
`
`
`____________________
`
`IPR2023-00224
`U.S. Patent No. 11,384,394
`____________________
`
`
`
`PETITION FOR INTER-PARTES REVIEW
`OF U.S. PATENT NO. 11,384,394
`
`
`
`
`
`
`
`Mail Stop: PATENT BOARD
`Patent Trial and Appeal Board
`U.S. Patent and Trademark Office
`P.O. Box 1450
`Alexandria, VA 22313-1450
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`IPR2023-00224
`U.S. Patent No. 11,384,394
`TABLE OF CONTENTS
`
`Page
`INTRODUCTION .................................................................................. 1
`I.
`II. GROUNDS FOR STANDING .............................................................. 4
`III. MANDATORY NOTICES .................................................................... 5
`A.
`Real Party-In-Interest ................................................................... 5
`B.
`Related Matters ............................................................................ 5
`C.
`Lead and Back-up Counsel and Service Information .................. 6
`D. Additional Service Information ................................................... 6
`IV. THE ’394 PATENT ................................................................................ 7
`V.
`LEVEL OF ORDINARY SKILL IN THE ART .................................... 8
`VI. BACKGROUND KNOWLEDGE OF A POSA .................................... 9
`A. Genes and Mutations .................................................................... 9
`B. Nucleic Acid Sequencing ........................................................... 10
`C. Amplification and Enrichment ................................................... 11
`D.
`Personalized Biomedical Monitoring ........................................ 14
`VII. KEY PRIOR ART ................................................................................ 16
`A.
`Leary ........................................................................................... 16
`B.
`Ley .............................................................................................. 17
`C.
`Chan ........................................................................................... 17
`D.
`Liao ............................................................................................. 18
`VIII. GROUNDS FOR THE CHALLENGES .............................................. 18
`IX. CLAIM CONSTRUCTION ................................................................. 19
`“subset” ...................................................................................... 19
`A.
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`U.S. Patent No. 11,384,394
`B.
`“capture probe” .......................................................................... 21
`C.
`“polymorphism” ......................................................................... 22
`D.
`“biomedical report” .................................................................... 22
`LISTING OF CHALLENGED CLAIMS ............................................ 24
`X.
`XI. THE BOARD SHOULD CANCEL THE CHALLENGED
`CLAIMS ............................................................................................... 28
`A. Ground 1: Leary in view of knowledge of a POSA. .................. 28
`1.
`Claim 1 ............................................................................. 31
`2.
`Claim 2 ............................................................................. 45
`3.
`Claim 3 ............................................................................. 45
`4.
`Claim 4 ............................................................................. 46
`5.
`Claim 5 ............................................................................. 47
`6.
`Claim 6 ............................................................................. 47
`7.
`Claim 7 ............................................................................. 48
`8.
`Claim 8 ............................................................................. 48
`9.
`Claim 9 ............................................................................. 49
`10. Claim 10 ........................................................................... 49
`11. Claim 11 ........................................................................... 50
`12. Claim 12 ........................................................................... 50
`13. Claim 13 ........................................................................... 50
`14. Claim 14 ........................................................................... 51
`15. Claim 15 ........................................................................... 51
`16. Claim 16 ........................................................................... 51
`17. Claim 17 ........................................................................... 52
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`18. Claim 18 ........................................................................... 52
`19. Claim 19 ........................................................................... 53
`B. Ground 2: Leary in view of Knowledge of a POSA and Ley .... 54
`1.
`Claim 1 ............................................................................. 54
`2.
`Claims 4-5 ........................................................................ 58
`C. Ground 3: Leary in view of Knowledge of a POSA, Chan and
`Liao ............................................................................................. 58
`1.
`Claim 1 ............................................................................. 63
`2.
`Claims 2-11, 13-19 .......................................................... 75
`3.
`Claim 3 ............................................................................. 76
`4.
`Claim 12 ........................................................................... 76
`XII. CONCLUSION .................................................................................... 77
`
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`IPR2023-00224
`U.S. Patent No. 11,384,394
`
`
`TABLE OF AUTHORITIES
`
` Page(s)
`
`Cases
`In re DiStefano,
`808 F.3d 845 (Fed. Cir. 2015) ...................................................................... 22
`In re Ngai,
`367 F.3d 1336 (Fed. Cir. 2004) .................................................................... 23
`Praxair Distribution, Inc. v. Mallinckrodt Hosp. Prod. IP Ltd.,
`890 F.3d 1024 (Fed. Cir. 2018) .............................................................. 22, 23
`Wellman, Inc. v. Eastman Chem. Co.,
`642 F.3d 1355 (Fed. Cir. 2011) .................................................................... 19
`Statutes
`35 U.S.C. §103(a) .............................................................................................. 18
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`IPR2023-00224
`U.S. Patent No. 11,384,394
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`
`
`PETITIONER’S EXHIBIT LIST
`
`Ex. 1001 U.S. Patent No. 11,384,394 to Bartha et al.
`
`Ex. 1002 Rebecca J. Leary et al., “Development of Personalized Tumor
`Biomarkers Using Massively Parallel Sequencing,” Science
`Translational Medicine (2010) (Leary)
`
`Ex. 1003
`
`Stephen R. Quake et al., WO 2011/057061 (Quake)
`
`Ex. 1004 Matthew W. Anderson & Iris Schrijver, “Next Generation DNA
`Sequencing and the Future of Genomic Medicine,” Genes
`(2010) (Anderson)
`
`Ex. 1005 Andreas Gnirke et al., “Solution hybrid selection with ultra-long
`oligonucleotides for massively parallel targeted sequencing,”
`Nature Biotechnology (2009) (Gnirke)
`
`Ex. 1006
`
`Florian Mertes et al., “Targeted enrichment of genomic DNA
`regions for next-generation sequencing, Briefings in Functional
`Genomics,” Briefings in Functional Genomics (2011) (Mertes)
`
`Ex. 1007
`
`Lira Mamanova et al., “Target-enrichment strategies for next-
`generation sequencing,” Nature (2010) (Mamanova)
`
`Ex. 1008 K.C. Allen Chan et al., “Cancer Genome Scanning in Plasma:
`Detection of Tumor-Associated Copy Number Aberrations,
`Single-Nucleotide Variants, and Tumoral Heterogeneity by
`Massively Parallel Sequencing,” Clinical Chemistry (2013)
`(Chan)
`
`Ex. 1009 Gary J.W. Liao et al., “Targeted Massively Parallel Sequencing
`of Maternal Plasma DNA Permits Efficient and Unbiased
`Detection of Fetal Alleles,” Clinical Chemistry (2011) (Liao)
`
`Ex. 1010
`
`Ex. 1011
`
`Personalis v. Foresight, First Amended Complaint, D. Colo.,
`Case No. 1:22-v-01913, Dkt. 9, filed August, 17, 2022 (“FAC”)
`
`Infringement Claim Chart for U.S. Patent No. 11,384,394; Ex. I
`to Patent Owner’s FAC
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`IPR2023-00224
`U.S. Patent No. 11,384,394
`Ex. 1012
`Timothy J. Ley et al., “DNA sequencing of a cytogenetically
`normal acute myeloid leukaemia genome,” Nature (2008) (Ley)
`
`Ex. 1013
`
`Ex. 1014
`
`Jay Shendure and Hanlee Ji, “Next-generation DNA
`sequencing,” Nature Biotechnology (2008) (Shendure)
`
`Jeffrey S. Ross and Maureen Cronin, “Whole Cancer Genome
`Sequencing by Next-Generation Methods,” American Journal of
`Clinical Pathology (2011) (Ross)
`
`Ex. 1015 David J. McBride, et al., “Use of Cancer-Specific Genomic
`Rearrangements to Quantify Disease Burden in Plasma from
`Patients with Solid Tumors,” Genes, Chromosomes & Cancer
`(2010) (McBride)
`
`Ex. 1016 David M. Kurtz, et al., “Enhanced detection of minimal residual
`disease by targeted sequencing of phased variants in circulating
`tumor DNA,” Nature Biotechnology (2021) (Kurtz) (Ex. J to
`FAC)
`
`Ex. 1017 Dennis Lo, “Cancer Genome Scanning in Plasma, Clinical
`Chemistry Journal,” Jan. 3, 2013
`https://www.aacc.org/science-and-research/clinical-
`chemistry/clinical-chemistry-podcasts/2013/cancer-genome-
`scanning-in-plasma-detection-of-tumor-associated-copy-
`number-aberrations
`
`Ex. 1018 NIH Spreadsheet Regarding DNA Sequencing Costs
`
`Ex. 1019
`
`https://www.genome.gov/about-genomics/fact-sheets/DNA-
`Sequencing-Costs-Data
`
`Ex. 1020 Declaration of John Quackenbush, Ph.D.
`
`Ex. 1021 Declaration of Ingrid Hsieh-Yee, Ph.D.
`
`Ex. 1022 Caroline Arbanas, “Wilson leads quest to reveal the genome's
`secrets,” The Source, Washington University St. Louis,
`April 16, 2008
`https://source.wustl.edu/2008/04/wilson-leads-quest-to-reveal-
`the-genome-secrets/
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`IPR2023-00224
`U.S. Patent No. 11,384,394
`Ex. 1023 Curriculum Vitae of John Quackenbush, Ph.D.
`
`Ex. 1024
`
`Ex. 1025
`
`https://www.garvan.org.au/research/kinghorn-centre-for-
`clinical-genomics/learn-about-genomics/for-gp/genetics-
`refresher-1/types-of-variants
`
`Seo Young Oh, et al., “Improved DNA Extraction Method for
`Molecular Diagnosis from Smaller numbers of Cells,” Korean
`Journal of Clinical Laboratory Science (2014) (Oh)
`
`Ex. 1026
`
`Leary Supplemental Information
`
`Ex. 1027 Hugo Lam, et al., “Performance comparison of whole-genome
`sequencing platforms,” Nature Biotechnology (2012) (Lam)
`
`Ex. 1028
`
`Illumina, Technical Note: Sequencing
`
`Ex. 1029
`
`Illumina, Specification Sheet: Illumina Sequencing
`
`Ex. 1030
`
`Tim Forshew, et al., “Noninvasive Identification and Monitoring
`of Cancer Mutations by Targeted Deep Sequencing of Plasma
`DNA,” Science Translational Medicine (2012) (Forshew)
`
`Ex. 1031 Matthew Meyerson, et. al., “Advances in understanding cancer
`genomes through second-generation sequencing,” Nature
`Reviews (2010) (Meyerson)
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`IPR2023-00224
`U.S. Patent No. 11,384,394
`
`I.
`
`INTRODUCTION
`Foresight Diagnostics Inc. (“Petitioner”) requests inter partes review and
`
`cancellation of all claims (1-19) of U.S. Patent No. 11,384,394 (“the ’394
`
`patent”), entitled “Methods and Systems for Genetic Analysis.”
`
`In its lawsuit against Petitioner, Patent Owner asserts that the ’394 patent
`
`“relates to methods for sample processing and analysis to aid in the diagnosis,
`
`monitoring, treatment, and prevention of disease.”1 It characterizes the claims as
`
`being directed to the following method: (1) “whole genome sequencing nucleic
`
`acid molecules obtained from a first biological sample,” (2) using “a set of
`
`capture probes that hybridize to polymorphisms that are based on or extracted
`
`from a database of polymorphisms or observed in a sample, or a combination
`
`thereof,” and sequencing them, (3) “repeating the capture probe hybridized
`
`sequencing on an additional sample from an additional timepoint,” and (4)
`
`“generating a biomedical report that identifies the presence or absence of the
`
`polymorphisms.”2
`
`Before January 17, 2013 (the’394 patent’s earliest potential priority date)
`
`– and long before Patent Owner began pursuing claims to what it now
`
`characterizes as its invention – those skilled in the art had monitored
`
`
`1 Ex. 1010 ¶29.
`2 Id. ¶30.
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`biomedically relevant genetic polymorphisms (i.e., variants of a given DNA
`
`sequence) by detecting them with a whole-genome sequencing assay before
`
`using such polymorphisms as biomarkers by capturing nucleic acids harboring
`
`the identified sequence for serial, targeted re-sequencing.
`
`By 2008, soon after whole-genome sequencing technology became
`
`available to the interested community, a group led by Timothy Ley and Richard
`
`Wilson at the Genome Center at Washington University put such “[f]aster, more
`
`efficient DNA sequencing” to work, becoming “the first to sequence the genome
`
`of a patient with acute myelogenous leukemia.”3 Their findings were reported in
`
`a 2008 Nature article that announced “whole-genome sequencing as an unbiased
`
`method for discovering cancer-initiating mutations in previously unidentified
`
`genes that may respond to targeted therapies.”4 The authors immediately
`
`recognized – from the first sequencing of the whole genome of a patient’s cancer
`
`– that “the use of next-generation whole genome sequencing approaches to
`
`reveal somatic mutations in cancer genomes” would help identify genetic
`
`“candidates for directed re-sequencing,” setting the stage for many others to
`
`pursue such approaches for cancer and other medical conditions involving
`
`genetic variation.5
`
`
`3 Ex. 1022 (Wilson leads quest to reveal the genome’s secrets).
`4 Ex. 1012 (Ley), 66.
`5 Id. at 66, 70.
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`By 2010, “highly sensitive assays for monitoring minimum residual
`
`disease (MRD) had become standard practice in several” hematological
`
`malignancies, emphasizing an “urgent” need “to have access to accurate and
`
`sensitive methods for quantifying response to cancer therapy, assessing residual
`
`disease burden, and predicting impending relapse.”6 That same year – nearly
`
`simultaneously – two groups further applied such methods to solid tumors.
`
`One group, led by Peter Campbell, head of the Sanger Institute, showed
`
`that “genomic rearrangements mapped with next-generation sequencing in
`
`individual cancers enable[s] the development of straightforward, sensitive and
`
`specific assays to quantify disease burden in serial blood samples.”7 Importantly,
`
`Campbell and colleagues observed that “[t]his fundamental concept is
`
`potentially applicable across most types of solid tumor and in diverse therapeutic
`
`settings.”8
`
`Indeed, while Campbell’s “manuscript was in preparation, another
`
`group,” led by Victor Velculescu and first author Rebecca Leary at Johns
`
`Hopkins University, “published similar paired-end rearrangement screens in six
`
`patients at diagnosis of colorectal cancer, with studies of plasma DNA in two
`
`
`6 Ex. 1015 (McBride), 1062.
`7 Id. at 1063.
`8 Id.
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`patients.”9 Dr. Campbell wrote that Leary “shows that tumor-specific
`
`rearrangements can be sensitively and specifically detected in plasma, with serial
`
`studies in one patient showing that levels correlated with decreasing disease-
`
`burden during treatment.”10 Subsequent papers and the parallel growth of
`
`knowledge how to apply next-generation sequencing techniques in the clinic led
`
`to even further ways to implement the fundamental approach to disease
`
`monitoring articulated in Ley, Campbell/McBride, and Leary: (1) identify
`
`polymorphisms of interest using whole-genome sequencing; (2) serially target
`
`those polymorphisms using well-characterized nucleic acid capture techniques;
`
`and (3) sequence the captured nucleic acids to provide information about the
`
`patient’s disease at different points in time.
`
`For the reasons set forth below, and as further explained in the declaration
`
`of Petitioner’s expert genome scientist John Quackenbush, Ph.D., Ex. 1020
`
`(“Quackenbush”), the challenged claims should be cancelled.
`
`II. GROUNDS FOR STANDING
`Petitioner certifies that the ’394 patent is available for inter partes review
`
`and that Petitioner is not barred or estopped from requesting an inter partes
`
`review challenging its claims on the grounds identified in this petition.
`
`
`9 Id. at 1068 (discussing Leary, Ex. 1002).
`10 Id.
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`IPR2023-00224
`U.S. Patent No. 11,384,394
`III. MANDATORY NOTICES
`A. Real Party-In-Interest
`Petitioner Foresight Diagnostics Inc. is the real party-in-interest with
`
`respect to this petition for inter partes review.
`
`B. Related Matters
`On August 2, 2022, Patent Owner filed a lawsuit against Petitioner
`
`alleging infringement of the ’394 patent and other patents assigned to Patent
`
`Owner. The case is pending in the United States District Court for the District of
`
`Colorado, bearing case number 1:22-cv-01913. Ex. 1010 (First Amended
`
`Complaint).
`
`The ’394 patent issued from Application No. 17/548,379, which claims
`
`priority to non-provisional Application No. 14/810,990. According to Patent
`
`Center, the ’394 patent is related to the applications below:
`
`• Application No. 17/548,379 is a continuation of Application No.
`17/078,857 (U.S. Patent 11,408,033);
`• Application No. 17/078,857 is a continuation of Application No.
`16/816,135 (Abandoned);
`• Application No. 16/816,135 is a continuation of Application No.
`16/526,928 (Abandoned);
`• Application No. 16/526,928 is a continuation of Application No.
`15/996,215 (U.S. Patent 10,415,091)
`• Application No. 15/996,215 is a continuation of Application No.
`14/810,337 (U.S. Patent No. 10,266,890);
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`• Application No. 14/810,337 is a continuation of Application No.
`14/141,990 (U.S. Patent No. 9,128,861);
`• Application No. 14/141,990 is a continuation of Provisional
`Application No. 61/753,828 (Expired).
`C. Lead and Back-up Counsel and Service Information
`
`LEAD COUNSEL
`Andrew E. Krause (Reg. No. 76,276)
`IRELL & MANELLA LLP
`1800 Avenue of the Stars, Suite 900
`Los Angeles, California 90067
`Telephone: (310) 277-1010
`Facsimile: (310) 203-7199
`akrause@irell.com
`ForesightIPRs@irell.com
`
`
`BACK-UP COUNSEL
`Amir Naini (Reg. No. 45,770)
`NAINI P.C.
`2632 Wilshire Blvd., Suite 268
`Santa Monica, California 90403
`Telephone: (310) 592-3030
`Facsimile: (310) 453-9008
`amir@nainipc.com
`
`
`D. Additional Service Information
`Please address all correspondence to the lead and back-up counsel as
`
`shown above. Petitioner consents to electronic service at:
`
`ForesightIPRs@irell.com
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`IV. THE ’394 PATENT
`According to its face, the ’394 patent issued on July 12, 2022 from
`
`Application No. 17/548,379. Ex. 1001, codes (45), (21). The ’394 patent claims
`
`priority to Provisional Application No. 61/753,828, filed on January 17, 2013.
`
`Id., code (60). According to Patent Center, the ’379 Application was not asserted
`
`to fall under the AIA’s first inventor to file provisions:
`
`
`The ’394 patent purports to disclose “systems and methods for sample
`
`processing and data analysis,” which can include sampling of a “nucleic acid
`
`sample and subsequent sequencing. Some or all of the nucleic acid sample may
`
`be sequenced to provide sequence information.” Ex. 1001, Abstract. The patent
`
`conclusorily states that such systems and methods can be used to “aid in the
`
`diagnosis, monitoring, treatment, and prevention of one or more diseases and
`
`conditions,” including for “monitoring the health of a fetus,” assessing
`
`“transplant tolerance,” and “suggest[ing]” therapies such as “anti-cancer
`
`therapies.” See id., Abstract, 54:1-26, 60:2-16. However, the specification
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`provides no data or working examples of any clinical application of the alleged
`
`invention in those or any other fields, let alone any data or working example
`
`supporting the claims as issued. Instead, the specification’s “Examples” are
`
`generally directed to nucleic acid library preparation steps whereby genomic
`
`DNA is divided into various “subsets” prior to sequencing. See id. (Examples).
`
`V. LEVEL OF ORDINARY SKILL IN THE ART
`As Dr. Quackenbush explains, a POSA in the field of the ’394 patent:
`
`[W]ould have had an advanced degree (such as an M.D. or the
`equivalent of a Ph.D. in a life or physical sciences, engineering, or
`mathematics discipline), and
`through further education or
`postdoctoral experience, an understanding of various sequencing
`and next generation sequencing methods, sample preparation
`methods, targeted enrichment methods, bioinformatics methods for
`interpreting sequencing data, and methods for identifying genetic
`variants in a sample. A POSA also would have had an
`understanding of clinical applications of sequencing technology to
`conditions associated with nucleic acid variation, such as cancer,
`non-invasive
`prenatal
`testing,
`and
`transplant
`rejection.
`Additionally, a POSA would have had an understanding of cancer
`biology as it relates to mutations associated with tumor diagnosis,
`progression, and treatment, as well as awareness of the various
`types of mutations that can occur in and influence the course of a
`patient’s cancer.
`
`Quackenbush ¶35, ¶¶37-91.
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`IPR2023-00224
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`VI. BACKGROUND KNOWLEDGE OF A POSA
`A. Genes and Mutations
`Genes contain the set of instructions for the development and maintenance
`
`of the cells of all organisms. Genes are made of deoxyribonucleic acid (“DNA”)
`
`and are located on chromosomes. Certain alterations, sometimes called
`
`“mutations,” “variations,” “variants,” or “polymorphisms,” can occur in all
`
`genes and portions of the human genome, contributing both to normal patterns
`
`of human variation as well as individual risk for developing diseases.
`
`Polymorphisms can include many types of genomic alteration, including
`
`insertions, deletions, point mutations, translocations, rearrangements, and copy
`
`number variations. The entire collection of an individual’s genetic variants is
`
`referred to as their “genotype.” Id. ¶¶39-50.
`
`Genetic mutations can be inherited (i.e., passed on from their parents to
`
`their offspring) or acquired (i.e., developed for the first time in a new cell).
`
`Inherited mutations are called “germline” mutations. Acquired, or non-inherited,
`
`mutations are called “somatic” mutations. Somatic mutations unique to a
`
`particular tumor can be a useful tool for detecting, tracking, and monitoring a
`
`patient’s cancer. Id. ¶51.
`
`Mutations known in the art included single nucleotide polymorphisms
`
`(“SNPs”), copy number variants (“CNVs”), and insertions or deletions
`
`(“indels”). An SNP (sometimes called a single nucleotide variant (“SNV”)) is a
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`change in one DNA base pair that may result in the substitution of one amino
`
`acid for another in the protein that is encoded by the gene. A POSA would have
`
`also been familiar with translocations, which involve the relocation of a gene
`
`from one chromosomal location to another. By 2013, many publicly accessible
`
`databases existed in which a POSA would have been able to search for a large
`
`number of catalogued cancer-associated mutations. Id. ¶¶52-54.
`
`B. Nucleic Acid Sequencing
`A POSA would have been familiar with multiple techniques for nucleic
`
`acid “sequencing,” i.e., determining the order of the bases in a nucleic acid
`
`molecule at the base-by-base level. For many years, sequencing was performed
`
`using “Sanger” sequencing, which terminates the synthesis of a template strand
`
`of DNA at different lengths. These different length DNA strands can be “read”
`
`to derive the DNA sequence. Id. ¶¶55-59.
`
`By around 2005, a new approach to sequencing called “next generation
`
`sequencing” (“NGS”), sometimes also called “massively parallel sequencing” or
`
`“sequencing by synthesis,” had been developed to allow multiplex sequencing
`
`of many different sequences simultaneously. By approximately 2008, techniques
`
`for NGS were well-known and commercially available. See, e.g., Ex. 1013. NGS
`
`is a high-throughput method for determining the base-by-base sequences of
`
`nucleic acid molecules, such as DNA. NGS is exponentially faster, cheaper, and
`
`more efficient than Sanger sequencing, though both techniques provide accurate
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`sequence
`information. Quackenbush ¶¶60-62.
`
` See also Ex. 1019
`
`(https://www.genome.gov/about-genomics/fact-sheets/DNA-Sequencing-
`
`Costs-Data).
`
`
`
`The development of NGS made more widely available “[t]he ability to
`
`sequence entire human genomes.” Ex. 1027. To obtain highly accurate
`
`sequencing information of the whole genome, a POSA would have understood
`
`that it was necessary to sequence, or “read,” each base in the genome multiple
`
`times to improve the accuracy of, and confidence in, sequencing results.
`
`Quackenbush ¶¶63-65.
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`C. Amplification and Enrichment
`Both Sanger sequencing and NGS require sufficient quantities and/or
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`relative abundances of target DNA. Thus, well before 2013, several techniques
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`had been developed to generate or isolate copies of DNA molecules of interest
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`to facilitate sequencing. A POSA would have been familiar with a number of
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`such techniques, including PCR and solution-phase hybridization. Id. ¶¶66-69.
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`Each technique has certain benefits over the others, but in many applications
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`they were used relatively interchangeably by those skilled in the art. Id. ¶69. See
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`Ex. 1006 (Table 1) (describing pros, cons, and overlapping applications of
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`“[c]urrently employed targeted enrichment techniques” as of 2011).
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`In PCR, DNA molecules are replicated in a manner that leverages the base
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`pairing of complementary DNA strands. In PCR, strands of double-stranded
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`DNA are first completely separated, leaving two complementary single-stranded
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`DNA strands, which serve as templates for replication. PCR “primers” or
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`“probes,” which are short oligonucleotides that are complementary to a small
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`portion of the DNA templates, can then be created. These primers/probes then
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`hybridize (i.e., bind through base pairing interactions) to, and thus “capture,” the
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`target region of interest on the DNA template strand. After the PCR primer
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`hybridizes to that target sequence, an enzyme called a “polymerase” synthesizes
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`a new nucleic acid molecule complementary to the single-stranded DNA
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`template. This process can be repeated, resulting in the exponential amplification
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`of the target sequence. Id. ¶¶70-75.
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`A POSA would also have been familiar with the use of solution-based
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`hybridization techniques for target enrichment. In short, this technique works by
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`mixing in solution the target DNA with an abundance of short nucleic acid
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`“baits.” Like the primers in the PCR approach, these “baits” hybridize to the
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`target DNA sequence of interest. The baits may also include an additional
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`component, such as biotin, that binds to a magnetic bead following the
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`hybridization step.
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`When such beads are mixed into the solution, the target sequence is captured
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`through bead-probe binding, and the target DNA can be isolated by washing
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`away the non-target, and hence unbound, DNA and then removing the beads and
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`baits. These techniques were well-characterized and widely used well before the
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`priority date, and a number of commercial vendors offered off the rack and on-
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`demand solutions to implement this approach. Id. ¶¶76-78. See also Ex. 1005,
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`Ex. 1006.
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`D.
`Personalized Biomedical Monitoring
`Once “[w]hole-genome sequencing [became] possible at reasonable cost
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`and timeframe,” Ley “use[d] this approach for the unbiased discovery of tumour-
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`specific somatic mutations that alter the protein-coding genes.” Id. Ley
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`established that a useful approach to cancer monitoring is to first fully
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`characterize the patient’s tumor using whole-genome sequencing to identify
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`polymorphisms of interest, and then serially monitor those polymorphisms to
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`track the tumor over time. As Dr. Quackenbush explains, a POSA would have
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`appreciated that in Ley’s approach, the results of the initial whole-genome
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`sequencing step would help clinicians avoid “miss[ing] key mutations,” and
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`allow them to create a specific set of probes to capture regions of interest
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`harboring the identified mutations for further sequencing. Quackenbush ¶¶79-
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`82. Shortly thereafter, Leary and McBride demonstrated the successful use of
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`the same concept, using structural variants (as opposed to SNPs/SNVs in Ley)
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`to serially monitor tumor DNA in the blood plasma of patients presenting with
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`solid tumors. Id. ¶83. Those skilled in the art further developed ways to report
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`the information obtained via such clinical protocols, and ways to leverage that
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`information, for example by identifying appropriate clinical trials or targeted
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`therapies. Id. ¶¶88-91.
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`Moreover, the use of whole-genome sequencing to develop targeted
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`monitoring assays was not limited to cancer, because the fundamental properties
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`of nucleic acids that enable this mode of analysis are universal. For example, by
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`2009, methods of analyzing nucleic acids to aid the diagnosis of transplant
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`rejection had been developed. Ex. 1003. Those methods, similar to those applied
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`in cancer surveillance, were based on the fact that a transplanted organ will have
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`a different genetic fingerprint (a different genotype, coming from the organ
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`donor) than the transplant recipient, and that once identified, that fingerprint may
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`be used to detect transplant rejection by monitoring the levels of cell free DNA
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`(cfDNA) observed in the transplant recipient’s blood. The underlying science is
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`that the cfDNA will be a mix of DNA from the recipient and the donor and that
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`the unique variants in the donor’s DNA will allow that DNA to be detected. See
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`generally id. ¶¶40-50, 69-70. Quake observed that such methods were
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`analytically similar to those used to detect and monitor cancer. Id. ¶41.
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`Following whole-genome sequencing, Quake explained that serial PCR or NGS
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`assays could be employed to “detect, identify, and/or quantify” the donor
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`specific markers in the transplant recipient following transplantation. See
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`id. ¶¶47-48, 73-75; Quackenbush ¶¶84-87.
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`VII. KEY PRIOR ART
`A. Leary
`Leary is an article that was published in Science Translational Medicine.
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`Ex. 1002. Petitioner’s expert librarian Dr. Ingrid Hsieh-Yee confirms that “Leary
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`would have been publicly accessible by February 25, 2010, on the internet, and
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`no later than June 16, 2010, when it became discoverable on PubMed.”
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`Ex. 1021 ¶22. See also Quackenbush ¶92. Leary is therefore prior art to the ’394
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`patent. The Supplementary Materials to Leary, Ex. 1026, are cited in the primary
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`manuscript and also would have been publicly accessible before the priority date.
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`Quackenbush ¶92.
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`B.
`Ley
`Ley is an article that was published in Nature by November 6, 2008.
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`Ex. 1012; Quackenbush ¶93. Ley is therefore prior art to the ’394 patent. See
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`Section VI.D (summarizing findings if Ley).
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`C. Chan
`Chan is an article that was published in Clinical Chemistry. Dr. Hsieh-
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`Yee confirms that Chan was accessible