throbber
Trials@uspto.gov
`Tel: 571-272-7822
`
`Paper 67
`Entered: June 21, 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 IPR2018-00291 (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.
`
`

`

`Cases IPR2018-00291, IPR2018-00318, IPR2018-00322, IPR2018-00385
`
`
`
`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
`
`challenging each claim of 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 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.
`
`A.
`
`Procedural History
`
`Petitioner filed four Petitions (Paper 1,2 “Pet.”) requesting an inter
`
`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
`
`
`
`
`
`

`

`Cases IPR2018-00291, IPR2018-00318, IPR2018-00322, IPR2018-00385
`
`Patent
`
`References
`
`Basis
`
`’852
`
`’139
`’139
`
`’358
`’358
`
`’480
`’480
`
`
`
`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
`
`After institution, the Trustees of Columbia University in the City of
`
`New York (“Patent Owner” or “Columbia”) filed identical Patent Owner
`
`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
`
`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;
`
`IPR 2018-00385, Paper 44. Additionally, Petitioner filed a motion to
`
`exclude evidence (Paper 53, “Mot. Excl.”), Patent Owner responded (Paper
`
`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).
`
` 3
`
`
`
`
`
`

`

`Cases IPR2018-00291, IPR2018-00318, IPR2018-00322, IPR2018-00385
`
`part of the record of each proceeding. Paper 62 (“Transcript”). After oral
`
`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
`
`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
`
`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
`
`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. 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
`
`IPR2013-00266, the Board found unpatentable the challenged claims of
`
`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
`
`Board decisions). In IPR2013-00517, the Board held that Intelligent Bio-
`
`Systems, Inc. failed to demonstrate that the challenged claims of Petitioner’s
`
` 4
`
`
`
`
`
`

`

`Cases IPR2018-00291, IPR2018-00318, IPR2018-00322, IPR2018-00385
`
`U.S. Patent No. 7,566,537 (“the ’537 patent”) were unpatentable.8 Pet. 76–
`
`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
`
`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.
`
` 5
`
`
`
`
`
`

`

`Cases IPR2018-00291, IPR2018-00318, IPR2018-00322, IPR2018-00385
`
`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
`
`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
`
` 6
`
`
`
`
`
`

`

`Cases IPR2018-00291, IPR2018-00318, IPR2018-00322, IPR2018-00385
`
`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
`
`
`
` 7
`
`
`
`
`
`

`

`Cases IPR2018-00291, IPR2018-00318, IPR2018-00322, IPR2018-00385
`
`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.
`
` 8
`
`
`
`
`
`

`

`Cases IPR2018-00291, IPR2018-00318, IPR2018-00322, IPR2018-00385
`
`’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:
`
`
`
` 9
`
`
`
`…
`
`
`
`

`

`Cases IPR2018-00291, IPR2018-00318, IPR2018-00322, IPR2018-00385
`
`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:
`
`
`
`…
`
`v) is capable of forming hydrogen bonds with guanine or a
`guanine nucleotide analogue.
`
`Ex. 1004, 34:1–35:4.
`
`II.
`
`PETITIONER’S MOTION TO EXCLUDE
`
`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
`
`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.
`
`
`
`10
`
`
`
`

`

`Cases IPR2018-00291, IPR2018-00318, IPR2018-00322, IPR2018-00385
`
`(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
`
`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.
`
`
`
`11
`
`
`
`

`

`Cases IPR2018-00291, IPR2018-00318, IPR2018-00322, IPR2018-00385
`
`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 (“Update”), 16 (“arguments
`
`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
`
`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
`
`
`
`12
`
`
`
`

`

`Cases IPR2018-00291, IPR2018-00318, IPR2018-00322, IPR2018-00385
`
`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.
`
`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.
`
`
`
`13
`
`
`
`

`

`Cases IPR2018-00291, IPR2018-00318, IPR2018-00322, IPR2018-00385
`
`
`
`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, 903–4 (Fed. Cir.
`
`1988).
`
`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. 1001, 1002, 1003, 1004, and 1075. Each of the four patents now
`
`subject to an inter partes review claim priority to the specification of this
`
`
`
`14
`
`
`
`

`

`Cases IPR2018-00291, IPR2018-00318, IPR2018-00322, IPR2018-00385
`
`application. The parties agree that the priority date for the patent at issue is
`
`October 6, 2000. Tr. at 24:21–24.
`
`
`
`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. 7–8), 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.
`
` 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)10; Cuozzo Speed Techs., LLC v. Lee, 136 S. Ct.
`
`
`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).
`
`
`
`15
`
`
`
`

`

`Cases IPR2018-00291, IPR2018-00318, IPR2018-00322, IPR2018-00385
`
`2131, 2144–46 (2016). Under that standard, claim terms are given their
`
`ordinary and customary meaning in view of the specification, as would be
`
`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 with reasonable clarity,
`
`deliberateness, and precision. In re Paulsen, 30 F.3d 1475, 1480 (Fed. Cir.
`
`1994).
`
`Here, Petitioner states that “no claim term requires express
`
`construction to evaluate patentability.” Pet. 7. Patent Owner requests
`
`construction of “small” and “chemical linker.” Resp. 9–11. We address
`
`these two issues below.
`
`“small”
`
`
`
`Each claim before us 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, e.g., Ex. 1001, 34:1–35:4. Patent Owner argues that
`
`“‘small’ means the group has a diameter less than 3.7 [Angstroms].” Resp.
`
`9.
`
`Here, each of Petitioner’s asserted invalidity grounds relies upon the
`
`obviousness of using an allyl blocking group. Transcript, 14:2-11. The
`
`parties agree that an allyl blocking group is “small” within the context of the
`
`claims at issue. Id. at 14:9–11; 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) (“only 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
`
`
`
`16
`
`
`
`

`

`Cases IPR2018-00291, IPR2018-00318, IPR2018-00322, IPR2018-00385
`
`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”
`
`Each challenged claim recites that the Y on the nucleotide structure
`
`“represents a chemically cleavable, chemical linker.” See, e.g., Ex. 1001,
`
`34:30–31. Patent 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 express construction in order to resolve the
`
`parties’ controversy. 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.
`
`(1966). Each finding is based upon consideration of the record as a whole
`
`and is supported by the preponderance of the evidence.
`
`1.
`
`Technology Overview
`
`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”).
`
`
`
`17
`
`
`
`

`

`Cases IPR2018-00291, IPR2018-00318, IPR2018-00322, IPR2018-00385
`
`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.
`
`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. 2099,11 1:29–45.
`
`2.
`
`The Asserted Prior Art References
`
`i.
`
`Dower (December 1990)
`
`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
`
`
`11
`Jones, U.S. 5,852,671, Jan. 12, 1999.
`
`
`
`18
`
`
`
`

`

`Cases IPR2018-00291, IPR2018-00318, IPR2018-00322, IPR2018-00385
`
`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,
`
`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. Id. at 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:
`
`
`
`
`
`
`
`
`
`19
`
`

`

`Cases IPR2018-00291, IPR2018-00318, IPR2018-00322, IPR2018-00385
`
`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, 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.
`
`
`
`20
`
`
`
`

`

`Cases IPR2018-00291, IPR2018-00318, IPR2018-00322, IPR2018-00385
`
`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.
`
`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:
`
`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

This document is available on Docket Alarm but you must sign up to view it.


Or .

Accessing this document will incur an additional charge of $.

After purchase, you can access this document again without charge.

Accept $ Charge
throbber

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.

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.

Become a Member

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

We are redirecting you
to a mobile optimized page.





Document Unreadable or Corrupt

Refresh this Document
Go to the Docket

We are unable to display this document.

Refresh this Document
Go to the Docket