Trustees of Columbia University in City of New York v...., 620 Fed.Appx. 916...
`
`[2] Board was entitled to weigh credibility of witnesses in
`light of their qualifications and evaluate their assertions
`accordingly;
`
`[3] substantial evidence supported finding by Board that
`person having ordinary skill in the art would have had
`reasonable expectation of success in achieving claimed
`invention, and thus patent was invalid for obviousness;
`
`[4] secondary considerations did not weigh strongly in
`favor of nonobviousness; and
`
`[5] patent claim on base-labeled, 3′–OH–capped
`nucleotide was anticipated.
`
`Affirmed.
`
`West Headnotes (7)
`
`620 Fed.Appx. 916
`This case was not selected for
`publication in West's Federal Reporter.
`See Fed. Rule of Appellate Procedure 32.1
`generally governing citation of judicial
`decisions issued on or after Jan. 1, 2007.
`See also U.S.Ct. of App. Fed. Cir. Rule 32.1.
`United States Court of Appeals,
`Federal Circuit.
`
`TRUSTEES OF COLUMBIA UNIVERSITY
`IN THE CITY OF NEW YORK, Appellant
`v.
`ILLUMINA, INC., Appellee.
`Trustees of Columbia University
`in the City of New York, Appellant
`v.
`Illumina, Inc., Appellee.
`Trustees of Columbia University
`in the City of New York, Appellant
`v.
`Illumina, Inc., Appellee.
`
`Nos. 2014–1547, 2014–1548, 2014–1550.
`|
`July 17, 2015.
`
`Synopsis
`Background: In inter partes reviews, the Patent and
`Trademark Office, Patent Trial and Appeal Board, 2014
`WL 1252940, 2014 WL 1252946, and 2014 WL 1252992,
`cancelled patents in part that were generally directed to
`determining nucleotide sequence of deoxyribonucleic acid
`(DNA). Patentee appealed.
`
`Holdings: The Court of Appeals, Wallach, Circuit Judge,
`held that:
`
`[1] claims in patents would have been obvious to person
`having ordinary skill in the art who had higher level of
`knowledge and ability, where those claims were obvious to
`such a person not necessarily possessing those additional
`skills;
`
`[2]
`
`[1]
`
`Patents
`Genes and genetic technology
`291 Patents
`291II Patentability and Validity
`291II(E) Obviousness; Lack of Invention
`291II(E)3 Particular Fields of Invention
`291k736 Biological Subject Matter;
` Biotechnology
`291k738 Genes and genetic technology
`Claims
`in patents
`that were generally
`directed to determining nucleotide sequence
`of deoxyribonucleic acid (DNA) would have
`been obvious to person having ordinary skill
`in the art who had higher level of knowledge
`and ability, where those claims were obvious
`to such a person not necessarily possessing
`those additional skills. 35 U.S.C.A. § 103(a).
`
`Cases that cite this headnote
`
`Patents
`Inter partes review
`291 Patents
`291IV Patent Applications and Proceedings
`291IV(G) Postissuance Proceedings
`291IV(G)5 Other Postissuance Proceedings
`291k1262 Inter partes review
`
` © 2016 Thomson Reuters. No claim to original U.S. Government Works.
`
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`Trustees of Columbia University in City of New York v...., 620 Fed.Appx. 916...
`
`Patent Trial and Appeal Board was entitled to
`weigh credibility of witnesses in light of their
`qualifications and evaluate their assertions
`accordingly, in inter partes review of patents
`that were generally directed to determining
`nucleotide sequence of deoxyribonucleic acid
`(DNA).
`
`in third party's sale of a patented invention
`was attributable to developments in the
`field that led to simultaneous invention or
`to copying, and evidence of unexpected
`results in comparison to technique that was
`not closest prior art was not probative of
`nonobviousness. 35 U.S.C.A. § 103.
`
`Cases that cite this headnote
`
`Cases that cite this headnote
`
`[3]
`
`[4]
`
`Patents
`Inter partes review
`291 Patents
`291IV Patent Applications and Proceedings
`291IV(G) Postissuance Proceedings
`291IV(G)5 Other Postissuance Proceedings
`291k1262 Inter partes review
`Substantial evidence supported finding by
`Patent Trial and Appeal Board in inter
`partes review that person having ordinary
`skill in the art would have had reasonable
`expectation of success in achieving claimed
`invention, and thus patent that was generally
`directed to determining nucleotide sequence
`of deoxyribonucleic acid (DNA) was invalid
`for obviousness, through prior art disclosure
`of base
`labeling, cleavable
`linkers, and
`deazapurine, taken together. 35 U.S.C.A. §
`103(a).
`
`Cases that cite this headnote
`
`Patents
`Genes and genetic technology
`291 Patents
`291II Patentability and Validity
`291II(E) Obviousness; Lack of Invention
`291II(E)3 Particular Fields of Invention
`291k736 Biological Subject Matter;
` Biotechnology
`291k738 Genes and genetic technology
`Secondary considerations did not weigh
`strongly in favor of nonobviousness of patent
`that was generally directed to determining
`nucleotide sequence of deoxyribonucleic acid
`(DNA), since each
`feature claimed
`to
`be responsible for commercial success of
`invention was disclosed in single prior art
`reference, it was unclear whether any success
`
`[5]
`
`[6]
`
`[7]
`
`Patents
`Genes and genetic technology
`291 Patents
`291II Patentability and Validity
`291II(C) Novelty; Anticipation
`291II(C)2 Particular Fields of Invention
`291k516 Biological Subject Matter;
` Biotechnology
`291k518 Genes and genetic technology
`Embodiment comprising 3′–OH–capped
`nucleotide, base-label, and cleavable linker
`could be envisaged clearly by one of ordinary
`skill in the art upon reading prior art
`disclosure of reversible chain-terminating
`nucleotide and label attached to base via
`cleavable tether, and therefore patent claim on
`base-labeled, 3′–OH–capped nucleotide was
`anticipated. 35 U.S.C.A. § 102.
`
`Cases that cite this headnote
`
`Patents
`In general; utility
`291 Patents
`291X Patents Enumerated
`291k2091 In general; utility
`US Patent 4,804,748, US Patent 5,547,839, US
`Patent 7,270,951. Cited as Prior Art.
`
`Cases that cite this headnote
`
`Patents
`In general; utility
`291 Patents
`291X Patents Enumerated
`291k2091 In general; utility
`US Patent 7,713,698, US Patent 7,790,869, US
`Patent 8,088,575. Cancelled in Part.
`
` © 2016 Thomson Reuters. No claim to original U.S. Government Works.
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`
`Cases that cite this headnote
`
`*917 Appeal from the United States Patent and
`Trademark Office, Patent Trial and Appeal Board in Nos.
`IPR2012–00006, IPR2012–00007, IPR2013–00011.
`
`Attorneys and Law Firms
`
`Paul Reinherz Wolfson, Wilmer Cutler Pickering Hale
`and Dorr LLP, Washington, DC, argued for appellant.
`Also represented by Matthew Guarnieri; Donald J. Curry,
`Robert Seth Schwartz, Anthony M. Zupcic, Fitzpatrick,
`Celia, Harper & Scinto, New York, NY; John P. White,
`Cooper & Dunham, LLP, New York, NY.
`
`Edward R. Reines, Weil, Gotshal & Manges LLP,
`Redwood Shores, CA, argued for appellee. Also
`represented by Derek C. Walter, Michele Gauger, *918
`Marion McLane Read, Redwood Shores, CA; Audrey
`Lynn Maness, Houston, TX.
`
`Before PROST, Chief Judge, SCHALL and WALLACH,
`Circuit Judges.
`
`Opinion
`
`WALLACH, Circuit Judge.
`
`This opinion addresses companion appeals from the inter
`partes reviews of three patents before the Patent Trial
`and Appeal Board (“PTAB”) of the United States Patent
`
`and Trademark Office, with Illumina, Inc. (“Illumina”),
`as petitioner and the Trustees of Columbia University
`in the City of New York (“Columbia University”) as
`patent owner. The patents are generally directed to
`sequencing (i.e., determining the nucleotide sequence
`of) deoxyribonucleic acid (“DNA”), and include U.S.
`Patent Nos. 7,713,698 (the “′698 patent”) (Appeal No.
`2014–1547), 8,088,575 (the “′575 patent”) (Appeal No.
`2014–1548), and 7,790,869 (the “′869 patent”) (Appeal
`No. 2014–1550). The PTAB found all challenged claims
`anticipated or obvious over the prior art. For the reasons
`set forth below, this court affirms.
`
`BACKGROUND
`
`I. The Science of DNA as It Relates to These Appeals
`
`DNA is a double-stranded molecule that encodes the
`genetic information of living organisms. Each strand
`consists of a series of chemical structures called
`nucleotides, the particular order of which determines
`the heritable characteristics of living organisms. DNA
`sequencing is useful in a variety of fields, especially
`medicine, where it can help researchers uncover the genetic
`bases of diseases and in turn design targeted therapies.
`
`Each nucleotide within the DNA molecule consists of
`three distinct parts, including a sugar, a base, and one or
`more phosphate groups:
`
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`Appellant's Br. 4. 1
`1
`All references to the briefs and Joint Appendix
`(“J.A.”) are to Appeal No. 2014–1547 unless
`otherwise indicated.
`
`Four bases exist in naturally-occurring DNA, including
`adenine (“A”), guanine *919 (“G”), cytosine (“C”), or
`thymine (“T”). A and G are known as “purines,” while C
`and T are known as “pyrimidines.” The sugar component
`of each nucleotide is comprised of five carbon atoms,
`
`conventionally numbered V (“one prime”) through 5′
`(“five prime”) and represented by the vertices of the
`pentagonal sugar structure, as illustrated. Nucleotides
`not incorporated into a DNA strand contain a hydroxyl
`group (oxygen bonded to hydrogen, or “OH”) at the
`3′ position (“3′–OH group”). When nucleotides join
`together to form DNA, a single oxygen atom (“O”)
`links the phosphate group with the sugar at the 3′–OH
`position:
`
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`Appellant's Br. 4.
`In living organisms, DNA exists as a double-stranded
`helical structure held together by hydrogen bonds between
`“complementary” base pairs. A and T are complementary,
`and thus pair with each other, and G and C are
`complementary, and thus pair with each other. During
`DNA replication (such as during sequencing), the two
`strands are separated and a short chain of nucleotides
`known as a “primer” binds to a portion of the single-
`stranded DNA where copying will begin. Polymerase, an
`enzyme, causes the primer to be extended in a manner
`complementary to the chain being copied (i.e., matching
`A to T, and G to C). Important to the present matter,
`the phosphate group of each new nucleotide added to the
`lengthening DNA strand bonds to the 3′–OH group of
`the last nucleotide already in the strand.
`
`In the 1970s, British biochemist Frederick Sanger and
`Alan Coulson
`invented a sequencing method that
`relies on modified nucleotides called dideoxynucleotides
`(“ddNTPs”), which have a hydrogen atom (“H”) rather
`than OH at the 3′ position. See Frederick Sanger et
`al., DNA Sequencing with Chain–Termination Inhibitors,
`74 Proc. Nat'l Acad. Scis. 5463 (1977). In the original
`version of Sanger sequencing, the DNA template molecule
`is mixed with polymerase, a primer, isolated nucleotides
`(“dNTPs”), and a small amount of *920 ddNTPs. When
`a ddNTP is randomly incorporated into the nucleotide
`chain, elongation of the new strand cannot continue
`because there is no 3′–OH group to which the next
`nucleotide would otherwise bond. This chain termination
`cannot be reversed, and the result is an array of fragments
`of different lengths, each containing a single ddNTP.
`
`Each ddNTP, and therefore each fragment, contains a
`radioactive label (or, in subsequently developed versions
`of Sanger sequencing, a fluorescent label) that can be
`detected. After the fragments are sorted by size using a
`process called electrophoresis, the length information can
`be combined with the label information to determine the
`sequence of the DNA. One challenge of Sanger sequencing
`is ensuring the fluorescent labels remain attached to the
`base. It was discovered that increased stability can be
`achieved if the label is attached to a carbon atom at the 7′
`position of a purine base (A or G) rather than to a nitrogen
`atom, which normally occupies the 7′ position. Purines
`in which the nitrogen atom at the 7′ position has been
`replaced by a carbon atom are known as “deazapurines.”
`
`Due to the electrophoresis step, Sanger sequencing was
`too slow to efficiently sequence entire genomes, which
`may contain bilhons of nucleotides. A new type of process
`called sequencing by synthesis (“SBS”) avoided the need
`for electrophoresis by placing removable, label-bearing
`“caps” at the 3′–OH group, which would block synthesis
`long enough to detect the label (and thereby identify the
`nucleotide) but would then be removed to allow synthesis
`to continue. Unfortunately, this type of SBS worked
`poorly because the “caps” were located near the “active
`site” of the polymerase and thereby interfered with its
`operation.
`
`According to Columbia University, Dr. Jingyue Ju and
`his colleagues avoided the problem caused by the bulky
`caps by placing an unlabeled removable cap on the 3′–
`OH group and attaching the label instead to a cleavable
`linker attached to the deazapurine base:
`
` © 2016 Thomson Reuters. No claim to original U.S. Government Works.
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`
`Appellant's Br. 10. Dr. Ju's method is the subject of
`the three patents at issue in this suit, each of which is
`titled “Massive Parallel Method for Decoding DNA and
`RNA.”
`
`II. Procedural Background
`
`In March 2012, Columbia University sued Illumina for
`infringement of five DNA sequencing patents, including
`the three at issue in these appeals. Illumina *921
`petitioned for inter partes review of the ′698, ′869, and
`′575 patents in September and October 2012. The PTAB
`found most of the challenged claims of the three patents
`obvious over one or more of the following prior art
`references: (1) Roger Tsien et al., WO 91/06678 (May
`16, 1991) (“Tsien”); (2) James Prober et al., A System
`for Rapid DNA Sequencing with Fluorescent Chain–
`Terminating Dideoxynucleo tide s, 238 Science 336 (1987)
`(“Prober”); (3) Rabani et al., WO 96/27025 (Sept. 6,
`1996) (“Rabani”) (J.A. 3095–3154); (4) U.S. Patent No.
`4,804,748 (issued Feb. 14, 1989) (“Seela”) (J.A. 3155–
`58); (5) U.S. Patent No. 5,547,839 (issued Aug. 20, 1996)
`(“Dower”); (6) U.S. Patent No. 7,270,951 B1 (issued Sept.
`18, 2007) (“Stemple”); (7) Takeshi Anazawa et al., WO
`98/33939 (Aug. 6, 1998) (“Anazawa”). In addition, the
`PTAB found a number of claims anticipated by Tsien,
`Stemple, or Dower. Columbia University timely appealed.
`This court has jurisdiction under 28 U.S.C. § 1295(a)(4)
`(A) (2012) and 35 U.S.C. § 141(c) (2012).
`
`DISCUSSION
`
`I. Standards of Review and the
`Legal Standard for Obviousness
`
`This court reviews the PTAB's factual findings for
`substantial evidence and
`its
`legal conclusions de
`novo. Rambus Inc. v. Rea, 731 F.3d 1248, 1251–52
`(Fed.Cir.2013). “A finding is supported by substantial
`evidence if a reasonable mind might accept the evidence
`to support the finding.” K/S Himpp v. Hear–Wear Techs.,
`LLC, 751 F.3d 1362, 1364 (Fed.Cir.2014). “Substantial
`evidence is more than a mere scintilla. It means such
`relevant evidence as a reasonable mind might accept as
`adequate to support a conclusion.” In re Gartside, 203
`F.3d 1305, 1312 (Fed.Cir.2000) (internal quotation marks
`and citation omitted).
`
`A patent is invalid for obviousness “if the differences
`between the subject matter sought to be patented and the
`prior art are such that the subject matter as a whole would
`have been obvious at the time the invention was made to
`a person having ordinary skill in the art [ (“PHOSITA”) ]
`to which said subject matter pertains.” 35 U.S.C. § 103(a)
`(2006). 2 Whether an invention would have been obvious
`at the time it was made is a question of law, which
`this court reviews de novo, based on underlying facts.
`Gartside, 203 F.3d at 1316. Underlying factual inquiries
`include: (1) “the scope and content of the prior art”; (2)
`“differences between the prior art and the claims at issue”;
`(3) “the level of ordinary skill in the pertinent art”; and (4)
`“secondary considerations [such] as commercial success,
`long felt but unsolved needs, [and] failure of others.”
`Graham v. John Deere Co., 383 U.S. 1, 17, 86 S.Ct. 684, 15
`L.Ed.2d 545 (1966).
`
`2
`
`Section 103 has since been amended. See Leahy Smith
`America Invents Act, Pub. L. No. 112–29, § 3(c), 125
`Stat. 284, 287–88 (2011) ( “AIA”). However, because
`the applications that led to the ′698, ′869, and ′575
`patents were filed before March 16, 2013, the pre-AIA
`§ 103(a) applies. See AIA, 125 Stat. at 293.
`
`II. Certain Challenged Claims Were
`Obvious at the Time of Invention
`
`A. The PTAB's Failure to Resolve the
`Dispute Regarding the PHOSITA's
`Qualifications Was Not Error
`
`[1]
` Columbia University asserts the PTAB erred in
`“fail[ing] to resolve the parties' dispute regarding the
`qualifications of the [PHOSITA].” Appellant's Br. 36. It
`argues its expert, Dr. Trainor, possessed the qualifications
`of a PHOSITA while Illumina's expert, Dr. Weinstock,
`did *922 not. According to Columbia University, a
`PHOSITA would be skilled in “both biology and synthetic
`nucleotide chemistry” and hold “a graduate degree in
`chemistry or chemical biology or a related discipline.”
`Id. (internal quotation marks and citation omitted).
`Columbia University asserts that because Dr. Weinstock
`had not worked in the area of nucleotide synthesis, he was
`unqualified to opine on matters of synthetic nucleotide
`chemistry.
`
` © 2016 Thomson Reuters. No claim to original U.S. Government Works.
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`Trustees of Columbia University in City of New York v...., 620 Fed.Appx. 916...
`
`This court has explained that the failure to make explicit
`findings regarding the level of skill in the art does not
`necessarily constitute reversible error:
`
`While it is always preferable for the factfinder below
`to specify the level of skill it has found to apply to the
`invention at issue, the absence of specific findings on the
`level of skill in the art does not give rise to reversible
`error “where the prior art itself reflects an appropriate
`level and a need for testimony is not shown.”
`
`Okajima v. Bourdeau, 261 F.3d 1350, 1355 (Fed.Cir.2001)
`(quoting Litton Indus. Prods., Inc. v. Solid State Sys.
`Corp., 755 F.2d 158, 163 (Fed.Cir.1985)). However, where
`the fact finder has failed to make a finding or has made
`an incorrect finding with respect to the level of ordinary
`skill in the art in a manner that impacts the ultimate
`conclusion of obviousness, the failure or incorrect finding
`could constitute reversible error. Custom Accessories,
`Inc. v. Jeffrey–Allan Indus., Inc., 807 F.2d 955, 963
`(Fed.Cir.1986).
`
`Here, Illumina's expert Dr. Weinstock asserted the
`PHOSITA need only have been skilled in molecular
`biology or associated sciences, but made no mention
`of chemistry. Columbia University proposes the level of
`ordinary skill should have additionally included skill in
`chemistry. See Appellant's Br. 36. That is, Columbia
`University argues the PTAB should have explicitly stated
`a PHOSITA would have possessed a higher level of skill
`than that advocated by Illumina. In general, the higher
`the PHOSITA's skill level, the more likely the PHOSITA
`would find an invention obvious. Kinetic Concepts, Inc. v.
`Smith & Nephew, Inc., 688 F.3d 1342, 1366 (Fed.Cir.2012)
`(“[I]t is generally easier to establish obviousness under a
`higher level of ordinary skill in the art.”). Because the
`PTAB found the claims would have been obvious to a
`PHOSITA not necessarily possessing the additional skill
`Columbia University proposed, the claims would have
`also been obvious to a PHOSITA with a higher level of
`knowledge and ability.
`
`[2]
` With respect to Columbia University's argument that
`Dr. Weinstock was “unqualified to opine on matters
`of synthetic nucleotide chemistry,” Appellant's Br. 36,
`the PTAB found Dr. Weinstock had “experience in
`DNA sequencing” and was “qualif[ied] to testify on the
`issues discussed in his declaration,” J.A. 3. The PTAB
`was entitled to weigh the credibility of the witnesses in
`light of their qualifications and evaluate their assertions
`
`accordingly. See Inwood Labs., Inc. v. Ives Labs., Inc.,
`456 U.S. 844, 856, 102 S.Ct. 2182, 72 L.Ed.2d 606 (1982)
`(“Determining the weight and credibility of the evidence
`is the special province of the trier of fact.”); Anchor
`Sav. Bank, FSB v. United States, 597 F.3d 1356, 1367
`(Fed.Cir.2010).
`
`B. Prior Art Disclosure of Base Labeling,
`Cleavable Linkers, and Deazapurine
`
`[3]
` All of the claims at issue in case number 14–1547
`involve modified nucleotides that contain: (1) a labeled
`base; (2) a removable 3′–OH cap; and (3) a deaza-
`substituted base. Columbia University first asserts it
`would not have been obvious at the time of invention to
`use “a *923 reversible chain-terminating nucleotide with
`a label attached to the base, rather than to the cap on the
`3′–OH group of the sugar.” Appellant's Br. 37. Second, it
`asserts using “a cleavable linker (as required by claim 15
`[of the ′698 patent] ) would not have been obvious.” Id.
`at 41. The PTAB made factual findings related to these
`arguments, which address the state of the art prior to
`October 2000, i.e., the date U.S. Patent Application No.
`09/684,670 was filed, to which each of the three patents-
`in-suit claims priority.
`
`Although Columbia University concedes that “[d]uring
`the 1990s [there was] some interest in baselabeled
`nucleotide analogues,” J.A. 5, it argues the most relevant
`reference, Tsien, contains a “marked preference” for
`labeling the 3′–OH caps as opposed to the base,
`Appellant's Br. 37–38. Illumina responds that “a labeled
`base and 3′–OH cap were preferred by the late 1990s.”
`Appellee's Br. 5 (capitalization omitted).
`
`The PTAB addressed this factual issue, concluding
`“Columbia's characterization of the prior art as having
`‘some interest in base-labeled nucleotide analogues'
`understates the interest level shown in the prior art.” J.A.
`5. This finding was supported by substantial evidence, as
`is apparent from an examination of the prior art references
`considered by the PTAB. Tsien, for example, which bears
`an international publication date of 1991, noted the
`label could be attached to the base, and cautioned its
`nomenclature should not be read to “imply that this is
`the sole place where labeling can occur.” J.A. 3011. Tsien
`described base labeling in some detail:
`
` © 2016 Thomson Reuters. No claim to original U.S. Government Works.
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`
`While the above-described approaches to labeling
`focus on incorporating the label into the 3′–hydroxyl
`blocking group, there are a number of alternatives
`—particularly the formation of a 3′–blocked dNTP
`analogue containing a label such as a fluorescent group
`coupled to a remote position such as the base....
`
`One method involves the use of a fluorescent tag
`attached to the base moiety. The tag may be chemically
`cleaved (either separately from or simultaneously with
`the deblocking step).... This method is included because
`a number of base moiety derivatized dNTP analogues
`have been reported to exhibit enzymatic competence....
`
`In another type of remote labeling the fluorescent
`moiety or other innocuous label can be attached to the
`dNTP through a spacer or tether. The tether can be
`cleavable if desired.... There are several cleavable tethers
`that permit removing the fluorescent group before the
`next successive nucleotide is added.... Long tethers may
`be used.... Typical tethers are from about 2 to about
`20 ... atoms in length.
`
`J.A. 3028–30 (emphases added). Tsien thus discloses
`a reversible chain-terminating nucleotide and a label
`attached to the base via a cleavable tether.
`
`Columbia University argues that although Tsien describes
`both (1) cleavable tethers and (2) cleavable labels attached
`to the base, it does not explicitly disclose the combination
`of these two elements (i.e., a label attached to the base
`via a cleavable tether). See J.A. 3029 (Tsien) (describing
`a “fluorescent tag attached to the base moiety” and
`noting “[t]he tag may be chemically cleaved”). Although
`Tsien does not expressly disclose a cleavable tether
`attached to the base, the excerpted portions above, which
`describe both base labeling and the use of cleavable
`tethers, are derived from two adjacent paragraphs of
`Tsien, supporting the PTAB's finding that “[a PHOSITA]
`reading Tsien would have recognized that its teaching of a
`cleavable tether to release the label would have been *924
`useful when the label is attached to the base.” J.A. 15; see
`also J.A. 3029 (“Long tethers may be used so that the large
`
`fluorescent groups are spaced sufficiently far away from
`the base and triphosphate moieties....”).
`
`The PTAB also cited Dower and Stemple as reflecting
`“recognition within the prior art that such nucleotides [i.e.,
`those that are base-labeled and contain removable 3′–OH
`moieties] were useful and effective in SBS methods.” J.A.
`6. Dower states:
`
`One important functional property of the monomers is
`that the label be removable.... The label position may be
`anywhere on the molecule compatible with appropriate
`polymerization.... Nucleotide analogs used as chain-
`terminating reagents will typically have both a labeling
`moiety and a blocking agent while remaining compatible
`with the elongation enzymology. As the blocking agent
`will usually be on the 3′ hydroxyl position of the
`sugar on a nucleotide, it would be most convenient to
`incorporate the label and the blocking agent at the same
`site providing for a single reaction for simultaneous
`removal of the label and blocking agent. However, it is
`also possible to put a label on another portion of the nucleo
`tide analog than the 3′ hydroxyl position of the sugar,
`thereby requiring a two-step reaction cycle for removing
`the blocking and labeling groups....
`
`There are several suitable labeled, terminator structures
`as follows: ... (b) The fluorophore is placed in a position
`other than the 3′OH of the nucleoside, [ 3 ] and a
`different group placed on the 3′OH of the dNTPs to
`function as the chain terminator. The fluorphore and
`the 3′ blocking group are removed [in a single step or
`separate steps].
`
`3
`
`“A ‘nucleoside,’ unlike a nucleotide, contains only
`a sugar and a base. Nucleotides can be equivalently
`referred to as nucleosides with added phosphate
`groups (hence, ‘deoxyribonucleoside triphosphate’).”
`Appellant's Br. 3 n. 1.
`
`Dower col. 15 l.52–col. 16 ll.6; col. 25 ll.23–37 (emphases
`added). Figure 1B of Stemple illustrates a fluorochrome
`attached to the base via a photolabile (i.e., cleavable by
`light) linker:
`
` © 2016 Thomson Reuters. No claim to original U.S. Government Works.
`
`8
`
`HYDRITE EXHIBIT 1026
`Hydrite v. Solenis
`Trial IPR2015-1592
`(8 of 16)
`
`

`

`Trustees of Columbia University in City of New York v...., 620 Fed.Appx. 916...
`
`Stemple, fig. 1B. Stemple explains: “Panel B depicts an
`alternative configuration in which the fluorochrome is
`attached to the base of the nucleotide by way of a
`photolabile *925 linker. The 3′–OH is blocked by a
`separate photolabile group....” Id. col. 10 ll. 44–47. This
`arrangement is described by Stemple as a “preferred
`embodiment.” Id. col. 31. 31. These disclosures constitute
`substantial evidence supporting the PTAB's findings that
`the prior art disclosed “nucleotides with a label on the
`nucleotide base with a removable 3′–OH group,” J.A. 6,
`and “a cleavable tether to release the label” from the base
`moiety, J.A. 15. 4
`4
`The PTAB found neither Stemple nor its predecessor
`PCT application was anticipatory because neither
`disclosed a deaza-substituted base. See J.A. 76–77.
`
`C. Motivation to Combine
`
`labels
`As discussed above, the prior art discloses
`attached to the base, cleavable tethers, and reversibly
`capped 3′–OH groups. There does not appear
`to be any dispute
`that
`the prior art discloses
`deazapurines. See, e.g., Natalya Ramzaeva et al., 7–
`Deazaguanine DNA, 80 Helvetica Chimica Acta 1809
`(1997) (J.A. 5257–59); F. Seela et al., Duplex Stability
`of Oligonucleotides Containing 7–Substituted 7–Deaza
`and 8–Aza7–Deazapurine Nucleosides, 16 Nucleosides
`& Nucleotides 963 (1997) (J.A. 5271–72). Columbia
`University argues, however, that “the [PTAB] erred in
`
`concluding that a skilled artisan would have combined the
`prior art to achieve Dr. Ju's invention.” Appellant's Br. 34
`(emphasis added) (capitalization omitted).
`
`The obviousness of an invention is not established
`“merely by demonstrating that each of its elements was,
`independently, known in the prior art.” KSR Int'l Co.
`v. Teleflex Inc., 550 U.S. 398, 418, 127 S.Ct. 1727,
`167 L.Ed.2d 705 (2007). In addition, the court must
`determine “whether there was an apparent reason to
`combine the known elements in the fashion claimed by
`the patent at issue.” Id.; see also Star Scientific, Inc.
`v. R.J. Reynolds Tobacco Co., 655 F.3d 1364, 1374–75
`(Fed.Cir.2011) (“[E]ven when all claim limitations are
`found in prior art references, the factfinder must not only
`determine what the prior art teaches, but whether prior
`art teaches away from the claimed invention and whether
`there is a motivation to combine teachings from separate
`references.”). “[T]he 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.” KSR, 550 U.S. at 418, 127 S.Ct.
`1727.
`
`Columbia University asserts that if “Tsien disclosed such
`nucleotides in 1991,” then it is difficult to explain the
`“decade-long SBS research efforts that followed.” 5 Reply
`Br. 29; see also Appellant's Br. 61. However, Illumina
`points out that Dr. Ju's invention “was not reduced to
`practice until six years later using important changes not
`
` © 2016 Thomson Reuters. No claim to original U.S. Government Works.
`
`9
`
`HYDRITE EXHIBIT 1026
`Hydrite v. Solenis
`Trial IPR2015-1592
`(9 of 16)
`
`

`

`Trustees of Columbia University in City of New York v...., 620 Fed.Appx. 916...
`
`disclosed in the patents at issue.” Appellee's Br. 53; see
`also J.A. 4130–31. Although the record does not provide a
`conclusive explanation for either of these long lags, some
`testimony suggests large capital investments may provide
`a partial answer. See J.A. 3581. With these principles and
`considerations in mind, the language of the claims of each
`patent at issue will be considered.
`
`5
`
`Although this argument might appropriately have
`been raised in support of the secondary consideration
`of long-felt need, Columbia University did not assert
`longfelt need.
`
`Claims 1 and 11 are the only independent claims of the
`′698 patent reviewed by the PTAB, and recite:
`
`1. A method of determining the identity of a nucleotide
`analogue incorporated *926 into a nucleic acid primer
`extension strand, comprising:
`
`a) contacting a nucleic acid template attached to a solid
`surface with a nucleic acid primer which hybridizes to
`the template;
`
`b) simultaneously contacting the product of step a)
`with a polymerase and four nucleotide analogues which
`are either (i) aA, aC, aG, and aT, or (ii) aA, aC, aG,
`and aU, so as to incorporate one of the nucleotide
`analogues onto the nucleic acid primer and form a
`nucleic acid primer extension strand, wherein each
`nucleotide analogue within (i) or (ii) comprises a base
`labeled with a unique label and contains a removable
`chemical moiety capping the 3′–OH group of the sugar
`of the nucleotide analogue, and wherein at least one of
`the four nucleotide analogues within (i) or (ii) is deaza-
`substituted; and
`
`c) detecting the unique label of the incorporated
`nucleotide analogue, so as to thereby determine the
`identity of the nucleotide analogue incorporated into
`the nucleic acid primer extension strand.
`
`′698 patent col. 35 ll. 2–23 (emphases added).
`
`11. A plurality of nucleic acid
`templates immobihzed on a solid
`surface, wherein a nucleic acid
`primer is hybridized to such nucleic
`acid templates each such nucleic
`acid primer comprising a labeled
`incorporated nucleotide analogue,
`at least one of which is deaza-
`
`substituted, wherein each labeled
`nucleotide analogue comprises a
`base labeled with a unique label
`and contains a removable chemical
`moiety capping the 3′–OH group of
`the sugar of the nucleotide analogue.
`
`Id. col. 36 ll. 24–31 (emphases added).
`
`The only challenged independent claim of the ′869 patent
`is claim 12, which recites:
`
`12. A nucleotide having a base that
`is attached to a detectable label
`through a cl