Case: 14-1547 Document: 61-2 Page: 1 Filed: 07/17/2015
`
`(2 of 36)
`
`NOTE: This disposition is nonprecedential.
`United States Court of Appeals
`for the Federal Circuit
`______________________
`
`TRUSTEES OF COLUMBIA UNIVERSITY IN THE
`CITY OF NEW YORK,
`Appellant
`
`v.
`
`ILLUMINA, INC.,
`Appellee
`______________________
`
`2014-1547
`______________________
`
`Appeal from the United States Patent and Trademark
`Office, Patent Trial and Appeal Board in No. IPR2012-
`00006.
`
`-----------------------------------------
`
`TRUSTEES OF COLUMBIA UNIVERSITY IN
`THE CITY OF NEW YORK,
`Appellant
`
`v.
`
`ILLUMINA, INC.,
`Appellee
`______________________
`
`2014-1548
`
`Illumina Ex. 1029
`IPR Petition - USP 10,435,742
`
`

`

`Case: 14-1547 Document: 61-2 Page: 2 Filed: 07/17/2015
`
`(3 of 36)
`
`2
`
`
`TRS. OF COLUMBIA UNIV. V. ILLUMINA, INC.
`
`
`
`______________________
`
`Appeal from the United States Patent and Trademark
`Office, Patent Trial and Appeal Board in No. IPR2012-
`00007.
`
`
`-----------------------------------------
`
`TRUSTEES OF COLUMBIA UNIVERSITY IN THE
`CITY OF NEW YORK,
`Appellant
`
` v.
`
`ILLUMINA, INC.,
`Appellee
`______________________
`
`2014-1550
`______________________
`
`Appeal from the United States Patent and Trademark
`Office, Patent Trial and Appeal Board in No. IPR2013-
`00011.
`
`______________________
`
`Decided: July 17, 2015
`______________________
`
`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, Cella, Harper & Scinto, New York,
`NY; JOHN P. WHITE, Cooper & Dunham, LLP, New York,
`NY.
`
`
`

`

`Case: 14-1547 Document: 61-2 Page: 3 Filed: 07/17/2015
`
`(4 of 36)
`
`TRS. OF COLUMBIA UNIV. V. ILLUMINA, INC.
`
`3
`
`EDWARD R. REINES, Weil, Gotshal & Manges LLP,
`Redwood Shores, CA, argued
`for appellee.
` Also
`represented by DEREK C. WALTER, MICHELE GAUGER,
`MARION MCLANE READ, Redwood Shores, CA; AUDREY
`LYNN MANESS, Houston, TX.
`
`______________________
`Before PROST, Chief Judge, SCHALL and WALLACH,
`Circuit Judges.
`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.
`
`

`

`Case: 14-1547 Document: 61-2 Page: 4 Filed: 07/17/2015
`
`(5 of 36)
`
`4
`
`
`TRS. OF COLUMBIA UNIV. V. ILLUMINA, INC.
`
`
`
`Each nucleotide within the DNA molecule consists of
`three distinct parts, including a sugar, a base, and one or
`more phosphate groups:
`
`Appellant’s Br. 4.1
`in naturally-occurring DNA,
`Four bases exist
`including adenine (“A”), guanine (“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 1’ (“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:
`
`
`1 All references to the briefs and Joint Appendix
`(“J.A.”) are to Appeal No. 2014-1547 unless otherwise
`indicated.
`
`

`

`Case: 14-1547 Document: 61-2 Page: 5 Filed: 07/17/2015
`
`(6 of 36)
`
`TRS. OF COLUMBIA UNIV. V. ILLUMINA, INC.
`
`5
`
`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
`
`

`

`Case: 14-1547 Document: 61-2 Page: 6 Filed: 07/17/2015
`
`(7 of 36)
`
`6
`
`
`TRS. OF COLUMBIA UNIV. V. ILLUMINA, INC.
`
`
`
`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 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 billions 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
`
`

`

`Case: 14-1547 Document: 61-2 Page: 7 Filed: 07/17/2015
`
`(8 of 36)
`
`TRS. OF COLUMBIA UNIV. V. ILLUMINA, INC.
`
`7
`
`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:
`
`
`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
`infringement of
`five DNA sequencing patents,
`for
`including the three at issue in these appeals. Illumina
`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 Dideoxynucleotides, 238 Science 336 (1987)
`(“Prober”); (3) Rabani et al., WO 96/27025 (Sept. 6, 1996)
`
`

`

`Case: 14-1547 Document: 61-2 Page: 8 Filed: 07/17/2015
`
`(9 of 36)
`
`8
`
`
`TRS. OF COLUMBIA UNIV. V. ILLUMINA, INC.
`
`
`
`(“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
`
`2 Section 103 has since been amended. See Leahy
`Smith America Invents Act, Pub. L. No. 112-29, § 3(c), 125
`
`

`

`Case: 14-1547 Document: 61-2 Page: 9 Filed: 07/17/2015
`
`(10 of 36)
`
`TRS. OF COLUMBIA UNIV. V. ILLUMINA, INC.
`
`9
`
`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 (1966).
`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
`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 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.
`
`
`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.
`
`

`

`Case: 14-1547 Document: 61-2 Page: 10 Filed: 07/17/2015
`
`(11 of 36)
`
`10
`
`
`TRS. OF COLUMBIA UNIV. V. ILLUMINA, INC.
`
`
`
`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
`
`

`

`Case: 14-1547 Document: 61-2 Page: 11 Filed: 07/17/2015
`
`(12 of 36)
`
`TRS. OF COLUMBIA UNIV. V. ILLUMINA, INC.
`
`11
`
`additional skill Columbia University proposed, the claims
`would have also been obvious to a PHOSITA with a
`higher level of knowledge and ability.
`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 (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
`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 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.
`that
`concedes
`Although Columbia University
`“[d]uring the 1990s [there was] some interest in base-
`labeled nucleotide analogues,” J.A. 5, it argues the most
`
`

`

`Case: 14-1547 Document: 61-2 Page: 12 Filed: 07/17/2015
`
`(13 of 36)
`
`12
`
`
`TRS. OF COLUMBIA UNIV. V. ILLUMINA, INC.
`
`
`
`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:
`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
`
`

`

`Case: 14-1547 Document: 61-2 Page: 13 Filed: 07/17/2015
`
`(14 of 36)
`
`TRS. OF COLUMBIA UNIV. V. ILLUMINA, INC.
`
`13
`
`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
`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:
`the
`One
`important
`functional property of
`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
`
`

`

`Case: 14-1547 Document: 61-2 Page: 14 Filed: 07/17/2015
`
`(15 of 36)
`
`14
`
`
`TRS. OF COLUMBIA UNIV. V. ILLUMINA, INC.
`
`
`
`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
`nucleotide 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].
`Dower col. 15 l. 52–col. 16 l. 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:
`
`
`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.
`
`

`

`Case: 14-1547 Document: 61-2 Page: 15 Filed: 07/17/2015
`
`(16 of 36)
`
`TRS. OF COLUMBIA UNIV. V. ILLUMINA, INC.
`
`15
`
`
`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 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. 3 l. 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
`C. Motivation to Combine
`As discussed above, the prior art discloses labels
`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
`
`its
`4 The PTAB
`found neither Stemple nor
`predecessor PCT application was anticipatory because
`neither disclosed a deaza-substituted base. See J.A. 76–
`77.
`
`

`

`Case: 14-1547 Document: 61-2 Page: 16 Filed: 07/17/2015
`
`(17 of 36)
`
`16
`
`
`TRS. OF COLUMBIA UNIV. V. ILLUMINA, INC.
`
`
`
`Helvetica Chimica Acta 1809 (1997) (J.A. 5257–59); F.
`Seela et al., Duplex Stability of Oligonucleotides
`Containing
`7-Substituted
`7-Deaza
`and
`8-Aza-
`7-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 (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 fact-
`finder 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.
`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
`
`5 Although this argument might appropriately have
`been raised in support of the secondary consideration of
`long-felt need, Columbia University did not assert long-
`felt need.
`
`

`

`Case: 14-1547 Document: 61-2 Page: 17 Filed: 07/17/2015
`
`(18 of 36)
`
`TRS. OF COLUMBIA UNIV. V. ILLUMINA, INC.
`
`17
`
`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
`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.
`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 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
`
`

`

`Case: 14-1547 Document: 61-2 Page: 18 Filed: 07/17/2015
`
`(19 of 36)
`
`18
`
`
`TRS. OF COLUMBIA UNIV. V. ILLUMINA, INC.
`
`
`
`the nucleic acid primer
`
`into
`incorporated
`extension strand.
`’698 patent col. 35 ll. 2–23 (emphases added).
`11. A plurality of nucleic acid
`templates
`immobilized 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 cleavable linker,
`wherein
`the nucleotide has a deoxyribose
`comprising a cleavable chemical group capping the
`3’ OH group, wherein the cleavable linker is
`cleaved by a means selected from the group
`consisting of one or more of a physical means, a
`chemical means, a physical chemical means, heat,
`and light, and wherein the cleavable chemical
`group capping the 3’ OH group is cleaved by a
`means selected from the group consisting of one or
`more of a physical means, a chemical means, a
`physical chemical means, heat, and light.
`’869 patent col. 33 ll. 40–50 (emphases added). In
`addition, claim 15 of the ’869 patent recites: “15. The
`nucleotide of claim 12, wherein
`the base
`is a
`deazapurine.” Id. col. 33 ll. 10–11 (emphasis added).
`
`

`

`Case: 14-1547 Document: 61-2 Page: 19 Filed: 07/17/2015
`
`(20 of 36)
`
`TRS. OF COLUMBIA UNIV. V. ILLUMINA, INC.
`
`19
`
`The only challenged independent claim of the ’575
`patent is claim 1, which recites:
`1. A method of determining the identity of a
`nucleotide analogue incorporated 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 small removable chemical moiety
`capping the 3’-OH group of the sugar of the
`nucleotide analogue, wherein said small cleavable
`chemical group does not
`interfere with the
`recognition of
`the nucleotide analogue by
`polymerase as a substrate; 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.
`’575 patent col. 33 ll. 30–45 (emphases added). In
`addition, claim 6 of the ’575 patent recites: “6. The method
`of claim 1, wherein said base of at least one of said
`nucleotide analogues is a deazapurine.” Id. col. 34 ll. 42–
`43 (emphasis added).
`Inter partes review of independent claims 1 and 11 of
`the ’698 patent was instituted on grounds of anticipation
`by Dower, and obviousness over Tsien, Prober, and Seela.
`Inter partes review of claim 12 of the ’869 patent was
`instituted on grounds of anticipation by Tsien and
`
`

`

`Case: 14-1547 Document: 61-2 Page: 20 Filed: 07/17/2015
`
`(21 of 36)
`
`20
`
`
`TRS. OF COLUMBIA UNIV. V. ILLUMINA, INC.
`
`
`
`Stemple, and claim 15 on grounds of obviousness over
`Tsien, Prober, Stemple, and Anazawa. Inter partes
`review of claim 1 of the ’575 patent was instituted on
`grounds of anticipation by Dower and Tsien, and of claim
`6 on grounds of obviousness over Tsien, Prober, and Seela.
`The PTAB evaluated the content of the prior art,
`finding Tsien disclosed an SBS method that used “a
`fluorescent tag attached to the base moiety,” and a
`removable 3’-OH blocking group. J.A. 10–11. The PTAB
`noted “Tsien does not disclose a deaza-substituted base,
`but references Prober I, which does.” J.A. 12.
`Columbia University argues Tsien’s citation to Prober
`does not render obvious its invention because “Tsien does
`not cite Prober for labeling purines,” but only for