IPR2018-00291
`Patent 9,718,852 B2
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`ILLUMINA, INC.,
`Petitioner,
`v.
`THE TRUSTEES OF COLUMBIA UNIVERSITY
`IN THE CITY OF NEW YORK,
`Patent Owner.
`
`Case IPR2018-00291
`Patent 9,718,852 B2
`
`
`
`
`
`
`
`
`
`Before JENNIFER MEYER CHAGNON, JAMES A. WORTH, and
`MICHELLE N. ANKENBRAND, Administrative Patent Judges.
`WORTH, Administrative Patent Judge.
`
`
`
`DECISION
`Institution of Inter Partes Review
`35 U.S.C. § 314(a)
`
`INTRODUCTION
`I.
`On December 8, 2017, Illumina, Inc. (“Illumina” or “Petitioner”) filed
`a Petition (Paper 1, “Pet.”) requesting an inter partes review of claim 1 (the
`“challenged claim”) of U.S. Patent No. 9,718,852 B2 (Ex. 1001, “the ’852
`patent”). On March 27, 2018, The Trustees of Columbia University in the
`
`1
`
`Columbia Ex. 2019
`Illumina, Inc. v. The Trustees
`of Columbia University
`in the City of New York
`IPR2020-01177
`
`
`Patent 9,718,852 B2
`
`
`
`
`
`Paper 16
`June 25, 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
`
`
`
`
`
`
`
`
`
`Before JENNIFER MEYER CHAGNON, JAMES A. WORTH, and
`MICHELLE N. ANKENBRAND, Administrative Patent Judges.
`WORTH, Administrative Patent Judge.
`
`
`
`DECISION
`Institution of Inter Partes Review
`35 U.S.C. § 314(a)
`
`INTRODUCTION
`I.
`On December 8, 2017, Illumina, Inc. (“Illumina” or “Petitioner”) filed
`a Petition (Paper 1, “Pet.”) requesting an inter partes review of claim 1 (the
`“challenged claim”) of U.S. Patent No. 9,718,852 B2 (Ex. 1001, “the ’852
`patent”). On March 27, 2018, The Trustees of Columbia University in the
`
`1
`
`Columbia Ex. 2019
`Illumina, Inc. v. The Trustees
`of Columbia University
`in the City of New York
`IPR2020-01177
`
`
`
`IPR2018-00291
`Patent 9,718,852 B2
`
`
`
`
`
`Paper 16
`June 25, 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
`
`
`
`
`
`
`
`
`
`Before JENNIFER MEYER CHAGNON, JAMES A. WORTH, and
`MICHELLE N. ANKENBRAND, Administrative Patent Judges.
`WORTH, Administrative Patent Judge.
`
`
`
`DECISION
`Institution of Inter Partes Review
`35 U.S.C. § 314(a)
`
`INTRODUCTION
`I.
`On December 8, 2017, Illumina, Inc. (“Illumina” or “Petitioner”) filed
`a Petition (Paper 1, “Pet.”) requesting an inter partes review of claim 1 (the
`“challenged claim”) of U.S. Patent No. 9,718,852 B2 (Ex. 1001, “the ’852
`patent”). On March 27, 2018, The Trustees of Columbia University in the
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`City of New York (“Columbia” or “Patent Owner”) filed a Preliminary
`Response (Paper 8, “Prelim. Resp.”).
`Institution of an inter partes review is authorized by statute when “the
`information presented in the petition filed under [35 U.S.C. §] 311 and any
`response filed under [35 U.S.C. §] 313 shows that 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). For the reasons set
`forth below, we determine that Petitioner has demonstrated that there is a
`reasonable likelihood that claim 1 is unpatentable, and we institute an inter
`partes review of claim 1 based on the grounds set forth in the Petition.
`
`A. Related Matters
`The parties note as related IPR2012-00007 (Final Written Decision,
`Paper 140, Ex. 1005) with respect to U.S. Patent No. 7,790,869; IPR2012-
`00006 (Final Written Decision, Paper 128, Ex. 1006) with respect to U.S.
`Patent No. 7,713,698; and IPR2013-00011 (Final Written Decision, Paper
`130, Ex. 1007) with respect to U.S. Patent No. 8,088,575. Pet. 1; Paper 4, 1.
`In these proceedings, the Board held all challenged claims unpatentable. Id.
`The Board decisions were affirmed sub. nom. Trustees of Columbia Univ. v.
`Illumina, Inc., 620 Fed. Appx. 916, 927–28, 934 (Fed. Cir. 2015) (see
`Ex. 1008).
`The parties state that Petitioner has filed petitions for inter partes
`review of U.S. Patents Nos. 9,719,139, 9,708,358, 9,725,480, 9,868,985
`(“the ’852, ’139, ’358, and ’480 patents”) alleged to be owned by Columbia,
`PTAB Case Nos. IPR2018-00291, -318, -322, -385, -797. Paper 4, 2; Paper
`5, 1; Paper 9, 1. Patent Owner states that the ’852, ’139, ’358, and ’480
`patents were asserted against Illumina in Trustees of Columbia University v.
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`Illumina, Inc., C.A. No. 17-cv-973-GMS (D. Del.). Id. Patent Owner
`further states that Columbia previously asserted related U.S. Patents Nos.
`7,790,869, 7,713,698, and 8,088,575 (“the ’869, ’698, and ’575 patents”)
`against Illumina in Trustees of Columbia University v. Illumina, Inc., C.A.
`No. 12-cv-376 (D. Del.). Id.
`Patent Owner also points to other proceedings in which Illumina is
`involved that relate to patents owned by Illumina. See Paper 4, 2; Paper 13,
`1.
`
`B. The ’852 Patent (Ex. 1001)
`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, 4:25–31.
`The ’852 patent discloses that electrophoresis was a bottleneck for
`high-throughput DNA sequencing and mutation detection projects. Id. at
`2:16–18. It was known to perform sequencing without electrophoresis,
`using a chip format and laser-induced fluorescent detection for DNA
`sequencing. Id. at 2:19–27. The ’852 patent discloses that long 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 nucleotide base or an analogue of the
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`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. Id. at 3:4–13; see also id. at 5:40–41. The approach disclosed
`in the ’852 patent is further to incorporate nucleotide analogues, which are
`labeled with cleavable, unique labels, such as fluorescent dyes, to mass tags
`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; see also id. at 5:43–44.
`
`C. Illustrative Claim
`Claim 1, reproduced below, is the sole challenged claim and is
`illustrative of the subject matter:
`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
`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;
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`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, 34:2–35:4.
`
`D. The Prior Art
`Petitioner relies on the following prior art:
`WO 91/06678, pub. May 16, 1991 (Ex. 1013, “Tsien”);
`US 5,547,839, iss. Aug. 20, 1996 (Ex. 1015, “Dower”);
`Michael L. Metzker et al., Termination of DNA synthesis by
`novel 3'-modified-deoxyribonucleoside 5'-triphosphates, 22(20)
`NUCLEIC ACIDS RESEARCH 4259–67 (1994) (Ex. 1016,
`“Metzker”);
`James M. Prober et al., System for Rapid DNA Sequencing with
`Fluorescent Chain-Terminating Dideoxynucleotides, 238
`SCIENCE 336–341 (Oct. 16, 1987) (Ex. 1014, “Prober”).
`E. The Alleged Grounds of Unpatentability
`Petitioner challenges claim 1 of the ’852 patent as unpatentable under
`35 U.S.C. § 103(a) over the combination of Tsien and Prober, and over the
`combination of Dower, Prober, and Metzker.
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`II. ANALYSIS
`A. Claim Construction
`In an inter partes review, the Board interprets claim terms in an
`unexpired patent according to the broadest reasonable construction in light
`of the specification of the patent in which they appear. 37 C.F.R.
`§ 42.100(b); see Cuozzo Speed Techs. v. Lee, LLC, 136 S. Ct. 2131, 2142–46
`(2016). Under that standard, and absent any special definitions, we give
`claim terms their ordinary and customary meaning, as would be understood
`by one of ordinary skill in the art at the time of the invention. See 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. See In re Paulsen, 30 F.3d 1475, 1480 (Fed.
`Cir. 1994).
`Petitioner does not request construction of any terms. Patent Owner
`requests construction of the following terms: “small” and “chemical linker.”
`Prelim. Resp. 9–11. We determine that none of the terms in the challenged
`claim requires express construction for purposes of this Decision in order to
`resolve the issues presented by the Petition. See Vivid Techs., Inc. v. Am.
`Sci. & Eng’g, Inc., 200 F.3d 795, 803 (Fed. Cir. 1999).
`
`B. Obviousness of Claim 1 over Tsien (Ex. 1013) and
`Prober (Ex. 1014)
`Petitioner contends that claim 1 is unpatentable as obvious over Tsien
`and Prober. Pet. 16–24. Patent Owner opposes. Prelim. Resp. 16–50.
`
`1. Overview of Tsien
`Tsien is titled “DNA Sequencing” and “relates to an instrument and a
`method to determine the nucleotide sequence in a DNA molecule without
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`the use of a gel electrophoresis step.” Ex. 1013, [54], [57]. Tsien discloses
`a method whereby an unknown primed single stranded DNA sequence is
`immobilized within a chamber with a polymerase so that sequentially
`formed cDNA can be monitored at each addition of a blocked nucleotide by
`measuring the presence of an innocuous marker on specified
`deoxyribonucleotides. Id. at [57]. By noting the identity of the bases
`present in this complementary molecule and using standard rules of DNA
`complementation, one can translate from the complementary molecule to the
`corresponding original subject molecule and, thus, obtain the
`deoxyribonucleotide sequence of the subject molecule. Id. at 7:9–14.
`Tsien’s 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 7:34–8:7. Tsien
`describes that a blocking group is present on the 3'-hydroxyl position of the
`added dNTP to prevent inadvertent multiple additions. Id. at 12:27–29. The
`identity of this first nucleotide can be determined by detecting and
`identifying the label attached to it, where a different label is used for each
`nucleotide. Id. at 13:1–3. Tsien discloses adding a deblocking solution to
`regenerate the 3'-hydroxyl position on the first nucleotide present. Id. at
`13:18–20.
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`Figure 1B of Tsien is a schematic diagram of the process (id. at 8:16–
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`17):
`
`2
`
`1
`~
`
`3'
`
`template DNA 5•
`I
`~
`0-A +
`3' x I I I I I I I_( I I I I I < I I I I I 5,
`L .... a•'. ... .. .l L, --7 ·· -' '--·--- a· -- :
`+
`0-A-X I I I I I I I ( I I I I I < I I I I I 5.
`Immobilized template DNA s•
`I s·~~-3·
`.
`T +
`· ·
`I I I I I
`5· I I I I I 3·
`0-A-X I I I I I I I< I I I I I < I I I I I s·
`+ 3'-8 dNTPs + polymerase
`/
`I I I < I I I I I 5 .
`
`primer 3 '
`
`·
`
`·
`template/primer hybrid g•
`
`10·
`
`11 ,12
`
`.\ i
`.
`I I I I I :·:· 3'
`0-A-X I I I 1.1-1 h
`I I
`. t f·
`
`5
`
`11', 12'
`
`FIG. 1 B
`
`
`
`Figure 1B is a schematic diagram of Tsien’s process on a molecular level.
`
`2. Overview of Prober
`Prober is titled “System for Rapid DNA Sequencing with Fluorescent
`Chain-Terminating Dideoxynucleotides” and relates to 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.
`1014, 336. Prober discloses that succinylfluorescein is attached via a linker
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`to a heterocyclic base, i.e., a nucleotide analogue. See id. at 337. In
`particular, the linker is attached to the 5 position in the pyrimidines and to
`the 7 position in the 7-deazapurines. Id.
`Fluorescence-tagged chain terminating reagents are depicted in Figure
`2A below (id. at 338):
`
`A
`
`
`Figure 2A of Prober depicts chemical structures of the reagents used in
`modified dideoxy reactions for DNA sequencing.
`3. Analysis
`In its Petition, Petitioner sets forth its contentions as to how the
`limitations of claim 1 are disclosed in, or obvious over, the combination of
`Tsien and Prober. Pet. 21–22, 24–42. Petitioner relies on the declaration of
`Floyd Romesberg, PhD. Ex. 1012. Patent Owner opposes. Prelim. Resp.
`16–50. We address these contentions below. We emphasize that the
`following determinations regarding the sufficiency of the Petition are
`preliminary in nature at this stage of the proceeding.
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`a. “An adenine deoxynucleotide analogue having the structure” as depicted
`in claim 1
`Petitioner asserts, inter alia, that Tsien discloses a 3'-blocked adenine
`
`analogue. Pet. 19 (citing, e.g., Ex. 1013, 9:30–10:15, 12:22–27, Fig. 2;
`Ex. 1012 ¶ 55).1 Patent Owner does not appear to dispute this limitation.
`See generally Prelim. Resp. 19–50. On this record, we are persuaded that
`Petitioner has made an adequate showing. In particular, Figure 2 of Tsien
`discloses “3'-BLOCKED d’ATP.” Ex. 1013, Fig. 2; see also id. at 12:22–
`27.
`Petitioner asserts that Prober discloses 7-substituted deazapurines, as
`
`depicted in claim 1. Pet. 20 (citing Ex. 1014, 337). On this record, we are
`persuaded that Petitioner has made an adequate showing. See Section II.B.2,
`supra.
`Petitioner asserts that Tsien recommends Prober’s nucleotides.
`Pet. 20, 35 (citing, e.g., Ex. 1013, 2:25, 5:22–23, 29:10–14, 31:11). On this
`record, we are persuaded that Petitioner has made an adequate showing that
`a person of ordinary skill would have modified Tsien’s chain termination
`method with Prober’s fluorescently labeled ddNTPs, i.e., by reason of
`express invitation. For example, Tsien discloses, by way of background,
`that there is an automated system (e.g., Prober’s) that uses fluorescently
`labeled ddNTPs to terminate the reaction instead of fluorescent primers.
`Ex. 1013, 2:23–27. Tsien also includes Prober in the list of alternatives
`showing “enzymatic competence,” stating that Prober shows enzymatic
`
`
`1 The parties are instructed to use spaces rather than dashes where
`appropriate so as not to circumvent word count limits in future filings, i.e., to
`use “Ex. 1013” rather than “Ex-1013” or “Ex. 2029” rather than “Ex.-2029.”
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`incorporation of ddNTPs by reverse transcriptase and Sequenase. Id. at
`28:5–18.
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`b. “wherein R (a) represents a small, chemically cleavable, chemical group
`capping the oxygen at the 3' position of the deoxyribose of the
`deoxyribonucleotide analogue”; “wherein R . . . (d) does not contain a
`ketone group”; and wherein OR is not a methoxy group or an ester group;”
`Petitioner asserts, inter alia, that Tsien discloses an adenine
`deoxyribonucleotide analogue having a blocking group capping the
`3'-oxygen of the deoxyribose and that an O-allyl ether group is an
`advantageous blocking group. See Pet. 21–23 (citing Ex. 1013, 12:27–29,
`24:25–25:3, Fig. 2; Ex. 1012 ¶ 61); Pet. 26. Petitioner also relies on
`experiments using allyl groups disclosed in Metzker, which we discuss in
`further detail with respect to other claim limitations. Pet. 23 (citing
`Ex. 1016, 4263); see Section II.B.3.c., infra.
`Patent Owner counters that Petitioner has not established that Tsien or
`Prober discloses a “small” capping group not containing a ketone and not
`forming an ester or a methoxy group with the 3'-oxygen of the nucleotide
`analogue. Prelim. Resp. 19–47. We address Patent Owner’s arguments as
`follows.
`Efficiency and mildness arguments
`Patent Owner argues that Tsien requires mild conditions for cleaving
`and argues that Petitioner has failed to show that Tsien’s allyl capping group
`could be cleaved quantitatively under mild conditions, or that a person of
`ordinary skill in the art would have had a reasonable expectation of success
`in using an allyl group. Prelim. Resp. 33 (citing Ex. 1013, 20–21), 43.
`Patent Owner argues that Petitioner has failed to demonstrate that allyl
`capping can be conducted under mild conditions because the references on
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`which Petitioner relies to support that teaching disclose conditions that are
`“not mild.” Id. at 33–34. Specifically, Patent Owner asserts that Qian2 uses
`methanol, which was known to denature DNA, Boss3 uses heat, and both
`Qian and Boss use PdCl2, which was not necessarily known to be compatible
`with DNA. Id. at 34 (citing Ex. 1036, 2185; Ex. 2007 ¶¶ 47, 55; Ex. 1035,
`558–559). Patent Owner also asserts that Qian required 2 hours for cleavage
`and Boss required “a few hours.” Id. at 33 (citing Ex. 1036, 2185; Ex. 1035,
`558–59). Patent Owner has not adduced testimonial evidence interpreting
`the references at this stage of the proceeding.
`Patent Owner further argues that Petitioner has not established a
`reason one of ordinary skill in the art would have selected Tsien’s allyl
`capping group. Prelim. Resp. 23–37. Patent Owner argues that Tsien also
`discloses ester capping groups that offer the advantage of preventing
`significant premature deblocking and identifies groups suitable for
`photochemical and enzymatic removal. Id. at 24 (citing Ex. 1013, 24–25).
`Patent Owner asserts that “Tsien discloses no preference or requirement
`regarding the size of the blocking group, and provides no other disclosures
`that would [have led] a POSA to use the allyl capping group.” Id. at 25; see
`also id. at 27–30.
`Petitioner asserts that Qian discloses “quantitative” allyl cleavage.
`Pet. 22, 32 (citing Ex. 1036, 2184). Petitioner also asserts that Patent Owner
`
`2 Xiangping Qian et al., Unexpected Enzymatic Fucosylation of the Hindered
`Tertiary Alcohol of 3-C-Methyl-N-Acetyllactosamine Produces a Novel
`Analogue of the LeX-Trisaccharide, 120 J. AM. CHEM. SOC. 2184–84 (1998)
`(Ex. 1036).
`3 Roland Boss & Rolf Scheffold, Cleavage of Allyl Ethers with Pd/C,
`15 ANGEW. CHEM. INT. ED. ENGL. 558–59 (1976) (Ex. 1035).
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`has admitted that it was known that an allyl group could be cleaved with
`high yield. Pet. 23 (quoting Ex. 1001, 3:41–44 (“[i]t is known that ... allyl
`(-CH2CH=CH2) groups can be used to cap an -OH group, and can be cleaved
`chemically with high yield.”); citing Ex. 1001, 26:22–25 (“The MOM
`(-CH2OCH3 ) or 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).”)).
`On this record, we determine that Petitioner has demonstrated a
`reason for using, and a reasonable expectation of success in using, an allyl
`group as a blocking group to cap the 3'-hydroxyl group of a nucleotide
`analogue based on the teachings of Tsien, Kamal4, Qian, and the admission
`in the ’852 patent as to what was well known in the art. Ex. 1013, 24;
`Ex. 1037, 371–72; Ex. 1036, 2184; Ex. 1001, 3:41–44, 26:22–25; see also
`Ex. 1035, 559. On the current record at this stage of the proceeding, Qian
`reports “quantitative” yield using PdCl2 to remove the O-allyl group.
`Ex. 1036, 2184. Further, whether or not Qian’s technique for deblocking
`allyl groups is sufficiently mild, other techniques were known. We note that
`Tsien’s teaching to deblock allyl ethers using Hg immediately follows the
`statement that care must be taken not to denature the DNA. Ex. 1013, 24.
`Further, the patentee has admitted that allyl capping was well known and
`effective, referring to Kamal. Ex. 1001, 3:41–44 (“[i]t is known that . . .
`allyl . . . groups . . . can be cleaved chemically with high yield”), 26:22–25
`(using “well-established synthetic procedures”). Based on the evidence at
`
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`4 Ahmed Kamal et al., Mild and Rapid Regeneration of Alcohols from their
`Allylic Ethers by Chlorotrimethylsilane/Sodium Iodide, 40 TETRAHEDRON
`LETTERS 371–72 (1999) (Ex. 1037).
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`this stage of the proceeding, we are persuaded that Petitioner has made a
`sufficient showing that a person of ordinary skill would have combined the
`teachings of Tsien to use the allyl group that Tsien discloses to be an
`advantageous blocking group, to block the 3'-oxygen, as elsewhere disclosed
`in Tsien’s method. See Ex. 1013, 12:27–29, 24:5–25:3. We invite further
`briefing on this issue at trial, including whether it was appreciated in the art
`that sufficiently mild conditions were known for cleaving allyl groups when
`working with nucleotide analogues.
`Estoppel arguments
`Patent Owner also argues that Kamal (Ex. 1037) establishes that
`cleavage was 93% and argues that such a cleavage rate (as a percent) is
`inconsistent with the requirements that Petitioner has argued for, or that the
`Federal Circuit has required, in previous proceedings involving Petitioner
`(and another party):
`Illumina cites Kamal (Ex-1037) as evidence the allyl capping
`group could be cleaved under mild conditions, but Kamal’s
`conditions do not result in what Illumina terms quantitative
`cleavage, resulting instead in 93% cleavage. Ex-1037 at 372,
`Entry 8 (reporting 93% cleavage of allyl on sugar). Illumina
`previously asserted 93% cleavage is not enough to practice
`Tsien’s methods, and that anything less than quantitative
`cleavage is insufficient. See Ex-2029[5] at 45 (“One skilled in
`the art would not have been motivated to combine the prior art
`references for SBS [sequencing by synthesis] unless there was a
`reasonable expectation that the combination would provide a 3’-
`protecting group that cleaves with nearly 100% efficiency.”), 28
`
`
`5 Illumina Cambridge Ltd. v. Intelligent Biosystems, Inc., Case. No. 2015-
`1123 (Brief of Patent-Owner-Appellant Illumina Cambridge Ltd.) (filed
`Mar. 10, 2015) (Ex. 2029).
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`(“[O]ver 97% . . . is required.”); Ex-2030[6] at 1 (“[T]he
`[cleavage] efficiency needed to be >97%.”); Ex-1045[7] at 6
`(Federal Circuit finding that: “In order for the deblocking (i.e.,
`the removal of the protecting group) to be quantitative, it must
`take place at 100% or near-100% efficiency.”).
`
`Prelim. Resp. 34–35.
`We do not find that Petitioner’s position in this proceeding is
`necessarily inconsistent with the cited papers, based on the current record—
`even under Patent Owner’s argument that Kamal resulted in 93% cleavage,
`Patent Owner has not persuaded us on this record that 93% is not sufficiently
`close to 100% cleavage for purposes of the experiments at issue here.8 To
`the extent that Petitioner has previously argued to the Board that over 97%
`cleavage is required, the full quotation from Ex. 2029 is “The experts for
`both parties agreed that SBS requires that the 3'-protecting group of the
`nucleotides be removed with greater than 90% efficiency. The evidence
`showed that over 97%, and preferably nearly 100%, removal efficiency of
`the 3'-protecting group is required.” Ex. 2029, 28. It is possible that
`Petitioner’s argument is simply characterizing the evidence from a different
`proceeding, and Patent Owner has not necessarily established the same
`requirement based on the evidence of record in this proceeding.
`
`
`6 Illumina Cambridge Ltd. v. Intelligent Biosystems, Inc., Case IPR2013-
`00266 (Patent Owner Illumina’s Reply to Petitioner’s Opposition to
`Illumina’s Motion To Amend) (filed Mar. 21, 2014) (Ex. 2030).
`7 Intelligent Biosystems, Inc. v. Illumina Cambridge Ltd., Case No. 2015-
`1693, slip op. (Fed. Cir. May 9, 2016) (Ex. 1045).
`8 Although the burden for proving estoppel against Petitioner rests with
`Patent Owner, we are mindful that the ultimate burden for establishing
`reasonable likelihood of success on the merits remains with Petitioner.
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`Patent Owner also contends that Petitioner has previously taken an
`inconsistent position in a reexamination proceeding, when it argued that
`Tsien describes an allyl group as part of a general description of blocking
`methods, but does not disclose a removable allyl group at the 3'-carbon.
`Prelim. Resp. 21–22 (quoting Ex. 20229, 10–11). Patent Owner argues that
`Petitioner breached its obligations by failing to disclose this inconsistent
`position. See id. at 22 (citing 37 C.F.R. § 42.11(a); 37 C.F.R.
`§ 42.51(b)(1)(iii)).
`At this stage of the proceeding, we are unpersuaded by Patent
`Owner’s contention that Petitioner has previously taken an inconsistent
`position because the asserted ground is based on obviousness rather than
`anticipation, which was the subject of the arguments in the previous
`reexamination to which Patent Owner refers. See Ex. 2022, 10.
`Accordingly, on the present record, Petitioner’s arguments are not “clearly
`inconsistent” with those made in the reexamination and, for at least this
`reason, do not give rise to a judicial estoppel. See Fitness Quest, Inc. v.
`Monti, 330 Fed. Appx. 904 (Fed. Cir. 2009) (discussing New Hampshire v.
`Maine, 532 U.S. 742, 750–51 (2001) (several factors inform the decision
`whether to apply the doctrine of judicial estoppel including whether a party’s
`later position is “clearly inconsistent” with its earlier position)). Further,
`Tsien suggests an allyl group as a blocking group in the very context of an
`application for a method of DNA sequencing. See Ex. 1013, 24–25.
`Patent Owner also contends that Petitioner has admitted that there was
`“no concrete embodiment of the successful cleavage of a 3'-allyl group
`
`9 In re Hiatt, Reexamination Application No. 90/008,152, Remarks (Apr. 30,
`2007) (Ex. 2022).
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`under DNA compatible conditions.” Prelim. Resp. 36 (citing Ex. 2015,
`2:60–65). However, Patent Owner has not established that this type of
`statement in an unrelated issued patent is binding as an admission against
`Petitioner in this inter partes review proceeding. Further, this statement
`appears to be, at most, a statement that there is no anticipatory reference, and
`does not preclude a determination of obviousness. See Ex. 2015, 2:60–65
`
`c. “wherein R . . . (b) does not interfere with recognition of the analogue as
`a substrate by a DNA polymerase”
`Petitioner asserts, inter alia, that Tsien discloses that criteria for
`successful use of 3'-blocking groups includes the ability of a polymerase
`enzyme to accurately and effectively incorporate the dNTPs carrying the
`3′-blocking groups into the cDNA chain. Pet. 24 (quoting Ex. 1013, 20:28–
`32; citing id. at 12:11–18, 19:4–18, 24:1–2). Petitioner further asserts that a
`person of ordinary skill in the art would have known that Tsien’s 3′-O-allyl
`group does not interfere with recognition by a DNA polymerase because
`Metzker demonstrated polymerase recognition in 1994. Id. (citing Ex. 1016,
`4263; Ex. 1012 ¶¶ 63, 66).
`Patent Owner alleges that Metzker indicates that O-allyl-dATPs
`achieved termination in a non-specific manner when it reports that certain
`other nucleotide analogues were specific. Prelim. Resp. 27 (citing Ex. 1016,
`4263). Although Metzker reports that three other capping groups resulted in
`specific termination, Metzker does not state that O-allyl-dATPs were
`non-specific and Patent Owner’s assertion appears to be based on an
`inference that is not necessarily justified. On the contrary, the legend to
`Table 2 of Metzker states that the label “Inhibition” is used to refer to
`nonspecific DNA synthesis. Metzker instead uses the “Termination*” label
`
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`for O-allyl-nucleotides, where Termination “means that termination bands
`mimic ddNTP termination bands.” Ex. 1016, 4263.
`Patent Owner further argues that Metzker indicates that termination
`was incomplete at a final concentration of 250 µM of 3'-O-allyl-dATPs.
`Prelim. Resp. 27–29 (citing, e.g., Ex. 1016, 4263; Ex. 1017, 6348). Patent
`Owner asserts that Metzker reported that only three compounds “proved to
`be interesting DNA synthesis terminators,” i.e., 3'-O-(2-nitrobenzyl)-dATP,
`3'-O-methyl-dATP, and 3'-O-methyl-dTTP. Id. at 28 (citing Ex. 1016,
`4265). Patent Owner argues that a person of ordinary skill would not have
`been interested in allyl capping groups because Tsien sets forth a
`requirement that a polymerase enzyme “accurately and efficiently”
`incorporate the 3'-modified dNTPs. Prelim. Resp. 30–32 (citing, e.g.,
`Ex. 1013, 20–21).
`As Patent Owner observes, Metzker reports that three other capping
`groups resulted in specific termination, and that the termination effect for the
`O-allyl capping group was incomplete at the studied concentration. See
`Ex. 1016, 4263 (“Termination*” where “‘*’ means the activity was
`incomplete at a final concentration of 250 µM”); Ex. 1012 ¶ 63. A different
`reference, Wu, further relates as follows:
`The novel RT, N6-(2-nitrobenzyl)-dATP IIIc, provides favorable
`enzymatic properties with a variety of wild-type and mutant
`DNA polymerases. This is unlike the situation for 3'-modified
`nucleotides, which typically act as poor substrates for DNA
`polymerases. For example, screening 3'-O-allyl-dATP with eight
`different DNA polymerases revealed limited activity at high
`micromolar concentrations with only Vent(exo–) DNA
`polymerase (8). The highly related 9°N(exo–) DNA polymerase
`(30), containing the A485L and Y409V amino acid variants
`(Therminator II), has been shown to incorporate 3’-O-allyl-
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`dNTPs, however, efficient incorporation requires up to 50 min
`per single base addition, highlighting
`the difficulty of
`incorporating these analogs (7,10).
`
`Ex. 101710, 6348 (referring to Ex. 1016, as “(8)”). Wu thus states that an
`allyl-modified nucleotide “typically act[s]” as a “poor substrate” because it
`only had activity with one DNA polymerase, and does so with limited
`activity at high micromolar concentrations. See id.
`Nevertheless, Petitioner’s Declarant testifies that a person of ordinary
`skill reading Metzker would have understood that DNA polymerase
`recognizes nucleotides with O-allyl blocking groups. Ex. 1012 ¶ 63. Patent
`Owner has not adduced any expert testimony at this stage of the proceeding
`with respect to the proper interpretation of Metzker or Wu.
`
`We determine, on this record, that Petitioner has made an adequate
`showing that a person of ordinary skill would have selected O-allyl
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