Trials@uspto.gov
`571-272-7822
`
` Paper 17
`
`Date: January 13, 2021
`
`
`
`
`
`
`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
`
`
`
`
`
`
`
`
`571-272-7822
`
` Paper 17
`
`Date: January 13, 2021
`
`
`
`
`
`
`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
`
`
`
`
`
`
`
`
`
`IPR2020-01323
`Patent 10,428,380 B2
`
`
`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
`
`2
`
`
`
`IPR2020-01323
`Patent 10,428,380 B2
`
`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).
`
`3
`
`
`
`IPR2020-01323
`Patent 10,428,380 B2
`
`
`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).
`
`4
`
`
`
`IPR2020-01323
`Patent 10,428,380 B2
`
`
`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
`
`5
`
`
`
`IPR2020-01323
`Patent 10,428,380 B2
`
`
`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).
`
`6
`
`
`
`IPR2020-01323
`Patent 10,428,380 B2
`
`
`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:
`
`
`
`
`
`7
`
`
`
`IPR2020-01323
`Patent 10,428,380 B2
`
`
`
`
`
`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
`8
`
`
`
`IPR2020-01323
`Patent 10,428,380 B2
`
`
`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).
`9
`
`
`
`IPR2020-01323
`Patent 10,428,380 B2
`
`
`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.
`10
`
`
`
`IPR2020-01323
`Patent 10,428,380 B2
`
`
`(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).
`11
`
`
`
`IPR2020-01323
`Patent 10,428,380 B2
`
`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).
`
`12
`
`
`
`IPR2020-01323
`Patent 10,428,380 B2
`
`
`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
`
`13
`
`
`
`IPR2020-01323
`Patent 10,428,380 B2
`
`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.
`14
`
`
`
`IPR2020-01323
`Patent 10,428,380 B2
`
`
`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.
`
`
`
`15
`
`
`
`IPR2020-01323
`Patent 10,428,380 B2
`
`
`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.
`
`16
`
`
`
`IPR2020-01323
`Patent 10,428,380 B2
`
`
`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:
`
`17
`
`
`
`IPR2020-01323
`Patent 10,428,380 B2
`
`
`
`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,
`
`18
`
`
`
`IPR2020-01323
`Patent 10,428,380 B2
`
`
`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,
`19
`
`
`
`IPR2020-01323
`Patent 10,428,380 B2
`
`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).
`
`20
`
`
`
`IPR2020-01323
`Patent 10,428,380 B2
`
`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
`
`21
`
`
`
`IPR2020-01323
`Patent 10,428,380 B2
`
`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).
`
`22
`
`
`
`IPR2020-01323
`Patent 10,428,380 B2
`
`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
Accessing this document will incur an additional charge of $.
After purchase, you can access this document again without charge.
Accept $ Charge
Still Working On It
This document is taking longer than usual to download. This can happen if we need to contact the court directly to obtain the document and their servers are running slowly.
Give it another minute or two to complete, and then try the refresh button.
A few More Minutes ... Still Working
It can take up to 5 minutes for us to download a document if the court servers are running slowly.
Thank you for your continued patience.
This document could not be displayed.
We could not find this document within its docket. Please go back to the docket page and check the link. If that does not work, go back to the docket and refresh it to pull the newest information.
Your account does not support viewing this document.
You need a Paid Account to view this document. Click here to change your account type.
Your account does not support viewing this document.
Set your membership
status to view this document.
With a Docket Alarm membership, you'll
get a whole lot more, including:
- Up-to-date information for this case.
- Email alerts whenever there is an update.
- Full text search for other cases.
- Get email alerts whenever a new case matches your search.
One Moment Please
The filing “” is large (MB) and is being downloaded.
Please refresh this page in a few minutes to see if the filing has been downloaded. The filing will also be emailed to you when the download completes.
Your document is on its way!
If you do not receive the document in five minutes, contact support at support@docketalarm.com.
Sealed Document
We are unable to display this document, it may be under a court ordered seal.
If you have proper credentials to access the file, you may proceed directly to the court's system using your government issued username and password.
Access Government Site
