Filed January 23, 2018
`
`
`On behalf of Illumina Cambridge Ltd.
`By: Kerry S. Taylor
`Michael L. Fuller
`Nathanael R. Luman
`KNOBBE, MARTENS, OLSON & BEAR, LLP
`2040 Main Street, 14th Floor
`Irvine, CA 92614
`Tel.: 858-707-4000
`Email: BoxIllumina2@knobbe.com
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`__________________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`__________________________________
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`COMPLETE GENOMICS, INC.
`
`Petitioner
`
`v.
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`ILLUMINA CAMBRIDGE LTD.
`
`Patent Owner
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`IPR2017-02172
`Patent 7,566,537
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`PRELIMINARY RESPONSE OF PATENT OWNER
`ILLUMINA CAMBRIDGE LTD.
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`Columbia Ex. 2009
`Illumina, Inc. v. The Trustees
`of Columbia University
`in the City of New York
`IPR2020-01177
`
`

`

`TABLE OF CONTENTS
`
`Page No.
`
`I.
`
`II.
`
`INTRODUCTION ........................................................................................... 1 
`ILLUMINA’S CLAIMED INVENTION INCLUDES A NOVEL
`AND NONOBVIOUS 3ʹ-OH PROTECTING GROUP FOR DNA
`SEQUENCING ................................................................................................ 6 
`III. THE BOARD, FEDERAL CIRCUIT, AND DISTRICT COURT
`PREVIOUSLY UPHELD PATENTABILITY OF THE
`CHALLENGED CLAIMS ............................................................................ 11 
`The Board previously upheld the same claims over the same art
`A. 
`and arguments in IPR2013-00517 ....................................................... 11 
`The Federal Circuit affirmed the Board’s decision from
`IPR2013-00517 ................................................................................... 14 
`The Federal Circuit affirmed that there was no
`1. 
`motivation ................................................................................. 15 
`Reasonable expectation of success is measured by the
`claims ........................................................................................ 16 
`The Northern District of California upheld the same claims over
`the same art and arguments ................................................................. 17 
`IV. BGI PROVIDES NO JUSTIFICATION FOR ITS REQUEST TO
`RELITIGATE PATENTABILITY OF THE CHALLENGED
`CLAIMS ........................................................................................................ 18 
`V. BGI’S PETITION SHOULD BE DENIED UNDER
`35 U.S.C. § 314(A) ........................................................................................ 21 
`Factor 1: Whether the same petitioner previously filed a
`A. 
`petition directed to the same claims of the same patent ...................... 23 
`Factor 2: Whether at the time of filing of the first petition the
`petitioner knew of the prior art asserted in the second petition or
`should have known of it ...................................................................... 26 
`
`B. 
`
`C. 
`
`2. 
`
`B. 
`
`-i-
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`

`

`TABLE OF CONTENTS
`(cont’d)
`
`Page No.
`
`C. 
`
`D. 
`
`Factor 3: Whether the petitioner already received the patent
`owner’s preliminary response to the first petition or received
`the Board’s decision on whether to institute review in the first
`petition ................................................................................................. 26 
`Factor 4: The length of time that elapsed between the time the
`petitioner learned of the prior art asserted in the second petition
`and the filing of the second petition .................................................... 28 
`Factor 5: Whether the petitioner provides adequate explanation
`for the time elapsed between the filings of multiple petitions
`directed to the same claims of the same patent ................................... 28 
`Factor 6: The finite resources of the Board ........................................ 29 
`Factor 7: The requirement under 35 U.S.C. § 316(a)(11) to
`issue a final determination not later than 1 year after the date on
`which the Director notices institution of review ................................. 30 
`VI. THE PETITION SHOULD BE DENIED UNDER 35 U.S.C. § 325(d) ....... 31 
`VII. THE PERSON OF ORDINARY SKILL ...................................................... 32 
`VIII. NEW CLAIM CONSTRUCTION IS UNNECESSARY ............................. 32 
`IX. THE LAW OF NONOBVIOUSNESS .......................................................... 32 
`X. THERE WAS NO MOTIVATION TO COMBINE TSIEN WITH
`GREENE & WUTS OR ZAVGORODNY ................................................... 33 
`A. 
`Introduction to Tsien, Greene & Wuts, and Zavgorodny ................... 33 
`B. 
`Criteria 1: A POSITA would not have expected a
`3’-O-azidomethyl group to be efficiently and accurately
`incorporated by a polymerase ............................................................. 36
`
`
`E. 
`
`F. 
`G. 
`
`-ii-
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`

`

`TABLE OF CONTENTS
`(cont’d)
`
`Page No.
`
`1. 
`
`There was no motivation to use an azidomethyl group in
`Tsien’s sequencing methods because there was no
`expectation of efficient and accurate polymerase
`incorporation ............................................................................. 36
`
`2. 
`
`C. 
`
`BGI has not shown there was a reasonable expectation of
`success in arriving at the claimed “incorporation” ................... 44 
`Criteria 2(i): A POSITA would not have expected azidomethyl
`removal conditions to be “mild” for Tsien’s DNA sequencing
`method ................................................................................................. 45 
`1. 
`Phosphine deblocking conditions produce amines ................... 46 
`2. 
`Pyridine was a known DNA denaturant ................................... 48 
`3. 
`Young’s cleavage conditions were not mild ............................. 49 
`Criteria 2(ii): A POSITA would not have expected quantitative
`azidomethyl removal ........................................................................... 49 
`Criteria 3: A POSITA would not have expected an azidomethyl
`ether to permit a polymerase to reinitiate synthesis subsequent
`to deblocking ....................................................................................... 52 
`XI. AZIDOMETHYL WAS NOT A SIMPLE SUBSTITUTION INTO
`TSIEN’S SBS METHOD .............................................................................. 56 
`XII. MOTIVATION IS LACKING FROM BGI’S PETITION THAT IS
`PRESENT IN ILLUMINA’S PETITIONS ................................................... 58 
`BGI relies on disclosure of a 3’-protecting group from outside
`A. 
`of Tsien, whereas Illumina’s petitions rely on protecting group
`disclosures within Tsien ...................................................................... 58 
`Polymerase incorporation distinction .................................................. 60
`
`D. 
`
`E. 
`
`B. 
`
`-iii-
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`

`

`TABLE OF CONTENTS
`(cont’d)
`
`Page No.
`
`C. 
`
`Illumina’s positions are consistent with previous Board and
`Federal Circuit decisions, whereas BGI’s petition and
`Columbia’s patents seek to undo those decisions ............................... 60 
`1. 
`BGI’s petition seeks to undo IPR2013-00517 .......................... 60 
`2. 
`Columbia’s patents seek to undo IPR2012-00006,
`IPR2012-00007, and IPR2013-00011 ....................................... 61 
`XIII. THE DEPENDENT CLAIMS ARE NONOBVIOUS .................................. 62 
`XIV. SECONDARY CONSIDERATIONS OF NONOBVIOUSNESS ............... 62 
`A. 
`BGI failed to address Illumina’s evidence of non-obviousness .......... 62 
`B. 
`BGI advances an unsupported and incorrect legal theory
`regarding unexpected results ............................................................... 63 
`BGI avoids addressing Illumina’s evidence of long-felt, unmet
`need ...................................................................................................... 64 
`BGI incorrectly argues that since there is no evidence of a
`competing commercial product, there can be no evidence of
`copying ................................................................................................ 65 
`XV. CONCLUSION .............................................................................................. 67 
`
`
`
`
`C. 
`
`D. 
`
`-iv-
`
`

`

`TABLE OF AUTHORITIES
`
`Page No(s).
`
`Akamai Tech, Inc.. v. Cable & Wireless Internet Servs., Inc.,
`344 F. 3d 1186 (Fed. Cir. 2003) ......................................................................... 66
`
`Boston Sci. Scimed, Inc. v. Cordis Corp.,
`554 F.3d 982 (Fed. Cir. 2009) ............................................................................ 59
`
`In re Chu,
`66 F.3d 292 (Fed. Cir. 1995) .............................................................................. 64
`
`Columbia v. Illumina,
`620 Fed. Appx. 916 (Fed. Cir. 2015) .................................................................. 61
`
`Demaco Corp. v. F. Von Langsdorff Licensing Ltd.,
`851 F.2d 1387 (Fed. Cir. 1988) .......................................................................... 65
`
`In re Fritch,
`972 F.2d 1260 (Fed Cir. 1992) ........................................................................... 62
`
`General Plastic Industrial Co. Ltd. v. Canon Kabushiki Kaisha,
`IPR2016-01357, Paper 19 (P.T.A.B. 2017) .................................................passim
`
`Genetics Institute, LLC v. Novartis Vaccines and Diagnostics, Inc.,
`655 F.3d 1291 (Fed. Cir. 2011) .......................................................................... 63
`
`Illumina, Inc. v. Qiagen N.V.,
`207 F.Supp.3d 1081 (N.D. Cal. 2016) ................................................ 2, 17, 19, 66
`
`Illumina, Inc. v. Trustees of Columbia University in the City of New York,
`IPR2012-00006, Paper 128 (P.T.A.B. 2014) ...................................................... 61
`
`Illumina, Inc. v. Trustees of Columbia University in the City of New York,
`IPR2012-00007, Paper 140 (P.T.A.B. 2014) ...................................................... 61
`
`Illumina, Inc. v. Trustees of Columbia University in the City of New York,
`IPR2013-00011, Paper 130 (P.T.A.B. 2014) ...................................................... 61
`
`
`
`-v-
`
`

`

`TABLE OF AUTHORITIES
`(cont’d)
`
`Page No(s).
`
`Intelligent Bio-Systems, Inc. v. Illumina Cambridge Ltd.,
`821 F.3d 1359 (Fed. Cir. 2016) ...................................................................passim
`
`Intelligent Bio-Systems, Inc. v. Illumina Cambridge Ltd.,
`IPR2013-00324, Paper 19 (P.T.A.B. 2013) ........................................................ 20
`
`KSR Int’l Co. v. Teleflex Inc.,
`550 U.S. 398 (2007) ............................................................................................ 33
`
`LG Elecs. Inc. v. Core Wireless Licensing S.A.R.L.,
`IPR2016-00986, Paper 12 (P.T.A.B. 2016) ............................................ 20, 22, 29
`
`Medtronic, Inc. v. Nuvasive, Inc.,
`IPR2014-00487, Paper 8 (P.T.A.B. 2014) .................................................... 20, 31
`
`NetApp Inc. v. Crossroads Systems, Inc.,
`IPR2015-00776, Paper 13 (P.T.A.B. 2015) ........................................................ 27
`
`NetApp Inc. v. Realtime Data LLC,
`IPR2017-01195, Paper 9 (P.T.A.B. 2017) .......................................................... 23
`
`NetApp Inc. v. Realtime Data LLC,
`IPR2017-01196, Paper 10 (P.T.A.B. 2017) ........................................................ 25
`
`NetApp Inc. v. Realtime Data LLC,
`IPR2017-01354, Paper 16 (P.T.A.B. 2017) ........................................................ 25
`
`NVIDIA Corp. v. Samsung Elec. Co.,
`IPR2016-00134, Paper 9 (P.T.A.B. 2016) .................................................... 20, 22
`
`Omron Oilfield & Marine, Inc. v. MD/Totco,
`IPR2013-00265, Paper 11 (P.T.A.B. 2013) .................................................. 62, 64
`
`R.J. Reynolds Vapor Co. v. Fontem Holdings 1 B.V.,
`IPR2017-01117, Paper 10 (P.T.A.B. 2017) ........................................................ 29
`
`Samsung Electronics Co., Ltd. v. ELM 3DS Innovations, LLC,
`IPR2017-01305, Paper 11 (P.T.A.B. 2017) ........................................................ 23
`
`-vi-
`
`

`

`TABLE OF AUTHORITIES
`(cont’d)
`
`Page No(s).
`
`Starbucks Corp. v. Ameranth, Inc.,
`CBM2017-00053, Paper 7 (P.T.A.B. 2017) ....................................................... 22
`
`Stratoflex, Inc. v. Aeroquip Corp.,
`713 F.2d 1530 (Fed. Cir. 1983) .................................................................... 62, 66
`
`TCL Corp. v. Lexington Luminance LLC,
`IPR2017-01780, Paper 8 (P.T.A.B. 2018) .......................................................... 31
`
`Travelocity.com L.P. v. Cronos Techs., LLC,
`CBM2015-00047, Paper 7 (P.T.A.B. 2015) ....................................................... 31
`
`Unified Patents, Inc. v. Personal Web Technologies, LLC,
`IPR2014-00702, Paper 13 (P.T.A.B. 2014) .................................................. 20, 25
`
`Viptela, Inc. v. Fatpipe Networks Private Ltd.,
`IPR2017-01125, Paper 9 (P.T.A.B. 2017) .......................................................... 25
`
`Xactware Solutions, Inc. v. Eagle View Techs. Inc.,
`IPR2017-00034, Paper 9 (P.T.A.B. 2017) .......................................................... 22
`
`OTHER AUTHORITIES
`
`35 U.S.C. § 313 .......................................................................................................... 1
`
`35 U.S.C. § 314 .................................................................................................passim
`
`35 U.S.C. § 316 .................................................................................................. 22, 30
`
`35 U.S.C. § 325 ...................................................................................... 20, 21, 31, 32
`
`37 C.F.R. § 42.1 ................................................................................................... 3, 29
`
`37 C.F.R. § 42.107 ..................................................................................................... 1
`
`37 C.F.R. § 42.108 ................................................................................................... 23
`
`H.R. Rep. No. 112098, part 1 (2011) ....................................................................... 32
`
`
`
`
`-vii-
`
`

`

`IPR2017-02172
`Complete Genomics v. Illumina
`
`
`
`Pursuant to 35 U.S.C. § 313, 37 C.F.R. § 42.107, and the Notice of Filing
`
`Date Accorded to Petition (Paper 3), Patent Owner Illumina Cambridge Ltd.
`
`(“Illumina”) submits its Preliminary Response to the Petition for Inter Partes
`
`Review filed by Complete Genomics, Inc. and its real party-in-interest, BGI
`
`Shenzhen Co., Ltd. (collectively “BGI”).
`
`I. INTRODUCTION
`BGI’s attempt to challenge the ’537 Patent is a prime example of a repetitive
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`challenge to a repeatedly-upheld patent that should be denied. Further investment
`
`of scarce judicial resources is unwarranted, especially given the low probability of
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`success implied by the past outcomes upholding the patent. Even beyond that,
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`Patent Owner deserves repose after expending so much time, effort and attention
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`successfully defending its duly issued and legally valid patent.
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`The ’537 Patent has been battle tested in the crucible of district court and
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`PTAB litigation based on the very same Tsien prior art reference that is the
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`centerpiece of this petition along with the same secondary references Greene &
`
`Wuts, Zavgorodny and Prober. Seven judges have considered and rejected this
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`prior art attack. This includes a three judge PTAB panel, a three judge Federal
`
`Circuit panel and Judge Alsup of the Northern District of California.
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`Judge Alsup specifically addressed the validity of the ’537 Patent in granting
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`a preliminary injunction and concluded that it was unlikely to be invalidated given
`
`1
`
`

`

`IPR2017-02172
`Complete Genomics v. Illumina
`
`the weakness of the prior art, including Tsien modified by Greene & Wuts.
`
`Illumina, Inc. v. Qiagen N.V., 207 F.Supp.3d 1081, 1088-1090 (N.D. Cal. 2016).
`
`He found a “weak” showing of a motivation to combine the prior art to show the
`
`claimed inventions and a low likelihood of success even if one were motivated to
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`modify the Tsien reference. Id. Given the high stakes in an injunction proceeding,
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`it is safe to conclude that the enjoined infringer had full motivation to make the
`
`best prior art argument it could based on Tsien. Yet, its obviousness attack on the
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`’537 Patent was soundly rejected. Id. After this loss, the infringer ultimately
`
`agreed to a consent decree enjoining it from infringing the ’537 Patent, further
`
`underlining the proven validity of the patent.
`
`Beyond that, all claims challenged by BGI’s petition withstood a full trial in
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`IPR2013-00517. The previous petition was filed by Intelligent Bio-Systems and
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`its parent company, Qiagen, a sophisticated, multinational company based in
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`Germany with offices throughout the U.S. The Board issued a final written
`
`decision upholding the patentability of all challenged claims over the prior art
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`Tsien reference in view of the Zavgorodny reference. Green & Wuts and Prober
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`were considered too. The Federal Circuit panel unanimously affirmed the Board’s
`
`decision. Intelligent Bio-Systems, Inc. (“IBS”) v. Illumina Cambridge Ltd., 821
`
`F.3d 1359, 1370 (Fed. Cir. 2016). The Federal Circuit considered all the same
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`references relied on in the pending petition and confirmed that the PTAB properly
`
`2
`
`

`

`IPR2017-02172
`Complete Genomics v. Illumina
`
`rejected the prior art challenge. Id. at 1366-69 (evaluating Tsien, Zavgorodny, and
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`Greene & Wuts).
`
`BGI has been in the sequencing business for years, including, but not limited
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`to, in the U.S. through its subsidiary CGI. BGI failed to file this petition during the
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`pendency of the prior IPR even though it addresses the same prior art as BGI
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`pursues now. Nor did it seek to join the prior proceeding. BGI sat on the sidelines
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`and apparently wanted to reap the benefit of the previous petitioner’s potential
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`success or wait to stage its own follow-on attack to take advantage of the Board
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`and Federal Circuit’s responses to the arguments and evidence presented in the
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`first IPR. The Board ruled in favor of Illumina in the original IPR. BGI’s belated
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`rehash of prior arguments based on the same prior art should not be rewarded.
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`Instituting another IPR proceeding would not “secure the just, speedy, and
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`inexpensive resolution of every proceeding.” 37 C.F.R. § 42.1(b).
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`The Board has put petitioners on notice that follow-on petitions will be
`
`heavily scrutinized under 35 U.S.C. §§ 314(a) and 325(d) even if there are no
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`district court decisions upholding the invalidity of the patent or Federal Circuit
`
`decisions addressing the same prior art. The Board has issued informative and
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`precedential decisions directing follow-on petitioners to explain why Board and
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`Patent Owner resources should be expended on their secondary petitions. In the
`
`3
`
`

`

`IPR2017-02172
`Complete Genomics v. Illumina
`
`face of 314(a) or 325(d), BGI does not even attempt to justify its belated secondary
`
`petition on the same prior art and should be rejected outright.
`
`Illumina is a U.S. company that began as a technology-driven start-up
`
`company in the biotechnology hotbed of San Diego, California, and merged with a
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`similarly driven company out of Cambridge, UK – Solexa – to jointly deliver
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`ground-breaking and highly popular sequencing technology. Today, Illumina has
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`become the leading innovator in the DNA sequencing industry, employing
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`approximately 5,500 workers. The challenged claims of ’537 patent protect
`
`Illumina’s highly successful sequencing products that use labeled nucleotides
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`having a reversible 3’-O-azidomethyl protecting group. Both BGI and Qiagen
`
`have been developing DNA sequencers but, to-date, they have been unable to
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`develop an alternative technology to effectively compete against Illumina’s
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`reversible 3’-O-azidomethyl terminator technology in the United States.
`
`The current petitioner, BGI, and the original failed petitioner, Qiagen, are
`
`not strangers. They have business ties and an aligned interest in gaining free
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`access to the valuable inventions protected by the ’537 patent as soon as they can.
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`BGI’s follow-on petition seeks to abuse the IPR process by retreading even though
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`Qiagen lost.
`
`BGI’s retread petition fails to establish a prima facie case of obviousness for
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`the same reasons that the Board determined Qiagen’s earlier petition failed, the
`
`4
`
`

`

`IPR2017-02172
`Complete Genomics v. Illumina
`
`Federal Circuit affirmed that decision and Judge Alsup enjoined their infringement.
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`BGI relies on Tsien as the primary reference in its obviousness challenge. Tsien
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`provides three distinct criteria for selecting a 3’-blocking group from the literature:
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`(1) the ability of a polymerase enzyme to accurately and efficiently
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`incorporate dNTPs carrying the 3’-blocking group into DNA,
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`(2) the availability of mild conditions for rapid and quantitative deblocking,
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`and
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`(3) the ability of a polymerase enzyme to reinitiate DNA synthesis
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`subsequent to deblocking.
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`BGI’s petition, however, fails to establish that an azidomethyl protecting
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`group would have been known to meet any of these criteria. A person of ordinary
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`skill in the art (“POSITA”) therefore would not have been motivated to use an
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`azidomethyl group as Tsien’s 3’-blocking group.
`
`Not only does BGI’s follow-on petition fail to establish a prima facie case of
`
`obviousness, it also fails to rebut Illumina’s significant evidence of secondary
`
`considerations of non-obviousness. In the previous IPR, Illumina raised significant
`
`evidence of secondary considerations of nonobviousness, including long-felt but
`
`unmet need, unexpected results, and evidence of copying. BGI fails to
`
`substantively address this evidence, and thus fails to carry its burden of
`
`demonstrating obviousness. BGI’s desire to gain access the claimed technology by
`
`5
`
`

`

`IPR2017-02172
`Complete Genomics v. Illumina
`
`attacking the patent that covers it only strengthens those secondary considerations.
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`For all of these reasons, the Board should deny institution of BGI’s follow-on
`
`petition.
`
`II. ILLUMINA’S CLAIMED INVENTION INCLUDES A NOVEL AND
`NONOBVIOUS 3ʹ-OH PROTECTING GROUP FOR DNA SEQUENCING
`
`Illumina is the undisputed innovative leader in the DNA sequencing
`
`industry. Illumina has been referred to as the “smartest company in the world”
`
`because it “commercializes a truly innovative technology” and causes competitors
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`“to refine or rethink their strategies.” Ex-2001 at 27-29. Illumina’s novel and
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`successful methods of labeling nucleic acid molecules use a reversible 3’-O-
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`azidomethyl ether protecting group in its DNA sequencing instruments. Illumina’s
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`successful sequencing instruments “account[] for the largest market share for
`
`sequencing instruments compared to other platforms.”
`
` Ex-2002 at 337.
`
`“Illumina’s highly successful suite of instruments have been the juggernaut of
`
`NGS [next generation DNA sequencing], relegating technologies that could not
`
`keep pace to niche applications or outright dissolution.” Id. at 348. Indeed, where
`
`Illumina has succeeded, Complete Genomics (“CGI”) and BGI1 have failed. For
`
`example, CGI and BGI instruments attempted to sequence DNA using the
`
`
`1 BGI, formerly Beijing Genomics Institute, is a Chinese company that acquired
`
`CGI in March of 2013. Ex-2003 at 1. BGI is a real party-in-interest. Petition at 4.
`
`6
`
`

`

`IPR2017-02172
`Complete Genomics v. Illumina
`
`“combinatorial probe-anchor ligation (cPAL)” technology, which CGI marketed
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`under the name “Revelocity.” Id. at 335. The Revelocity sequencing technology
`
`was not commercially viable and could not compete with Illumina’s 3’-O-
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`azidomethyl nucleotides. Id. at 348 (“The casualties of the NGS arms race have
`
`included… the Revelocity system from Complete Genomics.”), id. at 337
`
`(“although the cPAL-based Revelocity system [from CGI] was intended to
`
`compete with the Illumina HiSeq2 in terms of cost and throughout, its launch was
`
`suspended in 2016 and it is now only available as a service platform for human
`
`WGS [whole genome sequencing]”).
`
`BGI abandoned cPAL due to inferior read lengths, and instead adopted
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`Illumina’s polymerase-based sequencing-by-synthesis (“SBS”) approach. BGI
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`refers to its copycat polymerase approach as “combinatorial probe-anchor
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`synthesis (cPAS).” BGI asserts cPAS provides “longer reads ... compared to the
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`previously described combinatorial probe-anchor ligation (cPAL) chemistry.” Ex-
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`2004 at 2. BGI’s cPAS-based BGISEQ-500 platform “is limited to mainland
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`China” (Ex-2002 at 337), apparently due to “patent issues” excluding BGI from
`
`other markets. Ex-2005 at 2. BGI’s present petition seeking cancellation of the
`
`
`2 The HiSeq instrument is one of Illumina’s flagship DNA sequencing instruments
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`and, like all of Illumina’s sequencing instruments, uses 3’-O-azidomethyl protected
`
`nucleotides.
`
`7
`
`

`

`IPR2017-02172
`Complete Genomics v. Illumina
`
`’537 patent claims that protect Illumina’s labeling methods and reversible 3’-O-
`
`azidomethyl terminator technology is a strong signal that BGI wants to send its
`
`infringing sequencers into the U.S.
`
`BGI’s petition alleges that Claims 1-6 and 8 of the ’537 patent would have
`
`been obvious to a POSITA based on a combination of Tsien, Greene & Wuts, and
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`Zavgorodny. Tsien was published in 1991 and identified several criteria for a 3’-
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`protecting group to be used in DNA sequencing methods. Ex-1003 at 20:28-21:3,
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`23:27-24:5. With Tsien’s publication as a guide, researchers immediately set forth
`
`searching for nucleotide 3’-protecting groups compatible with the identified
`
`criteria. By August of 2002, at least 11 separate research teams had tried to
`
`identify 3’-protecting groups that were effective for use in DNA sequencing:
`
`(1) Tsien investigated at least 3’-O-allyl and various other groups (Ex-1003
`
`at 21:20-31);
`
`(2) Dower (Affymax) contemplated at least “acetyl, tBOC, NBOC, and
`
`NVOC” 3’-OH protecting groups (Ex-1004 at 25:47-51);
`
`(3) Metzker
`
`investigated 3’-O-methyl, 3’-O-acetyl, 3’-O-allyl, 3’-O-
`
`tetrahydropyran, 3’-O-4-nitrobenzoyl, 3’-O-2-aminobenzoyl,
`
`and 3’-O-2-
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`nitrobenzyl groups (Ex-1041 at 4263);
`
`(4) Canard investigated at least 3’-O-anthranyloyl and 3’-O-anthranyl
`
`derivatives (Ex-1042 at 10859);
`
`8
`
`

`

`IPR2017-02172
`Complete Genomics v. Illumina
`
`(5) Stemple (ASM Scientific) investigated at least 3’-O-(2-nitrobenzyl)
`
`groups (Ex-2006 at 13:18-20);
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`(6) Odedra (Amersham Pharmacia) investigated at least acetyl and
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`phenylacetamide groups (Ex-2007 at Figs. 2 & 11);
`
`(7) Cheeseman (Beckman Instruments) investigated at least 3’-O-succinyl
`
`and 3’-O-anhydride derivatives (Ex-1055 at 4:50-63);
`
`(8) Kwiatkowski (Helicos BioSciences)
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`investigated at
`
`least 3’-O-
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`hydrocarbyldithiomethyl and 3’-O-“functionalized acetal” groups (Ex-2008 at
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`2:40-60; Ex-2009 at 15:11-16:24);
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`(9) Rosenthal investigated 3’-blocking groups that “generate a 3’ hydroxyl
`
`group” (Ex-2010 at 11:3-10);
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`(10) Rabani investigated at least a 3’-O-(4-benzoyl)benzoyl group (Ex-2011
`
`at 2:15-21); and
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`(11) Ju investigated at least 3’-O-allyl and 3’-O-methoxymethyl groups (Ex-
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`1038 at Fig. 7).
`
`None of these researchers investigated or even suggested a protecting group
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`comprising an azido group that can be modified or removed to expose a 3’-OH
`
`group. These research efforts showed that Tsien’s 3’-O-allyl group was a
`
`reversible protecting group that could be incorporated effectively by polymerases.
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`Ex-1003 at 24:29; Ex-1041 at 4263; Ex-1038 at 3:7-22.
`
`9
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`

`

`IPR2017-02172
`Complete Genomics v. Illumina
`
`Despite the numerous research efforts by multiple teams, only Illumina
`
`identified the azidomethyl group as a protecting group for DNA sequencing. Ex-
`
`1001 at 19:49-20:4. Illumina found that the azidomethyl protecting group was
`
`incorporated by polymerases and was surprisingly cleaved in rapid and quantitative
`
`yield under conditions that permit polymerase incorporation for DNA sequencing.
`
`This resulted in sequencing successes unachievable with other 3’-OH protecting
`
`groups. These properties were not known in the prior art at the time the ’537
`
`patent was filed, and no knowledge in the art would have led a POSITA to expect
`
`that an azidomethyl group could be successful. To date, Illumina’s 3’-O-
`
`azidomethyl group remains the industry-leading reversible terminator technology
`
`for sequencing even though 15 years have passed since the ’537 patent was filed.
`
`The present petition asserts unpatentability of the same ’537 patent claims
`
`using the same references and arguments over which the Board and Federal Circuit
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`previously upheld patentability in IPR213-00517. The Board should deny
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`Petitioner’s request to re-litigate patentability of Illumina’s claims for the same
`
`reasons it upheld Illumina’s claims in the previous IPR. A summary of the
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`previous IPR proceeding and Federal Circuit affirmance is provided in the
`
`following section.
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`10
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`

`

`IPR2017-02172
`Complete Genomics v. Illumina
`
`III. THE BOARD, FEDERAL CIRCUIT, AND DISTRICT COURT
`PREVIOUSLY UPHELD PATENTABILITY OF THE
`CHALLENGED CLAIMS
`A. The Board previously upheld the same claims over the same art and
`arguments in IPR2013-00517
`
`On August 19, 2013, Intelligent Bio-Systems and its parent company,
`
`Qiagen,3 filed a petition for IPR of Claims 1-6 and 8 of the ’537 patent in
`
`IPR2013-00517. On August 30, 2013, they filed a revised petition. Ex-1090 at 2,
`
`49. The revised petition challenged Claims 1-6 and 8 based on the following
`
`grounds:
`
`Ground Claim(s) Obviousness Challenge
`
`1a
`
`1b
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`1c
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`1d
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`2a
`
`2b
`
`1-6 and 8
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`Ju and Zavgorodny
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`1-6 and 8
`
`Ju and Greene & Wuts
`
`1-6 and 8 Tsien and Zavgorodny
`
`1-6 and 8 Tsien and Greene & Wuts
`
`3
`
`3
`
`Tsien, Zavgorodny, and Prober
`
`Tsien, Greene & Wuts, and Prober
`
`
`Ex-1090 at 6-8. Grounds 1c-2b of the revised petition raised the same art against
`
`the same claims as BGI’s follow-on petition. Petition at 8-9.
`
`
`3 Qiagen acquired IBS in June of 2012. Ex-1092 at 1.
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`11
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`

`

`IPR2017-02172
`Complete Genomics v. Illumina
`
`Qiagen argued that “one of ordinary skill in the art, in order to improve the
`
`efficiency, reliability, and robustness of the sequencing by synthesis [SBS] method
`
`taught in Tsien, would have been motivated to use other protecting groups that
`
`meet the criteria of Tsien, such as the azidomethyl group taught by Zavgorodny.”
`
`Ex-1090 at 38. BGI’s follow-on petition relies on the same SBS motivation.
`
`Petition at 21.
`
`The Board instituted trial on Grounds 1a, 1c, and 2a, and denied grounds 1b
`
`and 2b as redundant. Ex-1091 at 15.
`
`
`
`In its Patent Owner response, Illumina argued, inter alia, that Claims 1-6
`
`and 8 were nonobvious because a POSITA would not have been motivated to
`
`combine Tsien or Ju with the azidomethyl group disclosed by Zavgorodny. Ex-
`
`1092 at 12-42. Illumina supported its arguments by analyzing Greene & Wuts,
`
`Loubinoux, and several other relevant references, along with the expert testimony
`
`of Dr. Romesberg and Dr. Burgess. Id. Illumina further presented significant
`
`evidence of secondary considerations of nonobviousness. Id. at 43-60.
`
`
`
`On February 11, 2015, the Board issued its final written decision upholding
`
`the patentability of Claims 1-6 and 8. Ex-1094 at 24. Significant resources were
`
`expended by the Board and Illumina in reaching this decision, including analyzing
`
`over 200 exhibits, 90 papers, 4 expert witnesses, and conducting an oral hearing.
`
`12
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`

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`IPR2017-02172
`Complete Genomics v. Illumina
`
`In the final written decision, the Board “agree[d] with Patent Owner that
`
`Petitioner has not shown, by a preponderance of the evidence, that an ordinary
`
`artisan would have considered it obvious to use Zavgorodny’s azidomethyl group
`
`as the 3’ hydroxyl protecting group in Tsien’s processes.” Id. at 9. The Board
`
`explained:
`
`the prior art suggests that an ordinary artisan would not have expected
`Zavgorodny’s azidomethyl group to be removed quantitatively, as
`Tsien requires. We, therefore, agree with Patent Owner that Petitioner
`has not shown that an ordinary artisan would have considered it
`obvious to use Zavgorodny’s azidomethyl protecting group in Tsien’s
`sequencing methods.
`
`Id. at 14. The Board also found that Illumina presented “evidence that an ord