Case 1:20-cv-01644-RGA Document 1-63 Filed 12/03/20 Page 1 of 92 PageID #: 1564
`Case 1:20-cv-01644-RGA Document 1-63 Filed 12/03/20 Page 1 of 92 PageID #: 1564
`
`EXHIBIT 63
`
`EXHIBIT 63
`
`

`

`Case 1:20-cv-01644-RGA Document 1-63 Filed 12/03/20 Page 2 of 92 PageID #: 1565
`
`Filed: June 13, 2019
`
`
`Filed on behalf of:
`Illumina, Inc.
`By: Kerry S. Taylor
`Michael L. Fuller
`Nathanael R. Luman
`KNOBBE, MARTENS, OLSON & BEAR, LLP
`2040 Main Street, 14th Floor
`Irvine, CA 92614
`Telephone: (858) 707-4000
`Facsimile: (858) 707-4001
`E-mail: BoxIllumina@knobbe.com
`
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`__________________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`__________________________________
`
`ILLUMINA, INC.,
`Petitioner,
`
`v.
`
`NATERA, INC.,
`Patent Owner.
`__________________________________
`
`Case No. IPR2019-01201
`Patent No. 8,682,592
`__________________________________
`
`PETITION FOR INTER PARTES REVIEW
`OF U.S. PATENT NO. 8,682,592
`
`
`
`
`

`

`Case 1:20-cv-01644-RGA Document 1-63 Filed 12/03/20 Page 3 of 92 PageID #: 1566
`
`TABLE OF CONTENTS
`
`Page No.
`
`I.
`
`II.
`
`INTRODUCTION ........................................................................................... 1
`
`CLAIM CONSTRUCTION ............................................................................ 5
`
`III. LEVEL OF ORDINARY SKILL .................................................................... 6
`
`IV. THE STATE OF THE ART ............................................................................ 6
`
`A.
`
`B.
`
`C.
`
`Introduction to Prenatal Diagnosis and IVF Screening ........................ 6
`
`Introduction to Chromosomes ............................................................... 7
`
`Single Nucleotide Polymorphisms (SNPs) and SNP
`Genotyping Arrays ................................................................................ 8
`
`V.
`
`REASONABLE LIKELIHOOD OF UNPATENTABILITY ......................... 9
`
`A. Grounds of Challenges .......................................................................... 9
`
`B.
`
`The Asserted References are Prior Art ................................................ 10
`
`1.
`
`2.
`
`3.
`
`4.
`
`U.S. 2004/0137470 (“Dhallan”) ............................................... 10
`
`Bianchi, British Journal of Haematology 105:574, 1999
`(“Bianchi”) ................................................................................ 10
`
`Sham, Nature Reviews Genetics 3:862, 2002 (“Sham”) .......... 10
`
`U.S. 2007/0184467 (“Rabinowitz”) .......................................... 10
`
`VI. GROUND 1: CLAIMS 1-12, 15-17, 19-23, AND 27 ARE
`OBVIOUS OVER DHALLAN ..................................................................... 11
`
`A.
`
`Introduction to Dhallan ....................................................................... 11
`
`B. Dhallan Renders Obvious Claims 1-12, 15-17, 19-23, and 27 ........... 14
`
`-i-
`
`

`

`Case 1:20-cv-01644-RGA Document 1-63 Filed 12/03/20 Page 4 of 92 PageID #: 1567
`
`TABLE OF CONTENTS
`(cont’d)
`
`Page No.
`
`1.
`
`Claim 1 ...................................................................................... 14
`
`a.
`
`b.
`
`c.
`
`d.
`
`e.
`
`f.
`
`Preamble ......................................................................... 14
`
`Limitation 1[i] ................................................................. 15
`
`Limitation 1[ii] ................................................................ 18
`
`i.
`
`ii.
`
`“a small amount of genetic material” ................... 18
`
`“the genetic data is noisy” .................................... 20
`
`Limitation 1[iii] .............................................................. 22
`
`Limitation 1[iv] ............................................................... 23
`
`Limitation 1[v] ................................................................ 26
`
`g. Motivation ....................................................................... 27
`
`h.
`
`Expectation of success .................................................... 31
`
`Claims 2 and 3 ........................................................................... 34
`
`Claim 4 ...................................................................................... 34
`
`Claim 5 ...................................................................................... 35
`
`Claim 6 ...................................................................................... 36
`
`Claim 7 ...................................................................................... 37
`
`Claim 8 ...................................................................................... 38
`
`Claim 9 ...................................................................................... 38
`
`Claim 10 .................................................................................... 39
`
`2.
`
`3.
`
`4.
`
`5.
`
`6.
`
`7.
`
`8.
`
`9.
`
`-ii-
`
`

`

`Case 1:20-cv-01644-RGA Document 1-63 Filed 12/03/20 Page 5 of 92 PageID #: 1568
`
`TABLE OF CONTENTS
`(cont’d)
`
`Page No.
`
`10. Claims 11 and 12....................................................................... 39
`
`11. Claim 15 .................................................................................... 40
`
`12. Claim 16 .................................................................................... 41
`
`13. Claim 17 .................................................................................... 42
`
`14. Claim 19 .................................................................................... 43
`
`15. Claim 20 .................................................................................... 44
`
`16. Claim 21 .................................................................................... 45
`
`17. Claim 22 .................................................................................... 45
`
`18. Claim 23 .................................................................................... 45
`
`19. Claim 27 .................................................................................... 46
`
`VII. GROUND 2: CLAIM 18 IS OBVIOUS OVER DHALLAN IN
`VIEW OF BIANCHI ..................................................................................... 46
`
`VIII. GROUND 3: CLAIMS 24-26 ARE OBVIOUS OVER DHALLAN
`IN VIEW OF SHAM ..................................................................................... 47
`
`A.
`
`B.
`
`Claim 24 .............................................................................................. 48
`
`Claims 25 and 26 ................................................................................. 49
`
`IX. GROUND 4: CLAIMS 1-27 ARE OBVIOUS OVER
`RABINOWITZ .............................................................................................. 51
`
`A. No Presumption of an Earlier Priority Date ........................................ 51
`
`B.
`
`The Priority Applications Do Not Disclose “High-
`Throughput DNA Sequencing” ........................................................... 52
`
`-iii-
`
`

`

`Case 1:20-cv-01644-RGA Document 1-63 Filed 12/03/20 Page 6 of 92 PageID #: 1569
`
`TABLE OF CONTENTS
`(cont’d)
`
`Page No.
`
`C.
`
`Rabinowitz Renders Obvious Claims 1-27 ......................................... 56
`
`1.
`
`Claim 1 ...................................................................................... 56
`
`a.
`
`b.
`
`c.
`
`d.
`
`e.
`
`f.
`
`Preamble ......................................................................... 56
`
`Limitation 1[i] ................................................................. 57
`
`Limitation 1[ii] ................................................................ 58
`
`Limitation 1[iii] .............................................................. 59
`
`Limitation 1[iv] ............................................................... 60
`
`Limitation 1[v] ................................................................ 60
`
`g. Motivation and expectation of success ........................... 61
`
`Claims 2 and 3 ........................................................................... 61
`
`Claim 4 ...................................................................................... 62
`
`Claim 5 ...................................................................................... 62
`
`Claim 6 ...................................................................................... 62
`
`Claim 7 ...................................................................................... 63
`
`Claim 8 ...................................................................................... 63
`
`Claim 9 ...................................................................................... 63
`
`Claim 10 .................................................................................... 63
`
`2.
`
`3.
`
`4.
`
`5.
`
`6.
`
`7.
`
`8.
`
`9.
`
`10. Claims 11 and 12....................................................................... 64
`
`11. Claim 13 .................................................................................... 64
`
`-iv-
`
`

`

`Case 1:20-cv-01644-RGA Document 1-63 Filed 12/03/20 Page 7 of 92 PageID #: 1570
`
`TABLE OF CONTENTS
`(cont’d)
`
`Page No.
`
`12. Claim 14 .................................................................................... 65
`
`13. Claim 15 .................................................................................... 65
`
`14. Claim 16 .................................................................................... 65
`
`15. Claim 17 .................................................................................... 66
`
`16. Claim 18 .................................................................................... 66
`
`17. Claim 19 .................................................................................... 66
`
`18. Claim 20 .................................................................................... 67
`
`19. Claim 21 .................................................................................... 67
`
`20. Claim 22 .................................................................................... 67
`
`21. Claim 23 .................................................................................... 68
`
`22. Claim 24 .................................................................................... 68
`
`23. Claims 25 and 26....................................................................... 68
`
`24. Claim 27 .................................................................................... 68
`
`X. NO SECONDARY CONSIDERATIONS .................................................... 69
`
`XI. MANDATORY NOTICES (37 C.F.R. §42.8(A)(1)) .................................... 69
`
`A.
`
`B.
`
`C.
`
`D.
`
`Real Party-In-Interest .......................................................................... 69
`
`Related Matters .................................................................................... 69
`
`Lead and Back-Up Counsel ................................................................. 69
`
`Service Information ............................................................................. 70
`
`-v-
`
`

`

`Case 1:20-cv-01644-RGA Document 1-63 Filed 12/03/20 Page 8 of 92 PageID #: 1571
`
`TABLE OF CONTENTS
`(cont’d)
`
`Page No.
`
`XII. PAYMENT OF FEES (37 C.F.R. §42.103) .................................................. 70
`
`XIII. REQUIREMENTS FOR REVIEW (37 C.F.R. §42.104) .............................. 70
`
`XIV. CONCLUSION .............................................................................................. 71
`
`
`
`
`
`-vi-
`
`

`

`Case 1:20-cv-01644-RGA Document 1-63 Filed 12/03/20 Page 9 of 92 PageID #: 1572
`
`TABLE OF AUTHORITIES
`
`Page No(s).
`
`Ariad Pharms., Inc. v. Eli Lilly and Co.,
`598 F.3d 1336 (Fed. Cir. 2010) (en banc) ............................................... 52, 54
`
`Boston Sci. Scimed, Inc. v. Cordis Corp.,
`554 F.3d 982 (Fed. Cir. 2009) ................................................................. 28, 61
`
`Dynamic Drinkware, LLC v. National Graphics, Inc.
`800 F.3d 1375 (Fed. Cir. 2015) ............................................................... 51, 52
`
`KSR Int’l Co. v. Teleflex Inc.,
`550 U.S. 398 (2007) ........................................................................................ 26
`
`In re NTP, Inc.,
`654 F.3d 1268 (Fed. Cir. 2011) ...................................................................... 52
`
`PowerOasis, Inc. v. T-Mobile USA, Inc.,
`522 F.3d 1299 (Fed. Cir. 2008) ...................................................................... 51
`
`Western Union Co. v. MoneyGram Payment Sys., Inc.,
`626 F.3d 1361 (Fed. Cir. 2010) ...................................................................... 26
`
`OTHER AUTHORITIES
`
`35 U.S.C. §112 .................................................................................... 5, 10, 51, 52
`
`35 U.S.C. §119 ..................................................................................................... 52
`
`35 U.S.C. §315 ..................................................................................................... 71
`
`37 C.F.R. §42.8 .................................................................................................... 69
`
`37 C.F.R. §42.15 .................................................................................................. 70
`
`37 C.F.R. §42.103 ................................................................................................ 70
`
`37 C.F.R. §42.104 ................................................................................................ 70
`
`-vii-
`
`

`

`Case 1:20-cv-01644-RGA Document 1-63 Filed 12/03/20 Page 10 of 92 PageID #: 1573
`Illumina v. Natera
`IPR Petition – U.S. Patent No. 8,682,592
`
`
`EXHIBIT LIST
`
`
`Exhibit No.
`1001
`1002
`1003
`1004
`1005
`1006
`1007
`
`1008
`
`1009
`
`1010
`
`1011
`
`1012
`
`1013
`
`1014
`1015
`1016
`1017
`1018
`
`Description
`
`U.S. Patent No. 8,682,592
`U.S. Patent Publication No. 2004/0137470 (“Dhallan”)
`U.S. Patent Publication No. 2007/0184467 (“Rabinowitz”)
`Declaration of David G. Peters, Ph.D.
`Exhibit number not used.
`Exhibit number not used.
`Exhibit number not used.
`Claim Construction Order, Illumina, Inc. v. Natera, Inc.,
`C.A. No. 18-cv-01662 (N.D. Cal.) (D.I. 81)
`Alberts et al., The Molecular Biology of the Cell (4th Ed. 2002),
`Chapters 4 and 20
`Hartwell et al., Genetics: From Genes to Genomes (2nd Ed.
`2004), Chapters 11 and 13
`Jenkins and Gibson, “High-throughput SNP genotyping,”
`3 Comparative and Functional Genomics 57-66 (2002)
`Antonarakis et al., “Chromosome 21 and Down Syndrome: From
`Genomics to Pathophysiology,” 5 Nature Reviews Genetics 725-
`738 (2004).
`Hattori et al., “The DNA sequence of human chromosome 21,”
`405 Nature 311-319 (2000).
`Curriculum Vitae of David Peters, Ph.D.
`List of Materials Considered by David Peters, Ph.D.
`Exhibit number not used.
`Exhibit number not used.
`Weiss, Introductory Statistics (6th Ed. 2002), Chapter 8
`
`Exhibit List, Page 1
`
`

`

`Case 1:20-cv-01644-RGA Document 1-63 Filed 12/03/20 Page 11 of 92 PageID #: 1574
`Illumina v. Natera
`IPR Petition – U.S. Patent No. 8,682,592
`
`
`Exhibit No.
`1019
`1020
`
`1021
`
`1022
`
`1023
`
`1024
`
`1025
`
`1026
`1027
`
`1028
`
`1029
`
`1030
`
`1031
`
`1032
`
`1033
`
`Description
`Illumina GenCall Data Analysis Software (2005)
`Exhibit number not used.
`Sham et al., “DNA Pooling: A Tool for Large-Scale Association
`Studies,” 3 Nature Reviews Genetics 862-871 (2002)
`Tiersch et al. “Reference Standards for Flow Cytometry and
`Application in Comparative Studies of Nuclear DNA Content,”
`10 Cytometry 706-710 (1989)
`Hellani et al., “Multiple displacement amplification on single cell
`and possible PGD applications” 10 Molecular Human
`Reproduction 847-852 (2004)
`The International HapMap Consortium, “The International
`HapMap Project,” 426 Nature 789-796 (2003)
`Natera, Inc.’s First Amended Answer, Affirmative Defenses and
`Counterclaims, Illumina, Inc. v. Natera, Inc., C.A. No. 18-cv-
`01662 (N.D. Cal.) (D.I. 61)
`U.S. Application No. 11/603,406 (’406 application)
`Claims as filed, U.S. Patent No. 8,682,592
`Pastinen et al., “Minisequencing: A Specific Tool for DNA
`Analysis and Diagnostics on Oligonucleotide Arrays,” 7 Genome
`Research 606-614 (1997)
`Exhibit number not used.
`Zhang et al., “Whole genome amplification from a single cell:
`Implications for genetic analysis,” 89 Proc. Nat’l. Acad. Sci.
`(USA) 5847-5851 (1992)
`U.S. Patent No. 6,124,120
`Zhao et al., “An Integrated View of Copy Number and Allelic
`Alterations in the Cancer Genome Using Single Nucleotide
`Polymorphism Arrays,” 64 Cancer Research 3060-3071 (2004)
`Exhibit number not used.
`
`Exhibit List, Page 2
`
`

`

`Case 1:20-cv-01644-RGA Document 1-63 Filed 12/03/20 Page 12 of 92 PageID #: 1575
`Illumina v. Natera
`IPR Petition – U.S. Patent No. 8,682,592
`
`
`Exhibit No.
`
`1034
`
`1035
`
`1036
`
`1037
`
`1038
`
`1039
`1040
`1041
`1042
`1043
`
`1044
`
`1045
`
`1046
`
`1047
`1048
`
`Description
`Bianchi, “Fetal Cells in the Maternal Circulation: Feasibility for
`Prenatal Diagnosis,” 105 British Journal of Haematology 574-583
`(1999)
`Dietmaier et al., “Multiple Mutation Analyses in Single Tumor
`Cells with Improved Whole Genome Amplification,” 154
`American Journal of Pathology 83-95 (1999)
`Hu et al., “Aneuploidy detection in single cells using DNA array-
`based comparative genomic hybridization,” 10 Molecular Human
`Reproduction 283-289 (2004)
`Wong et al., “Allelic imbalance analysis by high-density single-
`nucleotide polymorphic allele (SNP) array with whole genome
`amplified DNA,” 32 Nucleic Acids Research e69 (2004)
`Munné et al., “Improved implantation after preimplantation
`genetic diagnosis of aneuploidy,” 7 Reproductive BioMedicine
`Online 91-97 (2003)
`Provisional Application No. 60/817,741
`Provisional Application No. 60/739,882
`Provisional Application No. 60/754,396
`Provisional Application No. 60/774,976
`Provisional Application No. 60/789,506
`Natera, Inc.’s Supplemental Objections and Responses To
`Plaintiff Illumina, Inc.’s Interrogatory No. 8, Illumina, Inc. v.
`Natera, Inc., C.A. No. 18-cv-01662 (N.D. Cal.)
`Exhibit number not used.
`Béroud et al., “Prenatal diagnosis of spinal muscular atrophy by
`genetic analysis of circulating fetal cells,” 361 Lancet 1013-14
`(2003)
`Provisional Application No. 60/846,610
`Everitt, “Medical Statistics from A to Z” (2003).
`
`Exhibit List, Page 3
`
`

`

`Case 1:20-cv-01644-RGA Document 1-63 Filed 12/03/20 Page 13 of 92 PageID #: 1576
`Illumina v. Natera
`IPR Petition – U.S. Patent No. 8,682,592
`
`
`Exhibit No.
`
`1049
`
`Description
`Lo, et al., “Presence of fetal DNA in maternal plasma and serum,”
`350 The Lancet 485 (1997)
`
`
`
`
`Exhibit List, Page 4
`
`

`

`Case 1:20-cv-01644-RGA Document 1-63 Filed 12/03/20 Page 14 of 92 PageID #: 1577
`Illumina v. Natera
`IPR Petition – U.S. Patent No. 8,682,592
`
`
`Illumina, Inc. requests inter partes review of Claims 1-27 of U.S. 8,682,592
`
`(“’592 patent”) (Ex. 1001), purportedly owned by Natera, Inc.
`
`I.
`
`INTRODUCTION
`
`The ’592 patent is directed to analysis of genetic data. The claims of the
`
`’592 patent, however, are overly broad and detached from the focus of the
`
`specification. The specification is a labyrinth of mathematical equations. The
`
`Detailed Description comprises 53 columns (Ex. 1001, 10:50-62:37), with 46
`
`columns chronicling a complicated series of data cleaning equations (id., 11:21-
`
`57:3), and just 2 columns providing a laundry list of routine prior art methods for
`
`generating the genetic data to be cleaned (id., 57:4-58:54). The remaining 5
`
`columns describe proposed “combinations” (id., 58:55-60:63), “miscellaneous
`
`notes” (id., 60:64-62:4), and “definitions” (id., 62:6-37).
`
`The 46 columns of data cleaning equations start with a correlation analysis
`
`between a set of eight measured vectors as follows:
`
`
`
`Id., 12:6-12. Thereafter, conditional probabilities recast the correlation analysis to
`
`a more complex set of vectors:
`
`Id., 13:19-23. Additional mathematical manipulations are described (id., 14:66-
`
`
`
`-1-
`
`

`

`Case 1:20-cv-01644-RGA Document 1-63 Filed 12/03/20 Page 15 of 92 PageID #: 1578
`Illumina v. Natera
`IPR Petition – U.S. Patent No. 8,682,592
`
`17:50) before the following odds ratio is computed:
`
`Id., 17:64-18:15. The specification continues with numerous calculations
`
`involving recursive derivations, integrals, and probability algorithms. Id., 18:16-
`
`
`
`57:3.
`
`The data cleaning equations form the only possible contribution to the art
`
`described in the specification, but these equations are absent from the issued
`
`claims. Claim 1—the only independent claim—is reproduced below with
`
`bracketed labels added for convenient referencing to the limitations:
`
`Claim 1
`
`1. [preamble] An ex vivo method for determining a number of
`copies of a chromosome or chromosome segment of interest in the
`genome of an individual, the method comprising:
`
`-2-
`
`

`

`Case 1:20-cv-01644-RGA Document 1-63 Filed 12/03/20 Page 16 of 92 PageID #: 1579
`Illumina v. Natera
`IPR Petition – U.S. Patent No. 8,682,592
`
`
`[i] using a single nucleotide polymorphism (SNP) genotyping
`array or high throughput DNA sequencing to measure genetic material
`and produce genetic data for some or all possible alleles at a plurality
`of at least 100 loci on the chromosome or chromosome segment of
`interest in the individual,
`
`[ii] wherein the genetic data is noisy due to a small amount of
`genetic material from the individual; and wherein the small amount of
`genetic material from the individual is from fifty or fewer of the
`individual’s cells, 0.3 ng or less of the individual’s DNA, extracellular
`DNA from the individual found in maternal blood, or combinations
`thereof;
`
`[iii] creating a set of one or more hypotheses specifying the
`number of copies of the chromosome or chromosome segment of
`interest in the genome of the individual;
`
`[iv] determining, on a computer, the probability of each of the
`hypotheses given the produced genetic data; and
`
`[v] using the probabilities associated with each hypothesis to
`determine the most likely number of copies of the chromosome or
`chromosome segment of interest in the genome of the individual.
`
`The issued claims deviate so extensively from the focus of the specification
`
`that they bear no discernable relationship to the disclosed data cleaning equations.
`
`The ’592 patent admits that its mathematical data cleaning algorithms were meant
`
`-3-
`
`

`

`Case 1:20-cv-01644-RGA Document 1-63 Filed 12/03/20 Page 17 of 92 PageID #: 1580
`Illumina v. Natera
`IPR Petition – U.S. Patent No. 8,682,592
`
`to be applied to well-known and routine prior art methods for generating genetic
`
`data. Id., Abstract (admitting genetic data is acquired “using known methods”);
`
`id., 11:5-6 (conceding the disclosed statistical approach is “applied to the
`
`technology of today”); id., 57:5-14. The specification assumes that a person of
`
`ordinary skill in the art (“POSA”) would generate genetic data using well-known
`
`methods that are merely listed—without explanation—in the specification. For
`
`example, commercially available SNP genotyping arrays would be used to measure
`
`genetic data (id., 57:57-58:54), or a cell is isolated from an embryo “following
`
`techniques common in in vitro fertilization clinics” (id., 57:24-25). The claims
`
`abandon the mathematical analyses of the specification and reduce the data
`
`analysis to generalized steps that read on the prior art, including the prior art
`
`Dhallan reference (Ex. 1002) discussed herein.
`
`The Board should cancel Claims 1-12 and 15-27 of the ’592 patent based on
`
`Dhallan alone or in view of Bianchi (Claim 18) or Sham (Claims 24-26).
`
`Further, Patent Owner stretched the claims even further by reciting “high
`
`throughput DNA sequencing” in limitation 1[i] as an alternative to SNP
`
`genotyping arrays. The “high throughput DNA sequencing” alternative was added
`
`on March 11, 2013, when the ’592 patent application was filed. High throughput
`
`DNA sequencing is not disclosed in the specification, nor is it described in any of
`
`the priority applications. In fact, the specification admits that DNA sequencing
`
`-4-
`
`

`

`Case 1:20-cv-01644-RGA Document 1-63 Filed 12/03/20 Page 18 of 92 PageID #: 1581
`Illumina v. Natera
`IPR Petition – U.S. Patent No. 8,682,592
`
`technologies available as of its earliest non-provisional filing date were “not
`
`currently conducive to high-throughput parallel analysis.” Ex. 1001, 5:15-16. For
`
`reasons discussed herein, Claim 1 lacks §112 written description support for the
`
`“high throughput DNA sequencing” alternative of limitation 1[i]. Therefore, the
`
`issued claims are entitled to an effective filing date no earlier than March 11, 2013.
`
`The parent application (“Rabinowitz”) (Ex. 1003) published on August 9,
`
`2007 and is §102(b) prior art to the ’592 patent. Rabinowitz discloses the SNP
`
`genotyping array alternative listed in limitation 1[i] and all other claim limitations.
`
`Rabinowitz therefore renders the claims unpatentable.
`
`Claims 1-27 should be cancelled based on Rabinowitz.
`
`II. CLAIM CONSTRUCTION
`
`No term requires express construction in this proceeding. Two claim terms
`
`were construed in the co-pending district court litigation:
`
` “genetic data for some or all possible alleles” means “genetic data for
`
`some or all possible base pairs at a given locus”
`
` “at least 100 loci on the chromosome or chromosome segment of
`
`interest in the individual” means “at least 100 loci on the chromosome
`
`or chromosome segment of interest from only the individual”1
`
`
`1 Emphasis added throughout unless otherwise indicated.
`
`-5-
`
`

`

`Case 1:20-cv-01644-RGA Document 1-63 Filed 12/03/20 Page 19 of 92 PageID #: 1582
`Illumina v. Natera
`IPR Petition – U.S. Patent No. 8,682,592
`
`Ex. 1008, 12, 15. In construing the second term, the Court rejected Natera’s
`
`argument that “the individual” means “more than one” individual. Id., 13. The
`
`Court’s constructions are applied in this Petition. Dhallan and Rabinowitz render
`
`the claims unpatentable under either the Court’s construction or Natera’s rejected
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`construction.
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`III. LEVEL OF ORDINARY SKILL
`
`The POSA would have been a member of a team of scientists developing
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`genetic techniques to obtain and analyze genetic data. The POSA would have had
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`an M.D. or master’s or Ph.D. in molecular biology, genetics, bioinformatics, or a
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`related field and, through either education or work experience, 2-3 years of
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`experience with nucleic acid sequencing, sample preparation, and prenatal
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`diagnostics.
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`IV. THE STATE OF THE ART
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`The ’592 patent relies on commonly understood genetic principles and
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`utilizes routine prior art techniques to obtain genetic data for analysis, such as
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`prenatal diagnosis of chromosomal abnormalities. The following sections
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`summarize these well-known and routine biological techniques.
`
`A.
`
`Introduction to Prenatal Diagnosis and IVF Screening
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`Genetic material (e.g., DNA) can be found in a pregnant mother’s blood
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`from two sources—the mother and the developing fetus. Historically, fetal genetic
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`conditions were monitored by obtaining fetal DNA by invasive and risky
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`techniques such as amniocentesis or chorionic villus sampling. Ex. 1034, 574.
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`However, it was known before the ’592 patent that fetal cells and cell-free fetal
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`DNA could be detected and isolated from maternal blood to analyze the fetal
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`genome in a non-invasive manner. Id., 574-579; Ex. 1004 ¶¶ 59-62.
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`Also before the ’592 patent, it was routine to screen in vitro fertilized (IVF)
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`embryos for genetic disease. Ex. 1010, 371; Ex. 1001, 2:32-33, 57:23-25. This
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`screening involved obtaining a single cell from an embryo, isolating and
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`amplifying DNA, and genotyping the genetic material. Ex. 1010, 371; Ex. 1004
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`¶¶63-65.
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`B.
`
`Introduction to Chromosomes
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`The information stored in an organism’s DNA is referred to as its “genome”
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`(Ex. 1009, 196), which is stored in long pieces of double-stranded DNA, folded
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`into a compact structures called chromosomes. Id., 198. A normal human cell,
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`with some exceptions, has 24 different chromosomes—22 autosomal (non-sex)
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`chromosomes, and 2 possible sex chromosomes (either X or Y). Id.; Ex. 1004 ¶37-
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`44. Each cell typically includes two copies of each chromosome: one copy from
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`the mother (the maternal copy) and one from the father (the paternal copy).
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`Ex. 1009, 198. A cell with two copies of each chromosome is a “diploid” cell.
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`Occasionally, an embryo is missing a copy of one chromosome or includes
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`an extra copy of one chromosome. Id. An abnormal number of chromosomes is
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`called an “aneuploidy,” and this is often fatal. Ex. 1010, 466. However, an
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`embryo with an extra copy of chromosome 21 is viable, and will develop into a
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`child with a genetic condition called Down syndrome. Id.; Ex. 1004 ¶¶45-47.
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`C.
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`Single Nucleotide Polymorphisms (SNPs) and SNP Genotyping
`Arrays
`
`Human genomes typically differ from each other by approximately 0.1% of
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`the nucleotide sites within their genomes. Ex. 1024, 789. The most common
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`variant is a single nucleotide polymorphism, or SNP. Id. A SNP is a nucleotide
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`position (“locus”) in the chromosome that shows some variability. Any two copies
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`of a chromosome may have different nucleotides (or “alleles”) at that specific
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`position. Id.; Ex. 1004 ¶¶48-50.
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`Analyzing SNPs to determine the alleles present in a genome is called
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`“genotyping.” Ex. 1024, 790. The figure below illustrates three SNPs on the same
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`chromosome from four different genomes. The left-hand SNP has either a C or T
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`allele, while the middle and right-hand SNPs have either a G or A allele.
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`Id.
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`By 2004, several approaches were well-known for SNP genotyping. Id.,
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`379; Ex. 1012, 728.
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` One well-known approach, called allele-specific
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`oligonucleotide hybridization (ASO), analyzes SNPs using oligonucleotide probes
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`that hybridize to specific locations of interest in a genome (“genetic loci”).
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`Ex. 1010, 378-380.
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` ASO was miniaturized into a microarray format to
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`simultaneously analyze hundreds or thousands of SNP loci. Id., 381. Many
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`commercial SNP genotyping arrays were able to analyze thousands of SNP loci
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`with high-throughput. Ex. 1011. Commercial SNP genotyping arrays included
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`HuSNP GeneChip arrays and Illumina BeadArrays. Id. SNP genotyping arrays
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`were a known approach to detect chromosomal abnormalities, including in a fetus
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`or embryo. Ex. 1013, 318; Ex. 1034, 579; Ex. 1010, 371-372; Ex. 1004 ¶¶50-58.
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`V. REASONABLE LIKELIHOOD OF UNPATENTABILITY
`A. Grounds of Challenges
`
`Review is requested for the following grounds of unpatentability:
`
`Ground
`1
`2
`3
`4
`
`Reference(s)
`Dhallan
`Dhallan in view of Bianchi
`Dhallan in view of Sham
`Rabinowitz
`
`Ground Challenged Claims
`§103
`1-12, 15-17, 19-23, 27
`§103
`18
`§103
`24-26
`§103
`1-27
`
`
`
`-9-
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`
`B.
`
`The Asserted References are Prior Art
`
`The references asserted in this Petition are §102(b) prior art to the ’592
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`patent.
`
`1.
`
`U.S. 2004/0137470 (“Dhallan”)
`
`Dhallan (Ex. 1002) was published July 15, 2004, which was more than a
`
`year before the earliest possible priority date for the ’592 patent, November 26,
`
`2005. Thus, Dhallan is §102(b) prior art.
`
`2.
`
`Bianchi, British Journal of Haematology 105:574, 1999
`(“Bianchi”)
`
`Bianchi (Ex. 1034) published in 1999, and is §102(b) prior art.
`
`3.
`
`Sham, Nature Reviews Genetics 3:862, 2002 (“Sham”)
`
`Sham (Ex. 1021) published in 2002, and is §102(b) prior art.
`
`4.
`
`U.S. 2007/0184467 (“Rabinowitz”)
`
`Rabinowitz (Ex. 1003) was published August 9, 2007. As discussed below
`
`in Section IX.A-B, the claims of the ’592 patent do not have §112 written
`
`description support in any identified priority document, and are thus not entitled to
`
`a priority date earlier than the actual filing date of March 11, 2013. Rabinowitz is
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`the parent application to the ’592 patent, and it was published more than a year
`
`