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`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`COMPLETE GENOMICS, INC.
`Petitioner
`
`v.
`
`ILLUMINA CAMBRIDGE LTD.
`Patent Owner
`
`____________
`
`Case IPR2017-02172
`Patent 7,566,537 B2
`____________
`
`
`
`
`PETITION FOR INTER PARTES REVIEW OF
`U.S. PATENT NO. 7,566,537 B2
`
`
`
`
`
`
`
`Columbia Ex. 2008
`Illumina, Inc. v. The Trustees
`of Columbia University
`in the City of New York
`IPR2020-01177
`
`

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`IPR2017-02172
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`TABLE OF CONTENTS
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`Page No.
`
`I. 
`
`INTRODUCTION ........................................................................................... 1 
`
`II.  MANDATORY NOTICES UNDER 37 C.F.R. §42.8 .................................... 4 
`
` 
`
`A.
`Real Party-In-Interest (37 C.F.R. §42.8(b)(1)) ..................................... 4 
`B.
`Related Matters (37 C.F.R. §42.8(b)(2)) ............................................... 4 
` 
`C.
`Lead and Back-up Counsel (37 C.F.R. §42.8(b)(3)-(4)) ....................... 7 
` 
`D.
`Service Information (37 C.F.R. §42.8(b)(4)) ........................................ 7 
` 
`III.  REQUIREMENTS FOR INTER PARTES REVIEW .................................... 8 
`
` 
`
` 
`
`A.
`B.
` 
`C.
`
`Payment of Fees (37 C.F.R. §42.103) ................................................... 8 
`Grounds for Standing (37 C.F.R. §42.104(a)) ...................................... 8 
`Identification of Challenge and Precise Relief Requested (37
`C.F.R. §42.104(b)(1)-(2)) ...................................................................... 8 
`IV.  THE ’537 PATENT AND PRIOR PROCEEDINGS ...................................... 9 
`
` 
`
`The ’537 Patent ..................................................................................... 9 
`A.
`Impact of Prior Proceedings Regarding the ’537 Patent ..................... 12 
`B.
` 
`V.  DEFINITION OF A PERSON OF ORDINARY SKILL IN THE
`ART ............................................................................................................... 14 
`
`VI.  THE STATE OF THE ART .......................................................................... 15 
`
`A.
`  Advances in DNA Science .................................................................. 15 
`Knowledge of a POSITA Relating to SBS ......................................... 18 
`B.
` 
`1. 
`Use of the solid phase was well known in the art. .................... 18 
`2. 
`Labels and linkers were well known in the art. ........................ 20 
`3. 
`Enzymes capable of incorporation and conditions for their
`use were well known in the art. ................................................ 20 
`A POSITA would have known how to select a suitable
`protecting group and deblocking conditions. ............................ 21 
`
`4. 
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`5. 
`
`A POSITA would have known other methods to optimize
`the SBS process. ........................................................................ 22 
`A POSITA Would Have Appreciated Multiple Uses for Modified
`Nucleotides .......................................................................................... 23 
`VII.  CLAIM CONSTRUCTION .......................................................................... 24 
`
`C.
`
` 
`
`VIII.  ALL THE LIMITATIONS OF CLAIMS 1-6 & 8 WERE
`DISCLOSED IN THE PRIOR ART ............................................................. 25 
`
`2. 
`
`A.
`
` 
`
`B.
`
` 
`
`The “Azido” and “Azidomethyl” Protecting Groups of Claims 1
`and 6 Were Disclosed in Zavgorodny and Greene & Wuts. ............... 25 
`1. 
`Greene & Wuts discloses “azido” and “azidomethyl”
`protecting groups ....................................................................... 25 
`Zavgorodny discloses the “azido” and “azidomethyl”
`protecting groups of Claims 1 and 6, respectively. .................. 25 
`Tsien Discloses Each Limitation of Claims 1-2, 4-6, and 8 Except
`the Azido and Azidomethyl Protecting Groups. ................................. 26 
`IX.  THE CHALLENGED CLAIMS ARE OBVIOUS OVER THE
`PRIOR ART ................................................................................................... 30 
`
` 
`
`A.
`B.
` 
`
`C.
`
` 
`
`D.
`
` 
`
`Legal Standards for Obviousness ........................................................ 30 
`The Crux of this Petition is the Rationale for a “Motivation to
`Combine” ............................................................................................. 31 
`Tsien’s Disclosure Must Be Considered from the Perspective of a
`POSITA ............................................................................................... 32 
`Tsien’s Incorporation and Deblocking Criteria Would Have Led a
`POSITA to Modify Tsien’s SBS Method by Using the
`Azidomethyl Protecting Group of Zavgorodny and Greene &
`Wuts ..................................................................................................... 38 
`1. 
`A POSITA would have appreciated that each of Tsien’s
`incorporation and deblocking criteria suggest that
`azidomethyl would be a suitable alternative protecting
`group for use with Tsien’s SBS method and would therefore
`have been motivated to use an azidomethyl protecting
`group. ........................................................................................ 38 
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`i. 
`
`The ability of a polymerase enzyme to accurately and
`efficiently incorporate the dNTPs carrying the 3′-
`blocking groups .............................................................. 38 
`
`ii. 
`
`Reinitiation of DNA synthesis ........................................ 41 
`
`iii.  Mild deblocking conditions ............................................ 41 
`
`a. 
`
`b. 
`
`c. 
`
`Zavgorodny’s deblocking conditions are
`sufficiently “mild” ................................................ 42 
`
`Greene & Wuts refers to Loubinoux, which
`provides alternative “mild” deblocking
`conditions ............................................................. 43 
`
`A POSITA would have known that alternative
`“mild” conditions could be used to deblock an
`azidomethyl protecting group............................... 45 
`
`iv.  A quantitative or high yield of de-blocked 3′-OH
`groups ............................................................................. 46 
`
`v. 
`
`Rapid deblocking ............................................................ 50 
`
`2. 
`
`The obviousness of combining azidomethyl with Tsien’s
`SBS methods is further supported by the ’537 Patent and
`Illumina’s statements in other proceedings .............................. 52 
`A POSITA Would Have Recognized Azidomethyl As a Known
`Element That Could Be Simply Substituted Into Tsien’s SBS
`Method to Yield Predictable Results ................................................... 53 
`Ground 2: Claim 3 is Obvious Over Tsien in Combination with
`Greene & Wuts and Zavgorodny, In Further Combination with
`Prober. ................................................................................................. 55 
`X.  OBJECTIVE INDICIA OF NONOBVIOUSNESS DO NOT
`SUPPORT THE PATENTABILITY OF THE CHALLENGED
`CLAIMS ........................................................................................................ 57 
`
`E.
`
` 
`
`F.
` 
`
`A.
`
`  No Nexus Between the Satisfaction of a Long-Felt, Unmet Need
`and the Claimed Azidomethyl Group ................................................. 57 
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`B.
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`Illumina’s Arguments for New and Unexpected Results Do Not
`Have a Sufficient Nexus to the Claims and Are Based on
`Hindsight Bias ..................................................................................... 59 
`C.
`Evidence of Copying is Completely Absent ....................................... 60 
` 
`D.
`Praise by Others Was Likely Unrelated to the Claim Limitations ...... 61 
` 
`XI.  CONCLUSION .............................................................................................. 61 
`
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`TABLE OF AUTHORITIES
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` Page(s)
`
`Cases
`DyStar Textilfarben GmbH v. C.H. Patrick Co.,
`464 F.3d 1356 (Fed. Cir. 2006) .................................................................... 30, 38
`
`Ilumina Cambridge Ltd. v. Intelligent Bio-Systems, Inc.,
`638 Fed. Appx. 999 (Fed. Cir. 2016) (unpublished) ............................................ 4
`
`In re Epstein,
`32 F.3d 1559 (Fed. Cir. 1994) ...................................................................... 31, 53
`
`In re GPAC,
`57 F.3d 1573 (Fed. Cir. 1995) ............................................................................ 14
`
`Institut Pasteur v. Focarino,
`738 F.3d 1337 (Fed. Cir. 2013) .......................................................................... 57
`
`Intelligent Bio-Systems, Inc. v. Illumina Cambridge Ltd.,
`821 F.3d 1359 (Fed. Cir. 2016) ...................................................................passim
`
`KSR Int’l Co. v. Teleflex Inc.,
`550 U.S. 398 (2007) ................................................................................ 30, 31, 53
`
`Merck & Co., Inc. v. Teva Pharms. USA, Inc.,
`395 F.3d 1364 (Fed. Cir. 2005) .......................................................................... 57
`
`Pfizer Inc. v. Apotex, Inc.,
`480 F.3d 1348 (Fed. Cir. 2007) .................................................................... 31, 54
`
`Standard Oil Co. v. Am. Cyanamid Co.,
`774 F.2d 448 (Fed. Cir. 1985) ............................................................................ 30
`
`Trustees of Columbia University v. Illumina, Inc.,
`620 Fed. Appx. 916 (Fed. Cir. 2015) (unpublished) ................................ 5, 27, 56
`
`Wyers v. Master Lock Co.,
`616 F.3d 1231 (Fed. Cir. 2010) .......................................................................... 61
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`Statutes and Regulations
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`37 C.F.R. § 42.8 ..................................................................................................... 4, 7
`
`37 C.F.R. § 42.73 ............................................................................................... 12, 27
`
`37 C.F.R. § 42.104 ..................................................................................................... 8
`
`35 U.S.C. § 103 ...................................................................................................... 1, 8
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`1004
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`1005
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`1006
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`1007
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`TABLE OF EXHIBITS
`
`Description
`Ex. No.
`1001 Shankar Balasubramanian et al., U.S. Patent No. 7,566,537 B2 (Jul. 28,
`2009) (“’537”)
`1002 Excerpts of File History of U.S. Appl. No. 11/301,478
`(downloaded from Public PAIR)
`1003 Roger Y. Tsien et al., WO 91/06678 A1 (published May 16, 1991)
`(“Tsien”)
`William J. Dower et al., U.S. Patent No. 5,547,839 (Aug. 20, 1996)
`(“Dower”)
`PROTECTIVE GROUPS IN ORGANIC SYNTHESIS (Theodora W. Greene &
`Peter G.M. Wuts eds., 3rd ed. 1999) (excerpts) (“Greene & Wuts”)
`Bernard Loubinoux et al., Protection of Phenols by the Azidomethylene
`Group Application to the Synthesis of Unstable Phenols, TETRAHEDRON
`44:6055-64 (1988), including translation, supporting affidavit and
`original publication (“Loubinoux”)
`James M. Prober et al., A System for Rapid DNA Sequencing with
`Fluorescent Chain-Terminating Dideoxynucleotides, SCIENCE 238:336-
`41 (1987) (“Prober”)
`1008 Sergey Zavgorodny et al., 1-Alkylthioalkylation of Nucleoside Hydroxyl
`Functions and Its Synthetic Applications, TETRAHEDRON LETTERS
`32:7593-96 (1991) (“Zavgorodny”)
`1009 S.G. Zavgorodny et al., S,X-Acetals in Nucleoside Chemistry, III,
`Synthesis of 2- and 3-O-Azidomethyl Derivatives of Ribonucleosides,
`NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS 19:1977-91 (2000)
`(“Zavgorodny 2000”)
`J.D. Watson & F.H.C. Crick, Molecular Structure of Nucleic Acids,
`NATURE 171:737-38 (1953)
`1011 Steven M. Carr, Deoxyribose versus Ribose Sugars (2014), at
`https://www.mun.ca/biology/scarr/Ribose_sugar.html (downloaded
`Sept. 25, 2017)
`1012 Michael L. Metzker, Emerging Technologies in DNA Sequencing,
`GENOME RES. 15:1767-76 (2005) (“Metzker 2005”)
`1013 A. Kornberg et al., Enzymatic Synthesis of deoxyribonucleic acid,
`BIOCHIM. BIOPHYS. ACTA 21:197-198 (1956) (“Kornberg”)
`1014 Bruce Merrifield, Solid Phase Synthesis, SCIENCE 232:341-47 (1986)
`(“Merrifield”)
`
`1010
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`1015 William C. Copeland et al., Human DNA Polymerases α and β Are Able
`to Incorporate Anti-HIV Deoxynucleotides Into DNA, J. BIOL. CHEM.
`267:21459-64 (1992) (“Copeland 1992”)
`1016 Hamilton O. Smith & K.W. Wilcox, A Restriction Enzyme from
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`BIOL. 51:379-91 (1970)
`1017 Thomas J. Kelly, Jr. & Hamilton O. Smith, A restriction enzyme from
`Hemophilus influenzae. II. Base sequence of the recognition site, J.
`MOL. BIOL. 51:393-409 (1970)
`1018 F. Sanger & A.R. Coulson, A Rapid Method for Determining Sequences
`in DNA by Primed Synthesis with DNA Polymerase, J. MOL. BIOL.
`94:441-48 (1975) (“Sanger & Coulson”)
`1019 Allan M. Maxam & Walter Gilbert, A New Method for Sequencing
`DNA, PROC. NATL. ACAD. SCI. USA 74:560-64 (1977) (“Maxam &
`Gilbert”)
`1020 F. Sanger et al., DNA Sequencing with Chain-Termination Inhibitors,
`PROC. NATL. ACAD. SCI. USA 74:5463-67 (1977) (“Sanger”)
`1021 Radoje Drmanac et al., Sequencing of Megabase Plus DNA by
`Hybridization, GENOMICS 4:114-28 (1989) (“Drmanac”)
`1022 Edwin Southern & William Cummings, U.S. Patent 5,770,367 (June 23,
`1998)
`1023 ALDRICH HANDBOOK OF FINE CHEMICALS AND LABORATORY EQUIPMENT
`2000-2001 (Sigma Aldrich Co. 2000)
`1024 Bruno Canard & Robert S. Sarfati, DNA Polymerase Fluorescent
`Substrates with Reversible 3′-tags, GENE 148:1-6 (1994) (“Canard
`1994”)
`1025 Robert A. Stockman, Book Review, J. AM. CHEM. SOC. 122:426-26
`(reviewing Greene & Wuts) (2000)
`Joyce, C.M. Choosing the right sugar: How polymerases select a
`nucleotide substrate, PROC. NATL. ACAD. SCI. USA 94:1619-1622
`(March 1997)
`Jari Hovinen et al., Synthesis of 3'-O-(ω-Aminoalkoxymethyl)thymidine
`5'-Triphosphates, Terminators of DNA Synthesis that Enable 3'-
`Labelling, J. CHEM. SOC. PERKIN TRANS. 1:211-17 (1994)
`1028 Yuri G. Gololobov & Leonid F. Kasukhin, Recent Advances in the
`Staudinger Reaction, TETRAHEDRON 48:1353-406 (1992) (“Gololobov
`1992”)
`
`1027
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`1026
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`1029 Eliana Saxon & Carolyn R. Bertozzi, Cell Surface Engineering by a
`Modified Staudinger Reaction, SCIENCE 287:2007-10 (2000) (“Saxon &
`Bertozzi”)
`1030 D.H. Dube and C.R. Bertozzi, Metabolic oligosaccharide engineering
`as a tool for glycobiology, CURR. OPIN. CHEM. BIOL. 7:616-625 (2003)
`1031 Eliana Saxon & Carolyn R. Bertozzi, U.S. Pub. 2002/0016003 A1,
`Chemoselective Ligation (published Feb. 7, 2002)
`1032 Eliana Saxon et al., Investigating Cellular Metabolism of Synthetic
`Azidosugars with the Staudinger Ligation, J. AM. CHEM. SOC.
`124:14893-902 (2002)
`1033 Saul Kit, Deoxyribonucleic Acids, ANNU. REV. BIOCHEM. 32:43–82
`(1963) (“Kit”)
`1034 Che-Hung Lee et al., Unwinding of Double-stranded DNA Helix by
`Dehydration, PROC. NATL. ACAD. SCI. USA 78:2838-42 (1981) (“Lee”)
`1035 Gordon et al., Abstract, Biophysical Society 6th Annual Meeting
`(Washington, 1962)
`1036 Lawrence Levine et al., The Relationship of Structure to the
`Effectiveness of Denaturing Agents for Deoxyribonucleic Acid,
`BIOCHEM. 2:168-75 (1963)
`1037 Derek L. Stemple et al., U.S. Patent No. 7,270,951 B1 (Sept. 18, 2007)
`(“Stemple III”)
`Jingyue Ju et al., U.S. Patent 6,664,079 B2 (Dec. 16, 2003) (“Ju”)
`1038
`1039 David Bentley et al., Accurate Whole Human Genome Sequencing
`Using Reversible Terminator Chemistry, NATURE 456:53-59 (2008)
`(“Bentley”)
`1040 Elaine R. Mardis, A Decade’s Perspective on DNA Sequencing
`Technology, NATURE 470:198-203 (2011) (“Mardis”)
`1041 Michael L., Metzker, et al., Termination of DNA synthesis by novel 3′-
`modified deoxyribonucleoside 5′-triphosphates, NUC. ACIDS RES.
`22:4259-67 (1994) (“Metzker 1994”)
`1042 Bruno Canard et al., Catalytic Editing Properties of DNA Polymerases,
`PROC. NATL. ACAD. SCI. USA 92:10859-63 (1995) (“Canard 1995”)
`1043 Fabrice Guillier et al., Linkers and Cleavage Strategies in Solid-Phase
`Organic Synthesis and Combinatorial Chemistry, CHEM. REV. 100,
`100:2091-157 (2000) (“Guillier”)
`1044 Y.G. Gololobov et al., Sixty years of Staudinger reaction,
`TETRAHEDRON 37:437-72 (1981) (“Gololobov 1981”)
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`1045 Kevin Davies, The British Invasion, in THE $1,000 GENOME: THE
`REVOLUTION IN DNA SEQUENCING AND THE NEW ERA OF PERSONALIZED
`MEDICINE 102-15 (Ch. 5), 298-99 (Ch. 5 Notes) (2010) (“Davies”)
`1046 Vincent P. Stanton et al., WO 02/21098 A2 (published Sept. 5, 2000)
`(“Stanton”)
`1047 Seela, U.S. Patent No. 4,804,748 (Feb. 14, 1989)
`1048 Declaration of Michael Cohen (Sept. 28, 2017)
`Exhibit A: Filed as Ex. 1049
`Exhibit B: Screenshot from the OCLC WorldCat database
`Exhibit C: Definition of “date entered” from OCLC website
`Exhibit D: Screenshot of University of Wisconsin-Madison Library
`System Catalog
`Exhibit E: Spreadsheet of data extracted from Voyager Integrated
`Library System
`1049 Exhibit A to Declaration of Michael Cohen:
`Travis Young, A Strategy for the Synthesis of Sulfated Peptides, A
`dissertation submitted in partial fulfillment of the requirements for the
`degree of Doctor of Philosophy (Chemistry) at the University of
`Wisconsin-Madison (2001)
`1050 Declaration of Thomas Hyatt (Sept. 28, 2017) (Attachment filed as Ex.
`1051)
`1051 Attachment to Declaration of Thomas Hyatt:
`Travis Young, A Strategy for the Synthesis of Sulfated Peptides, A
`dissertation submitted in partial fulfillment of the requirements for the
`degree of Doctor of Philosophy (Chemistry) at the University of
`Wisconsin-Madison (2001) (“Young”)
`1052 Declaration of Bonnie Phan (Sept. 28, 2017)
`Exhibit A: DISSERTATION ABSTRACTS INTERNATIONAL, Volume 62,
`Number 7 (2002) (excerpts)
`Exhibit B: Guidelines to counsel & researchers seeking discovery from
`Stanford University Libraries, at https://library.stanford.edu/using/
`special-policies/guidelines-counsel-researchers-seeking-discovery-
`stanford-university (printed Sept. 28, 2017)
`1053 Pentti Oksman et al., Solution Conformations and Hydrolytic Stability of
`2′- and 3′-Substituted 2′,3′-Dideoxyribonucleosides, Including some
`Potential Inhibitors of Human Immunodeficiency Virus, J. OF PHYSICAL
`ORGANIC CHEM. 5:741-47 (1992) (“Oksman”)
`1054 Eric F.V. Scriven et al., Azides: Their Preparation and Synthetic Uses,
`CHEMICAL REVIEWS 88:297-368 (1988)
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`1057
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`1055 Peter C. Cheeseman, U.S. Patent No. 5,302,509 (Apr. 12, 1994)
`(“Cheeseman”)
`1056 M. Vaultier et al., General Method to Reduce Azides to Primary Amines
`by Using the Staudinger Reaction, TETRAHEDRON LETTERS 24:763-64
`(1983). including translation, supporting affidavit and original
`publication (“Vaultier”)
`John A. Burns et al., Selective Reduction of Disulfides by Tris(2-
`carboxyethyl)phosphine, J. OF ORGANIC CHEM. 56:2648-2650 (1991)
`1058 Anthony L. Handlon & Norman J. Oppenheimer, Thiol Reduction of 3′-
`Azidothymidine to 3′-Aminothymidine: Kinetics and Biomedical
`Implications, PHARM. RES. 5:297-99 (1988) (“Handlon”)
`1059 Mark D. Uehling, Wanted: The $1000 Genome, Bio-IT World (Nov.
`15, 2002), http://www.bio-itworld.com/archive/111202/genome (printed
`Oct. 2, 2017)
`1060 Kevin Davies, 13 years ago, a beer summit in an English pub led to the
`birth of Solexa and—for now at least —the world’s most popular
`second-generation sequencing technology, Bio-IT World (Sept. 28,
`2010), http://www.bio-itworld.com/2010/issues/sept-oct/solexa.html
`(printed Aug. 2, 2017)
`1061 Wikipedia, Shankar Balasubramanian,
`https://en.wikipedia.org/wiki/Shankar_Balasubramanian (last visited
`Aug. 2, 2017)
`1062 Past Group Members - Balasubramanian Group,
`http://www.balasubramanian.co.uk/past-group-members (printed Aug.
`2, 2017)
`1063 Sarah Houlton, Profile: Flexibility on the move, Chemistry World (Nov.
`29, 2010) https://www.chemistryworld.com/news/profile-flexibility-on-
`the-move/3003307.article (printed Aug. 2, 2017)
`1064 LinkedIn, Harold Swerdlow, https://www.linkedin.com/in/harold-
`swerdlow-9aa6981/ (printed Aug. 2, 2017)
`1065 LinkedIn, Xiaolin Wu, https://www.linkedin.com/in/xiaolin-wu-
`68821313/?ppe=1 (printed Aug. 2, 2017)
`1066 Xiaolin Wu, Synthesis of 5′-C- and 2′-O-Substituted
`Oligoribonucleotide Analogues and Evaluation of their Pairing
`Properties, A dissertation submitted in partial fulfillment of the
`requirements for the degree of Doctor of Nature Science at the Swiss
`Federal Institute of Technology (ETH) Zurich (2000)
`1067 LinkedIn, Colin Barnes, https://www.linkedin.com/in/colin-barnes-
`73678145/?ppe=1 (printed Aug. 2, 2017)
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`1073
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`1069
`
`1068 The Chinese Society of Chemical Science and Technology in the UK,
`Members of the Fourth Executive Committee,
`https://www.jiscmail.ac.uk/cgi-bin/filearea.cgi?LMGT1=CHEM-
`CSCST-UK&a=get&f=/4cmmtt.htm (printed Aug. 2, 2017)
`Jonathan A. Eisen, Sequencing: The Now Generation, presentation at
`the Bodega Bay Applied Phylogenetics, slide 39 (Mar. 4, 2013),
`downloaded from http://treethinkers.org/wp-content/uploads/2013/01/
`EisenBodega2013.pdf
`1070 Number Not Used
`Illumina, Genome Analyzer System Specification Sheet (2007),
`1071
`http://www.geneworks.com.au/library/GenomeAnalyzer_SpecSheet.pdf
`(downloaded Oct. 2, 2017)
`1072 A. Masoudi-Nejad et al., Emergence of Next-Generation Sequencing,
`Ch. 2 in NEXT GENERATION SEQUENCING AND SEQUENCE ASSEMBLY,
`11-39, 15 (2013)
`J. Bidwell et al., Cytokine gene polymorphism in human disease: on-line
`databases, GENES & IMMUNITY 1:3-19 (1999) (“Bidwell”)
`1074 Pui-Yan Kwok, Methods for Genotyping Single Nucleotide
`Polymorphisms, ANN. REV. GENOMICS HUMAN GENETICS 2:235-58
`(2001) (“Kwok”)
`1075 Ann-Christine Syvanen, Accessing genetic variation: genotyping single
`nucleotide polymorphisms, NATURE REVIEWS GENETICS 2:920-942
`(2001) (“Syvanen”)
`1076 A. A. Kraeveskii et al., Substrate inhibitors of DNA biosynthesis,
`MOLECULAR BIOLOGY 21:25-29 (1987) (“Kraeveskii”)
`1077 William B. Parker et al., Mechanism of Inhibition of Human
`Immunodeficiency Virus Type 1 Reverse Transcriptase and Human DNA
`Polymerases α, β, and  by the 5′-Triphosphates of Carbovir, 3′-Azido-
`3′-deoxythymidine, 2′,3′-Dideoxyguanosine, and 3′-Deoxythymidine, J.
`BIOL. CHEM. 266:1754-1762 (1991) (“Parker”)
`1078 Elise Burmeister Getz et al., A comparison between the Sulfhydryl
`reductants Tris(2-carboxyethyl)phosphine and Dithiothreitol for Use in
`Protein Biochemistry, ANALYTICAL BIOCHEM. 273:73-80 (1999)
`(“Getz”)
`1079 William S. Mungall et al., Use of the Azido Group in the Synthesis of 5′-
`Terminal Aminodeoxythymidine Oligonucleotides, J. ORG. CHEM.
`40:1659-1662 (1975) (“Mungall”)
`1080 Serge Pilard et al., A stereospecific synthesis of (+) α-conhydrine and
`(+) β-conhydrine, TETRAHEDRON LETTERS 25:1555-56 (1984)
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`
`
`1081 R. Ranganathan et al., Facile conversion of adenosine into new 2′-
`substituted-2′-deoxy-arabinofuranosyladenine derivatives:
`stereospecific syntheses of 2′-azido-2′-deoxy-,2′-amino-2′deoxy-, and 2′-
`mercapto-2′deoxy-β-D-arabinofuranosyladenines, TETRAHEDRON
`LETTERS 45:4341-4344 (1978).
`1082 K.S. Kirby, A New Method for the Isolation of Deoxyribonucleic Acids:
`Evidence on the Nature of Bonds between Deoxyribonucleic Acid and
`Protein, BIOCHEM. J. 66:495-504 (1957) (“Kirby”)
`1083 David Moore & Dennis Dowhan, 2.1.1 - Manipulation of DNA in
`CURRENT PROTOCOLS IN MOLECULAR BIOLOGY (Wiley, 2002)
`(“Moore”)
`1084 G.E. Tiller et al., Dinucleotide insertion/deletion polymorphism in
`intron 50 of the COL2A1 gene, NUCLEIC ACIDS RESEARCH, 19, 4305
`(1991) (“Tiller”)
`1085 Kamada, Ltd. v. Grifols Therapeutics Inc., IPR2014-00899, Paper 22
`(Mar. 4, 2015)
`1086 Summary Table of Prior IPR Proceedings
`1087
`2014-1547, Appellee’s Brief (Dec. 29, 2014) (appeal of IPR2012-
`00006)
`IPR2013-00518, Paper 28, Illumina Request for Adverse Judgment
`(May 5, 2014)
`IPR2013-00518, Paper 29, Judgment Request for Adverse Judgment
`(May 6, 2014)
`IPR2013-00517, Paper 7, Revised Petition for Inter Partes Review of
`U.S. Pat. No. 7,566,537 (Aug. 13, 2013)
`IPR2013-00517, Paper 16, Decision - Institution of Inter Partes Review
`(Feb. 13, 2014)
`IPR2013-00517, Paper 32, Illumina’s Patent Owner Response (May 5,
`2014) (Redacted)
`IPR2013-00517, Paper 54, Petitioner IBS’s Reply (July 28, 2014)
`(Redacted)
`IPR2013-00517, Paper 87, Final Written Decision (Feb. 11, 2015)
`2015-1693, Brief of Patent Owner-Appellee Illumina Cambridge Ltd.
`(Oct. 28, 2015)
`1096 Number Not Used
`1097
`Illumina, Inc. v. Qiagen, N.V (N.D. Cal, Aug. 25, 2016) Plaintiff’s
`Reply in Support of Motion for Preliminary Injunction
`IPR2013-00517, Ex. 2011, Declaration of Floyd Romesberg, Ph.D.
`(May 5, 2014) (Redacted) (“Romesberg Decl.”)
`
`1092
`
`1093
`
`1094
`1095
`
`1098
`
`
`
`IPR2017-02172
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`xiii
`
`1088
`
`1089
`
`1090
`
`1091
`
`

`

`
`
`
`
`
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`
`
`IPR2017-02172
`
`1099
`
`1100
`
`IPR2013-00517, Ex. 2089, Declaration of Dr. Kevin Burgess (May 5,
`2014) (Redacted) (“Burgess Decl.”)
`IPR2013-00517, Ex. 1026, Transcript, July 15, 2014 Deposition of
`Kevin Burgess, Ph.D. (Redacted)
`1101 Declaration of John D. Sutherland (IPR2017-02172) (“Sutherland
`Decl.”)
`1102 Curriculum Vitae of Dr. John D. Sutherland
`1103
`IPR2012-00006, Paper 128, Final Written Decision (Feb. 11, 2015)
`IPR2013-0011, Paper 4, Petition for Inter Partes Review of U.S. Pat.
`1104
`No. 8,088,575 (Aug. 3, 2012)
`
`xiv
`
`

`

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`IPR2017-02172
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`I.
`
`INTRODUCTION
`
`Petitioner requests inter partes review of claims 1-6, and 8 of U.S. Patent No.
`
`7,566,537 B2 (“’537,” Ex. 1001) as obvious under 35 U.S.C. § 103. The ’537 patent
`
`claims a method for labeling nucleic acid molecules where the label is attached to
`
`the base via a cleavable linker, and the 3′-OH of the sugar moiety is reversibly
`
`blocked with a protecting group comprising an azido group, such as azidomethyl.
`
`Based on prior proceedings, there can be no dispute that all of the limitations of the
`
`challenged independent claim are present in a single reference (Tsien, Ex. 1003),
`
`except for the azido protecting group, which was disclosed in multiple other
`
`references—including Zavgorodny (Ex. 1008), Loubinoux (Ex. 1006), and Young
`
`(Ex. 1051)—and would have been obvious to a person of ordinary skill in the art
`
`(“POSITA”). Indeed, the ’537 patent itself admits that suitable protecting groups
`
`would be apparent to a POSITA, that such groups could be formed from any suitable
`
`group described in the go-to reference of Greene & Wuts (Ex. 1005), and that the
`
`conditions for attaching and removing such groups were within the knowledge of a
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`POSITA. Ex. 1001, 7:57-8:4.
`
`The ’537 patent was previously challenged by another party in two IPRs. One
`
`resulted in cancellation of claims 7 and 11-14 in response to Illumina’s request for
`
`adverse judgment. Exs. 1088 & 1089 (IPR2013-00518). The other petition was
`
`instituted on the basis of Tsien or Ju (Ex. 1038) in combination with Zavgorodny,
`
`but the combination of Tsien or Ju in combination with Greene & Wuts was denied
`
`
`
`1
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`

`

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`IPR2017-02172
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`on the basis of redundancy. Ex. 1091, 5, 15 (IPR2013-00517). In the Final Written
`
`Decision, the Board found that Tsien in combination with Zavgorodny disclosed
`
`each element of the claims, but that the petitioner nevertheless failed to meet its
`
`burden to establish obviousness. Ex. 1094, 7, 18, 21-22. On review, the Federal
`
`Circuit noted that the “Board’s precise legal underpinnings are difficult to discern,”
`
`and that the Board’s decision was improper to the extent it was based on an absence
`
`of a reasonable expectation of success. Intelligent Bio-Systems, Inc. v. Illumina
`
`Cambridge Ltd., 821 F.3d 1359, 1365-67 (Fed. Cir. 2016). The Federal Circuit
`
`affirmed the Board’s judgment on the basis that “the petitioner’s sole argument for
`
`why one of skill in the art would be motivated to combine Zavgorodny’s
`
`azidomethyl group with Tsien’s [sequencing-by-synthesis (“SBS”)] method was
`
`because it would meet Tsien’s quantitative deblocking requirement” and that the
`
`Board had not abused its discretion in refusing to consider new arguments raised in
`
`IBS’s Reply brief and evidence filed therewith. Id., 1368-70. Because many critical
`
`“motivation to combine”-related issues were not adequately addressed in the
`
`Petition, and were then belatedly — and still inadequately — addressed in the Reply
`
`and supporting declarations, the Board’s decision and the Federal Circuit’s
`
`affirmance were based on an incomplete and factually flawed record presented by
`
`the prior petitioner. See id.; Ex. 1094, 14-19.
`
`Nevertheless, the prior IPRs and Federal Circuit decisions demonstrate
`
`several key facts. First, all of the limitations of claims 1-6 and 8 of the ’537 patent
`
`are disclosed in Tsien or Tsien in combination with Prober, except the azido and
`
`
`
`2
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`

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`IPR2017-02172
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`azidomethyl protecting groups (821 F.3d at 1363-64; Ex. 1094, 22; Ex. 1091, 12),
`
`which is disclosed by Zavgorodny and Greene & Wuts. 821 F.3d at 1364-65, 1368.
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`Second, none of the challenged claims require removal of the protecting group (i.e.,
`
`deblocking), much less quantitative deblocking. Id., 1367. Finally, the Federal
`
`Circuit determined that a POSITA would have had a reasonable expectation of
`
`success in combining the teachings of Tsien with the azidomethyl protecting group
`
`of Zavgorodny to arrive at the challenged claims. Id.
`
`This petition focuses on explaining that Tsien’s reference to “quantitative
`
`deblocking” would not have deterred a POSITA from combining an azidomethyl
`
`protecting group with Tsien’s SBS-related teachings. In particular, the POSITA
`
`would have understood that, while high efficiency of the deblocking reactions is
`
`desirable (i.e., a high percentage of blocking groups are removed to reveal a 3′-OH),
`
`Tsien itself teaches that the methods described therein will work at less than 100%
`
`efficiency. Moreover, the reported yields following synthesis and purification in the
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`blocking group art were positive indicators to a POSITA that — when used with
`
`conditions known to be appropriate for SBS — the azidomethyl protecting group
`
`would be cleaved with high efficiency. In addition, a POSITA would have
`
`appreciated that use of Tsien’s methods with an azidomethyl protecting group as
`
`claimed in the ’537 patent would be useful for applications where quantitative
`
`deblocking was not required, such as the detection of polymorphisms. See Ex. 1001,
`
`2:7-9; Ex. 1101, ¶¶88-89. Thus, a POSITA would have had ample motivation to
`
`combine Tsien with the azidomethyl group disclosed in Zavgorodny and Greene &
`
`
`
`3
`
`

`

`
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`Wuts.
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`IPR2017-02172
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`This Petition provides new arguments, testimony, and secondary references
`
`demonstrating why it would have been obvious to a POSITA to combine an
`
`azidomethyl protecting group with Tsien’s methods. This Petition and the
`
`Declaration of Dr. Sutherland also correct several scientific inaccuracies that appear
`
`to have had a material impact on the outcome of the prior proceeding. See Part
`
`IX.D, infra; Ex. 1101. For these reasons, Petitioner respectfully requests inter partes
`
`review and cancellation of the challenged claims.
`
`II. MANDATORY NOTICES UNDER 37 C.F.R. §42.8
` Real Party-In-Interest (37 C.F.R. §42.8(b)(1))
`A.
`In accordance with 37 C.F.R. §42.8(b)(1), Petitioner Complete Genomics,
`
`Inc. (“CGI”) identifies itself and the following entities as real parties-in-interest:
`
`BGI Shenzhen Co., Ltd.; BGI Groups USA Inc.; BGI Genomics Co., Ltd.; and BGI
`
`Americas Corporation.
` Related Matters (37 C.F.R. §42.8(b)(2))
`B.
`Petitioner is concurrently filing IPR2017-02174, which challenges the ’537
`
`patent on different grounds than asserted herein or in the prior proceeding.
`
`Prior proceedings between Illumina and other parties may also affect this
`
`proceeding because they involved the challenged patent or patents with similar
`
`disclosures and/or claims. See Intelligent Bio-Systems, Inc. v. Illumina Cambridge
`
`Ltd., 821 F.3d 1359 (Fed. Cir. 2016) (appeal from IPR2013-00517); Ilumina
`
`Cambridge Ltd. v. Intelligent Bio-Systems, Inc., 638 Fed.Appx. 999 (Fed. Cir. 2016)
`
`
`
`4
`
`

`

`
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`
`
`IPR2017-02172
`
`(unpublished) (appeals from IPR2013-00128 and IPR2013-00266); Trustees of
`
`Columbia University v. Illumina, Inc., 620 Fed.Appx. 916 (Fed. Cir. 2015)
`
`(unpublished) (appeals from IPR2012-00006, IPR2012-00007, and IPR2013-
`
`00011); The Trustees of Columbia University v. Illumina, Inc., 1:12-cv-00376-GMS
`
`(D.