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`Paper No. _
`Filed: October 16, 2020
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`_______________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_______________
`
` ILLUMINA, INC.,
`Petitioner,
`
`v.
`
` THE TRUSTEES OF COLUMBIA UNIVERSITY
`IN THE CITY OF NEW YORK
`Patent Owner.
`_______________
`
`IPR2020-01177 (Patent 10,435,742)
`
`PATENT OWNER’S PRELIMINARY RESPONSE
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`Case IPR2020-01177
`Patent No. 10,435,742
`
`Table of Contents
`
`I.
`
`Introduction ...................................................................................................... 1
`
`II.
`
`Level Of Ordinary Skill In The Art ................................................................. 6
`
`III. Claim Construction .......................................................................................... 6
`
`A.
`
`“Small” .................................................................................................. 6
`
`B.
`
`No Other Claim Construction Is Necessary .......................................... 6
`
`IV.
`
`Illumina’s Ground 1 and 2 Challenges Fail ................................................... 11
`
`A.
`
`B.
`
`Illumina’s Petition Is Incompatible With The SBS Prior
`Art, Which Did Not Suggest Using The MOM Capping
`Group For SBS .................................................................................... 13
`
`Illumina’s Petition Ignores The Board’s Established
`Framework For Assessing Obviousness in This Particular
`Field ..................................................................................................... 16
`
`1.
`
`2.
`
`Illumina ignores the efficiency requirement ............................. 16
`
`A POSA would not have been motivated to use the
`MOM group because there was no expectation of
`efficient incorporation ............................................................... 23
`
`C.
`
`Illumina’s Petition Fails Even Under The Deficient
`Framework Used By Illumina ............................................................. 26
`
`1.
`
`2.
`
`There was no motivation to combine Hiatt’s non-
`SBS methods with Tsien’s/Dower’s SBS methods .................. 27
`
`Even if a POSA were motivated to combine Hiatt
`with Tsien/Dower, the POSA would not have been
`motivated to select Hiatt’s MOM capping group ..................... 29
`
`a.
`
`b.
`
`No motivation to narrow Hiatt’s capping
`groups to alkyl ethers ...................................................... 31
`
`No motivation to narrow Hiatt’s capping
`groups to small capping groups ...................................... 32
`
`
`
`i
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`

`

`
`
`c.
`
`d.
`
`No motivation to narrow Hiatt’s capping
`groups because Hiatt describes all capping
`groups as being preferred ............................................... 38
`
`No motivation to select Hiatt’s MOM
`capping group based on Hovinen ................................... 40
`
`3.
`
`There was no expectation that the MOM
`embodiment would satisfy the claimed
`requirement of “not interfer[ing] with recognition
`of the analogue” ........................................................................ 44
`
`4.
`
`Illumina’s enablement arguments fail ....................................... 45
`
`V.
`
`Illumina’s Ground 3 and 4 Challenges Fail ................................................... 50
`
`VI.
`
`Illumina’s Petition Should Be Denied Under 35 U.S.C. § 314(a) ................ 54
`
`VII.
`
`Illumina’s Petition Should Be Denied Under 35 U.S.C. § 325(d) ................ 60
`
`VIII. Conclusion ..................................................................................................... 61
`
`
`
`ii
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`

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`Case IPR2020-01177
`Patent No. 10,435,742
`
`Cases
`
`Table of Authorities
`
`Allergan, Inc. v. Sandoz Inc.,
`796 F.3d 1293 (Fed. Cir. 2015) .....................................................................45
`
`Apple Inc. v. Fintiv, Inc.,
`IPR2020-00019, Paper No. 11 (March 20, 2020) ...................... 55, 56, 57, 58
`
`Becton, Dickinson & Co. v. B. Braun Melsungen AG,
`IPR2017-01586, Paper 8 (Dec. 15, 2017) .....................................................61
`
`Cuozzo Speed Techs., LLC v. Lee,
`136 S. Ct. 2131 (2016) ...................................................................................22
`
`Erfindergemeinschaft UroPep GbR v. Eli Lilly,
`276 F. Supp. 3d 629 (E.D. Tex. 2017) ..........................................................53
`
`Illumina Inc. v. Trustees of Columbia Univ. in the City of New York,
`2014 WL 1252946 (PTAB March 6, 2014) ..................................................... 7
`
`Illumina Inc. v. Trustees of Columbia Univ. in the City of New York,
`2018 WL 8619911 (PTAB June 21, 2018) ...................................................... 8
`
`In re Kubin,
`2007 WL 2070495 (B.P.A.I. 2007) ...............................................................51
`
`Intelligent Bio-Sys., Inc. v. Illumina Cambridge Ltd.,
`821 F.3d 1359 (Fed. Cir. 2016) .....................................................................21
`
`KSR Intern. Co. v. Teleflex, Inc.,
`550 U.S. 398 (2007).......................................................................................51
`
`Otsuka Pharm. Co. v. Sandoz, Inc.,
`678 F.3d 1280 (Fed. Cir. 2012) .....................................................................35
`
`Taiwan Semiconductor Mfg. Co. v. DSS Tech. Mgmt., Inc.,
`IPR2014-01030, Paper 28 (November 30, 2015) ..........................................10
`
`Trustees of Columbia Univ. in the City of New York v. Illumina, Inc.,
`620 F. App’x 916 (Fed. Cir. 2015) .................................................................. 7
`
`
`
`iii
`
`

`

`
`
`Statutes
`Statutes
`
`35 U.S.C. § 103 ....................................................................................... 5, 46, 51, 53
`35 U.S.C. § 103 ....................................................................................... 5, 46, 51, 53
`
`35 U.S.C. § 112 ........................................................................................................46
`35 U.S.C. § 112 ........................................................................................................46
`
`35 U.S.C. § 314(a) ...............................................................................................5, 59
`35 U.S.C. § 314(a) ............................................................................................... 5, 59
`
`35 U.S.C. § 325(d) ...............................................................................................5, 60
`35 U.S.C. § 325(d) ............................................................................................... 5, 60
`
`
`
`
`
`
`
`
`
`iv
`iV
`
`

`

`
`
`
`
`Exhibit No. Description
`
`TABLE OF EXHIBITS
`
`2001
`
`2002
`
`2003
`
`2004
`
`2005
`
`2006
`
`2007
`
`2008
`
`2009
`
`2010
`
`Defendant Illumina, Inc.’s Response to Plaintiffs’ Opening Claim
`Construction Brief
`
`Metzker, et al., “Elimination of residual natural nucleotides from
`3’-O-modified-dNTP syntheses by enzymatic mop-up,”
`BioTechniques, 25:814-817 (1998)
`PCT Publication WO 00/53805 (“Stemple”)
`
`Defendant Illumina, Inc.’s Initial Invalidity Contentions, The
`Trustees of Columbia University in the City of New York and
`Qiagen Sciences, LLC v. Illumina, Inc., 19-cv-01681 (D. Del.)
`U.S. Patent No. 6,087,095 (“Rosenthal”)
`
`Welch & Burgess, “Synthesis of fluorescent, photolabile 3’-O-
`protected nucleoside triphosphates for the base addition
`sequencing scheme,” Nucleosides & Nucleotides, 18:197-201
`(1999)
`Canard & Sarfati, “DNA polymerase fluorescent substrates with
`reversible 3’-tags,” Gene, 148:1-6 (1994)
`
`IPR2017-02172 Petition for Inter Partes Review of U.S. Patent
`No. 7,566,537
`
`IPR2017-02172 Preliminary Response of Patent Owner Illumina
`Cambridge Ltd.
`
`IPR2017-02174 Preliminary Response of Patent Owner Illumina
`Cambridge Ltd.
`
`2011
`
`IPR2013-00517 Illumina’s Patent Owner Response
`
`2012
`
`IPR2013-00517 Final Written Decision
`
`2013
`
`IPR2013-00517 Deposition of Floyd Romesberg, Ph.D., July 8,
`2014
`
`2014
`
`IPR2018-00291 Petitioner’s Reply
`
`v
`
`

`

`
`
`
`
`2015
`
`U.S. Patent No. 5,808,045
`
`2016
`
`Curriculum Vitae of Kenneth A. Johnson, Ph.D.
`
`2017
`
`2018
`
`2019
`
`IPR2018-00291, IPR2018-00318, IPR2018-00322, IPR2018-
`00385, IPR2018-00797 Illumina’s Demonstratives for Oral
`Hearing
`IPR2018-00291, IPR2018-00318, IPR2018-00322, IPR2018-
`00385, IPR2018-00797 Illumina’s Reply to Patent Owner’s
`Opposition to Motion to Exclude
`IPR2018-00291 Institution Decision
`
`2020
`
`Exhibit Number Not Used
`
`2021
`
`WO 96/23807 (“Kwiatkowski”)
`
`2022
`
`2023
`
`2024
`
`Ronaghi, et al. “A sequencing method based on real-time
`pyrophosphate,” Science, 281(5375):363-365 (1998)
`
`Brief of Patent Owner-Appellant Illumina Cambridge Ltd.,
`Illumina Cambridge Ltd. v. Intelligent Bio-Systems, Inc., D.I. 27,
`2015-1123 (Fed. Cir.)
`U.S. Patent No. 5,858,671 (“Jones”)
`
`2025
`
`U.S. Patent No. 6,013,445 (“Albrecht”)
`
`2026
`
`2027
`
`2028
`
`2029
`
`Excerpts from the Prosecution History of U.S. Patent No.
`9,718,852
`
`Complaint for Patent Infringement, The Trustees of Columbia
`University in the City of New York and Qiagen Sciences, LLC v.
`Illumina, Inc., D.I. 1, 19-cv-01681 (D. Del.)
`Exhibit Number Not Used
`
`Amended Complaint for Patent Infringement, The Trustees of
`Columbia University in the City of New York and Qiagen
`Sciences, LLC v. Illumina, Inc., D.I. 12, 19-cv-01681 (D. Del.)
`
`vi
`
`

`

`
`
`
`
`2030
`
`2031
`
`2032
`
`2033
`
`2034
`
`Exhibit 7 to Complaint for Patent Infringement, The Trustees of
`Columbia University in the City of New York and Qiagen
`Sciences, LLC v. Illumina, Inc., D.I. 1-7, 19-cv-01681 (D. Del.)
`Exhibit 8 to Complaint for Patent Infringement, The Trustees of
`Columbia University in the City of New York and Qiagen
`Sciences, LLC v. Illumina, Inc., D.I. 1-8, 19-cv-01681 (D. Del.)
`Docket, The Trustees of Columbia University in the City of New
`York and Qiagen Sciences, LLC v. Illumina, Inc., 19-2302 (Fed.
`Cir.)
`Zhu, Z., et al., “Directly labeled DNA probes using fluorescent
`nucleotides with different length linkers,” Nucleic Acids Res.,
`22:3418-3422 (1994)
`IPR2018-00291, Petition for Inter Partes Review of U.S. Patent
`No. 9,718,852
`
`2035
`
`U.S. Patent No. 7,566,537
`
`2036
`
`2037
`
`2038
`
`Joint Claim Construction Brief, The Trustees of Columbia
`University in the City of New York and Qiagen Sciences, LLC v.
`Illumina, Inc., D.I. 54, 19-cv-01681 (D. Del.)
`Excerpts of Joint Claim Construction Appendix (Declaration of
`John Kuriyan, Ph.D. in Support Of Plaintiffs’ Opening Claim
`Construction Brief; Expert Declaration of Dr. Floyd Romesberg in
`Support of Illumina’s Response to Plaintiffs’ Opening Claim
`Construction Brief), The Trustees of Columbia University in the
`City of New York and Qiagen Sciences, LLC v. Illumina, Inc., D.I.
`55, 19-cv-01681 (D. Del.)
`Exhibit Number Not Used
`
`2039
`
`IPR2012-00007 Illumina Reply
`
`2040
`
`IPR2012-00007 Illumina Expert Declaration
`
`2041
`
`IPR2012-00007 Illumina Petition
`
`2042
`
`Claim Construction Order, The Trustees of Columbia University in
`the City of New York and Qiagen Sciences, LLC v. Illumina, Inc.,
`D.I. 60, 19-cv-01681 (D. Del.)
`
`vii
`
`

`

`
`
`
`
`
`
`
`
`2043
`
`2044
`
`2045
`
`2046
`
`Plaintiffs’ Motion for Reconsideration of the Court’s Claim
`Construction Order, The Trustees of Columbia University in the
`City of New York and Qiagen Sciences, LLC v. Illumina, Inc., D.I.
`63, 19-cv-01681 (D. Del.)
`Defendant Illumina, Inc.’s Answer to Plaintiffs’ Motion for
`Reconsideration of the Court’s Claim Construction Order, D.I. 64,
`19-cv-01681 (D. Del.)
`Docket, The Trustees of Columbia University in the City of New
`York and Qiagen Sciences, LLC v. Illumina, Inc., 19-cv-01681 (D.
`Del.) (printed 10/2/2020)
`Exhibit Number Not Used
`
`2047
`
`Exhibit Number Not Used
`
`2048
`
`Declaration of Kenneth A. Johnson
`
`viii
`
`

`

`Case IPR2020-01177
`Patent No. 10,435,742
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`I.
`
`INTRODUCTION
`
`In 2017-2018, Illumina filed IPRs against another set of Columbia’s DNA
`
`Sequencing by Synthesis (“SBS”) patents, arguing that a single embodiment of those
`
`claims would have been obvious, specifically a labeled 3’-O-allyl nucleotide (the
`
`“allyl embodiment”).1 The presently challenged claims exclude the allyl
`
`embodiment, negating Illumina’s arguments in the Allyl Claim IPRs. Illumina
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`admits that Columbia’s new claims “represent the narrowest versions of Columbia’s
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`claims to date[.]” Ex. 2001 at 2.
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`In Grounds 1 and 2, since Illumina can no longer rely on the allyl prior art that
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`it alleged taught the allyl embodiment, it now contends that a labeled 3’-O-MOM
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`nucleotide embodiment (the “MOM embodiment”) would have been obvious to a
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`POSA as of the priority date. Illumina’s new theory goes too far, as demonstrated
`
`
`1 Columbia’s SBS patents with the allyl embodiment are U.S. Patent Nos.
`
`9,718,852; 9,719,139; 9,708,358; 9,725,480; and 9,868,985. They were challenged
`
`in IPR2018-00291, IPR2018-00318, IPR2018-00322, IPR2018-00385, and
`
`IPR2018-00797, respectively (collectively, “the Allyl Claim IPRs”). Columbia
`
`does not agree with the Board’s 2-1 decision that the allyl embodiment is obvious,
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`and is appealing the decision before the Federal Circuit.
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`by even a cursory comparison of Illumina’s current arguments (and evidence) with
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`the arguments in the Allyl Claim IPRs.
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`In the Allyl Claim IPRs, two findings led a 2-1 majority to opine that the allyl
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`embodiment would have been obvious to a POSA:
`
`1.
`
`Tsien prominently disclosed using the allyl capping group for SBS;
`
`2. Metzker provided experimental data demonstrating the usefulness of
`the allyl capping group for SBS.2
`
`While Columbia disputes the majority’s view that those references would have
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`motivated a POSA to try allyl with success, Tsien and Metzker were SBS references.
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`Here, to the contrary, neither Tsien nor Metzker nor any other prior art references
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`relied upon in the Allyl Claim IPRs or Illumina’s current Petition discloses using the
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`MOM capping group in the context of SBS.
`
`With no prior art suggesting the use of the MOM capping group for SBS,
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`Illumina relies instead on two non-SBS references, Hiatt and Hovinen. Neither teach
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`use of MOM as a capping group for SBS. Hiatt’s methods are for making synthetic
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`nucleic acids of a predetermined sequence, which methods cannot be used for DNA
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`sequencing, much less for SBS. Indeed, in its prior decision, the Board criticized
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`2 The dissent found that the allyl embodiment was not obvious. On appeal,
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`Columbia is disputing the majority’s findings.
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`the use of such non-SBS references as a basis of obviousness for SBS methods,
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`because non-SBS references require lower nucleotide incorporation efficiency
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`(known as a lower “termination rate”) than required for SBS. Ex. 1024 at 32.
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`Moreover, the Board has previously concluded that Hiatt discloses “an immense
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`number of possibilities for the blocking group[.]” Ex. 1024 at 27. For at least these
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`reasons, a POSA would not have been motivated to select Hiatt’s non-SBS MOM
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`capping group from its immense number of capping groups for the modified
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`nucleotides and method of Columbia’s patents here and certainly would not have
`
`had a reasonable expectation of success in using MOM in SBS.
`
`Recognizing Hiatt’s deficiencies, Illumina next argues that Hovinen
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`supplements Hiatt by suggesting that Hiatt’s MOM capping group could be
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`accurately incorporated by a polymerase in SBS. However, Hovinen’s method is
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`based on Sanger sequencing, not SBS. Moreover, Hovinen did not even use a MOM
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`capping group, but instead used an entirely different, larger capping group:
`
`Hiatt’s MOM capping group:
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`Hovinen’s capping group:
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`
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`Use of Hovinen’s non-MOM capping group in a non-SBS method would have
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`provided no reason to select a MOM capping group for SBS, or to believe it would
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`have an expectation of success in SBS.
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`Despite the developments in sequencing technologies at the time of the
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`invention, the prior art never pursued the MOM capping group for SBS, and
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`Illumina’s attempt to manufacture an obviousness theory based on non-SBS
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`references falls far short of satisfying Illumina’s burden. Illumina’s theory ignores
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`that the Board has itself consistently applied the principle that a POSA would not
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`have been motivated to use a particular 3’-O-capped nucleotide in Tsien’s or
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`Dower’s SBS methods absent an expectation that such nucleotide would be useful
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`for SBS, one requirement of which is “efficient” incorporation. Illumina itself has
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`relied upon this efficiency requirement to defend its own modified nucleotide
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`patents. Despite having repeatedly advocated for this framework in the past for its
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`own patents and in challenges to Columbia’s patents, Illumina’s current Petition
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`abandons it. Illumina’s sudden abandonment of this basic principle underscores the
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`deficiencies of the Petition and its failure to meet its burden.
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`Illumina’s Grounds 3 and 4 also fail. Those Grounds are based on the flawed
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`legal premise that Illumina can invalidate Columbia’s claims by demonstrating that
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`the allyl embodiment was obvious, despite the claims explicitly excluding that
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`embodiment. That premise contravenes 35 U.S.C. § 103, under which the
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`obviousness analysis turns on the obviousness of claimed subject matter, not on the
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`obviousness of unclaimed subject matter. Illumina cannot invalidate the present
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`claims by arguing the obviousness of the unclaimed allyl embodiment; its attempt to
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`do so exposes Illumina’s lack of confidence in its Grounds based on the MOM
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`capping group.
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`Lastly, the Board should deny institution under 35 U.S.C. § 314(a) because
`
`the parties here are litigating the challenged patent in a parallel District Court
`
`proceeding involving the same patent claims, the same prior art, and the same
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`invalidity arguments. Institution would be an inefficient use of Board resources.
`
`The Board should also deny institution under 35 U.S.C. § 325(d) because the Petition
`
`ignores the Board’s prior findings in the Allyl Claim IPRs, regarding the reliance on
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`non-SBS prior art in general and Hiatt in particular to support a finding of
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`obviousness.
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`II. LEVEL OF ORDINARY SKILL IN THE ART
`
`Columbia does not dispute, for purposes of this IPR, Illumina’s criteria for
`
`defining a POSA.
`
`III. CLAIM CONSTRUCTION
`
`A.
`
`“Small”
`
`The claims require the use of a “small” capping group. The term “small”
`
`should be construed to mean a capping group that is less than 3.7A in diameter, for
`
`the reasons explained in Section IV(C)(2)(b), below.
`
`B. No Other Claim Construction Is Necessary
`
`Illumina states that “[t]here is no need to construe ‘chemical linker.’” Petition
`
`at 12. Columbia agrees. “Chemical linker” has a plain and ordinary meaning,
`
`namely the chemical structure, made up of one or more chemical groups, that links
`
`the base to the tag. As explained below, this construction is consistent with the
`
`Federal Circuit’s and the Board’s previous decisions on related patents, as well as
`
`Illumina’s arguments in its previous petitions and in the present one.
`
`As an initial matter, it is undisputed that Prober (a key reference cited by the
`
`Federal Circuit, the Board, and Illumina) discloses a linker made of more than one
`
`chemical group. Ex. 2048 at ¶¶ 75-76 (testifying that Prober’s linker as disclosed in
`
`Figure 2A is “made of multiple chemical groups”); Ex. 2017 at Slide 49 (Illumina
`
`acknowledging that Prober’s linker is made of multiple chemical groups (each of
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`which Illumina refers to as a separate linker)). Since at least 2013, Illumina has
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`consistently described Prober as disclosing a “linker,” even though that linker is
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`made of more than one chemical group.
`
`For example, in IPR2012-00007, Illumina referred to “the linker used in
`
`Prober.” Ex. 2039 at 10; see also Ex. 2041 at 24, 29 (quoting Prober’s description
`
`of “a linker”)3; Ex. 2040 at 27, 23 (Illumina’s expert noting that Prober “showed a
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`linker and four label system”). In the IPR2012-00007 Final Written Decision, the
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`Board similarly described Prober as disclosing a “linker.” Illumina Inc. v. Trustees
`
`of Columbia Univ. in the City of New York, 2014 WL 1252946, at *13 (PTAB March
`
`6, 2014) (herein Ex. 1021 at 23); see also Petition at 73 (citing Ex. 1021). The
`
`Federal Circuit affirmed the Board’s decision, also noting that “Prober discloses
`
`attaching a fluorescent label via a linker[.]” Trustees of Columbia Univ. in the City
`
`of New York v. Illumina, Inc., 620 F. App’x 916, 928 (Fed. Cir. 2015) (herein Ex.
`
`1029 at 22); see also Petition at 73 (citing Ex. 1029). In IPR2018-00291, Illumina
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`again noted that Prober “discloses a deaza-adenine nucleotide analogue having a
`
`fluorescent label attached through a linker at the 7-position.” Ex. 2034 at 46-47
`
`(citing Prober Figure 2A), see also 63-64 (relying on Prober’s linker in combination
`
`with Dower to satisfy the claim limitation “a chemically cleavable, chemical
`
`
`3 Emphases added unless otherwise indicated.
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`linker”). The Board again agreed. Illumina Inc. v. Trustees of Columbia Univ. in
`
`the City of New York, 2018 WL 8619911, at *11 (PTAB June 21, 2018) (herein Ex.
`
`1024 at 26-27) (referring to Prober’s Figure 2A and noting that Prober discloses “that
`
`succinylfluorescein is attached via a linker to a heterocyclic base”), *23
`
`(determining that “Dower and Prober would have disclosed or suggested a
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`chemically cleavable, chemical linker”); see also Ex. 1024 at 53 n.33 (the Board
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`concluding that a “linker” means one or more linkers). In its current Petition,
`
`Illumina again describes Prober as disclosing “a linker.” See Petition at 10, 42, 52,
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`53, 54 (citing Prober Figure 2A, explaining “Prober discloses a label attached
`
`through a linker to the 5-position of thymine.”); see also IPR2020-00988 Petition at
`
`9, 14, 23, 41, 53.
`
`Further, Illumina’s current Petition is accompanied by an expert declaration,
`
`in which the expert likewise describes Prober as disclosing “a linker.” Ex. 1131 at
`
`¶¶ 73, 121 (describing Prober’s Figure 2A as “showing the label and linker of the
`
`nucleotide analogue”), 171-172, 195, 197, 205.
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`
`This plain and ordinary meaning of “chemical linker” is consistent with the
`
`specification.4
`
`In its Petition, Illumina stated “that no proposed litigation construction [before
`
`the Court in a parallel district court litigation] affects the merits of this petition.”
`
`Petition at 13. However, in that parallel district court litigation, Illumina has
`
`proposed construing “Y” differently than the positions it has taken since 2013 and
`
`differently than it implicitly seeks to construe here. Specifically, Illumina has
`
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`4 See e.g., Ex. 1004, Fig. 7 (showing a linker made up of two chemical groups); Ex.
`
`2048 at ¶ 73 (testifying the same regarding Figure 7); see also Ex. 1004, Figs. 8, 16
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`(showing the synthesis of the “linker” shown in Figure 7) and Figs. 19, 21
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`(showing a linker with two chemical groups); Ex. 2048 at ¶ 74 (testifying the same
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`regarding Figure 19, which has the same chemical linker as in Figure 21); Ex. 2033
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`at 3418, 3419 (incorporated by reference (Ex. 1004 at 1:30-38, 2:57-63, 32:54-56))
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`(using the term “linker” to refer to the chemical structure that attaches the base to
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`the tag, consisting of multiple chemical groups); Ex. 1041 (incorporated by
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`reference (Ex. 1004 at 1:30-38, 23:60-63, 26:58-62, 31:40-44)) (same); see also
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`Ex. 2035 at Figs. 1-3, 2:19-24, 2:33-36, 4:37-39, 7:38-43, and Examples 1-3
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`(Illumina patent using linker to refer to overall structure to attach the base to the
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`tag and teaching that a linker may be made of more than one chemical group).
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`proposed in the litigation construing “Y” to mean “a single linker that directly
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`connects the base to the label.” See Ex. 2036 (Joint Claim Construction Brief); Ex.
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`2037 (excerpts of Joint Claim Construction Appendix, including declarations by
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`Columbia’s expert (Ex. 2037 at 1-76) and Illumina’s expert (Ex. 2037 at 77-123)).
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`While the district court has recently adopted Illumina’s construction of “Y” to mean
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`“a single linker …,” this Board is not bound by a district court’s construction.
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`Taiwan Semiconductor Mfg. Co. v. DSS Tech. Mgmt., Inc., IPR2014-01030, Paper
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`28 at 8 (November 30, 2015).
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`Columbia has filed a motion seeking clarification and reconsideration of that
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`decision, to determine whether the single linker can consist of multiple chemical
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`groups under the Court’s construction, which would be consistent with the plain and
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`ordinary meaning described here. Ex. 2042 (claim construction order); Ex. 2043
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`(Columbia’s motion for reconsideration). Illumina responded to Columbia’s motion
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`by arguing that “Illumina’s position is that there is no patentable distinction between
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`a single and double linker.” See Ex. 2044 at 6. However, Illumina’s Petition does
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`not propose modifying the linker disclosed in Prober to meet the “Y” limitation, and
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`instead relies on Prober’s disclosed linker. See Petition at 52-54; see also Petition
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`at 54 (equating Prober’s linker to the “bulky groups” described in the specification
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`(citing Ex. 1004, 2:57-63)).
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`Moreover, Illumina mischaracterized Columbia’s motion as seeking to clarify
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`that “multiple linkers in series somehow qualify as a single linker.” Instead,
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`Columbia sought to clarify that the single linker could itself be made from multiple
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`chemical groups. Indeed, Illumina’s response does not address the fact that, since at
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`least 2013, Illumina has argued and continues to argue in its present Petition that
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`Prober discloses a “linker,” even though Prober’s structure is made of multiple
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`chemical groups. As noted above, Columbia has never sought to rebut Illumina’s
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`invalidity argument by contending that Prober’s linker falls outside the scope of the
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`claims because it is made of multiple chemical groups.5 Instead, it is and always has
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`been Columbia’s position that the claims cover a linker made of multiple smaller
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`chemical groups.
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`IV.
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`ILLUMINA’S GROUND 1 AND 2 CHALLENGES FAIL
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`As noted above, Columbia’s claims cover nucleotides with particular
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`structural (and functional) properties, as depicted in the claims:
`
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`5 Columbia has only contended that Prober’s linker falls outside the scope of the
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`claims because it is not “chemically cleavable.”
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`Illumina’s Grounds 1 and 2 rely on a single premise—that it would have been
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`obvious to make an embodiment of Columbia’s claims wherein R is a
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`methoxymethyl (“MOM”) capping group, i.e., -CH2OCH3. To arrive at this
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`embodiment, Illumina combines Hiatt (which allegedly discloses using the MOM as
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`the capping group R) with Tsien or Dower (which allegedly disclose the remaining
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`portions of the embodiment, including Y and Tag).
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`Grounds 1 and 2 fail because Illumina’s theory (A) is incompatible with the
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`SBS prior art, (B) ignores the Board’s well-established framework for assessing
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`obviousness of a 3’-O-capped nucleotide for SBS, and (C) fails to establish, even
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`under Illumina’s deficient framework, that a POSA would have been motivated to
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`arrive at the MOM embodiment with a reasonable expectation of success.
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`A.
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`Illumina’s Petition Is Incompatible With The SBS Prior Art,
`Which Did Not Suggest Using The MOM Capping Group For
`SBS
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`It is undisputed that successful SBS was not achieved prior to Columbia’s
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`invention, even though researchers had been pursuing SBS for a decade before the
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`priority date. See Section IV(C)(4), below. Illumina’s Grounds 1 and 2 contend that
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`a POSA would have been motivated to use the MOM capping group in Tsien’s and
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`Dower’s proposed SBS methods, and would have believed the same to be an obvious
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`way to overcome the ongoing failure in the field. No prior art evidence supports this
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`conclusion, and in fact, the evidence proves otherwise. The Columbia inventors
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`were the first to disclose using the MOM capping group for SBS.
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`By 1990, Tsien and Dower described prophetic methods for SBS and listed a
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`large number of 3’-O-capped nucleotides that were allegedly potentially useful for
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`their methods, including “esters and ethers,” “phosphate blocking groups,”
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`“carbonate blocking groups,” “-F, -NH2, -OCH3, -N3, OPO3, -NHCOCH3, 2-
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`nitrobeneze carbonate, 2,4-dinitrobenzene sulfenyl and tetrahydrofuranyl ether,”
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`“ester blocking groups such as lower (1-4 carbon) alkanoic acid and substituted
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`lower alkanoic acid esters, for example formyl, acetyl, isopropanoyl, alpha fluoro-
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`and alpha chloroacetyl esters and the like,” “ether blocking groups such as alkyl
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`ethers,”
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`“2-nitrobenzyl,”
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`“6-nitoveratryloxycarbonyl
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`(NVOC),
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`2-
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`nitobenzyloxycarbonyl
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`(NBOC),
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`α,α-dimethyl-dimethoxybenzyloxycarbonyl
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`(DDZ), 5-bromo-7-nitroindolinyl, o-hydroxy-2-methyl cinnamoyl, 2-oxymethylene
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`anthraquinone, and t-butyl oxycarbonyl (TBOC).” Ex. 1031 at 21; Ex. 1030 at
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`18:52-63; see also Ex. 1024 at 23 (“Tsien identifies many possible blocking
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`groups”).
`
`In the decade following 1990, numerous other researchers also pursued 3’-O-
`
`capped nucleotides for SBS, including:
`
`• Metzker 1994 investigated methyl, acyl, allyl, tetrahydropyran, 4-
`nitrobenzoyl, 2-aminobenzoyl, and 2-nitrobenzyl (Ex. 1039 at Figure
`2, Table 2);
`
`• Metzker 1998 investigated methyl and 2-nitrobenzyl (Ex. 2002 at 814-
`817);
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`• Welch 1999 investigated 2-nitrobenzyl and modifications thereof (Ex.
`1033 at 951-956);
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`• Anazawa investigated 2-nitrobenzyl (Ex. 1073 at 7);
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`• Stemple investigated 2-nitrobenzyl (Ex. 2003 at 13);
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`• Cheeseman investigated at least succinyl and anhydride derivatives
`(Ex. 1042 at 4:50-63);
`
`• Canard investigated at least 3’-O-anthranyloyl derivatives (Ex. 2007 at
`1-6; Ex. 2006 at 197, 201 (Welch characterizing Canard as BASS,
`another name for SBS));
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`• Rosenthal (Ex. 2005; Ex. 2006 at 197, 201 (Welch characterizing
`Rosenthal as BASS, another name for SBS)).
`
`Despite these efforts, by the October 2000 priority date, not a single researcher had
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`proposed using the MOM capping group for SBS, and Illumina does not contend
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`otherwise.
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`The present situation is dramatically different from the Allyl Claim IPRs.
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`There, the majority held that it would have been obvious to use the allyl capping
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`group for SBS after finding that the prior art prominently disclosed such use (a
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`finding that Columbia is appealing). Specifically, the majority found that “important
`
`to the issues at hand, Tsien teaches the use of an allyl ether as a blocking group[,]”
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`and that Tsien’s teaching was “prominent.” Ex. 1024 at 23, 39, 42. The majority
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`further found that “Metzker confirms that Tsien’s suggestion to use an allyl blocking
`
`group has merit, at least in part, by indicating that one polymerase was able to
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`incorporate an allyl blocking group.” Ex. 1024 at 43, 48 (“Tsien teaches use of the
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`allyl group in conjunction with nucleotide analogues for SBS, and Metzker reports
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`actually achieving such a molecule.”). However, despite Metzker’s use of the allyl
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`group, the dissent states that Metzker’s actual experimental results would have
`
`“sufficiently eroded the motivation created by of Tsien to use an allyl nucleotide.”
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`Ex. 1024 at 77.
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`However, neither Tsien nor Metzker nor any other prior art suggested using
`
`the MOM capping group for SBS. If it had been obvious to use the MOM capping
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`group for SBS, as Illumina contends, someone would have identified it during the
`
`decade of efforts preceding the Columbia inventors’ discovery. There is no such
`
`suggestion. Illumina concedes as much, having made this same argument when
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`defending its own SBS patents covering 3’-O-capped nucleotides, specifically the
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`3’-O-azidomethyl nucleotide. In IPR2017-02172, Petitioner Complete Genom