`571-272-7822
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` Paper 17
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`Date: January 13, 2021
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`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`ILLUMINA, INC.,
`Petitioner,
`
`v.
`
`TRUSTEES OF COLUMBIA UNIVERSITY
`IN THE CITY OF NEW YORK,
`Patent Owner.
`____________
`
`IPR2020-01323
`Patent 10,428,380 B2
`____________
`
`
`
`Before ZHENYU YANG, JAMES A. WORTH, and
`ROBERT A. POLLOCK, Administrative Patent Judges.
`
`YANG, Administrative Patent Judge.
`
`
`
`
`DECISION
`Granting Institution of Inter Partes Review
`35 U.S.C. § 314
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`IPR2020-01323
`Patent 10,428,380 B2
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`I.
`INTRODUCTION
`Illumina, Inc. (“Petitioner”) filed a Petition (Paper 2 (“Pet.”)), seeking
`an inter partes review of claims 1–4 of U.S. Patent No. 10,428,380 B2
`(Ex. 1005, “the ’380 patent”). Trustees of Columbia University in the City of
`New York (“Patent Owner”) filed a Preliminary Response (Paper 11
`(“Prelim. Resp.”)). With our authorization (Paper 12), Petitioner filed a
`Reply (Paper 13), and Patent Owner filed a Sur-Reply (Paper 15).
`We have authority under 35 U.S.C. § 314, which provides that an
`inter partes review may not be instituted “unless . . . there is a reasonable
`likelihood that the petitioner would prevail with respect to at least 1 of the
`claims challenged in the petition.” 35 U.S.C. § 314(a). The Federal Circuit
`has interpreted the statute to require “a simple yes-or-no institution choice
`respecting a petition, embracing all challenges included in the petition.” PGS
`Geophysical AS v. Iancu, 891 F.3d 1354, 1360 (Fed. Cir. 2018).
`For the reasons provided below, we determine Petitioner has satisfied
`the threshold requirement set forth in 35 U.S.C. § 314(a). Thus, based on the
`information presented, we institute an inter partes review of claims 1–4 of
`the ’380 patent on all grounds.
`A. Related Matters
`According to the parties, the ’380 patent is the subject of Trustees of
`Columbia Univ. v. Illumina, Inc., Case No. 19-cv-1681 (D. Del.). Pet. 73;
`Paper 4, 1. In that same litigation, Patent Owner also asserted against
`Petitioner U.S. Patent Nos. 10,407,458, 10,407,459, 10,435,742, and
`10,457,984. Pet. 73; Paper 4, 1. Petitioner filed IPR2020-00988, IPR2020-
`01065, IPR2020-01177, and IPR2020-01125, respectively, seeking inter
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`partes review of claims of those patents. Pet. 73; Paper 4, 1. The Board has
`instituted an inter partes review in each of those IPRs.
`Petitioner previously filed two sets of petitions, challenging claims of
`several of Patent Owner’s other patents. In the first set, Petitioner challenged
`U.S. Patent Nos. 7,790,869 and 8,088,575 (“the ’869 patent” and “the ’575
`patent,” respectively), two patents in the same family as the ’380 patent at
`issue here, as well as U.S. Patent No. 7,713,698. Pet. 75–76; Paper 4, 2. The
`Board held all challenged claims of those patents unpatentable over much of
`the same art asserted here (see IPR2012-00007, Paper 140 (Ex. 1021);
`IPR2012-00006, Paper 128 (Ex. 1022); IPR2013-00011, Paper 130
`(Ex. 1023)); and the Federal Circuit affirmed that judgment (see Trustees of
`Columbia Univ. in the City of New York v. Illumina, Inc., 620 F. App’x. 916
`(Fed. Cir. 2015) (Ex. 1029)). Pet. 75–76; Paper 4, 2.
`In the second set, Petitioner challenged U.S. Patent Nos. 9,718,852;
`9,719,139; 9,708,358; 9,725,480; and 9,868,985 (“the ’985 patent”) in
`IPR2018-00291; IPR2018-00318; IPR2018-00322; IPR2018-00385;
`IPR2018-00797, respectively (collectively, “the Allyl Claim IPRs”).
`Pet. 74–75; Paper 4, 1–2; Prelim. Resp. 1 n.1. The Board held all challenged
`claims of those patents unpatentable over much of the same art asserted here
`(see Exs. 1024, 1028), and Patent Owner has appealed those decisions (see
`Pet. 74–75; Paper 4, 1–2; Prelim. Resp. 1 n.1).
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`Petitioner points out that the Board previously held claim 1 of the
`’985 patent unpatentable over Tsien1 in view of Prober;2 claim 2
`unpatentable over Tsien in view of Prober and Pallas;3 and claims 1 and 2
`unpatentable over Dower4 in view of Prober and Metzker.5 Pet. 75 (citing
`Ex. 1028). Petitioner relies on these same references in this proceeding. Id.
`at 10. Petitioner argues that claim 1–4 of the ’985 patent “are nearly
`identical to claims 1–4 of the ’380 patent.” Id. at 75. Petitioner asserts, and
`we agree, that the only difference between the unpatentable claim 1 of the
`’985 patent and the claims of the ’380 patent is that the latter “excludes an
`allyl capping group (which the Board determined was unpatentable in the
`last round of IPRs).” Id.; compare Ex. 1005, claims 1–4, with Ex. 1020,
`claims 1 and 2.
`
`B. The ’380 Patent
`The ’380 patent issued from an application that is a child of a series of
`applications having essentially the same specification. See Ex. 1005, code
`(60). Some of those applications matured into patents, including the ’575
`and ’869 patents, which Petitioner previously challenged in IPR2012-00007
`and IPR2013-00011, respectively.
`
`
`1 Tsien, WO 91/06678, published May 16, 1991 (Ex. 1031).
`2 Prober et al., A System for Rapid DNA Sequencing with Fluorescent Chain-
`Terminating Dideoxynucleotides, 238 SCIENCE 336–41 (1987) (Ex. 1041).
`3 Pallas et al., WO 98/53300, published Nov. 26, 1998 (Ex. 1137).
`4 Dower et al., U.S. Patent 5,547,839, issued Aug. 20, 1996 (Ex. 1030).
`5 Metzker et al., Termination of DNA Synthesis by Novel 3'-Modified-
`Deoxyribonucleoside 5'-Triphosphates, 22 NUCLEIC ACIDS RES. 4259–67
`(1994) (Ex. 1039).
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`The ’380 patent “provides methods for attaching a nucleic acid to a
`solid surface and for sequencing nucleic acid by detecting the identity of
`each nucleotide analog after the nucleotide analog is incorporated into a
`growing strand of DNA in a polymerase reaction.” Ex. 1005, Abstract. It
`also “provides nucleotide analogues which comprise unique labels attached
`to the nucleotide analogue through a cleavable linker, and a cleavable
`chemical group to cap the –OH group at the 3'-position of the deoxyribose.”
`Id.
`
`The ’380 patent acknowledges several prior-art methods for DNA
`sequencing, including capillary sequencing (a version of the Sanger
`sequencing method, see Ex. 1141 ¶ 49), and sequencing by synthesis
`(“SBS”). Ex. 1005, 1:60–65, 2:20–24. According to the ’380 patent, the
`concept of SBS was first introduced in 1988 and “involves detecting the
`identity of each nucleotide as it is incorporated into the growing strand of
`DNA in a polymerase reaction.” Id. at 2:20–24.
`The ’380 patent states that both the Sanger method and the prior-art
`SBS methods had several drawbacks, and needed to be improved. See, e.g.,
`id. at 2:2–19, 41–46, 2:53–3:3. The ’380 patent discloses that
`The approach disclosed [therein] 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
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`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 ’380 patent states that “[i]f small chemical moieties that can be
`easily cleaved chemically with high yield can be used to cap the 3'-OH
`group, such nucleotide analogues should also be recognized as substrates for
`DNA polymerase.” Id. at 3:22–26. “It [wa]s known that MOM (–CH2OCH3)
`[methoxymethyl] and allyl (–CH2CH==CH2) groups can be used to cap an –
`OH group, and can be cleaved chemically with high yield.” Id. at 3:41–43.
`The ’380 patent states that its approach is to incorporate nucleotide
`analogues, which are labeled with cleavable, unique labels, and where the 3'-
`OH is capped with a cleavable chemical moiety, such as either a MOM
`group or an allyl group, into the growing strand DNA as terminators. Id. at
`3:44–51.
`According to the ’380 patent, the improved SBS method disclosed
`therein “allow[s] the development of an ultra high-throughput and high
`fidelity DNA sequencing system for polymorphism, pharmacogenetics
`applications and for whole genome sequencing.” Id. at 4:32–36.
`C. Illustrative Claim
`Claims 1 and 3 of the ’380 patent are independent. Claim 3 differs
`from claim 1 in only one aspect, that is, while claim 1 recites that R “(e) is
`not a –CH2CH==CH2 group” (Ex. 1005, 36:34), claim 3 recites that “OR is
`not . . . an allyl ether group” (id. at 38:22–23).
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`Claim 1 is illustrative and is 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:
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`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 interfere
`with recognition of the analogue as a substrate by DNA
`polymerase, (c) is stable during a DNA polymerase reaction,
`(d) does not contain a ketone group, and (e) is not a
`–CH2CH==CH2 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
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`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,
`(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.
`
`D. Asserted Grounds of Unpatentability
`Petitioner asserts the following grounds of unpatentability:
`Claims Challenged 35 U.S.C. §6
`References
`1, 3
`103
`Tsien, Prober, Hiatt7
`2, 4
`103
`Tsien, Prober, Hiatt, Pallas
`1–4
`103
`Dower, Prober, Hiatt
`1–4
`103
`Tsien, Prober, Pallas
`1–4
`103
`Dower, Prober, Metzker
`
`6 The Leahy-Smith America Invents Act (“AIA”), Pub. L. No. 112-29,
`125 Stat. 284, 287–88 (2011), amended 35 U.S.C. §§ 102, 103, and 112,
`effective March 16, 2013. On the face of the ’984 patent, the earliest priority
`of the challenged claims is before the effective date of the AIA. Ex. 1005,
`code (60). Thus, pre-AIA version of 35 U.S.C. § 103 applies.
`7 Hiatt et al., U.S. Patent No. 5,763,594, issued June 9, 1998 (Ex. 1043).
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`In support of their respective positions, Petitioner relies on the
`Declaration of Floyd Romesberg, Ph.D. (Ex. 1141), and Patent Owner relies
`on the Declaration of Kenneth A. Johnson, Ph.D. (Ex. 2049).
`II. ANALYSIS
`A. Discretionary Denial under 35 U.S.C. § 325(d)8
`Relying on arguments Petitioner made in related Board proceedings,
`Patent Owner asks us to exercise our discretion under 35 U.S.C. § 325(d)
`and deny institution. Prelim Resp. 61–62. We are not persuaded for at least
`the following reason.
`Under § 325(d),
`In determining whether to institute or order a proceeding under
`. . . chapter 31, the Director may take into account whether, and
`reject the petition or request because, the same or substantially
`the same prior art or arguments previously were presented to the
`Office.
`In evaluating whether to exercise our discretion under § 325(d), we
`weigh the following non-exclusive factors:
`(a) the similarities and material differences between the asserted
`art and the prior art involved during examination;
`(b) the cumulative nature of the asserted art and the prior art
`evaluated during examination;
`(c) the extent to which the asserted art was evaluated during
`examination, including whether the prior art was the basis for
`rejection;
`
`
`8 In its Preliminary Response, Patent Owner also asks us to exercise our
`discretion under 35 U.S.C. § 314(a) and deny this Petition. Prelim.
`Resp. 55–60. Later, Patent Owner states that it no longer seeks denial of
`institution under § 314(a). Sur-Reply 1 n.1.
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`(d) the extent of the overlap between the arguments made during
`examination and the manner in which Petitioner relies on the
`prior art or Patent Owner distinguishes the prior art;
`(e) whether Petitioner has pointed out sufficiently how the
`Examiner erred in its evaluation of the asserted prior art; and
`(f) the extent to which additional evidence and facts presented in
`the Petition warrant reconsideration of prior art or arguments.
`Becton, Dickinson & Co. v. B. Braun Melsungen AG, IPR2017-01586,
`Paper 8 at 17–18 (PTAB Dec. 15, 2017) (precedential as to § III.C.5, first
`paragraph).
`Factors (a), (b), and (d) relate to whether the art and arguments
`presented in the petition are the same or substantially the same as those
`previously presented to the Office. Advanced Bionics, LLC v. Med-El
`Electromedizinishe Gerӓte GmbH, IPR2019-01469, Paper 6 at 10 (PTAB
`Feb. 13, 2020) (precedential). Factors (c), (e), and (f) “relate to whether the
`petitioner has demonstrated a material error by the Office” in its prior
`consideration of that art or arguments. Id. Only if the same or substantially
`the same art or arguments were previously presented to the Office do we
`then consider whether petitioner has demonstrated error. Id.
`In this case, according to Patent Owner, Petitioner relies on Hovinen9
`to show that “a POSA would pursue the MOM capping group for SBS,”
`even though Hovinen relates to Sanger sequencing reactions, and not SBS.
`Prelim. Resp. 61. Patent Owner contends that Petitioner’s argument here is
`
`
`9 Hovinen et al., Synthesis of 3´-O-(ω-Aminoalkoxymethyl)thymidine
`5'-Triphosphates, Terminators of DNA Synthesis that Enable 3'-Labeling,
`1 J. CHEM. SOC. PERKIN TRANS. 211–17 (1994) (Ex. 1060).
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`similar to the one in the Allyl Claim IPRs, where Petitioner contended that
`“a POSA would pursue the allyl capping group for SBS based on references
`describing such use for Sanger sequencing.” Id.
`The Board, however, did not address Hovinen in the Allyl Claim
`IPRs. And Hovinen is not a reference in the asserted grounds in this case
`either. Rather, Petitioner cites to Hovinen only as further evidence that 3'-O-
`MOM capped nucleotides were recognized as a substrate and incorporated
`by polymerase. Pet. 20–21. Thus, we are not persuaded that Hovinen, or
`related argument, was previously presented to the Office within the meaning
`of § 325(d).
`Patent Owner also argues that “the Petition ignores the Board’s prior
`statements concerning Hiatt.” Prelim. Resp. 61. According to Patent Owner,
`Petitioner “previously argued that Hiatt provided motivation for a POSA to
`select a particular capping group, specifically the allyl capping group,” but
`the Board found that Hiatt “presents an immense number of possibilities for
`the blocking group.” Id. at 61–62 (citing Ex. 1024, 27).
`Petitioner, however, did not rely on Hiatt in the grounds asserted in
`the Allyl Claim IPRs. See Ex. 1024, 2–3 (listing grounds); Ex. 1028, 2
`(same). In addition, as Patent Owner concedes, the Board’s statement
`regarding the scope of Hiatt was not dispositive to its decision holding the
`claims in the Allyl Claim IPRs unpatentable. Prelim. Resp. 62; see also
`Ex. 1024, 35–67 (explaining reasoning regarding unpatentability); Ex. 1028,
`37–70. Thus, we are not persuaded that Hiatt, or arguments as asserted here,
`was previously presented to the Office within the meaning of § 325(d).
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`In sum, weighing factors (a), (b), and (d), we find that the statements
`Patent Owner cites from the Allyl Claim IPRs, while pertinent to the
`teachings of Hovinen and Hiatt, do not sufficiently bear on the patentability
`determination of the claims at issue to be considered the “same or similar
`arguments” under Advanced Bionics. Accordingly, for at least this reason,
`we decline to exercise our discretion to deny institution.
`B. Claim Construction
`In an inter partes review, we construe a claim term “using the same
`claim construction standard that would be used to construe the claim in a
`civil action under 35 U.S.C. [§] 282(b).” 37 C.F.R. § 42.100(b). Under that
`standard, the words of a claim “are generally given their ordinary and
`customary meaning,” which is “the meaning that the term would have to a
`person of ordinary skill in the art in question at the time of the invention, i.e.,
`as of the effective filing date of the patent application.” Phillips v. AWH
`Corp., 415 F.3d 1303, 1312–13 (Fed. Cir. 2005) (en banc).
`Petitioner proposes that we construe the terms “allyl ether” and “any
`of . . . or.” Pet. 11–12. Patent Owner proposes that we construe the term
`“small.” Prelim. Resp. 6. On this record and for purposes of this Decision,
`we see no need to construe any of these terms expressly. See Wellman, Inc.
`v. Eastman Chem. Co., 642 F.3d 1355, 1361 (Fed. Cir. 2011) (stating that
`claim terms need only be construed to the extent necessary to resolve the
`controversy).
`Patent Owner argues that “the preamble ‘a method for sequencing a
`nucleic acid’ should be given its plain and ordinary meaning, i.e., a method
`for sequencing a strand of nucleotides.” Prelim. Resp. 6. According to Patent
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`Owner, “[a]s the Board found and as [Petitioner] has previously admitted,
`SBS methods require sequencing at least twenty nucleotides.” Id. at 44
`(citing Ex. 1024, 28 n.16; Ex. 2023, 6).
`Petitioner counters that construing the preamble to require
`“sequencing at least twenty nucleotides” is overly narrow and should be
`rejected. Reply 5. Petitioner notes that the district court determined that the
`preamble of the ’380 patent is limiting and adopted its plain and ordinary
`meaning. Id. (citing Ex.1161, 69:3–7). Petitioner also points out that, when
`discussing the preamble of the ’985 patent claims,10 the Board previously
`stated that to the extent it requires sequencing, “it does not recite that an
`entire DNA strand must be sequenced,” and it was “not necessary” to further
`construe the preamble. Id. (quoting Ex. 1028, 16, 17).
`We agree with both the district court and the Board’s previous
`assessment that the preamble does not need express construction. We also
`agree that the preamble does not require sequencing an entire DNA strand.11
`See Ex. 1028, 16.
`
`
`10 As discussed earlier, the only difference between claim 1 of the ’985
`patent and the claims of the ’380 patent is that the latter “excludes an allyl
`capping group (which the Board determined was unpatentable in the last
`round of IPRs).” Pet. 75; compare Ex. 1005, claims 1–4, with Ex. 1020,
`claims 1 and 2.
`11 We further acknowledge the Board’s previous findings that an ordinarily
`skilled artisan “would have been interested in SBS methods that could
`approach or reach sequencing twenty base pairs or more” and that “a person
`of skill in the art would have been interested in sequencing even short DNA
`sequences” at the relevant time. See Ex. 1024, 42; Ex. 1028, 44. Those
`findings, however, are pertinent to the analysis on the motivation to combine
`and/or modify prior art, not to claim construction.
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`On this record and for purposes of this Decision, we see no need to
`construe any other terms expressly. See Wellman, 642 F.3d at 1361.
`C. Obviousness over Tsien, Prober, and Hiatt
`Petitioner asserts that claims 1 and 3 of the ’380 patent would have
`been obvious over the combination of Tsien, Prober, and Hiatt. Pet. 13–39.
`Based on this record, we determine Petitioner has established a reasonable
`likelihood that it would prevail in this assertion.
`1. Tsien
`Tsien “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. 1031, Abstract. The parties agree that Tsien
`describes an SBS method. Ex. 1141 ¶ 45; Ex. 2049 ¶ 25. Figure 1B of Tsien
`depicting Tsien’s synthesis process is reproduced below.
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`Figure 1B is a schematic diagram of Tsien’s process on a molecular
`level. Ex. 1031, 8:16–17.
`Tsien teaches determining the sequence of a single stranded DNA
`molecule by synthesizing the complementary DNA molecule. Id. at
`6:34–7:14. In Tsien, deoxyribonucleotide triphosphates (dNTP) are used to
`build up numerous copies of the complementary molecule. Id. at 7:3–7. As
`each dNTP is added, it is identified by a label. Id. at 7:7–9. According to
`Tsien, its method
`can be practiced to create the growing complementary DNA
`chain without interruption or it can be practiced in stages wherein
`a portion of the complementary chain is created and its sequence
`determined; this portion of the chain is then removed; a sequence
`corresponding to a region of the removed chain is separately
`synthesized and used to prime the template chain for subsequent
`chain growth.
`Id. at 7:34–8:5.
`Tsien teaches employing 3' hydroxyl-blocked dNTPs to prevent
`inadvertent extra additions. Id. at 12:27–29, 20:25–27. “The identity of this
`first nucleotide can be determined by detecting and identifying the label
`attached to it.” Id. at 13:1–3. According to Tsien, the criteria for the
`successful use of a 3'-blocking groups include:
`(1)
` the ability of a polymerase enzyme to accurately and
`efficiently incorporate the dNTPs carrying the 3´-blocking
`groups into the cDNA chain,
`(2)
` the availability of mild conditions for rapid and
`quantitative deblocking, and
`(3)
`the ability of a polymerase enzyme to reinitiate the
`cDNA synthesis subsequent to the deblocking stage.
`Id. at 20:28–21:3.
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`Tsien teaches that “[t]he most common 3'-hydroxyl blocking groups
`are esters and ethers. Other blocking modifications to the 3'-OH position of
`dNTPs include the introduction of groups such as -F, -NH2, -OCH3,
`-N3, -OPO3, -NHCOCH3, 2-nitrobenzene carbonate, 2,4-dinitrobenzene
`sulfenyl and tetrahydrofuranyl ether.” Id. at 21:12–17. Tsien states that
`“[i]ncorporation and chain termination have been demonstrated with dNTPs
`containing many of these blocking groups.” Id. at 21:17–19.
`Tsien also teaches deblocking to remove the blocking group
`and label from the 3' position on the first dNTP, which “generates an
`active 3' hydroxyl position on the first nucleotide present in the
`complementary chain and makes it available for coupling to the 5'
`position of the second nucleotide.” Id. at 13:14–22, see also id. at
`23:28–31 (the same). Tsien states that although “the exact deblocking
`chemistry selected . . . depend[s] to a large extent upon the blocking
`group employed,” the deblocking method should:
`(a)
`proceed rapidly,
`(b)
`yield a viable 3'-OH function in high yield, and
`(c)
`not interfere with future enzyme function or denature the
`DNA strand.
`Id. at 23:27–24:5.
`
`2. Prober
`Prober describes a “DNA sequencing system based on the use of a
`novel set of four chain-terminating dideoxynucleotides, each carrying a
`different chemically tuned succinylfluorescein dye distinguished by its
`fluorescent emission.” Ex. 1041, 336. Fluorescence-tagged chain terminating
`reagents are depicted in Figure 2A, reproduced below:
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`Figure 2A depicts “[c]hemical structures of the reagents used in
`modified dideoxy reactions for DNA sequencing.” Id. at 338. In these
`dNTPs, succinylfluorescein is attached via a linker to a heterocyclic base,
`i.e., a nucleotide analogue. Id. at 337. “The linker is attached to the 5
`position in the pyrimidines and to the 7 position in the 7-deazapurines.” Id.
`3. Hiatt
`
`Hiatt relates to
`A method for the stepwise creation of phosphodiester bonds
`between desired nucleosides resulting in the synthesis of
`polynucleotides having a predetermined nucleotide sequence by
`preparing an initiation substrate containing a free and unmodified
`3'-hydroxyl group; attaching a mononucleotide selected
`according to the order of the predetermined nucleotide sequence
`to the 3'-hydroxyl of the initiating substrate in a solution
`containing a catalytic amount of an enzyme capable of catalyzing
`the 5' to 3' phosphodiester linkage of the 5'-phosphate of the
`mononucleotide to the 3'-hydroxyl of the initiating substrate,
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`wherein the mononucleotide contains a protected 3'-hydroxyl
`group, whereby the protected mononucleotide is covalently
`linked to the initiating substrate and further additions are
`hindered by the 3'-hydroxyl protecting group.
`Ex. 1043, Abstract. This process is depicted in Figure 1, reproduced below.
`
`
`
`Figure 1 is a diagram showing “enzymatic synthesis of an
`oligonucleotide using a template independent polymerase and a nucleoside
`5' triphosphate having a removable blocking moiety at its 3' position.” Id. at
`5:41–44.
`Hiatt states that “[p]referred removable blocking moieties can be
`removed in under 10 minutes to produce a hydroxyl group at the 3' position
`of the 3' nucleoside.” Id. at 4:61–64. Such removable blocking groups
`include carbonitriles, phosphates, carbonates, carbamates, esters, ethers,
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`borates, nitrates, sugars, phosphoramidates, phenylsulfenates, sulfates, and
`sulfones. Id. at 4:64–67.
`Hiatt teaches that:
`In more preferred embodiments, a nucleoside 5' phosphate of the
`present invention has a removable blocking moiety protecting
`the 3' position which is an ether and which has the following
`formula:
`
`
`wherein R2 is triphosphate, diphosphate or monophosphate; and
`wherein R1 is CH3, CH3(CH2)N where N is an integer from 1–10,
`methyl, methoxymethyl, methoxyethoxymethyl, trimethlsilyl,
`and triethylsilyl.
`Id. at 13:35–52.
`
`4. Analysis
`For claim 1, Petitioner argues that the combination of Tsien, Prober,
`and Hiatt teaches each limitation.12 Id. at 13–30. According to Petitioner, an
`ordinarily skilled artisan would have been motivated to combine the
`
`
`12 For certain limitations, Petitioner also points to the final written decisions
`in the first two sets of IPRs between the parties where the Board previously
`found that Tsien teaches these limitations. See Pet. 13–30 (citing
`Exs. 1021–1024, 1028).
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`teachings of Tsien, Prober, and Hiatt (id. at 30–35), and would have had a
`reasonable expectation of success in doing so (id. at 35–37).
`Patent Owner contends that Petitioner’s challenge relies on a labeled
`3'-O-MOM nucleotide embodiment. Prelim. Resp. 1, 11. According to
`Patent Owner, Petitioner’s argument
`(A) is incompatible with the SBS prior art, (B) ignores the
`Board’s well-established framework for assessing obviousness
`of a 3'-O-capped nucleotide for SBS, and (C) fails to establish,
`even under [Petitioner]’s deficient framework, that a POSA
`would have been motivated to arrive at the claimed method of
`sequencing using the MOM embodiment with a reasonable
`expectation of success.
`Id. at 12.
`Based on the current record, we find Petitioner’s arguments more
`persuasive. Below, we summarize Petitioner’s arguments before addressing
`Patent Owner’s counter arguments. Our analysis here focuses on the
`disputed MOM capping group for SBS.
`Petitioner argues that prior art teaches methods using labeled
`nucleotide analogues for DNA sequencing, including Sanger sequencing and
`SBS. Pet. 7 (citing Exs. 1030; 1031; 1039–1042; 1141 ¶ 49). According to
`Petitioner, labeled nucleotide analogues include those containing
`with removable 3'-OH capping groups and labeled bases. Id.
`Petitioner points out that in the first two sets of IPRs (discussed in
`section I.A, above), the Board found that Tsien teaches nucleotide analogues
`DNA sequencing having both a small, removable 3'-OH cap and a detectable
`label attached to the base. Id. (citing Ex. 1021, 5–6; Ex. 1028, 37–38;
`Ex. 1031, 10:17–18:33, 27:33–28:10). Petitioner argues that Tsien teaches
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`small 3'-capping groups were desirable, and “specifically recommends an
`alkyl ether capping group.” Id. at 7–8 (citing Ex. 1031, 26:17–27:1;
`Ex. 1141 ¶¶ 61–62), 32 (citing Ex. 1031, 21:9–13, 21:20–28; Ex. 1141
`¶ 174). Petitioner also asserts that Tsien teaches base-labeled nucleotide
`analogues.
`Petitioner refers to Hiatt as teaching capping groups for reversibly
`blocking a nucleotide’s 3'-OH during enzymatic DNA synthesis. Id. at 18
`(citing Ex. 1043, Abstract, Figure 1). According to Petitioner, Hiatt
`identifies a 3'-O-MOM capping group as a preferred embodiment, and
`provides a working example synthesizing the nucleotide. Id. at 18–19 (citing
`Ex. 1043, 13:35–52, 30:22–40). Petitioner argues that “[t]his nucleotide is
`one of only three ether capped nucleotides that Hiatt prepares, thereby
`elevating the MOM group in prominence.” Id. at 19 (citing Ex. 1043,
`27:27–30:40; Ex. 1141 ¶¶ 107–113).
`Petitioner contends that “Hiatt’s MOM group is also the smallest of
`the three prepared ethers.” Id. (citing Ex. 1141 ¶ 114). Because it was known
`that smaller capping groups were desirable, Petitioner continues, “a MOM
`group would have been the most desirable choice from Hiatt’s three ethers.”
`Id. (citing Ex. 1141 ¶ 115). Petitioner concludes that an ordinarily skilled
`artisan “would have found Hiatt’s MOM group obvious by its presentation
`in a reference discussing polymerase-mediated DNA synthesis.” Id. at 20
`(citing Ex. 1141 ¶¶ 107–119).
`According to Petitioner, even Patent Owner “admitted that MOM was
`a known capping group that could be cleaved chemically in high yield under
`DNA-compatible conditions.” Id. (citing Ex. 1005, 3:41–51, 27:18–29).
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`Petitioner also argues that during prosecution, the applicant admitted that a
`MOM capping group meets the structural and functional features recited in
`the claims. Id. (citing Ex. 1143 ¶ 22).
`Petitioner also cites to Hovinen as further evidence that 3'-O-MOM
`capped nucleotides were recognized as a substrate and incorporated by
`polymerase. Id. at 20–21 (citing Ex. 1060, 212–13, Fig. 1; Ex. 1141
`¶¶ 122–128). Petitioner asserts that “Hovinen discloses recognition and
`incorporation of a nucleotide having a substituted 3'-O-MOM group,”
`which, according to Petitioner, “provides a reasonable expectation that the
`unsubstituted MOM group would not interfere with polymerase
`recognition.” Id. (citing Ex. 1141 ¶ 128).
`Patent Owner argues that at relevant time, prior art did not suggest
`using the MOM capping group for SBS, and an ordinarily skilled artisan
`would not have had a reason to choose the MOM group because there was
`no expectation of efficient incorporation. Prelim. Resp. 12–26. Patent Owner
`also asserts that an ordinarily skilled artisan would not have been motivated
`to combine Hiatt’s non-SBS methods with Tsien’s SBS methods, or to select
`Hiatt’s MOM capping group. Id. at 26–43. Patent Own