`Tel: 571-272-7822
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`Paper 66
`Entered: June 21, 2018
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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.
`_______________
`
`Case IPR2018-00291 (Patent 9,718,852 B2)
`Case IPR2018-00318 (Patent 9,719,139 B2)
`Case IPR2018-00322 (Patent 9,708,358 B2)
`Case IPR2018-00385 (Patent 9,725,480 B2)1
`_______________
`
`Before JAMES A. WORTH, MICHELLE N. ANKENBRAND, and
`BRIAN D. RANGE, Administrative Patent Judges.
`
`Opinion for the Board per curiam.
`Opinion Dissenting filed by Administrative Patent Judge WORTH.
`
`Per curiam
`
`1
`
`The proceedings have not been consolidated. The parties are not
`authorized to use a combined caption unless an identical paper is being
`entered into each proceeding and the paper contains a footnote indicating the
`same.
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`
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`Cases IPR2018-00291, IPR2018-00318, IPR2018-00322, IPR2018-00385
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`
`
`FINAL WRITTEN DECISION
`35 U.S.C. § 318(a) and 37 C.F.R. § 42.73
`
`I.
`
`INTRODUCTION
`
`This is a Final Written Decision addressing four inter partes reviews
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`challenging each claim of U.S. Patent Nos. 9,718,852 B2 (“the ’852
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`patent”), 9,719,139 B2 (“the ’139 patent”), 9,708,358 B2 (“the ’358
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`patent”), and 9,725,480 B2 (“the ’480 patent”). We have jurisdiction under
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`35 U.S.C. § 6. For the reasons that follow, we determine that Illumina, Inc.
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`(“Petitioner” or “Illumina”) demonstrates, by a preponderance of the
`
`evidence, that the challenged claims are unpatentable.
`
`A.
`
`Procedural History
`
`Petitioner filed four Petitions (Paper 1,2 “Pet.”) requesting an inter
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`partes review of the ’852 patent, the ’139 patent, the ’358 patent, and the
`
`’480 patent. We instituted trial on the following grounds:3
`
`Patent
`
`’852
`
`References
`
`Basis
`
`Tsien,4 Prober5
`
`§ 103(a)
`
`Claim
`Challenged
`1
`
`
`2
`Unless this opinion otherwise indicates, all citations are to IPR2018-
`00291 (“the ’291 IPR”).
`
`3
`
`See IPR2018-00291, Paper 16 (June 25, 2018); IPR2018-00318, Paper
`16 (July 2, 2018); IPR2018-00322, Paper 16 (July 2, 2018); IPR2018-00385,
`Paper 20 (July 26, 2018).
`
`4
`
`Tsien et al., WO 91/06678, May 16, 1991 (“Tsien”) (Ex. 1013).
`
`5
`
`James M. Prober et al., A System for Rapid DNA Sequencing with
`Fluorescent Chain-Terminating Dideoxynucleotides, 238 SCIENCE 336–341
`(Oct. 16, 1987) (“Prober”) (Ex. 1014).
`
` 2
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`Cases IPR2018-00291, IPR2018-00318, IPR2018-00322, IPR2018-00385
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`Patent
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`References
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`Basis
`
`’852
`
`’139
`’139
`
`’358
`’358
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`’480
`’480
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`
`
`Dower,6 Prober,
`Metzker7
`Tsien
`Dower, Prober,
`Metzker
`Tsien
`Dower, Prober,
`Metzker
`Tsien, Prober
`Dower, Prober,
`Metzker
`
`§ 103(a)
`
`§ 103(a)
`§ 103(a)
`
`§ 103(a)
`§ 103(a)
`
`§ 103(a)
`§ 103(a)
`
`Claim
`Challenged
`1
`
`1
`1
`
`1
`1
`
`1
`1
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`After institution, the Trustees of Columbia University in the City of
`
`New York (“Patent Owner” or “Columbia”) filed identical Patent Owner
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`Responses in each of the four inter partes proceedings. See Patent Owner’s
`
`Response (“Resp.”), Paper 31 (public version), Paper 34 (sealed version);
`
`Patent Owner’s Surreply (“Surreply”), Paper 49. Petitioner filed
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`substantively similar Reply Briefs in each of the four cases. IPR 2018-
`
`00291, Paper 45; IPR 2018-00318, Paper 47; IPR 2018-00322, Paper 45;
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`IPR 2018-00385, Paper 44. Additionally, Petitioner filed a motion to
`
`exclude evidence (Paper 53, “Mot. Excl.”), Patent Owner responded (Paper
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`56, “Opp. Mot. Excl.”), and Petitioner provided a Reply brief (Paper 58).
`
`We heard oral argument for the four inter partes review (as well as for
`
`related IPR2018-00797) on March 5, 2019, and a transcript of the hearing is
`
`
`6
`Dower et al., U.S. Patent No. 5,547,839, Aug. 20, 1996 (“Dower”)
`(Ex. 1015).
`
`7
`
`Michael L. Metzker et al., Termination of DNA synthesis by novel 3'-
`modified-deoxyribonucleoside 5'-triphosphates, 22(20) NUCLEIC ACIDS
`RESEARCH 4259–67 (1994) (“Metzker”) (Ex. 1016).
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`part of the record of each proceeding. Paper 62 (“Transcript”). After oral
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`argument, we requested additional briefing regarding certain estoppel issues.
`
`Paper 61. The parties provided such briefing. Papers 63 (Illumina’s
`
`Supplemental Brief Regarding Estoppel (“Pet. Supp. Br.”)), 64 (Patent
`
`Owner’s Additional Brief (“PO Supp. Br.)), 65 (Illumina’s Supplemental
`
`Reply Regarding Estopel (“Pet. Supp. Reply”)), 66 (Patent Owner’s Reply to
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`Petitioner’s Supplemental Brief (“PO Supp. Reply”)).
`
`B.
`
`Related Proceedings
`
`The parties indicate that the ’852 patent, ’139 patent, ’358 patent, and
`
`’480 patent are the subject of the following district court proceeding
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`involving Petitioner and Patent Owner: Trustees of Columbia University v.
`
`Illumina, Inc., Case No. 17-cv-973-GMS (D. Del.). Pet. 74–75; Paper 4, 1.
`
`On March 16, 2018, Petitioner filed a Petition requesting an inter
`
`partes review of related U.S. Patent No. 9,868,985 B2. IPR2018-00797,
`
`Paper 1. We address that Petition in a separate decision.
`
`The parties note that in IPR2012-00006, IPR2012-00007, and
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`IPR2013-00011, the Board found unpatentable the challenged claims of
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`Patent Owner’s U.S. Patent Nos. 7,713,698; 7,790,869; and 8,088,575.
`
`Pet. 74–75; Paper 4, 1; see Ex. 1006; Ex. 1005; Ex. 1007; Ex. 1008 (Federal
`
`Circuit decision affirming these Board decisions). In IPR2013-00128 and
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`IPR2013-00266, the Board found unpatentable the challenged claims of
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`Petitioner’s U.S. Patent Nos. 7,057,026 and 8,158,346. Pet. 76; see
`
`Ex. 1048; Ex. 1049; Ex. 1050 (Federal Circuit decision affirming these
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`Board decisions). In IPR2013-00517, the Board held that Intelligent Bio-
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`Systems, Inc. failed to demonstrate that the challenged claims of Petitioner’s
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`U.S. Patent No. 7,566,537 (“the ’537 patent”) were unpatentable.8 Pet. 76–
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`77; see Ex. 1044; Ex. 1045 (Federal Circuit decision affirming this Board
`
`decision).
`
`C.
`
`The ’852, ’139, ’358, and ’480 Patents
`
`As to technical substance, only the claims of the ’852, ’139, ’358, and
`
`’480 patents differ. For ease of discussion, we refer to the Specification of
`
`the ’852 patent. The ’852 patent is titled “Massive Parallel Method for
`
`Decoding DNA and RNA” and relates to a “system for DNA sequencing by
`
`the synthesis approach which employs a stable DNA template, which is able
`
`to self prime for the polymerase reaction, covalently linked to a solid surface
`
`such as a chip, and 4 unique nucleotides analogues.” Ex. 1001, 4:25–30.
`
`The ’852 patent discloses that electrophoresis was a bottleneck for
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`high-throughput DNA sequencing and mutation detection projects. Id. at
`
`2:15–18. It was known to perform sequencing without electrophoresis,
`
`using a chip format and laser-induced fluorescent detection for DNA
`
`sequencing. Id. at 2:19–26. The ’852 patent discloses that “[l]ong stretches
`
`of the same bases cannot be identified unambiguously with [a]
`
`pyrosequencing method.” Id. at 2:44–46. The ’852 patent also describes
`
`limited success in the prior art for the incorporation of 3'-modified
`
`nucleotides by DNA polymerase. Id. at 2:52–53.
`
`The approach disclosed in the ’852 patent is
`
`to make nucleotide analogues by linking a unique label such as
`a fluorescent dye or a mass tag through a cleavable linker to the
`
`
`8
`A third party also challenged the ’537 patent in Cases IPR2017-02172
`and IPR2017-02174, but the Board denied institution in each case. Pet. 80;
`Paper 10, 1.
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`nucleotide base or an analogue of the nucleotide base, such as
`to the 5-position of the pyrimidines (T and C) and to the
`7-position of the purines (G and A), to use a small cleavable
`chemical moiety to cap the 3'-OH group of the deoxyribose to
`make it nonreactive, and to incorporate the nucleotide
`analogues into the growing DNA strand as terminators.
`Detection of the unique label will yield the sequence identity of
`the nucleotide. Upon removing the label and the 3'-OH capping
`group, the polymerase reaction will proceed to incorporate the
`next nucleotide analogue and detect the next base.
`
`Id. at 3:4–17. The ’852 patent further discloses its approach as
`
`“incorporate[ing] nucleotide analogues, which are labeled with cleavable,
`
`unique labels such as fluorescent dyes . . . and where the 3'-OH is capped
`
`with a cleavable chemical moiety, such as either a MOM group (–
`
`CH2OCH3) or an allyl group (–CH2CH=CH2), into the growing strand DNA
`
`as terminators.” Id. at 3:44–51.
`
`The ’852 patent presents the same polymerase efficiency
`
`incorporation requirement as the Tsien prior art reference discussed below.
`
`Ex. 1001, 20:65–21:8. The ’852 patent indicates that the allyl group can be
`
`used as a cap “using well-established synthetic procedures” and cites the
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`Metzker prior art reference. Id. at 26:22–25; 28:15–18.
`
`The ’852 patent does not provide data establishing good incorporation
`
`or efficiency of an allyl group. See Ex. 1112, 284:6–18 (Dr. Menchen
`
`testifying that he does not remember seeing in the application how allyl
`
`groups could be incorporated efficiently).
`
`The ’852 patent does not disclose any special chemistry to, for
`
`example, provide for appropriate cleavability of an allyl group. Instead, its
`
`disclosure teaches that, according to prior art references such as Kamal, the
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` 6
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`allyl group “can be removed chemically with high yield.” Ex. 1001, 26:13–
`
`29. In particular, the disclosure explains:
`
`[The] allyl (–CH2CH=CH2) group is used to cap the 3'-OH group
`using well-established synthetic procedures (FIG. 13) (Fuji et al.
`1975, Metzker et al, 1994). These groups can be removed chemically
`with high yield as shown in FIG. 14 (Ireland, et al, 1986; Kamal et al.
`1999). The chemical cleavage of the . . . allyl groups is fairly mild
`and specific, so as not to degrade the DNA template moiety. For
`example, the cleavage of the allyl group takes 3 minutes with more
`than 93% yield (Kamal et al. 1999) . . . .
`
`Id.
`
`D. Challenged Claims
`
`The ’852 patent, ’139 patent, ’358 patent, and ’480 patent each have a
`
`single claim (i.e., claim 1). Each of the four claims corresponds to an
`
`analogue of one of the four nucleotides of DNA (adenine, guanosine,
`
`thymine, and cytosine). The claims are reproduced below with ellipses used
`
`to omit recitations that are identical for each claim:
`
`’852 patent, claim 1. An adenine deoxyribonucleotide analogue
`having the structure:
`
`wherein R (a) represents a small, chemically cleavable,
`chemical group capping the oxygen at the 3' position of the
`deoxyribose of the deoxyribonucleotide analogue, (b) does not
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`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 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 adenine 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 thymine or
`a thymine nucleotide analogue.
`
`Ex. 1001, 34:1–35:4.9
`
`
`
`9
`In the exhibits and briefing, the R group is sometimes referred to a
`capping group (because it caps the molecule) and is sometimes referred to as
`a blocking group (because it blocks other groups from joining the molecule).
`We likewise use the terms capping group and blocking group
`interchangeably.
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`’139 patent, claim 1. A thymine deoxyribonucleotide analogue
`having the structure:
`
`
`
`…
`
`wherein the thymine deoxyribonucleotide analogue:
`
`…
`
`v) is capable of forming hydrogen bonds with adenine or
`an adenine nucleotide analogue.
`
`Ex. 1003, 34:1–35:6.
`
`
`’358 patent, claim 1: A cytosine deoxyribonucleotide analogue
`having the structure:
`
`…
`
`wherein the cytosine deoxyribonucleotide analogue:
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`…
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`v) is capable of forming hydrogen bonds with guanine or a
`guanine nucleotide analogue.
`
`Ex. 1002, 34:1–35:6.
`
`’480 patent, claim 1: A guanine deoxyribonucleotide analogue
`having the structure:
`
`…
`
`wherein the guanine deoxyribonucleotide analogue:
`
`
`
`…
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`v) is capable of forming hydrogen bonds with guanine or a
`guanine nucleotide analogue.
`
`Ex. 1004, 34:1–35:4.
`
`II.
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`PETITIONER’S MOTION TO EXCLUDE
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`In support of its briefing, Patent Owner provided a declaration of
`
`Dr. Stephen M. Menchen. Ex. 2116. Petitioner moves to exclude
`
`Dr. Menchen’s Declaration (Ex. 2116), or in the alternative, to exclude
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`portions thereof. Mot. Excl. 1–9. Specifically, Petitioner argues that
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`Dr. Menchen “appeared to know very little about the very subjects on which
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`he had opined” at his deposition, that his Declaration is not based on
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`sufficient facts or data, and that his opinions would cause confusion. Id.
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`Cases IPR2018-00291, IPR2018-00318, IPR2018-00322, IPR2018-00385
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`(citing Federal Rule of Evidence (“FRE”) 403, FRE 702(a); Ex. 1112, 12:8–
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`13:6, 235:19–237:18, 239:19–240:21, 262:6–17; Ex. 1113, 363:2–14,
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`374:16–376:8, 379:18–380:16, 381:2–6, 383:10–20). Petitioner also argues
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`that Patent Owner “put blinders on its testifying witness” that would call into
`
`question the credibility of the Declaration. Id. at 2 (citing Braun v. Lorillard
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`Inc., 84 F.3d 230, 234–35 (7th Cir. 1996)). Petitioner argues that
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`Dr. Menchen did not form an opinion on certain topics, was unable to
`
`testify, or admitted that he did not know when asked about the meaning of
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`the term “small,” what would meet certain claim limitations, whether a 3'-
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`capping group would be efficiently incorporated, and whether any
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`polymerases would work to incorporate nucleotides falling in claim 1. Id. at
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`1–2 (citing Ex. 1112, 144:7–151:25, 248:13–249:14, 252:20–254:11;
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`171:11–177:10, 179:11–180:9, 181:10–15, 240:22–241:9, 286:15–287:17,
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`Ex. 1112, 178:11–179:6, 239:19–240:21, 286:4–14, 242:9–245:12;
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`Ex. 1113, 378:5–380:16, 323:2–11, 378:14–19, 394:12–397:25).
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`In the alternative, Petitioner seeks to strike the following portions of
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`Dr. Menchen’s Declaration based on FRE 403 or 702: paragraphs 31, 33–34,
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`38–39, 43, 51, 94–97, 100–106, 109. Id. at 2–8. Petitioner asserts that
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`Dr. Menchen admitted that he is not an expert in polymerases and has never
`
`worked with polymerases. Id. at 2–3, 5 (citing Ex. 1112, 141:21–142:5,
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`141:9–20, 142:21–143:18, 178:22–179:6, 193:13–18, 270:2–16, 218:13–18,
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`288:16–289:1; Ex. 1113, 347:9–25).
`
`Petitioner also argues that Dr. Menchen’s testimony was unsupported
`
`or contradicted by other evidence and in some cases was ipse dixit. Id. at 4–
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`9 (citing, e.g., Gen. Elec. Co. v. Joiner, 522 U.S. 136, 146 (1997); Delaware
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`Valley Floral Grp., Inc. v. Shaw Rose Nets, LLC, 597 F.3d 1374, 1381 (Fed.
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`Cir. 2010); Pharmastem Therapeutics, Inc. v. ViaCell, Inc., 491 F.3d 1342,
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`1355 (Fed. Cir. 2007)). Patent Owner responds that Petitioner’s motion
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`serves as an improper merits brief. Opp. Mot. Excl. 1 (citing Office Patent
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`Trial Practice Guide August 2018 Update (“Update”), 16 (“arguments
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`regarding weight should appear only in the merits documents”); Liberty Mut.
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`Ins. v. Progressive Cas. Ins., CBM2012-00002, Paper 66 at 62 (Jan. 23
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`2014) (a motion to exclude “is not an opportunity to file a sur-reply”)).
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`We determine that Petitioner’s arguments regarding Dr. Menchen’s
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`experience go to issues of credibility, weight, and the sufficiency of the
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`evidence rather than admissibility. See Update at 3 (“There is . . . no
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`requirement of a perfect match between the expert’s experience and the
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`relevant field.”), available at www.uspto.gov/sites/default/files/documents/
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`2018_Revised_Trial_Practice_Guide.pdf; see generally Sundance, Inc. v.
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`DeMonte Fabricating Ltd., 550 F.3d 1356, 1363–64 (Fed. Cir. 2008); Mytee
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`Prods., Inc. v. Harris Research, Inc., 439 F. App’x 882, 886–87 (Fed. Cir.
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`2011) (non-precedential) (upholding admission of the testimony of an expert
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`who “had experience relevant to the field of the invention,” despite
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`admission that he was not a person of ordinary skill in the art). We
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`determine that Dr. Menchen has relevant experience, with a Ph.D. in
`
`Organic Chemistry and over 30 years of experience developing DNA
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`sequencing technology. See Ex. 2016 ¶¶ 3–5.
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`Similarly, we agree with Patent Owner that Petitioner’s arguments
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`about the evidentiary basis for Dr. Menchen’s opinions are directed to the
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`sufficiency rather than the admissibility of evidence and are improperly
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`advanced in a motion to exclude. See Office Patent Trial Practice Guide,
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`77 Fed. Reg. 48,756, 48,767 (Aug. 14, 2012) (stating that a motion to
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`exclude may not be used to challenge the sufficiency of the evidence to
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`prove a particular fact).
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`Petitioner also argues that “Columbia selectively cites portions of
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`Dr. Romesberg’s deposition transcript (Exhibit 2140) in an incomplete and
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`misleading fashion, and the selective citations should be excluded or read in
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`fuller context under FRE 106, 401–403.” Mot. Excl. 9–15. This appears to
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`be more properly a motion to strike portions of Patent Owner’s Sur-Reply
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`rather than a motion to exclude (see id.), but Petitioner did not seek
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`authorization for a motion to strike, as required. See 37 C.F.R. § 42.20(b)
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`(requiring prior authorization for motions); Update at 16–17. Such a process
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`would have allowed the Board and the parties to consider, inter alia,
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`whether further briefing would have been necessary to remedy any such
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`problem. See Update at 16–17. In any event, whether or not Patent Owner
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`used incomplete citations, we have read the briefs in the context of the
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`record, and we deny this aspect of Petitioner’s motion as well.
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`Accordingly, Petitioner’s Motion to Exclude is denied.
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`III. DISCUSSION OF UNPATENTABILITY CHALLENGES
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`Petitioner bears the burden of proving unpatentability of the
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`challenged claims, and that burden never shifts to Patent Owner. Dynamic
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`Drinkware, LLC v. Nat’l Graphics, Inc., 800 F.3d 1375, 1378 (Fed. Cir.
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`2015). To prevail, Petitioner must establish the facts supporting its
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`challenge by a preponderance of the evidence. 35 U.S.C. § 316(e);
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`37 C.F.R. § 42.1(d). Below, we explain how Petitioner has met its burden
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`with respect to the challenged claims.
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`Principles of Law
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`Obviousness is a question of law based on underlying determinations
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`of fact. Graham v. John Deere Co., 383 U.S. 1, 17 (1966); Richardson-
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`Vicks, Inc. v. Upjohn Co., 122 F.3d 1476, 1479 (Fed. Cir. 1997). The
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`underlying factual determinations include: (1) the scope and content of the
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`prior art; (2) any differences between the claimed subject matter and the
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`prior art; (3) the level of skill in the art; and (4) objective evidence of
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`nonobviousness, i.e., secondary considerations. See Graham, 383 U.S. at
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`17–18. Subsumed within the Graham factors are the requirements that all
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`claim limitations be found in the prior art references and that the skilled
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`artisan would have had a reasonable expectation of success in combining the
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`prior art references to achieve the claimed invention. Pfizer, Inc. v. Apotex,
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`Inc., 480 F.3d 1348, 1361 (Fed. Cir. 2007). “Obviousness does not require
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`absolute predictability of success . . . all that is required is a reasonable
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`expectation of success.” In re O’Farrell, 853 F.2d 894, 903–4 (Fed. Cir.
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`1988).
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`Moreover, “[t]he combination of familiar elements according to
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`known methods is likely to be obvious when it does no more than yield
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`predictable results.” KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416
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`(2007). “If a person of ordinary skill can implement a predictable variation,
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`§ 103 likely bars its patentability.” Id. at 417.
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`
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`Priority Date
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`U.S. Patent Application No. 09/684,670 was filed on October 6, 2000.
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`See Ex. 1001, 1002, 1003, 1004, and 1075. Each of the four patents now
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`subject to an inter partes review claim priority to the specification of this
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`Cases IPR2018-00291, IPR2018-00318, IPR2018-00322, IPR2018-00385
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`application. The parties agree that the priority date for the patent at issue is
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`October 6, 2000. Tr. at 24:21–24.
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`Level of Ordinary Skill in the Art
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`We consider each asserted ground of unpatentability in view of the
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`understanding of a person of ordinary skill in the art. Petitioner proposes a
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`definition of the level of skill in the art (Pet. 7–8), and Patent Owner does
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`not dispute this definition (Resp. 3). Petitioner’s proposal is consistent with
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`the evidence before us. See Findings of Fact, infra. We, therefore, adopt
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`Petitioner’s proposal and find that a person of ordinary skill in the art would
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`have been a member of a team of scientists developing nucleotide analogues,
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`researching DNA polymerases, and/or addressing DNA techniques. A
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`person of ordinary skill in the art would have held a doctoral degree in
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`chemistry, molecular biology, or a closely related discipline, and would have
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`had at least five years of practical academic or industrial laboratory
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`experience.
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` Claim Construction
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` The Board interprets claims in an unexpired patent using the
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`“broadest reasonable construction in light of the specification of the patent.”
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`37 C.F.R. § 42.100(b) (2017)10; Cuozzo Speed Techs., LLC v. Lee, 136 S. Ct.
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`10
`The Office recently changed the claim construction standard
`applicable to an inter partes review. See Changes to the Claim Construction
`Standard for Interpreting Claims in Trial Proceedings Before the Patent Trial
`and Appeal Board, 83 Fed. Reg. 51,340 (Oct. 11, 2018). The rule changing
`the claim construction standard, however, does not apply to this proceeding
`because Petitioner filed its Petition before the effective date of the final rule,
`i.e., November 13, 2018. Id. at 51,340 (rule effective date and applicability
`date), 51,344 (explaining how the Office will implement the rule).
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`2131, 2144–46 (2016). Under that standard, claim terms are given their
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`ordinary and customary meaning in view of the specification, as would be
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`understood by one of ordinary skill in the art at the time of the invention. In
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`re Translogic Tech., Inc., 504 F.3d 1249, 1257 (Fed. Cir. 2007). Any
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`special definitions for claim terms must be set forth with reasonable clarity,
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`deliberateness, and precision. In re Paulsen, 30 F.3d 1475, 1480 (Fed. Cir.
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`1994).
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`Here, Petitioner states that “no claim term requires express
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`construction to evaluate patentability.” Pet. 7. Patent Owner requests
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`construction of “small” and “chemical linker.” Resp. 9–11. We address
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`these two issues below.
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`“small”
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`Each claim before us recites that the nucleotide capping group, R,
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`“represents a small, chemically cleavable, chemical group capping the
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`oxygen at the 3' position of the deoxyribose of the deoxyribonucleotide
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`analogue.” See, e.g., Ex. 1001, 34:1–35:4. Patent Owner argues that
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`“‘small’ means the group has a diameter less than 3.7 [Angstroms].” Resp.
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`9.
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`Here, each of Petitioner’s asserted invalidity grounds relies upon the
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`obviousness of using an allyl blocking group. Transcript, 14:2-11. The
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`parties agree that an allyl blocking group is “small” within the context of the
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`claims at issue. Id. at 14:9–11; Resp. 9. There is, therefore, no need for us
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`to further construe “small.” See Vivid Techs., Inc. v. Am. Sci. & Eng’g, Inc.,
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`200 F.3d 795, 803 (Fed. Cir. 1999) (“only those terms need be construed that
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`are in controversy, and only to the extent necessary to resolve the
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`controversy”); see also Nidec Motor Corp. v. Zhongshan Broad Ocean
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`Motor Co. Ltd., 868 F.3d 1013, 1017 (Fed. Cir. 2017) (quoting Vivid Techs
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`when addressing an inter partes review proceeding on appeal).
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`“chemical linker”
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`Each challenged claim recites that the Y on the nucleotide structure
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`“represents a chemically cleavable, chemical linker.” See, e.g., Ex. 1001,
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`34:30–31. Patent Owner argues that “‘chemical linker’ means a chemical
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`moiety attached by covalent bonds at one end to a specified position on the
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`base of a nucleotide and at the other end to a tag (detectable fluorescent
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`moiety).” Resp. 10. Based on our review of the record, we determine that
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`this term does not require express construction in order to resolve the
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`parties’ controversy. Vivid Techs., 200 F.3d at 803.
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`Fact Findings
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`The fact findings below focus on issues that must be resolved in order
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`to assess Petitioner’s obviousness challenges. Graham 383 U.S. at 17–18.
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`(1966). Each finding is based upon consideration of the record as a whole
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`and is supported by the preponderance of the evidence.
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`1.
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`Technology Overview
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`Deoxyribonucleotides make up the building blocks of DNA, and the
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`chemical formula, nomenclature, and uses of deoxyribonucleotides were
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`generally known before October 6, 2000. Ex. 1011, 46, 47, 58–60, 98–103.
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`A strand of DNA consists of deoxyribonucleotides where the 5'-phosphate of
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`one nucleotide is attached to the 3´-oxygen of the adjacent nucleotide. Ex.
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`1078 ¶¶ 33–36; Pet. 12–13.
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`Before October 6, 2000, persons having ordinary skill in the art would
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`have been aware of several methods for determining the sequence of DNA,
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`including Sanger sequencing and sequencing-by-synthesis (“SBS”).
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`17
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`Ex. 1078 ¶ 38 (citing as examples of Sanger sequencing Ex. 1014 (Prober)
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`and Ex. 1018 (Sanger); citing as examples of SBS Ex. 1013 (Tsien),
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`Ex. 1015 (Dower), Ex. 1016 (Metzker), and Ex. 1020 (Cheeseman)).
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`The sequencing method of primary focus in this IPR is SBS.
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`Ex. 1078 ¶ 38; Pet. 14. SBS incorporates modified nucleotides (“nucleotide
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`analogs”) having a detectable label into a growing strand of DNA. Ex. 1078
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`¶ 38. The label on the incorporated nucleotide analogue is detected to
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`determine the DNA sequence. Id.
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`SBS may be distinguished from Sanger sequencing. Sanger
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`sequencing was the favored DNA sequencing method in the 1990s. Ex.
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`2114 ¶ 11. Sanger sequencing had certain limitations to “both the number of
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`DNA segments that can be sequenced in parallel, and the number of
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`operations which may be carried out in sequence.” Ex. 2099,11 1:29–45.
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`2.
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`The Asserted Prior Art References
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`i.
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`Dower (December 1990)
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`Dower is titled “Sequencing Of Surface Immobilized Polymers
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`Utilizing Microflourescence Detection” and “relates to the determination of
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`the sequences of polymers immobilized to a substrate.” Ex. 1015, [54],
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`1:21–22. The Dower patent application was filed Dec. 6, 1990, and issued
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`Aug. 20, 1996.
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`One Dower embodiment “provides a method and apparatus for
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`sequencing many nucleic acid sequences immobilized at distinct locations
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`on a matrix surface.” Id. at 1:22–25. Dower describes a problem with prior
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`art methods, i.e., that certain methods required “isolation and purification of
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`the nucleic acid to be sequenced and separation of nucleic acid molecules
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`11
`Jones, U.S. 5,852,671, Jan. 12, 1999.
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`18
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`differing in length by single nucleotides.” Id. at 2:35–39. According to
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`Dower, prior art methods also “suffer[ed] from the requirement to isolate
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`and work with distinct homogeneous molecules in each determination.” Id.
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`at 2:43–44.
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`Dower describes SBS methods. Resp. 4; Ex. 2114 ¶ 12. In one
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`embodiment for the synthesis of nucleotides, Dower discloses that a
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`polymerase is used to extend a primer complementary to a target template,
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`where the primer is elongated one nucleotide at a time by using a particular
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`modified nucleotide analogue to which a blocking agent is added and which
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`prevents further elongation. Id. at 14:48–53. Dower discloses that, in
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`certain embodiments, the blockage is reversible. Id. at 14:53–56. The
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`analogue also is labeled with a removable moiety, e.g., a fluorescent label so
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`that a scanning system can detect the particular nucleotide. Id. at 14:56–58.
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`Figure 8A of Dower is reproduced below:
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`19
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`Figure 8A, above, illustrates schematically, at a molecular level, the
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`sequence of events which occur during a particular sequencing cycle. Id. at
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`5:30–32.
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`Dower suggests that choosing an appropriate terminator that is easily
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`removed is not difficult:
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`A second, unlabeled and reversible, set of terminators is also required.
`Examples of these compounds are deoxynucleotide triphosphates with
`small blocking groups such as acetyl, tBOC, NBOC and NVOC on
`the 3'OH. These groups are easily and efficiently removed under
`conditions of high or low pH, exposure to light or heat, etc.
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`Id. at 25:47–53.
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`Dower does not describe any actual experiments or provide data.
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`Resp. 5 (citing Ex. 2116 ¶ 13). While attempting to obtain its own patent
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`claims that stood rejected over Dower, Petitioner argued that undue
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`experimentation would be required to successfully choose one of Dower’s
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`blocking groups:
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`Undue experimentation would be required to determine which of the
`multitude of potential blocking groups would be expected to be
`removable blocking moieties that also protect the 3' position of said
`mononucleoside 5'-triphosphates, as required by the instant claims.
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`Ex. 2009, 17 (March 2011, Response to Office Action).
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`ii.
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`Tsien (May 1991)
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`Tsien is titled “DNA Sequencing” and “relates to an instrument and a
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`method to determine the nucleotide sequence in a DNA molecule without
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`the use of a gel electrophoresis step.” Ex. 1013, at [54], [57]. Tsien
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`published on May 16, 1991, has an October 26, 1990, international filing
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`date, and claims priority to an October 26, 1989, United States patent
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`application. Id.
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`20
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`Tsien describes an SBS method. Ex. 1078 ¶ 38; Ex. 2114 ¶ 12; Resp.
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`4. In particular, Tsien describes determining the sequence of a single
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`stranded DNA molecule by synthesizing the complementary DNA molecule.
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`Ex. 1013, 6:28–7:14. Tsien explains that deoxyribonucleotide triphosphates
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`(dNTP) are used to build up numerous copies of the complementary
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`molecule and that, as each dNTP is added, it is identified by a label. Id.
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`Tsien suggests employing 3' hydroxyl-blocked dNTPs to prevent inadvertent
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`extra additions. Id. at 20:24–21:19.
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`Figure 1B of Tsien is reproduced below:
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`Figure 1B is a schematic diagram of Tsien’s process on a molecular level.
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`
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`Id. at 8:16–17.
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`Tsien indicates that its method can assemble “25 to 300, or more”
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`nucleotides. Id. at 17:34–18:2. Tsien explains that its