Trials@uspto.gov
`Tel: 571-272-7822
`
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`_______________
`
`Paper 87
`Entered: February 11, 2015
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_______________
`
`INTELLIGENT BIO-SYSTEMS, INC.,
`Petitioner,
`
`v.
`
`ILLUMINA CAMBRIDGE LTD,
`Patent Owner.
`_______________
`
`Case IPR2013-00517
`Patent 7,566,537 B2
`_______________
`
`
`
`Before LORA M. GREEN, FRANCISCO C. PRATS, and
`SCOTT E. KAMHOLZ, Administrative Patent Judges.
`
`PRATS, Administrative Patent Judge.
`
`
`
`FINAL WRITTEN DECISION
`35 U.S.C. § 318(a) and 37 C.F.R. § 42.73
`
`
`
`
`
`
`
`
`
`2012
`Columbia
`Ex.
`v.
`Illumina, Inc.
`The Trustees
`of Columbia University
`in the City of New York
`IPR2020-01177
`
`
`Tel: 571-272-7822
`
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`_______________
`
`Paper 87
`Entered: February 11, 2015
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_______________
`
`INTELLIGENT BIO-SYSTEMS, INC.,
`Petitioner,
`
`v.
`
`ILLUMINA CAMBRIDGE LTD,
`Patent Owner.
`_______________
`
`Case IPR2013-00517
`Patent 7,566,537 B2
`_______________
`
`
`
`Before LORA M. GREEN, FRANCISCO C. PRATS, and
`SCOTT E. KAMHOLZ, Administrative Patent Judges.
`
`PRATS, Administrative Patent Judge.
`
`
`
`FINAL WRITTEN DECISION
`35 U.S.C. § 318(a) and 37 C.F.R. § 42.73
`
`
`
`
`
`
`
`
`
`2012
`Columbia
`Ex.
`v.
`Illumina, Inc.
`The Trustees
`of Columbia University
`in the City of New York
`IPR2020-01177
`
`
`
`IPR2013-00517
`Patent 7,566,537 B2
`
`
`I. INTRODUCTION
`
`A. Statement of the Case
`
`Intelligent Bio-Systems, Inc. (“Petitioner”) filed a revised Petition
`(Paper 7, “Pet.”) requesting inter partes review of claims 1–6 and 8 of
`U.S. Patent No. 7,566,537 B2 (Ex. 1001, “the ’537 patent”). Illumina
`Cambridge Ltd (“Patent Owner”) waived the filing of a preliminary response
`(Paper 10). We instituted trial on the following grounds of unpatentability:
`References
`Basis
`Claims challenged
`Ju,1 Zavgorodny2
`§ 103
`1–6, 8
`
`Tsien,3 Zavgorodny
`
`Tsien, Zavgorodny, Prober4
`
`§ 103
`
`§ 103
`
`1–6, 8
`
`3
`
`
`Decision to Institute 15 (Paper 16, “Dec.”).
`After trial was instituted, Patent Owner filed redacted and unredacted
`versions of its Patent Owner Response (Papers 32 and 33, “PO Resp.”),
`along with a Motion to Seal and proposed Protective Order (Paper 34).
`
`1 U.S. Patent No. 6,664,079 B2 (filed Oct. 5, 2001) (Ex. 1002).
`2 Sergey Zavgorodny et al., 1-Alkylthioalkylation of Nucleoside Hydroxyl
`Functions and Its Synthetic Applications: A New Versatile Method in
`Nucleoside Chemistry, 32 TETRAHEDRON LETTERS 7593–96 (1991) (Ex.
`1004).
`3 Roger Y. Tsien, WO 91/06678 A1 (published May 16, 1991) (Ex. 1008).
`4 James M. Prober et al., A System for Rapid DNA Sequencing with
`Fluorescent Chain-Terminating Dideoxynucleotides, 238 SCIENCE 336–41
`(1987) (Ex. 1009).
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`Petitioner filed unredacted and redacted versions of its Reply (Papers 54 and
`55, “Pet. Reply”), along with its own Motion to Seal (Paper 52).
`Both parties filed Motions to Exclude Evidence. Paper 61 (“Pet. Mot.
`to Exclude”) and Paper 62 (“PO Mot. to Exclude”). Patent Owner’s Motion
`to Exclude Evidence was accompanied by an additional Motion to Seal.
`Paper 63.
`Both parties filed Oppositions to the Motions to Exclude Evidence.
`Paper 68 (“Pet. Opp.”); Papers 71, 72 (“PO Opp.”). Patent Owner’s
`Opposition was accompanied by a Motion to Seal (Paper 70); Paper 72 is the
`unredacted version of Paper 71. Both parties filed Replies to the
`Oppositions to the Motions to Exclude Evidence. Papers 74, 75.
`Patent Owner filed a Motion for Observations on Cross Examination.
`Paper 64 (“PO Mot. Obs.”). Petitioner filed a Response to that Motion.
`Paper 67 (“Resp. to Mot. Obs.”).
`Petitioner supports its Petition with a Declaration by Bruce P.
`Branchaud, Ph.D. Ex. 1011 (“Branchaud Pet. Decl.”). Petitioner supports
`its Reply with a second Declaration by Dr. Branchaud (“Branchaud Reply
`Decl.”), and a Declaration by Michael L. Metzker, Ph.D. (“Metzker Decl.”).
`Ex. 1031; Ex. 1046. Patent Owner relies on Declarations by Floyd
`Romesberg, Ph.D. (“Romesberg Decl.”) and Kevin Burgess, Ph.D.
`(“Burgess Decl.”). Ex. 2011; Ex. 2089.
`Oral Hearing was held on October 10, 2014, and the Hearing
`Transcript (“Tr.”) has been entered in the record. Paper 84.
`We have jurisdiction under 35 U.S.C. § 6(c). This Final Written
`Decision is entered pursuant to 35 U.S.C. § 318(a). We conclude that
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`Petitioner has not proved by a preponderance of the evidence that claims 1–6
`and 8 of the ʼ537 patent are unpatentable. Petitioner’s Motion to Exclude
`Evidence is dismissed as moot. Patent Owner’s Motion to Exclude
`Evidence is dismissed as moot also.
`
`B. Related Proceedings
`
`Petitioner states that the ’537 patent is “the subject of the litigation
`captioned The Trustees of Columbia University in the City of New York v.
`Illumina, Inc., 1:12-cv-00376-GMS, currently pending in the United States
`District Court for the District of Delaware (the ‘Delaware Action’)” in which
`Patent Owner alleges infringement by Petitioner of the ’537 patent. Pet. 3.
`Also, concurrently with the Petition in this proceeding, Petitioner filed
`a petition requesting cancellation of claims 7 and 11–14 of the ’537 patent.
`Pet. 3; IPR2013-00518. That proceeding was terminated upon Patent
`Owner’s request for adverse judgment. IPR2013-00518, Papers 28 and 29.
`Petitioner states that it also filed three other petitions for inter partes
`review, IPR2013-00128, IPR2013-00266, and IPR2013-00324, challenging
`the patentability of claims of two related patents, U.S. Patent Nos. 7,057,026
`B2 and 8,158,346 B2, which also are asserted in the Delaware Action, and
`which “share inventors, specifications, and a priority date with the ‘537
`Patent.” Pet. 3.
`Final Judgment was entered in IPR2013-00128 on July 25, 2014, and
`Patent Owner appealed that decision on September 24, 2014. IPR2013-
`00128, Papers 92 and 95. Final Judgment was entered in IPR2013-00266 on
`October 28, 2014, and Patent Owner appealed that decision on November
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`26, 2014. IPR2013-00266, Papers 73 and 75. The Board declined to
`institute trial in IPR2013-00324. IPR2013-00324, Paper 19.
`
`C. The ’537 Patent (Ex. 1001)
`
`The ’537 patent discloses a nucleotide or nucleoside molecule “having
`a base that is linked to a detectable label via a cleavable linker.” Ex. 1001,
`2:23–24. The labeled nucleotide or nucleoside also has a protecting group
`removably attached to the 2´ or 3´ oxygen of the molecule’s deoxyribose or
`ribose moiety. Id. at 2:26–27. “The protecting group can be removed to
`expose a 3´-OH.” Id. at 2:27–28. The ’537 patent describes a method of
`labeling nucleic acids, in which a terminal transferase, a polymerase, or a
`reverse transcriptase is used to incorporate a labeled nucleotide into a
`nucleic acid molecule. Id. at 2:32–38.
`The ’537 patent also describes nucleic acid sequencing methods that
`are performed by synthesizing the complementary strand of a single-
`stranded polynucleotide of interest, using a polymerase to incorporate the
`labeled nucleotides into the complementary strand. Id. at 2:50–53; 8:50–57.
`The protecting group allows the polymerase to incorporate only one
`nucleotide at a time into the complementary strand. See id. at 7:51–54. The
`detectable label allows identification of the particular type of nucleotide
`incorporated into the complementary strand. Id. at 2:55–57. After removing
`the label and protecting group, subsequent nucleotides may be added one at
`a time, and their identities determined in sequential fashion, thereby
`determining the sequence of the nucleic acid of interest. See id. at 2:67–3:3.
`
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`Claim 1, the only independent claim under review, is reproduced
`below (emphasis added):
`1. A method of labeling a nucleic acid molecule, the
`method comprising incorporating into the nucleic acid molecule
`a nucleotide or nucleoside molecule, wherein the nucleotide or
`nucleoside molecule has a base that is linked to a detectable
`label via a cleavable linker and the nucleotide or nucleoside
`molecule has a ribose or deoxyribose sugar moiety, wherein the
`ribose or deoxyribose sugar moiety comprises a protecting
`group attached via the 2´ or 3´ oxygen atom, and said
`protecting group can be modified or removed to expose a 3´
`OH group and the protecting group comprises an azido group.
`
`II. DISCUSSION
`
`A. Claim Construction
`
`Consistent with the statute and legislative history of the Leahy-Smith
`America Invents Act, Pub. L. No. 112-29, 125 Stat. 284 (2011) (“AIA”), the
`Board interprets claims in an unexpired patent using the “broadest
`reasonable construction in light of the specification of the patent in which
`[they] appear[].” 37 C.F.R. § 42.100(b). Under that standard, claim terms
`are given their ordinary and customary meaning as would be understood by
`one of ordinary skill in the art in the context of the entire disclosure. In re
`Translogic Tech., Inc., 504 F.3d 1249, 1257 (Fed. Cir. 2007).
`In the Decision to Institute, we construed claim 1 as encompassing the
`use of any protecting group attached via the 2´ or 3´ oxygen atom of a ribose
`or deoxyribose moiety, in which the protecting group can be modified or
`removed to expose a 3´ OH group. Dec. 6–7. In doing so, we clarified that,
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`under the broadest reasonable construction standard, claim 1 does not
`require removal of the protecting group to allow subsequent nucleotide
`incorporation. Id. The parties do not dispute that claim construction and we
`see no reason to modify it in light of the record developed during trial.
`
`B. Obviousness of Claims 1–6 and 8 over Tsien and Zavgorodny
`
`Petitioner cites Tsien as describing a nucleic acid sequencing process
`substantially as required by claims 1–6 and 8, in which the nucleic acid is
`labeled by incorporating into the nucleic acid molecule a labeled nucleotide
`having a removable 3´ OH protecting group. Pet. 31–37. Petitioner notes
`Tsien’s disclosure that the protecting group may include an azido moiety.
`Id. at 34. Petitioner cites Zavgorodny to show that an azidomethyl group,
`encompassed by claim 1 and recited in claim 6, was known in the art to be a
`suitable 3´ OH protecting group. Id. at 33–34, 36. Based on the references’
`teachings, Petitioner contends that an ordinary artisan, “to improve the
`efficiency, reliability, and robustness of the sequencing by synthesis method
`taught in Tsien, would have been motivated to use other protecting groups
`that meet the criteria of Tsien, such as the azidomethyl group taught by
`Zavgorodny.” Id. at 38.
`Petitioner contends further that, because an ordinary artisan would
`have recognized that Zavgorodny’s azidomethyl group met Tsien’s criteria
`for a suitable 3´ OH protecting group, the artisan “would have expected to
`succeed in combining the teachings of Tsien and Zavgorodny to carry out a
`nucleic acid labeling method using a modified nucleotide having a
`protecting group attached via the 3´ oxygen atom, wherein the protecting
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`group comprises an azido group, such as azidomethyl.” Id. at 39. Thus,
`Petitioner concludes, “Tsien combined with Zavgorodny renders claims 1-6
`and 8 obvious under 35 U.S.C. § 103(a).” Id. at 40.
`Patent Owner contends that an ordinary artisan would not have
`considered it obvious to employ Zavgorodny’s azidomethyl group as the 3´
`hydroxyl protecting group in Tsien’s sequencing by synthesis (SBS)
`processes, because the pyridine used in removing Zavgorodny’s azidomethyl
`protecting group was known in the art to denature DNA. PO Resp. 19–20.
`Thus, Patent Owner argues, the conditions described by Zavgorodny for
`removing its azidomethyl group would not have been considered sufficiently
`mild for use in Tsien’s sequencing methods. Id. at 21–23.
`Patent Owner contends also that an ordinary artisan would not have
`expected the azidomethyl group to meet Tsien’s criteria of quantitative and
`rapid removal from a nucleic acid molecule. Id. at 23–30. In particular,
`Patent Owner contends that an ordinary artisan would have understood
`Tsien’s requirement for quantitative removal of the 3´ OH protecting group
`to mean essentially 100% removal. Id. at 24 (citing Branchaud Deposition
`98:8–16 (Ex. 2039)). In contrast, Patent Owner argues, prior art of record,
`including the Loubinoux5 reference, demonstrates that an ordinary artisan
`would have expected Zavgorodny’s azidomethyl group to be removed at a
`much lower efficiency than required by Tsien’s methods. Id. at 24–29. In
`
`5 Bernard Loubinoux et al., Protection of Phenols by the Azidomethylene
`Group Application to the Synthesis of Unstable Phenols, 44 TETRAHEDRON
`6055–64 (1988) (Ex. 1006) (as translated).
`
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`sum, Patent Owner contends, Petitioner “offered no evidence that one of
`ordinary skill in the art would have expected Zavgorodny’s azidomethyl
`group to have quantitative and rapid cleavage when combined with Tsien’s
`methods, and the evidence of record demonstrates that no such expectation
`existed.” Id. at 30.
`We agree with Patent Owner that Petitioner has not shown, by a
`preponderance of the evidence, that an ordinary artisan would have
`considered it obvious to use Zavgorodny’s azidomethyl group as the 3´
`hydroxyl protecting group in Tsien’s processes.
`In KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 415 (2007), the
`Supreme Court emphasized “an expansive and flexible approach” to the
`obviousness question, noting in particular that the analysis “need not seek
`out precise teachings directed to the specific subject matter of the challenged
`claim, for a court can take account of the inferences and creative steps that a
`person of ordinary skill in the art would employ.” Id. at 418; see also id. at
`421 (“A person of ordinary skill is . . . a person of ordinary creativity, not an
`automaton.”).
`
`Nonetheless, the Court reaffirmed that a conclusion of obviousness
`requires a reasonable expectation of success:
`When there is a design need or market pressure to solve a
`problem and there are a finite number of identified, predictable
`solutions, a person of ordinary skill has good reason to pursue
`the known options within his or her technical grasp. If this
`leads to the anticipated success, it is likely the product not of
`innovation but of ordinary skill and common sense. In that
`instance the fact that a combination was obvious to try might
`show that it was obvious under § 103.
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`Id. at 421 (emphases added).
`As the Court of Appeals for the Federal Circuit has explained,
`“[a]lthough predictability is a touchstone of obviousness, the ‘predictable
`result’ discussed in KSR refers not only to the expectation that prior art
`elements are capable of being physically combined, but also that the
`combination would have worked for its intended purpose.” Depuy Spine,
`Inc v. Medtronic Sofamor Danek, Inc., 567 F.3d 1314, 1326 (Fed. Cir. 2009)
`(citations omitted).
`In the instant case, Tsien describes a process of sequencing a nucleic
`acid in which labeled and blocked nucleotides are incorporated into a nucleic
`acid molecule by a polymerase. Ex. 1008, Abstract (“The method employs
`an unknown primed single stranded DNA sequence which is immobilized or
`entrapped within a chamber with a polymerase so that the sequentially
`formed cDNA can be monitored at each addition of a blocked nucleotide by
`measurement of the presence of an innocuous marker on specified
`deoxyribonucleotides.”). As claim 1 of the ’537 patent requires, Tsien
`discloses that each of its deoxyribonucleotides has a protecting group
`attached to the 3´ oxygen atom of the deoxyribose moiety, the protecting
`group being removable to expose a 3´ hydroxyl group:
`The blocking group present on the 3´-hydroxyl position of the
`added dNTP
`[deoxyribonucleotide
`triphosphate] prevents
`inadvertent multiple additions. . . .
`. . . .
`[A] deblocking solution is added . . . to remove the 3´
`hydroxyl labeled blocking group. This then generates an active
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`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 12:27–13:22.
`Tsien discloses the following regarding suitable protecting groups at
`the 3´ hydroxyl position:
`The criteria for the successful use of 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.
`As to the azido protecting group required by claim 1, as Petitioner
`points out (Pet. 34), Zavgorodny describes the chemical synthesis of a
`number of 3´ hydroxyl-substituted nucleosides, among them, an
`azidomethyl-substituted nucleoside. See Ex. 1004, 7594. Zavgorodny
`explains that its substituted nucleosides “are useful specifically blocked
`synthons . . . . Azidomethyl group is of special interest, since it can be
`removed under very specific and mild conditions, viz. with
`triphenylphosphine in aqueous pyridine at 20 °C.” Id. at 7595.
`In urging that claims 1–6 and 8 would have been obvious over the
`combination of Tsien and Zavgorodny, Petitioner pointed to Zavgorodny’s
`teaching that its azidomethyl moiety was a suitable protecting group for the
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`3´ hydroxyl position of nucleosides, precisely the position requiring
`protection in Tsien’s process, as well Zavgorodny’s disclosure that the
`azidomethyl group was cleavable from the nucleoside under specific and
`mild conditions, thus meeting another requirement of Tsien’s protecting
`group. Pet. 38–39.
`As Patent Owner points out, however, Tsien’s second set of criteria
`for removal of the 3´ hydroxyl protecting group includes “quantitative
`deblocking,” in addition to mild conditions. Ex. 1008, 20:34; PO Resp. 24.
`As Patent Owner contends (PO Resp. 30), the Petition does not point to any
`specific evidence explaining why an ordinary artisan would have expected
`Zavgorodny’s azidomethyl protecting group to meet that requirement (see
`Pet. 31–40), despite acknowledging the “quantitative deblocking”
`requirement of Tsien’s methods (id. at 37).
`As Patent Owner contends (PO Resp. 24), Petitioner’s expert, Dr.
`Branchaud, testified that quantitative deblocking would have been
`understood to mean essentially 100% removal of the protecting group:
`Q. And could you explain to me what does it mean
`that the use of a three prime blocking group must include
`criteria 2 that would be availability of mild conditions for rapid
`and quantitative deblocking? . . .
`A. Well, again, I think that’s an operational definition.
`It’s just saying that in order for the process to happen
`effectively or efficiently, that deblocking step has to be rapid
`and -- and efficient.
`Q.
`Is efficient analogous to quantitative?
`A. Not necessarily. I think it could be. Rapid means
`it goes fast. Quantitative means it goes in high, essentially
`hundred percent yield.
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`Ex. 2039, 97–98 (Branchaud Deposition, emphasis added). In contrast, as
`Patent Owner points out, Loubinoux discloses that removal of an
`azidomethyl protecting group from a phenolic hydroxyl using
`triphenylphosphine, followed by water in tetrahydrofuran at 25 °C, resulted
`in deprotected phenols “as pure products at a yield between 60 and 80%.”
`Ex. 1006, 5; PO Resp. 24.
`Patent Owner also advances evidence that an ordinary artisan would
`have expected an azidomethyl group to be removed from a simple aliphatic
`alcohol, such as that present at the 3´ hydroxyl of a deoxyribonucleotide, at a
`lower efficiency than that described in Loubinoux, because a phenol is a
`better leaving group. See PO Resp. 24–25 (citing Ex. 2026 (“Greene and
`Wuts”6), 248 (“Ethers are the most widely used protective groups for
`phenols, and in general, they are more easily cleaved than the analogous
`ethers of simple alcohols.”)). Petitioner acknowledges that Greene and Wuts
`“is widely recognized by those of skill in the art as the definitive guide to
`techniques for the formation and cleavage of protecting groups in organic
`synthesis.” Pet. 13.
`In sum, despite having acknowledged the quantitative deblocking
`requirement in Tsien (Pet. 37), the Petition did not provide a specific or
`credible explanation why an ordinary artisan would have expected
`Zavgorodny’s azidomethyl protecting group to meet Tsien’s quantitative
`
`
`6 THEODORA W. GREENE & PETER G.M. WUTS, PROTECTIVE GROUPS IN
`ORGANIC SYNTHESIS 246–92 (John Wiley & Sons, Inc., 3d ed. 1999) (Ex.
`2026).
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`deblocking requirement under conditions suitable for use in Tsien’s
`sequencing methods. As discussed above, moreover, the prior art suggests
`that an ordinary artisan would not have expected Zavgorodny’s azidomethyl
`group to be removed quantitatively, as Tsien requires. We, therefore, agree
`with Patent Owner that Petitioner has not shown that an ordinary artisan
`would have considered it obvious to use Zavgorodny’s azidomethyl
`protecting group in Tsien’s sequencing methods.
`Petitioner does not persuade us to the contrary. In particular, we find
`that Petitioner’s Reply exceeds the proper scope of a reply. As provided in
`37 C.F.R. § 42.23(b), a “reply may only respond to arguments raised in the
`corresponding opposition or patent owner response.” Thus, “a reply that
`raises a new issue or belatedly presents evidence will not be considered and
`may be returned. The Board will not attempt to sort proper from improper
`portions of the reply.” Office Patent Trial Practice Guide, 77 Fed. Reg.
`48,756, 48,767 (Aug. 14, 2012). One indication that a new issue has been
`raised in a reply is where a petitioner submits “new evidence necessary to
`make out a prima facie case” of unpatentability of an original claim. Id.
`As noted above, in urging obviousness based on Tsien and
`Zavgorodny, the Petition relies expressly on the fact that “Zavgorodny
`teaches the desired property [in Tsien] that the azidomethyl group ‘can be
`removed under very specific and mild conditions.’” Pet. 38–39 (quoting
`Ex. 1004, 7595 (Zavgorodny)). The Reply, presented with evidence that an
`ordinary artisan would not have considered Zavgorodny’s conditions
`suitably mild for Tsien’s sequencing purposes, offers a distinct new line of
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`reasoning—that an ordinary artisan would have considered it obvious to use
`deprotecting conditions other than those described in Zavgorodny:
`[Patent Owner]’s argument is based on the faulty
`assumption that a POSITA would be limited to the specific
`removal conditions discussed in Zavgorodny. . . . A POSITA
`would use ordinary creativity to modify the removal conditions
`suggested by Zavgorodny to meet the requirements of Ju and
`Tsien, if needed.
`
`Reply 4–5 (quotations removed, citations omitted, emphasis added). Thus,
`the Reply presents new issues by changing the unpatentability rationale from
`express reliance on Zavgorodny’s deprotecting conditions, to asserting that
`those conditions would have been obvious to modify, as well as presenting
`new evidence to support the new rationale and explain the modifications to
`Zavgorodny. See id. at 5–6 (citing Ex. 1031 (Branchaud Reply Decl.)).
`Moreover, despite having acknowledged the quantitative deblocking
`requirement in Tsien (Pet. 37), the Reply does not indicate where, in the
`Petition, Petitioner explained specifically why an ordinary artisan would
`have expected Zavgorodny’s azidomethyl moiety to meet Tsien’s
`quantitative deblocking requirement for the 3´ hydroxyl protecting group.
`On that issue, the Reply advances, instead, a number of arguments which
`were not presented previously, as well as Dr. Branchaud’s Reply
`Declaration. Reply 7–8 (citing Ex. 1031). In his Reply Declaration, Dr.
`Branchaud, in turn, expands on the assertions in the Reply by presenting a
`number of additional new arguments explaining why quantitative deblocking
`would have been expected, and cites a number of non-patent literature
`references which were not relied upon to support unpatentability in the
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`Petition. See Ex. 1031 ¶¶ 19–26. Because the Petition did not address
`Tsien’s quantitative deblocking requirement, and because the Reply proffers
`argument and evidence not presented previously on that issue, the Reply
`presents new issues, rather than merely rebutting the Patent Owner
`Response.
`In addition, in asserting that quantitative deblocking would have been
`expected using Zavgorodny’s conditions, the Reply relies extensively on in-
`depth explanations and supporting documentary evidence presented in Dr.
`Branchaud’s Reply Declaration. The Reply does not explain, however, the
`basis of its arguments with nearly the same degree of specificity as that
`presented in Dr. Branchaud’s Reply Declaration, nor does the Reply cite any
`of the exhibits advanced in Dr. Branchaud’s Declaration. See Reply 7–8.
`For example the Reply states that, “[f]or SBS, a POSITA would use a much
`higher concentration of cleavage reagent to drive the reaction rapidly to
`completion.” Id. at 8 (citing Ex 1031 ¶¶ 25–26). None of the extensive
`reasoning or analysis or evidence cited in paragraphs 25 and 26 of the
`Branchaud Reply Declaration appears in the Reply, however. Accordingly,
`the Reply also does not comply with 37 C.F.R. § 42.6(a)(3), which states
`that “[a]rguments must not be incorporated by reference from one document
`into another document.”
`Further, even if we were to overlook the procedural infirmities in
`Petitioner’s Reply arguments, we would not find them persuasive. Petitioner
`advances evidence that Loubinoux’s pure product yields of 60 to 80 percent
`(Ex. 1006, 5) would have been viewed as a “poor proxy for actual reaction
`efficiency” (Reply 7). The fact that pure product yields might be a poor
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`Patent 7,566,537 B2
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`indicator of actual reaction efficiency does not substitute, however, for
`evidence showing that an ordinary artisan would have expected
`Zavgorodny’s azidomethyl group to be removed quantitatively under
`conditions suitable for performing Tsien’s sequencing processes. Moreover,
`while Petitioner cites to Exhibits 1038 and 1041 as evidence that an ordinary
`artisan would have expected a quantitative yield using Zavgorodny’s
`deblocking conditions (Reply 8; Ex. 1031 ¶ 21; Resp. to Mot. Obs. 7),
`Petitioner does not explain why an ordinary artisan would have expected the
`deprotection conditions in those references to be suitable for use in the
`sequencing processes taught in Tsien, even if the concentration of cleavage
`reagent was increased significantly. As to the new patentability rationale
`advanced in the Reply, that an ordinary artisan would have used reagents
`different from those taught in Zavgorodny (Reply 5–6), Petitioner fails to
`explain with adequate specificity why an ordinary artisan would have
`considered TCEP (tris(2-carboxyethyl)-phosphine) an obviously equivalent
`removal reagent to that described in Zavgorodny. Moreover, the sole
`reference cited by Petitioner to show that TCEP would have been expected
`to provide the quantitative removal required by Tsien has a publication date
`after the August 23, 2002 effective filing date of the ’537 patent. Compare
`Ex. 10367 (cited in Ex. 1031 ¶ 18 (Branchaud Reply Decl.)), with Ex. 1001,
`front page (’537 patent). Lastly, as to Petitioner’s argument that an ordinary
`
`7 Anne-Marie Faucher et al., tris(2-Carboxyethyl)phosphine (TCEP) for the
`Reduction of Sulfoxides, Sulfonylchlorides, N-Oxides, and Azides, 33
`SYNTHETIC COMMUNICATIONS 3503–11 (2003).
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`IPR2013-00517
`Patent 7,566,537 B2
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`artisan would have been prompted to combine Tsien and Zavgorodny for
`reasons other than performing Tsien’s sequencing processes (Reply 8–9),
`Petitioner does not direct us to any specific non-sequencing-related
`teachings in those references that would have prompted the references’
`combination, nor does Petitioner explain, specifically, where that rationale
`for combining the references was advanced in the Petition.
`In sum, for the reasons discussed, we determine that Petitioner has not
`shown that a preponderance of the evidence supports a conclusion that an
`ordinary artisan would have considered it obvious to use Zavgorodny’s
`azidomethyl protecting group in the processes described in Tsien.
`Accordingly, we conclude that Petitioner has not established by a
`preponderance of the evidence that the processes recited in claims 1–6 and 8
`of the ’537 patent would have been obvious under § 103(a), over Tsien and
`Zavgorodny.
`
`C. Obviousness of Claims 1–6 and 8 over Ju and Zavgorodny
`
`Petitioner’s obviousness challenge based on Ju and Zavgorodny is
`very similar to the ground of unpatentability based on Tsien and
`Zavgorodny, discussed above. Petitioner cites Ju as describing nucleic acid
`sequencing methods in which the nucleic acid is labeled by incorporating
`into the nucleic acid molecule a labeled nucleotide having a removable 3´
`hydroxyl protecting group, substantially as required by claims 1–6 and 8.
`Pet. 18–23. As above, Petitioner cites Zavgorodny as evidence that an
`ordinary artisan would have considered it obvious to use an azidomethyl
`group as the 3´ hydroxyl protecting group in Ju’s process, noting in
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`Patent 7,566,537 B2
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`particular that the mild removal conditions described in Zavgorodny would
`have met one of Ju’s criteria for 3´ hydroxyl protecting groups. Id. at 24–26.
`Patent Owner responds to this ground of unpatentability with
`arguments similar to those discussed above. Specifically, Patent Owner
`contends that an ordinary artisan would have understood Ju’s sequencing
`methods to require nearly quantitative removal of the 3´ hydroxyl protecting
`group under conditions in which the template and complement were not
`denatured. PO Resp. 38, 40. In contrast, Patent Owner contends, an
`ordinary artisan would not have expected Zavgorodny’s method to remove
`azidomethyl groups to a degree sufficient for use in Ju’s methods. Id. at 39.
`Moreover, Patent Owner argues, Zavgorodny’s method would have been
`expected to denature the DNA being analyzed, because it uses pyridine. Id.
`at 40.
`
`We find that the preponderance of the evidence does not support a
`conclusion that an ordinary artisan would have considered it obvious to use
`Zavgorodny’s azidomethyl protecting group in Ju’s sequencing methods.
`Ju describes a process of labeling, and ultimately sequencing, a
`nucleic acid molecule, in which a polymerase is used to “incorporate a
`nucleotide analogue into the growing strand of DNA, wherein the
`incorporated nucleotide analogue terminates the polymerase reaction.”
`Ex. 1002, 4:31–35. As claim 1 of the ’537 patent requires, Ju discloses that
`its nucleotide analogues have “a unique label attached through a cleavable
`linker to the base or to an analogue of the base.” Id. at 4:39–41. As claim 1
`of the ’537 patent also requires, Ju further discloses that its nucleotide
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`IPR2013-00517
`Patent 7,566,537 B2
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`analogues have “a cleavable chemical group to cap an –OH group at a 3´-
`position of the deoxyribose.” Id. at 4:41–42.
`Regarding the cleavable chemical group capping the 3´ hydroxyl of its
`nucleotide analogues, Ju discloses that “[a]ny chemical group could be used
`as long as the group 1) is stable during the polymerase reaction, 2) does not
`interfere with the recognition of the nucleotide analogue by polymerase as a
`substrate, and 3) is cleavable,” as Petitioner contends. Id. at 10:4–7; Pet. 24.
`As Patent Owner argues (PO Resp. 38), however, and Petitioner
`acknowledges (Pet. 21), Ju also teaches that the “group capping the 3´–OH
`need[s] to be removed with high yield to allow the incorporation and
`detection of the next nucleotide.” Ex. 1002, 21:11–13 (emphasis added).
`Evidence of record supports Patent Owner’s assertions (PO Resp. 38–39)
`that an ordinary artisan would have understood Ju’s sequencing processes to
`require nearly quantitative removal of the 3´ hydroxyl group. As Patent
`Owner argues (id. at 38), Ju describes using its methods to perform 100
`sequencing cycles (Ex. 1002, 21:63
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