`Tel: 571-272-7822
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`Paper 65
`Entered: September 9, 2019
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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 IPR2018-00797
`Patent 9,868,985 B2
`_______________
`
`
`Before MICHELLE N. ANKENBRAND, Acting Vice Chief Administrative
`Patent Judge, JAMES A. WORTH and BRIAN D. RANGE, Administrative
`Patent Judges.
`
`Opinion for the Board per curiam.
`Opinion Dissenting filed by Administrative Patent Judge, WORTH.
`
`Per curiam
`
`
`
`FINAL WRITTEN DECISION
`35 U.S.C. § 318(a) and 37 C.F.R. § 42.73
`
`Illumina Ex. 1028
`IPR Petition - USP 10,435,742
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`IPR2018-00797
`Patent 9,868,985 B2
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`INTRODUCTION
`I.
`This is a Final Written Decision addressing the inter partes review
`challenging each claim of U.S. Patent No. 9,868,985 B2 (“the ’985 patent”).
`We have jurisdiction under 35 U.S.C. § 6. For the reasons that follow, we
`determine that Illumina, Inc. (“Petitioner” or “Illumina”) demonstrates, by a
`preponderance of the evidence, that the challenged claims are unpatentable.
`
`Procedural History
`A.
`Petitioner filed a Petition (Paper 1, “Pet.”) requesting an inter partes
`review of the ’985 patent. We instituted trial on the following grounds:1
`Patent
`References
`Basis
`Claim
`Challenged
`1
`2
`
`§ 103(a)
`§ 103(a)
`
`§ 103(a)
`
`1, 2
`
`’985
`’985
`
`’985
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`
`
`Tsien,2 Prober3
`Tsien, Prober,
`and Pallas4
`Dower,5 Prober,
`Metzker6
`
`
`See Paper 20.
`1
`2
`Tsien et al., WO 91/06678, May 16, 1991 (“Tsien”) (Ex. 1013).
`James M. Prober et al., A System for Rapid DNA Sequencing with
`3
`Fluorescent Chain-Terminating Dideoxynucleotides, 238 SCIENCE 336–41
`(Oct. 16, 1987) (“Prober”) (Ex. 1014).
`Pallas et al., WO 98/53300, pub. Nov. 26, 1998 (“Pallas”) (Ex. 1080).
`4
`Dower et al., U.S. 5,547,839, Aug. 20, 1996 (“Dower”) (Ex. 1015).
`Michael L. Metzker et al., Termination of DNA synthesis by novel 3'-
`6
`modified-deoxyribonucleoside 5'-triphosphates, 22(20) NUCLEIC ACIDS
`RESEARCH 4259–67 (1994) (“Metzker”) (Ex. 1016).
`2
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`5
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`IPR2018-00797
`Patent 9,868,985 B2
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`After institution, the Trustees of Columbia University in the City of
`New York (“Patent Owner” or “Columbia”) filed a Patent Owner Response.
`See Patent Owner’s Response (“Resp.”), Paper 29 (public version), Paper 32
`(sealed version). Petitioner filed a Reply (Paper 43, “Reply”), and Patent
`Owner filed a Sur-Reply (Paper 47, “Sur-Reply”). Additionally, Petitioner
`filed a motion to exclude evidence (Paper 51, “Mot. Excl.”), Patent Owner
`responded (Paper 54, “Opp. Mot. Excl.”), and Petitioner provided a Reply
`brief (Paper 56).
`We heard oral argument for this inter partes review (as well as for
`four other related inter partes reviews) on March 5, 2019, and a transcript of
`the hearing is part of the record of this proceeding. Paper 60 (“Tr.”). After
`oral argument, we requested additional briefing regarding certain estoppel
`issues. Paper 59. The parties provided such briefing. Papers 61 (Patent
`Owner’s Additional Brief (“PO Supp. Br.)), 62 (Illumina’s Supplemental
`Brief Regarding Estoppel (“Pet. Supp. Br.”)), 63 (Illumina’s Supplemental
`Reply Regarding Estoppel (“Pet. Supp. Reply”)), 64 (Patent Owner’s Reply
`to Petitioner’s Supplemental Brief (“PO Supp. Reply”)).
`
`Related Proceedings
`B.
`The parties indicate that the ’985 patent is the subject of the following
`district court proceeding involving Petitioner and Patent Owner: Trustees of
`Columbia University v. Illumina, Inc., Case No. 17-cv-973-GMS (D. Del.).
`Pet. 78; Paper 3, 1.
`Petitioner filed Petitions requesting an inter partes review of related
`U.S. Patent Nos. 9,718,852 B2 (“the ’852 patent”), 9,719,139 B2 (“the ’139
`patent”), 9,708,358 B2 (“the ’358 patent”), and 9,725,480 B2 (“the ’480
`
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`patent”). We instituted trial in each matter. See IPR2018-00291, Paper 16
`(June 25, 2018); IPR2018-00318, Paper 16 (July 3, 2018); IPR2018-00322,
`Paper 16 (July 3, 2018); IPR2018-00385, Paper 20 (July 27 2018). On June
`21, 2019, we entered a Final Written Decision determining that Petitioner
`demonstrated, by a preponderance of the evidence, that each challenged
`claim of the four patents is unpatentable. See, e.g., IPR2018-00291,
`Paper 67; see also IPR2018-00291 Paper 69 (providing minor errata).
`The parties note that in IPR2012-00006, IPR2012-00007, and
`IPR2013-00011, the Board found unpatentable the challenged claims of
`Patent Owner’s U.S. Patent Nos. 7,713,698; 7,790,869; and 8,088,575.
`Pet. 78–79; Paper 3, 1; see Ex. 1006; Ex. 1005; Ex. 1007; Ex. 1008 (Federal
`Circuit decision affirming these Board decisions). In IPR2013-00128 and
`IPR2013-00266, the Board found unpatentable the challenged claims of
`Petitioner’s U.S. Patent Nos. 7,057,026 and 8,158,346. Pet. 79; see
`Ex. 1048; Ex. 1049; Ex. 1050 (Federal Circuit decision affirming these
`Board decisions). In IPR2013-00517, the Board held that Intelligent Bio-
`Systems, Inc. failed to demonstrate that the challenged claims of Petitioner’s
`U.S. Patent No. 7,566,537 (“the ’537 patent”) were unpatentable.7 Pet. 79–
`80; see Ex. 1044; Ex. 1045 (Federal Circuit decision affirming this Board
`decision).
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`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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`Patent 9,868,985 B2
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`The ’985 Patent
`C.
`The ’985 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. 1075, 4:25–30.
`The ’985 patent discloses that electrophoresis was a bottleneck for
`high-throughput DNA sequencing and mutation detection projects. Id. at
`2:16–19. It was known to perform sequencing without electrophoresis,
`using a chip format and laser-induced fluorescent detection for DNA
`sequencing. Id. at 2:20–27. The ’985 patent discloses that “[l]ong stretches
`of the same bases cannot be identified unambiguously with [a]
`pyrosequencing method.” Id. at 2:44–46. The ’985 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 ’985 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
`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.
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`Id. at 3:4–17. The ’985 patent further discloses its approach as
`“incorporat[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 ’985 patent presents the same polymerase efficiency
`incorporation requirement as the Tsien prior art reference discussed below.
`Ex. 1075, 20:65–21:13. The ’985 patent indicates that the allyl group can be
`used as a cap “using well-established synthetic procedures” and cites the
`Metzker prior art reference. Id. at 26:18–21; 28:14–19.
`The ’985 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 ’985 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
`allyl group “can be removed chemically with high yield.” Ex. 1075, 26:12–
`31. 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
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`cleavage of the allyl group takes 3 minutes with more than 93%
`yield (Kamal et al. 1999) . . . .
`
`Id.
`
`D. Challenged Claims
`The ’985 patent has two claims. The two claims are reproduced
`below:
`1. A method for sequencing a nucleic acid which comprises
`detecting the identity of a nucleotide analogue incorporated into
`the end of a growing strand of DNA in a polymerase reaction,
`wherein the nucleotide analogue is any of the following:
`
`
`
`
`
`wherein R (a) represents a small, chemically cleavable,
`chemical group capping the oxygen at the 3' position of the
`deoxyribose of tl [sic, 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;
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`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;
`wherein the nucleotide 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, and
`iv) no longer includes a tag on the base upon cleavage of
`
`Y;
`and wherein if the nucleotide analogue is: (A), it is capable of
`forming hydrogen bonds with cytosine or a cytosine nucleotide
`analogue; (B), it is capable of forming hydrogen bonds with
`thymine or a thymine nucleotide analogue; (C), it is capable of
`forming hydrogen bonds with guanine or a guanine nucleotide
`analogue; or (D), it is capable of forming hydrogen bonds with
`adenine or an adenine nucleotide analogue.8
`
`A method for simultaneously sequencing a plurality of
`2.
`different nucleic acids which comprises simultaneously applying
`the method of claim 1 to the plurality of different nucleic acids.
`Ex. 1075, 34:1–36:32.
`
`8
`In the exhibits and briefing, the parties sometimes refer to the R group
`as a capping group (because it caps the molecule) and sometimes refer to it
`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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`PETITIONER’S MOTION TO EXCLUDE
`II.
`In support of its briefing, Patent Owner provided a declaration of
`Dr. Stephen M. Menchen. Ex. 2114. Petitioner moves to exclude
`Dr. Menchen’s Declaration (Ex. 2114), or in the alternative, to exclude
`portions thereof. Mot. Excl. 1–9. Specifically, Petitioner argues that
`Dr. Menchen “appeared to know very little about the very subjects on which
`he had opined” at his deposition, that his Declaration is not based on
`sufficient facts or data, and that his opinions would cause confusion. Id. at 1
`(citing Federal Rule of Evidence (“FRE”) 403, FRE 702(a); Ex. 1112, 12:8–
`13:6, 235:19–237:18, 239:19–240:21, 262:6–17; Ex. 1113, 363:2–14,
`374:16–376:8, 379:18–380:16, 381:2–6, 383:10–20). Petitioner also argues
`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
`Inc., 84 F.3d 230, 234–35 (7th Cir. 1996)). Petitioner argues that
`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
`the term “small,” what would meet certain claim limitations, whether a 3'-
`capping group would be efficiently incorporated, and whether any
`polymerases would work to incorporate nucleotides falling in claim 1. Id. at
`1–2 (citing Ex. 1112, 144:7–151:25, 248:13–249:14, 252:20–254:11;
`171:11–177:10, 179:11–180:9, 181:10–15, 240:22–241:9, 286:15–287:17,
`Ex. 1112, 178:11–179:6, 239:19–240:21, 286:4–14, 242:9–245:12;
`Ex. 1113, 378:5–380:16, 323:2–11, 378:14–19, 394:12–397:25).
`In the alternative, Petitioner seeks to strike the following portions of
`Dr. Menchen’s Declaration based on FRE 403 or 702: paragraphs 31, 33–34,
`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,
`141:9–20, 142:21–143:18, 178:22–179:6, 193:13–18, 270:2–16, 218:13–18,
`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–
`9 (citing, e.g., Gen. Elec. Co. v. Joiner, 522 U.S. 136, 146 (1997); Delaware
`Valley Floral Grp., Inc. v. Shaw Rose Nets, LLC, 597 F.3d 1374, 1381 (Fed.
`Cir. 2010); PharmaStem Therapeutics, Inc. v. ViaCell, Inc., 491 F.3d 1342,
`1355 (Fed. Cir. 2007)). Patent Owner responds that Petitioner’s motion
`serves as an improper merits brief. Opp. Mot. Excl. 1 (citing Office Patent
`Trial Practice Guide August 2018 Update, 16 (“Update”), (“[A]rguments
`regarding weight should appear only in the merits documents”); Liberty Mut.
`Ins. v. Progressive Cas. Ins., CBM2012-00002, Paper 66 at 62 (Jan. 23
`2014) (a motion to exclude “is not an opportunity to file a sur-reply”)).
`We determine that Petitioner’s arguments regarding Dr. Menchen’s
`experience go to issues of credibility, weight, and the sufficiency of the
`evidence rather than admissibility. See Update at 3 (“There is . . . no
`requirement of a perfect match between the expert’s experience and the
`relevant field.”), available at www.uspto.gov/sites/default/files/documents/
`2018_Revised_Trial_Practice_Guide.pdf; see generally Sundance, Inc. v.
`DeMonte Fabricating Ltd., 550 F.3d 1356, 1363–64 (Fed. Cir. 2008); Mytee
`Prods., Inc. v. Harris Research, Inc., 439 F. App’x 882, 886–87 (Fed. Cir.
`2011) (non-precedential) (upholding admission of the testimony of an expert
`who “had experience relevant to the field of the invention,” despite
`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
`sequencing technology. See Ex. 2016 ¶¶ 3–5.
`Similarly, we agree with Patent Owner that Petitioner’s arguments
`about the evidentiary basis for Dr. Menchen’s opinions are directed to the
`sufficiency rather than the admissibility of evidence and are improperly
`advanced in a motion to exclude. See Office Patent Trial Practice Guide,
`77 Fed. Reg. 48,756, 48,767 (Aug. 14, 2012) (stating that a motion to
`exclude may not be used to challenge the sufficiency of the evidence to
`prove a particular fact).
`Petitioner also argues that “Columbia selectively cites portions of
`Dr. Romesberg’s deposition transcript (Exhibit 2140) in an incomplete and
`misleading fashion, and the selective citations should be excluded or read in
`fuller context under FRE 106, 401–403.” Mot. Excl. 9–15. This appears to
`be more properly a motion to strike portions of Patent Owner’s Sur-Reply
`rather than a motion to exclude (see id.), but Petitioner did not seek
`authorization for a motion to strike, as required. See 37 C.F.R. § 42.20(b)
`(requiring prior authorization for motions); Update at 16–17. Such a process
`would have allowed the Board and the parties to consider, inter alia,
`whether further briefing would have been necessary to remedy any such
`problem. See Update at 16–17. In any event, whether or not Patent Owner
`used incomplete citations, we have read the briefs in the context of the
`record, and we deny this aspect of Petitioner’s motion as well.
`Accordingly, Petitioner’s Motion to Exclude is denied.
`
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`III. DISCUSSION OF UNPATENTABILITY CHALLENGES
`Petitioner bears the burden of proving unpatentability of the
`challenged claims, and that burden never shifts to Patent Owner. Dynamic
`Drinkware, LLC v. Nat’l Graphics, Inc., 800 F.3d 1375, 1378 (Fed. Cir.
`2015). To prevail, Petitioner must establish the facts supporting its
`challenge by a preponderance of the evidence. 35 U.S.C. § 316(e);
`37 C.F.R. § 42.1(d). Below, we explain how Petitioner has met its burden
`with respect to the challenged claims.
`
`Principles of Law
`
`Obviousness is a question of law based on underlying determinations
`of fact. Graham v. John Deere Co., 383 U.S. 1, 17 (1966); Richardson-
`Vicks, Inc. v. Upjohn Co., 122 F.3d 1476, 1479 (Fed. Cir. 1997). The
`underlying factual determinations include: (1) the scope and content of the
`prior art; (2) any differences between the claimed subject matter and the
`prior art; (3) the level of skill in the art; and (4) objective evidence of
`nonobviousness, i.e., secondary considerations. See Graham, 383 U.S. at
`17–18. Subsumed within the Graham factors are the requirements that all
`claim limitations be found in the prior art references and that the skilled
`artisan would have had a reasonable expectation of success in combining the
`prior art references to achieve the claimed invention. Pfizer, Inc. v. Apotex,
`Inc., 480 F.3d 1348, 1361 (Fed. Cir. 2007). “Obviousness does not require
`absolute predictability of success . . . all that is required is a reasonable
`expectation of success.” In re O’Farrell, 853 F.2d 894, 903–04 (Fed. Cir.
`1988) (citations omitted).
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`Moreover, “[t]he combination of familiar elements according to
`known methods is likely to be obvious when it does no more than yield
`predictable results.” KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416
`(2007). “If a person of ordinary skill can implement a predictable variation,
`§ 103 likely bars its patentability.” Id. at 417.
`
`Priority Date
`
`U.S. Patent Application No. 09/684,670 was filed on October 6, 2000.
`See Ex. 1075. The ’985 patent claims priority to the specification of this
`application. The parties agree that the priority date for the ’985 patent is
`October 6, 2000. Paper 60, 24:21–24 (“Tr.”).
`
`Level of Ordinary Skill in the Art
`
`We consider each asserted ground of unpatentability in view of the
`understanding of a person of ordinary skill in the art. Petitioner proposes a
`definition of the level of skill in the art (Pet. 11), and Patent Owner does not
`dispute this definition (Resp. 3). Petitioner’s proposal is consistent with the
`evidence before us. See Findings of Fact, infra. We, therefore, adopt
`Petitioner’s proposal and find that a person of ordinary skill in the art would
`have been a member of a team of scientists developing nucleotide analogues,
`researching DNA polymerases, and/or addressing DNA techniques. A
`person of ordinary skill in the art would have held a doctoral degree in
`chemistry, molecular biology, or a closely related discipline, and would have
`had at least five years of practical academic or industrial laboratory
`experience.
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` Claim Construction
` The Board interprets claims in an unexpired patent using the
`“broadest reasonable construction in light of the specification of the patent.”
`37 C.F.R. § 42.100(b) (2017)9; Cuozzo Speed Techs., LLC v. Lee, 136 S. Ct.
`2131, 2144–46 (2016). Under that standard, claim terms are given their
`ordinary and customary meaning in view of the specification, as would have
`been understood by one of ordinary skill in the art at the time of the
`invention. In re Translogic Tech., Inc., 504 F.3d 1249, 1257 (Fed. Cir.
`2007). Any special definitions for claim terms must be set forth in the
`specification with reasonable clarity, deliberateness, and precision. In re
`Paulsen, 30 F.3d 1475, 1480 (Fed. Cir. 1994).
`Here, Petitioner addresses claim 1’s recitation of “or” between the
`claim’s recitation of the four nucleotide analogues. Pet. 11. Patent Owner
`requests construction of “small” and “chemical linker.” Resp. 9–10.
`Additionally, the parties address claim 1’s recitation of “[a] method for
`sequencing a nucleic acid.” Id. at 11; Reply 3–5. We address these four
`issues below.
`
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`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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`“or”
`Petitioner argues that in reciting “or,” claim 1 requires use of any one
`
`of the four recited nucleotide analogues. Pet. 11. Patent Owner’s Response
`does not address this claim term. Resp. 9–11. We agree with Petitioner’s
`interpretation because it is consistent with claim 1’s recitation of “wherein
`the nucleotide analogue is any of the following” and the ordinary meaning of
`the word “or.”
`
`“small”
`Claim 1 recites that the nucleotide capping group, R, “represents a
`
`small, chemically cleavable, chemical group capping the oxygen at the 3'
`position of the deoxyribose of [the] deoxyribonucleotide analogue.” See
`Ex. 1075, 35:27–29. Patent Owner argues that “‘small’ means the group has
`a diameter less than 3.7 [Angstroms].” Resp. 9–10.
`Here, each of Petitioner’s asserted invalidity grounds relies upon the
`obviousness of using an allyl group. Tr., 14:2–11. The parties agree that an
`allyl blocking group is “small” within the context of the claims at issue. Id.
`at 15:9–11; Resp. 9. There is, therefore, no need for us to further construe
`“small.” See Vivid Techs., Inc. v. Am. Sci. & Eng’g, Inc., 200 F.3d 795, 803
`(Fed. Cir. 1999) (“[O]nly those terms need be construed that are in
`controversy, and only to the extent necessary to resolve the controversy”);
`see also Nidec Motor Corp. v. Zhongshan Broad Ocean Motor Co. Ltd., 868
`F.3d 1013, 1017 (Fed. Cir. 2017) (quoting Vivid Techs. when addressing an
`inter partes review proceeding on appeal).
`“chemical linker”
`Claim 1 recites that the Y on the nucleotide structure “represents a
`chemically cleavable, chemical linker.” See, e.g., Ex. 1075, 36:6–7. Patent
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`Owner argues that “‘chemical linker’ means a chemical moiety attached by
`covalent bonds at one end to a specified position on the base of a nucleotide
`and at the other end to a tag (detectable fluorescent moiety).” Resp. 10.
`Based on our review of the record, we determine that this term does not
`require construction in order to resolve the parties’ controversy, and we
`decline to construe it. Vivid Techs., 200 F.3d at 803.
`“[a] method for sequencing a nucleic acid”
`In our Decision to Institute, we invited the parties to address whether
`either claim of the ’985 patent “necessarily requires sequencing, for
`example, of whole genomes.” Paper 20 at 26. Patent Owner responds by
`contending that claim 1’s recitation of “[a] method for sequencing a nucleic
`acid” requires multiple cycles of SBS. Resp. 11. Petitioner disagrees and
`emphasizes that a cycle of SBS requires many steps that are not recited in
`claim 1 and that those steps should not be incorporated into claim 1. Reply
`3–4.
`
`As we explain in more detail in Section III(F)(3)(i), infra, we find that
`a person having ordinary skill in the art would not have pursued the prior
`art’s nucleotide analogues unless they had a reasonable expectation that the
`nucleotide analogue could be used to perform an sequencing-by-synthesis
`method that could approach or reach sequencing twenty base pairs or more.
`Similarly, to the extent claim 1 (or claim 2) requires sequencing, it does not
`recite that an entire DNA strand must be sequenced with the recited method.
`Indeed, Patent Owner does not contend that these claims require sequencing
`an entire DNA strand. See Resp. 11.
`Because, as explained below, we find that a person of ordinary skill in
`the art would have pursued the method of claim 1 to achieve some
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`sequencing, it is not necessary for us to further construe this claim term.
`Vivid Techs., 200 F.3d at 803.
`
`Fact Findings
`
`The fact findings below focus on issues that must be resolved in order
`to assess Petitioner’s obviousness challenges. Graham, 383 U.S. at 17–18.
`Each finding is based upon consideration of the record as a whole and is
`supported by the preponderance of the evidence.
`Technology Overview
`1.
`Deoxyribonucleotides make up the building blocks of DNA, and the
`chemical formula, nomenclature, and uses of deoxyribonucleotides were
`generally known before October 6, 2000. Ex. 1011, 46, 47, 58–60, 98–103.
`A strand of DNA consists of deoxyribonucleotides where the 5'-phosphate of
`one nucleotide is attached to the 3´-oxygen of the adjacent nucleotide.
`Ex. 1078 ¶¶ 33–36; Pet. 12–13.
`Before October 6, 2000, persons having ordinary skill in the art would
`have been aware of several methods for determining the sequence of DNA,
`including Sanger sequencing and sequencing-by-synthesis (“SBS”).
`Ex. 1078 ¶ 38 (citing as examples of Sanger sequencing Ex. 1014 (Prober)
`and Ex. 1018 (Sanger); citing as examples of SBS Ex. 1013 (Tsien),
`Ex. 1015 (Dower), Ex. 1016 (Metzker), and Ex. 1020 (Cheeseman)).
`The sequencing method of primary focus in this IPR is SBS.
`Ex. 1078 ¶ 38; Pet. 14. SBS incorporates modified nucleotides (“nucleotide
`analogs”) having a detectable label into a growing strand of DNA. Ex. 1078
`¶ 38. The label on the incorporated nucleotide analogue is detected to
`determine the DNA sequence. Id.
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`SBS may be distinguished from Sanger sequencing. Sanger
`sequencing was the favored DNA sequencing method in the 1990s.
`Ex. 2114 ¶ 11. Sanger sequencing had certain limitations to “both the
`number of DNA segments that can be sequenced in parallel, and the number
`of operations which may be carried out in sequence.” Ex. 2099,10 1:29–45.
`The Asserted Prior Art References
`2.
`Dower (December 1990)
`i.
`Dower is titled “Sequencing Of Surface Immobilized Polymers
`Utilizing Microflourescence Detection” and “relates to the determination of
`the sequences of polymers immobilized to a substrate.” Ex. 1015, [54],
`1:21–22. The Dower patent application was filed Dec. 6, 1990, and issued
`Aug. 20, 1996.
`One Dower embodiment “provides a method and apparatus for
`sequencing many nucleic acid sequences immobilized at distinct locations
`on a matrix surface.” Id. at 1:22–25. Dower describes a problem with prior
`art methods, i.e., that certain methods required “isolation and purification of
`the nucleic acid to be sequenced and separation of nucleic acid molecules
`differing in length by single nucleotides.” Id. at 2:35–39. According to
`Dower, prior art methods also “suffer[ed] from the requirement to isolate
`and work with distinct homogeneous molecules in each determination.” Id.
`at 2:43–44.
`Dower describes SBS methods. Resp. 4; Ex. 2114 ¶ 12. In one
`embodiment for the synthesis of nucleotides, Dower discloses that a
`polymerase is used to extend a primer complementary to a target template,
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`Jones, U.S. 5,858,671, Jan. 12, 1999.
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`where the primer is elongated one nucleotide at a time by using a particular
`modified nucleotide analogue to which a blocking agent is added and which
`prevents further elongation. Ex. 1015, 14:48–53. Dower discloses that, in
`certain embodiments, the blockage is reversible. Id. at 14:53–56. The
`analogue also is labeled with a removable moiety, e.g., a fluorescent label so
`that a scanning system can detect the particular nucleotide. Id. at 14:56–58.
`Figure 8A of Dower is reproduced below:
`
`
`
`Figure 8A, above, illustrates schematically, at a molecular level, the
`sequence of events which occur during a particular sequencing cycle. Id. at
`5:30–32.
`Dower suggests that choosing an appropriate terminator that is easily
`removed is not difficult:
`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,
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`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.
`
`Id. at 25:47–53.
`Dower does not describe any actual experiments or provide data.
`Resp. 5 (citing Ex. 2116 ¶ 13). While attempting to obtain its own patent
`claims that stood rejected over Dower, Petitioner argued that undue
`experimentation would be required to successfully choose one of Dower’s
`blocking groups:
`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].
`Ex. 2009, 17 (March 2011, Response to Office Action).
`ii.
`Tsien (May 1991)
`Tsien is titled “DNA Sequencing” and “relates to an instrument and a
`method to determine the nucleotide sequence in a DNA molecule without
`the use of a gel electrophoresis step.” Ex. 1013, at [54], [57]. Tsien
`published on May 16, 1991, has an October 26, 1990, international filing
`date, and claims priority to an October 26, 1989, United States patent
`application. Id.
`Tsien describes an SBS method. Ex. 1078 ¶ 38; Ex. 2114 ¶ 12; Resp.
`4. In particular, Tsien describes determining the sequence of a single
`stranded DNA molecule by synthesizing the complementary DNA molecule.
`Ex. 1013, 6:28–7:14. Tsien explains that deoxyribonucleotide triphosphates
`(dNTP) are used to build up numerous copies of the complementary
`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
`extra additions. Id. at 20:24–21:19.
`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.
`Id. at 8:16–17.
`Tsien indicates that its method can assemble “25 to 300, or more”
`nucleotides. Id. at 17:34–18:2. Tsien explains that its method can be useful
`even if only creating a portion of a DNA chain at one time:
`[the method] can be practiced to create the growing
`complement