`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Paper No. 13
`Filed: May 4, 2018
`
`
`
`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.
`_______________
`
` Case IPR2018-00385
`Patent 9,725,480
`_______________
`
`PATENT OWNER’S PRELIMINARY RESPONSE
`
`
`
`
`
`
`
`
`Illumina Ex. 1049
`IPR Petition - USP 10,435,742
`
`
`
`A.
`B.
`
`C.
`D.
`E.
`F.
`
`TABLE OF CONTENTS
`Introduction ........................................................................................... 1
`The Challenged Claim Is Patentably Distinct From
`Claims The Board Previously Considered ............................................ 4
`Level Of Ordinary Skill In The Art ....................................................... 8
`Claim Construction ............................................................................... 9
`State of the Art .................................................................................... 11
`Illumina’s Ground 1 Challenge For Obviousness Over
`Tsien In View Of Prober Is Flawed .................................................... 16
`1.
`Illumina Has Not Established That Tsien Or
`Prober Disclose A “Small” Capping Group Not
`Containing A Ketone And Not Forming An Ester
`Or A Methoxy Group With The 3’-Oxygen Of The
`Nucleotide Analogue ................................................................ 19
`Illumina Has Not Established A Motivation To
`Select The Allyl Capping Group .............................................. 22
`a.
`Tsien Does Not Provide Motivation To
`Select The Allyl Capping Group .................................... 23
`The Art Subsequent To Tsien Shows The
`Field Was Not Interested In The Allyl
`Capping Group ................................................................ 26
`A POSA Would Have Been Motivated To
`Select Only A 3’-OH Capping Group That
`Met Tsien’s SBS Requirements ...................................... 30
`Illumina’s Contention That A Small 3’-OH
`Capping Group Would Have Been
`“Desirable” Is Unsupported ............................................ 40
`Illumina Has Not Established A Reasonable
`Expectation of Success ............................................................. 43
`
`d.
`
`2.
`
`3.
`
`b.
`
`c.
`
`i
`
`
`
`
`4.
`5.
`
`G.
`
`2.
`
`The Lead Compound Analysis.................................................. 46
`The Board Should Also Deny Institution On
`Ground 1 Based On 35 U.S.C. §325(d) .................................... 48
`Illumina’s Ground 2 Challenge For Obviousness Over
`Dower In View Of Prober And Metzker Is Flawed ............................ 50
`1. Missing Claim Features In Illumina’s Challenge ..................... 50
`a.
`Dower Does Not Disclose A Chemically
`Cleavable, Chemical Linker ........................................... 50
`Since None Of Dower, Prober, Or Metzker
`Disclose A “Chemically Cleavable,
`Chemical Linker” Y, They Cannot Disclose
`Features (a) Or (b) Of Feature Y .................................... 52
`None Of Dower, Prober, Or Metzker
`Disclose The Functional Features Present In
`The Claimed Deaza-guanine Nucleotide
`Analogue ......................................................................... 53
`Illumina Has Not Established A Motivation To
`Select The Allyl Capping Group And A
`Deazapurine Nucleotide ............................................................ 54
`a. Metzker 1994 Provides No Motivation To
`Select The Allyl Capping Group .................................... 54
`A POSA Reading Dower Would Have Been
`Motivated To Select Only A 3’-OH Capping
`Group That Met Three SBS Requirements .................... 55
`Illumina’s Contention That A Small 3’-OH
`Capping Group Would Have Been
`“Desirable” Is Unsupported ............................................ 57
`Illumina Admitted A POSA Would Not
`Select An Ether Capping Group ..................................... 59
`
`b.
`
`c.
`
`b.
`
`c.
`
`d.
`
`
`
`ii
`
`
`
`e.
`
`3.
`
`Illumina Has Not Established That A POSA
`Would Have Been Motivated To Use
`Prober’s Deazapurines In Dower’s Methods .................. 60
`Illumina Has Not Established A Reasonable
`Expectation of Success ............................................................. 62
`Patent Owner Estoppel Does Not Apply ............................................. 63
`Conclusion ........................................................................................... 68
`
`iii
`
`H.
`I.
`
`
`
`
`
`
`
`TABLE OF AUTHORITIES
`
`
`Cases
`Becton, Dickinson & Co. v. B. Braun Melsungen Ag,
`IPR2017-01586, Paper 8 (Dec. 15, 2017) ..................................................... 49
`CFMT, Inc. v. Yieldup Int’l Corp.,
`349 F.3d 1333 (Fed. Cir. 2003) ..................................................................... 19
`In re Etter,
`756 F.2d 852 (Fed. Cir. 1985) ....................................................................... 27
`In re Stepan Co.,
`868 F.3d 1342 (Fed. Cir. 2017) .............................................................. 23, 39
`Kayak Software Corp. v. Int’l Bus. Machines Corp.,
`CBM2016-00075, Paper 16 (Dec. 15, 2016) ................................................. 49
`Lupin Ltd. v. Pozen Inc.,
` IPR2015-01773, Paper 36 (Feb. 28, 2017) ................................................... 43
`Medtronic, Inc., v. Barry,
`IPR2014-01210, Paper 10 (Feb. 10, 2015) .................................................... 19
`Neil Ziegman, N.P.Z., Inc. v. Stephens,
`IPR2015-01860, Paper 13 (Sept. 6, 2017) ..................................................... 49
`Otsuka Pharm. Co. v. Sandoz, Inc.,
`678 F.3d 1280 (Fed. Cir. 2012) ..................................................................... 29
`Skechers USA, Inc. v. Adidas AG,
`IPR2017-00320, Paper 7 (May 30, 2017) ..................................................... 49
`Sprint Spectrum L.P. v. General Access Solutions, Ltd.,
`IPR2017-01885, Paper 8 (March 9, 2018) .................................................... 18
`Tristar Products, Inc. v. Choon’s Design, LLC,
`IPR2015-01883, Paper 6 (March 9, 2016) .................................................... 65
`Other Authorities
`35 U.S.C. §102(b) .................................................................................................... 42
`
`
`
`iv
`
`
`
`35 U.S.C. §325(d) ....................................................................................... 48, 49, 50
`35 U.S.C. §325(d) ....................................................................................... 48, 49, 50
`37 C.F.R. §42.11(a) ............................................................................... 18, 22, 26, 36
`37 C.F.R. §42.11(a) ............................................................................... 18, 22, 26, 36
`37 C.F.R. §42.2 ........................................................................................................ 18
`37 C.F.R. §42.2 ........................................................................................................ 18
`37 C.F.R. §42.51(b)(1)(iii) .................................................................... 18, 22, 26, 36
`37 C.F.R. §42.51(b)(1)(iii) .................................................................... 18, 22, 26, 36
`37 C.F.R. §42.73(d)(3)(i) ......................................................................................... 63
`37 C.F.R. §42.73(d)(3)(i) ......................................................................................... 63
`M.P.E.P. §804.02 ..................................................................................................... 65
`M.P.E.P. §804.02 ..................................................................................................... 65
`
`
`
`v
`
`
`
`TABLE OF EXHIBITS
`
`Exhibit No. Description
`Declaration of Robert S. Schwartz in Support of Patent Owner’s
`2001
`Motion for Admission Pro Hac Vice Under 37 C.F.R. §42.10
`U.S. Patent No. 7,790,869
`
`2002
`
`2003
`
`U.S. Patent No. 7,713,698
`
`2004
`
`U.S. Patent No. 8,088,575
`
`2005
`
`Exhibit number not used.
`
`2006
`
`Exhibit number not used.
`
`2007
`
`2008
`
`2009
`
`2010
`
`IPR2013-00517, Ex. 2011, Declaration of Floyd Romesberg,
`Ph.D. (May 5, 2014)
`IPR2013-00517, Paper 32, Illumina’s Patent Owner Response
`(May 5, 2014)
`Excerpts from the Ex Parte Reexamination History of U.S. Patent
`No. 5,808,045
`Assignment data in connection with U.S. Patent No. 5,808,045
`
`2011
`
`PCT Publication WO 98/33939 (“Anazawa”) (English translation)
`
`2012
`
`2013
`
`2014
`
`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”)
`
`Metzker, et al., “Stop-Start DNA Synthesis in the Base Addition
`Sequencing Scheme (BASS),” Genome Mapping & Sequencing
`(1994)
`
`
`
`vi
`
`
`
`2015
`
`U.S. Patent No. 7,541,444
`
`2016
`
`U.S. Patent No. 7,771,973
`
`2017
`
`U.S. Patent Application Publication No. 2007/0166705
`
`2018
`
`2019
`
`2020
`
`2021
`
`2022
`
`2023
`
`2024
`
`2025
`
`2026
`
`2027
`
`2028
`
`Boons, et al., “A New Procedure for the Isomerisation of
`Substituted and Unsubstituted Allyl Ethers of Carbohydrates,”
`Chemical Communications, 141-142 (1996)
`Ochiai, et al., “Hypervalent (tert-Butylperoxy)iodanes Generate
`Iodine-Centered Radicals at Room Temperature in Solution:
`Oxidation and Deprotection of Benzyl and Allyl Ethers, and
`Evidence for Generation of α-Oxy Carbon Radicals,” J. Am.
`Chem. Soc., 118:7716-7730 (1996)
`Olivero & Dunach, “Nickel-catalysed Electrochemical Reductive
`Deprotection of Ally1 Ethers,” J. Chem. Soc., Chem. Commun.,
`2497-2498 (1995)
`U.S. Patent No. 6,232,465
`
`Excerpts from the Ex Parte Reexamination History of U.S. Patent
`No. 6,232,465
`Solexa, Inc.’s Fed. R. Civ. P. 7.1 Statement (Feb. 19, 2010)
`
`Solexa, Inc.’s Schedule 13D-A Submission to the United States
`Securities and Exchange Commission (Feb. 2, 2007)
`Litosh, et al., “Improved Nucleotide Selectivity and Termination
`of 3’-OH Unblocked Reversible Terminators by Molecular Tuning
`of 2-Nitrobenzyl Alkylated HOMedU Triphosphates,” Nucleic
`Acids Research, 39:1-13 (2011)
`IPR2017-02172, Paper 6, Preliminary Response of Patent Owner
`Illumina Cambridge Ltd. (January 23, 2018)
`IPR2017-02174, Paper 6, Preliminary Response of Patent Owner
`Illumina Cambridge Ltd. (January 23, 2018)
`U.S. Patent No. 7,566,537
`
`
`
`vii
`
`
`
`2029
`
`2030
`
`2031
`
`2032
`
`2033
`
`2034
`
`2035
`
`2036
`
`2037
`
`2038
`
`2039
`
`2040
`
`2041
`
`2042
`
`2043
`
`No. 2015-1123 (CAFC), Brief of Patent Owner-Appellant
`Illumina Cambridge Ltd., D.I. 27 (March 10, 2015)
`IPR2013-00266, Paper 39, Patent Owner Illumina’s Reply to
`Petitioner’s Opposition to Illumina’s Motion to Amend (March 21,
`2014)
`Canard & Sarfati, “DNA Polymerase Fluorescent Substrates with
`Reversible 3’-Tags,” Gene, 148:1-6 (1994)
`IPR2013-00517, Paper 84, Oral Hearing Transcript (February 2,
`2015)
`IPR2013-00517, Paper 64, Illumina’s Motion for Observations on
`the Cross-Examination Testimony of Bruce Branchaud, Ph.D. and
`Michael Metzker, Ph.D. (September 2, 2014)
`IPR2012-00007, Paper 5, Petition for Inter Partes Review of U.S.
`Pat. No. 7,790,869 (September 16, 2012)
`IPR2013-00517, Exhibit 1025, Deposition of Floyd Romesberg,
`Ph.D. (July 28, 2014)
`IPR2012-00007, Paper 38, Decision on Petition for Inter Partes
`Review (March 12, 2013)
`Assignment data in connection with U.S. Patent Application
`Publication No. 2007/0166705 and U.S. Patent No. 7,541,444
`Assignment data in connection with U.S. Patent No. 6,232,465
`
`PCT Publication WO 98/33939 (Japanese language version of
`Anazawa)
`Translation Affidavit for Anazawa
`
`Welch & Burgess, “Synthesis of Fluorescent, Photolabile 3’-O-
`Protected Nucleoside Triphosphates for the Base Addition
`Sequencing Scheme,” Nucleosides & Nucleotides, 18:197-201
`(1999)
`IPR2013-00517, Paper 68, Illumina’s Opposition to IBS Motion
`To Exclude Evidence
`Excerpts from the Prosecution History of U.S. Patent No.
`7,771,973
`
`
`
`viii
`
`
`
`2044
`
`Exhibit number not used.
`
`2045
`
`Exhibit number not used.
`
`2046
`
`2047
`
`2048
`
`2049
`
`Exhibit number not used.
`
`Excerpts from the Prosecution History of U.S. Patent No.
`9,725,480 not included in Ex-1068
`Excerpts from the Prosecution History of U.S. Patent No.
`9,718,852 not included in Ex-1072
`IPR2018-00291, Petition for Inter Partes Review of U.S. Patent
`No. 9,718,852 (December 8, 2017)
`
`
`
`ix
`
`
`
`Case IPR2018-00385
`Patent No. 9,725,480
`A.
`Introduction
`In 2000, Columbia Professor Dr. Jingyue Ju and Zengmin Li, John Robert
`
`Edwards, and Yasuhiro Itagaki (“the Columbia inventors”) solved a decade-old
`
`problem that Petitioner, Illumina, and its expert admitted was a “major challenge”
`
`and a “formidable obstacle.” Ex-2007 ¶60; Ex-2008 at 4-5; Ex-2042 at 6. They
`
`invented nucleotide analogues that permitted Sequencing by Synthesis (SBS) to
`
`become a practical reality. Others described a wide variety of features for a
`
`deoxyribonucleotide analogue for use in SBS, but no one defined the combination
`
`of features necessary for success. The Columbia inventors conceived nucleotide
`
`analogues comprising, inter alia, (i) on the deoxyribose 3’-oxygen, a chemically
`
`cleavable, chemical capping group having a “small” diameter (i.e., less than 3.7Å),
`
`which does not contain a ketone and does not form an ester or a methoxy group
`
`with the 3’-oxygen and (ii) on the 7-position of a deaza-guanine base, a chemically
`
`cleavable, chemical linker attached to a detectable fluorescent moiety.
`
`Contrary to Illumina’s arguments, the ’480 patent claim (“the challenged
`
`claim”) differs from the claims found unpatentable in prior IPR proceedings.
`
`Specifically, the challenged claim is substantially narrower than, and patentably
`
`distinct from, those earlier claims. Before allowing the challenged claim, the
`
`Examiner considered the prior art and the Board’s earlier rulings and correctly
`
`1
`
`
`
`
`Case IPR2018-00385
`Patent No. 9,725,480
`determined the challenged claim recites novel and non-obvious nucleotide
`
`analogues.
`
`Illumina’s Ground 1 challenge relies principally on Tsien. Tsien discusses,
`
`without differentiation, a vast number of capping groups that include groups that
`
`contradict key limitations of the challenged claim. For example, Tsien teaches the
`
`use of capping groups that were not small, and/or that were esters, both of which
`
`are structural features excluded from the challenged claim. Illumina argues that
`
`one embodiment of the challenged claim would have been obvious to a person of
`
`ordinary skill in the art (“POSA”), i.e., a nucleotide analogue with the 3-carbon
`
`allyl (-CH2CH=CH2) group capping the 3’-oxygen of the sugar, because a POSA
`
`reading Tsien’s disclosure of capping groups would have selected the 3-carbon
`
`allyl capping group. This challenge fails because Tsien does not disclose the 3-
`
`carbon allyl capping group and, even if Tsien did disclose this group, Illumina has
`
`not established that a POSA would have been motivated to select this group from
`
`Tsien’s disclosure, which Illumina in 2011 admitted “encompasses broad classes of
`
`compounds, perhaps hundreds or more potential blocking groups.” Ex-2009 at 15.
`
`Illumina also ignores publications in the field subsequent to Tsien, which
`
`demonstrate there was no reason to select the 3-carbon allyl capping group.
`
`Indeed, in 2000 the only experimental results concerning a nucleotide analogue
`
`with this allyl capping group taught it was a poor choice for DNA sequencing and
`2
`
`
`
`
`
`
`Case IPR2018-00385
`Patent No. 9,725,480
`pointed to other 3’-OH capping groups. Illumina offers no reason why a POSA
`
`would have diverged so drastically from the conventional understanding in 2000.
`
`Importantly, Illumina previously argued the opposite position to the Patent
`
`Office. During a reexamination of its own U.S. Patent No. 6,232,465 claiming a
`
`nucleotide analogue with an allyl capping group, Illumina in 2007 admitted that
`
`“Tsien does not teach or suggest” a nucleotide analogue with the 3-carbon allyl
`
`group, and a POSA in 2000 “would not have been motivated to prepare” that
`
`nucleotide analogue “with a reasonable expectation that [it] could be used for DNA
`
`synthesis.” Ex-2022 at 14, 16. These admissions further demonstrate that Illumina
`
`cannot meet its burden of establishing that a POSA reading Tsien would have
`
`selected a 3-carbon allyl capping group for use in Tsien’s methods. Furthermore,
`
`Illumina’s failure to disclose its inconsistent positions in its Petition is a violation
`
`of its duty of candor to the Board.
`
`Illumina’s Ground 2 challenge fails because none of Illumina’s references
`
`disclose or suggest a “chemically cleavable, chemical linker” on the nucleotide
`
`analogue’s base for attaching a fluorescent label. Illumina asserts Dower discloses
`
`this feature, but the Board previously rejected that argument, unambiguously
`
`finding Dower does not disclose such a linker. It is axiomatic that a claim cannot
`
`be rendered obvious by a combination of references none of which discloses or
`
`suggests a feature of the claim.
`
`
`
`
`3
`
`
`
`Case IPR2018-00385
`Patent No. 9,725,480
`Finally, Illumina’s Petition is long on allegations that the Federal Circuit and
`
`Board made determinations in prior IPRs that should be adopted here, but short on
`
`evidence establishing the prior art teaches what Columbia claims in the ’480
`
`patent. Illumina’s reliance on alleged findings in prior IPRs concerning different
`
`claims is a smokescreen seeking to hide the lack of support for its challenges. For
`
`the reasons discussed herein, Illumina has not met its burden of establishing a
`
`reasonable likelihood the challenged claim is unpatentable under Ground 1 or
`
`Ground 2.
`
`B.
`
`The Challenged Claim Is Patentably Distinct
`From Claims The Board Previously Considered
`Prior to 2012, Columbia obtained several patents for what it believed to be
`
`the broad scope of its invention, including U.S. Patent Nos. 7,790,869; 7,713,698;
`
`and 8,088,575. Exs-2002, 2003, 2004. In September and October 2012, in the
`
`infancy of AIA trials, Illumina filed Petitions for Inter Partes Review challenging
`
`certain claims of these patents (“the Columbia Patent IPRs”). During those
`
`proceedings, in which the challenged claims were found unpatentable, the Board
`
`made findings regarding the prior art, including Tsien, Prober, and Dower. Exs-
`
`1005, 1006, 1007.
`
`The challenged claim was prosecuted subsequent to those proceedings and is
`
`narrower and more precisely defines Columbia’s invention. During prosecution,
`
`
`
`
`4
`
`
`
`Case IPR2018-00385
`Patent No. 9,725,480
`Columbia made the Examiner fully aware of the Board’s earlier findings. Ex-2047
`
`at 113, 120, 128. The Examiner reviewed those findings and prior art references
`
`submitted by Columbia, including those cited by Illumina in its Petition (Ex-2047
`
`at 78 (Metzker), 79 (Prober), 93 (Tsien (WO 1991/06678), Dower)), and allowed
`
`the challenged claim. At no time did Columbia “mislead the Examiner.” Petition
`
`at 52.
`
`Asserting the challenged claim is the “same” as claims the Board previously
`
`considered, Illumina presents a comparison of a portion of the challenged claim
`
`and claim 16 of the ’869 patent. Petition at 20. A complete comparison reveals
`
`numerous features of the challenged claim not present in ’869 patent claim 16.
`
`Claim 1 of ’480 patent
`1. A guanine1 deoxyribonucleotide
`analogue having the structure:
`
`Claim 16 of ’869 patent
`16. The nucleotide of claim 15,
`wherein said deazapurine is
`selected from the group consisting
`of deaza-adenine and deaza-
`guanine, each comprising a unique
`label attached through a cleavable
`linker to a 7-position of deaza-
`adenine or deaza-guanine.
`
`
`
`1 Features singly underlined are narrower than features in ’869 patent claim 16.
`
`
`
`
`5
`
`
`
`Case IPR2018-00385
`Patent No. 9,725,480
`Claim 1 of ’480 patent
`wherein R (a) represents a small,2
`chemically cleavable, chemical group
`capping the oxygen at the 3’ position of
`the deoxyribose of the
`deoxyribonucleotide analogue, (b) does
`not interfere with recognition of the
`analogue as a substrate by a DNA
`polymerase, (c) is stable during a DNA
`polymerase reaction, and (d) does not
`contain a ketone group;
`
`wherein OR is not a methoxy group or an
`ester group;
`
`wherein the covalent bond between the
`3’-oxygen and R is stable during a DNA
`polymerase reaction;
`
`wherein tag represents a detectable
`fluorescent moiety;
`
`wherein Y represents a chemically
`
`Claim 16 of ’869 patent
`15. The nucleotide of claim 12,
`wherein the base is a deazapurine.
`
`12. A nucleotide having a base
`that is attached to a detectable
`label through a cleavable linker,
`wherein the nucleotide has a
`deoxyribose comprising a
`cleavable chemical group capping
`the 3’ OH group, wherein the
`cleavable linker is cleaved by a
`means selected from the group
`consisting of one or more of a
`physical means, a chemical means,
`a physical chemical means, heat,
`and light, and wherein the
`cleavable chemical group capping
`the 3’ OH group is cleaved by a
`means selected from the group
`consisting of one or more of a
`physical means, a chemical means,
`a physical chemical means, heat,
`
`
`2 Features doubly underlined are not present in ’869 patent claim 16.
`
`
`
`
`6
`
`
`
`Claim 16 of ’869 patent
`and light.
`
`Case IPR2018-00385
`Patent No. 9,725,480
`Claim 1 of ’480 patent
`cleavable, chemical linker which (a) does
`not interfere with recognition of the
`analogue as a substrate by a DNA
`polymerase and (b) is stable during a
`DNA polymerase reaction;
`
`and wherein the guanine
`deoxyribonucleotide analogue:
`
`
`i) is recognized as a substrate by a
`DNA polymerase,
`
`ii) is incorporated at the end of a
`growing strand of DNA during a
`DNA polymerase reaction,
`
`iii) produces a 3’-OH group on the
`deoxyribose upon cleavage of R,
`
`iv) no longer includes a tag on the
`base upon cleavage of Y, and
`
`v) is capable of forming hydrogen
`bonds with cytosine or a cytosine
`nucleotide analogue.
`
`7
`
`
`
`
`
`
`Case IPR2018-00385
`Patent No. 9,725,480
`The complete comparison demonstrates the challenged claim is not the same
`
`as claim 16 of the ’869 patent, nor is it the same as any of the other claims held
`
`unpatentable in the earlier Columbia Patent IPRs. Indeed, despite its assertions,
`
`Illumina failed to provide to the Board copies of the claims previously held
`
`unpatentable (Ex-2002 (claims 12, 13, 15-17, 20-26, 28, 29, 31, 33); Ex-2003
`
`(claims 1-7, 11, 12, 14, 15, 17); Ex-2004 (claims 1-3, 6)), and it has admitted that
`
`Columbia’s newly issued patents (such as the ’480 patent) include negative
`
`limitations that are “carve-outs that Columbia added to avoid prior art.” Ex-2049
`
`at 41. Illumina’s Petition also undermines its argument that there is nothing new
`
`about the challenged claim. Illumina’s Grounds are based solely on obviousness,
`
`while several of the Board’s previous findings were based on anticipation (see Ex-
`
`1005 at 7; Ex-1006 at 7-8; Ex-1007 at 7-8). Illumina thus implicitly acknowledges
`
`the challenged claim differs from Columbia’s earlier claims. Furthermore, the one
`
`claim embodiment that Illumina argues was obvious (the 3’-O-allyl nucleotide
`
`analogue) was not at issue in the earlier IPRs. As explained in Section H, the
`
`challenged claim is patentably distinct from those earlier claims.
`
`C. Level Of Ordinary Skill In The Art
`Columbia agrees with Illumina’s criteria for defining a POSA.
`
`
`
`
`8
`
`
`
`Case IPR2018-00385
`Patent No. 9,725,480
`D. Claim Construction
`Illumina asserts claim term construction is unnecessary.
`
` Columbia
`
`disagrees. To properly evaluate the differences between the challenged claim and
`
`the cited art, the following claim terms should be construed consistently with the
`
`Examiner’s understanding of these terms:3
`
`1. “Small”
`
`In the context of the claimed feature R (the capping group on the 3’-oxygen
`
`of the sugar of the nucleotide analogue), “small” refers to the ability of the capping
`
`group to fit into the active site of the DNA polymerase whose three-dimensional
`
`structure is shown in Figure 1 of the ’480 patent. More specifically, “small” means
`
`the group has a diameter less than 3.7Å. This construction is based on the ’480
`
`patent specification (Ex-1004 at 2:63-3:54, 5:52-59, Fig. 1, 7:51-8:28). As
`
`explained during prosecution of the patent, “[a]s of October 6, 2000, the POSA
`
`reading the specification would have understood that ‘small’ referred to the ability
`
`to fit into the active site of the polymerase defined by reference to the three-
`
`dimensional structure shown in FIG. 1” (Ex-1068 at 12), and capping group R
`
`
`3 A second Examiner concurred during prosecution of related U.S. Patent Nos.
`
`9,718,852
`
`(IPR2018-00291), 9,719,139
`
`(IPR2018-00318), and 9,708,358
`
`(IPR2018-00322). E.g., Ex-2048 at 5, 17-18, 19-20, 28-30, 31.
`
`
`
`
`9
`
`
`
`Case IPR2018-00385
`Patent No. 9,725,480
`must have “a diameter less than 3.7Å so that it would fit into the active site of the
`
`polymerase” (id. at 13, 23-25). The Examiner adopted this meaning in the Notice
`
`of Allowability. Ex-1068 at 7 (“The declaration of Jingyue Ju . . . explaining what
`
`is meant by ‘small’ . . . [is] persuasive.”).
`
`2. “Chemical linker”
`
`In the context of claimed feature Y, “chemical linker” means a chemical
`
`moiety attached by covalent bonds at one end to a specified position on the base of
`
`a nucleotide analogue and at the other end to a tag (detectable fluorescent moiety).
`
`It does not mean merely a covalent bond between the base and the label as
`
`disclosed in Dower. The specification supports this construction (Ex-1004 at
`
`10:64-66, 14:8-10, the structures shown at columns 13-20, and Figs. 7, 8, 10, and
`
`15A), which was expressly addressed during prosecution. Ex-1068 at 14-15, 26
`
`(“Y is defined as a chemically cleavable, chemical linker and as shown in the
`
`structure shown in the pending claim, Y is attached by covalent bonds at one end
`
`to the base of a nucleotide analogue at a specific position and at the other end to a
`
`detectable fluorescent moiety.”).
`
`Columbia also directed the Examiner to Tsien and Stemple for examples of
`
`chemical linkers. Ex-1068 at 14, 26. The linkers in those references are chemical
`
`moieties. See Ex-1013 at 28:26-29:2 (disclosing, e.g., silyl ethers, allyl ethers, and
`
`2,4-dinitrophenylsulfenyls, and noting that “[t]ypical tethers are from about 2 to
`10
`
`
`
`
`
`
`Case IPR2018-00385
`Patent No. 9,725,480
`about 20, and preferably from about 3 to about 10 atoms in length”). The
`
`Examiner found Columbia’s definitions “persuasive.” Ex-1068 at 7.
`
`E.
`State of the Art
`Instead of proving its case, Illumina spends an inordinate amount of time
`
`alleging, incorrectly, admissions made by Columbia about the prior art. But there
`
`is no dispute that when Columbia filed its patent application in October 2000 there
`
`had been more than a decade of unsuccessful efforts to define a nucleotide
`
`analogue that could take SBS from a desired goal to a practical reality. Even
`
`Illumina and its expert acknowledge this was a “major challenge” and a
`
`“formidable obstacle.” Ex-2007 ¶60; Ex-2008 at 4-5; Ex-2042 at 6.4
`
`The challenged claim defines nucleotide analogues having the features
`
`necessary for successfully performing SBS. These features include (i) a capping
`
`
`4 Ex-2008 and Ex-2042 are Illumina Cambridge Ltd.’s documents from IPR2013-
`
`00517. In its Petition in IPR2018-00385, as well as in IPR2017-02172, Illumina
`
`refers to itself as both Illumina Inc. and Illumina Cambridge Ltd. See Petition at
`
`78 (noting that Illumina is Patent Owner in IPR2017-02172), 41 (noting that
`
`IPR2013-00517 involved “Illumina’s nucleotides”); Ex-2026 at 58-61 (Illumina
`
`Cambridge Ltd. representing that it is the Petitioner in the present Petition
`
`(IPR2018-00385)).
`
`
`
`
`11
`
`
`
`Case IPR2018-00385
`Patent No. 9,725,480
`group small enough (less than 3.7Å in diameter) to fit into the active site of a
`
`polymerase, but not containing a ketone and not forming a methoxy or an ester
`
`group with the 3’-oxygen of the sugar; and (ii) a chemically cleavable, chemical
`
`linker attached at one end to the 7-position of a deaza-guanine base and at the other
`
`end to a detectable fluorescent moiety. As explained below, these insights were
`
`not obvious given the state of the art in October 2000.
`
`By 1991, Tsien (Ex-1013) and Dower (Ex-1015) set forth prophetic methods
`
`for conducting SBS, both of which Illumina admits “encompass[] broad classes of
`
`compounds[.]” Ex-2009 at 15, 17.5 Tsien discloses a wide variety of preferred
`
`embodiments for the 3’-OH “blocking group,” including:
`
`i.
`
`“[E]ster blocking groups such as lower (1-4 carbon)
`
`alkanoic acid and substituted lower alkanoic acid esters, for
`
`example formyl, acetyl, isopropanoyl, alpha fluoro- and
`
`alpha chloroacetyl esters and the like;”
`
`5 Ex-2009 contains submissions by Illumina to the Patent Office during
`
`reexamination of its U.S. Patent No. 5,808,045. See Ex-2009 at 3 (showing
`
`Illumina as patent assignee); see also Ex-2010 at 1. The Tsien reference discussed
`
`is the same Tsien at issue here. The Dower reference discussed is a PCT
`
`application substantially identical to the Dower at issue here.
`
`
`
`
`12
`
`
`
`Case IPR2018-00385
`Patent No. 9,725,480
`ii.
`iii.
`iv.
`v.
`
`“[E]ther blocking groups such as alkyl ethers;”
`“[P]hosphate blocking groups;”
`“[C]arbonate blocking groups such as 2-nitrobenzyl;” and
`“2,4-dinitrobenzene-sulfenyl and tetrahydrothiofuranyl ether
`
`blocking groups.”
`
`Ex-1013 at 21. In Illumina’s words from 2011, when it was trying to overcome the
`
`references in a reexamination proceeding (see supra note 5), Tsien and Dower
`
`“constitute[] speculation about the existence of” useful nucleotide analogues. Ex-
`
`2009 at 15, 17 (emphasis added). In further characterizing Tsien as speculative,
`
`Illumina explained “[n]ot surprisingly, Tsien’s PCT publication never ultimately
`
`issued into a patent in apparent recognition of the general inoperability of the
`
`disclosure at that time.” Ex-2009 at 15.
`
`In 1994, Metzker reported experimental results on 3’-OH capped nucleotide
`
`analogues in a DNA sequencing setting. As detailed in Section F(2)(b), Metzker
`
`examined the allyl capping group and abandoned it after reporting that it was a
`
`poor choice for DNA sequencing.6 Metzker instead concluded that one of the only
`
`
`6 Throughout its Petition, Illumina refers to the “3’-O-allyl capping group.” This
`
`terminology is inaccurate and conflates a capping group and a capped sugar. The
`
`allyl group referred to in the ’480 patent is a specific 3-carbon allyl group
`
`
`
`
`
`
`13
`
`
`
`Case IPR2018-00385
`Patent No. 9,725,480
`“interesting” capping groups for SBS was the 2-nitrobenzyl capping group (Ex-
`
`1016 at 4265), and a nucleotide analogue with this capping group was incorporated
`
`by several polymerases in his experiments (Ex-1016 at 4263, 4266), and was
`
`selected for further SBS experimentation because it was capable of a “complete
`
`cycle of termination, deprotection, and reinitiation of DNA synthesis.” Ex-1016 at
`
`4259, 4265-67. This capping group is larger than 3.7Å. Ex-1068 at 18, 27-28.
`
`Metzker concluded the 2-nitrobenzyl capping group “sets the stage in the
`
`development of [SBS],” and consistent with that conclusion, noted that his
`
`laboratory intended to continue developing nucleotide analogues with a 2-
`
`nitrobenzyl capping group. Ex-1016 at 4267 (emphasis added), see also 4259
`
`(abstract).
`
`Following Metzker’s teachings, other researchers sought to advance SBS
`
`technology using the 2-nitrobenzyl capping group. In 1997, Anazawa filed a PCT
`
`Application disclosing sequencing DNA using dNTPs with capping groups on the
`
`3’-oxygen of the sugar that contain 2-nitrobenzyl groups. Ex-2011 at 5, Figs. 27-
`
`(-CH2CH=CH2), which is an example of an R group attached to the 3’-oxygen of
`
`the sugar in the challenged claim. In this Patent Owner Preliminary Response,
`
`Columbia refers to this group as “the allyl
Accessing this document will incur an additional charge of $.
After purchase, you can access this document again without charge.
Accept $ Charge
Still Working On It
This document is taking longer than usual to download. This can happen if we need to contact the court directly to obtain the document and their servers are running slowly.
Give it another minute or two to complete, and then try the refresh button.
A few More Minutes ... Still Working
It can take up to 5 minutes for us to download a document if the court servers are running slowly.
Thank you for your continued patience.
This document could not be displayed.
We could not find this document within its docket. Please go back to the docket page and check the link. If that does not work, go back to the docket and refresh it to pull the newest information.
Your account does not support viewing this document.
You need a Paid Account to view this document. Click here to change your account type.
Your account does not support viewing this document.
Set your membership
status to view this document.
With a Docket Alarm membership, you'll
get a whole lot more, including:
- Up-to-date information for this case.
- Email alerts whenever there is an update.
- Full text search for other cases.
- Get email alerts whenever a new case matches your search.
One Moment Please
The filing “” is large (MB) and is being downloaded.
Please refresh this page in a few minutes to see if the filing has been downloaded. The filing will also be emailed to you when the download completes.
Your document is on its way!
If you do not receive the document in five minutes, contact support at support@docketalarm.com.
Sealed Document
We are unable to display this document, it may be under a court ordered seal.
If you have proper credentials to access the file, you may proceed directly to the court's system using your government issued username and password.
Access Government Site
