Court Opinion

ID: 2818127
Source: CourtListenerOpinion
Date Created: 2015-07-17 15:05:01.331999+00
Date Added: 2024-06-11T11:30:47.155243
License: Public Domain

NOTE: This disposition is nonprecedential.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
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.
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.
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
     Four bases exist in naturally-occurring DNA,
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.
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
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
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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
for infringement of five DNA sequencing patents,
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)
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
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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.
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
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.
    Although Columbia University concedes that
“[d]uring the 1990s [there was] some interest in base-
labeled nucleotide analogues,” J.A. 5, it argues the most
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
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    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:
    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
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.
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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

    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.
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.
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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
18                   TRS. OF COLUMBIA UNIV. V. ILLUMINA, INC.

     incorporated into    the   nucleic   acid   primer
     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).
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
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 labeling
pyrimidines.      Appellant’s Br. 43.      However, Tsien
explicitly invites the PHOSITA to consider Prober in a
paragraph discussing both purines and pyrimidines.
Although Tsien asserts “[t]he C-8 position of the purine
structure presents an ideal position for the attachment of
a label,” J.A. 3030, it also states:
     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. This dNTP can be
     incorporated and the fluorescence measured and
     removed according to the methods described
     below. . . . One method involves the use of a
     fluorescent tag attached to the base moiety. The
     tag may be chemically cleaved. . . . This method is
     included because a number of base moiety
     derivatized dNTP analogues have been reported
     to exhibit enzymatic competence. . . . Prober et al.
     (1987) show enzymatic incorporation of fluorescent
TRS. OF COLUMBIA UNIV. V. ILLUMINA, INC.                  21

    ddNTPs    by       reverse     transcriptase    and
    Sequenase .
             TM

J.A. 3028–29 (emphases added). Tsien thus invites use of
the “method[] described [in Prober]” in combination with a
“3’-blocked dNTP analogue” and a fluorescent label
“coupled to a remote position such as the base.” Id.
Prober’s method includes the use of a fluorescent dye
“attached . . . to the 7 position in the 7-deazapurines” and
explains “the 7-deazapurines were used to facilitate stable
linker attachment at that site.” J.A. 3063.
    A PHOSITA may find reason to combine references to
achieve a claimed invention even absent an explicit
mention in one reference of the other. See KSR, 550 U.S.
at 417 (“[I]f a technique has been used to improve one
device, and a person of ordinary skill in the art would
recognize that it would improve similar devices in the
same way, using the technique is obvious unless its actual
application is beyond his or her skill.”). Here, the express
invitation to incorporate a 3’-blocked dNTP having a
fluorescent base label using the method disclosed in
Prober provides a motivation to combine Tsien with the
7-deazapurine of Prober.
    Seela, issued in 1989, also helps to provide a
motivation by teaching, according to the PTAB, that
deazapurine nucleotides “can advantageously be used . . .
in polymerase-based sequencing methods,” such as SBS.
J.A. 80. In addition, Dr. Weinstock testified that a
PHOSITA would be motivated to use the 7-deazapurines
of Prober “to improve similar Tsien systems and
methods.” J.A. 3181. When asked whether “[t]he use of
ddNTP that . . . had fluorescent labels attached to the
7-deazapurine position . . . was common by the year 2000
[for Sanger sequencing],” Columbia University’s witness,
Dr. Trainer, conceded that it was. J.A. 4250. Taken
together, the testimony and references provide
substantial evidence to support the PTAB’s finding that a
22                   TRS. OF COLUMBIA UNIV. V. ILLUMINA, INC.

PHOSITA would combine the two references to achieve
the claimed invention.
    Columbia University argues the PTAB “never
identified any affirmative motivation that would have led
a skilled artisan to abandon the ‘ideal,’ natural C-8
position taught by Tsien.” Appellant’s Br. (-1550) 44.
However, Tsien itself specifically references Prober as
“show[ing] enzymatic incorporation of fluorescent
ddNTP’s by reverse transcriptase and SequenaseTM,” J.A.
3029, and Prober discloses attaching a fluorescent label
via a linker only at the 7-deaza position, J.A. 4335
(Question: “[Attaching a label to the 7-deaza position is]
the only way that you [Trainer] disclose in this particular
article [i.e., Prober]?” Answer: “Yes.”); see also J.A. 3063.
Although Tsien described the C-8 position as “ideal,” J.A.
3030, this court has previously explained that “just
because better alternatives exist in the prior art does not
mean that an inferior combination is inapt for
obviousness purposes,” In re Mouttet, 686 F.3d 1322, 1334
(Fed. Cir. 2012); see also In re Mills, 470 F.2d 649, 651
(CCPA 1972) (“We find no merit in appellants’ contention
that the disclosure of propylene is so submerged in
Cooper, and the teaching of the use of ethylene so
predominant, that Cooper cannot be said to place foams
composed of the claimed ingredients in the possession of
the public. All the disclosures in a reference must be
evaluated . . . .”).
    Columbia University further argues there was no
motivation for a PHOSITA to use deazapurines with SBS
because “the need for ‘stable’ linkers was unique to
Sanger sequencing, with its harsh conditions” associated
with electrophoresis.     Appellant’s Br. (-1550) 44.
However, although Prober was concerned only with
Sanger sequencing, Tsien’s explicit reference to Prober
combined with the wide use of deazapurines with prior art
sequencing techniques, see J.A. 4335 (use of deazapurines
was part of a “preferred embodiment” in Prober that was
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“commercialized by Applied Bio-Systems”), 3401
(deazapurines were “wide[ly] availab[le]” and “widely
used”), provides substantial evidence supporting the
PTAB’s finding of motivation to combine, see J.A. (-1550)
21–24.
          D. Reasonable Expectation of Success
    To render a claim obvious, a PHOSITA must have had
not only a “reason to combine the teaching of the prior art
references to achieve the claimed invention,” but also “a
reasonable expectation of success from doing so.” In re
Cyclobenzaprine Hydrochloride Extended-Release Capsule
Patent Litig., 676 F.3d 1063, 1069 (Fed. Cir. 2012)
(internal quotation marks and citation omitted).
Columbia University challenges the PTAB’s finding that a
PHOSITA “would have had a reasonable expectation of
success in combining Tsien with Prober or with Seela to
synthesize a 3’-OH-capped nucleotide with a label
attached to a deazapurine base (via a cleavable linker, for
claim 15).” Appellant’s Br. 45. Specifically, it cites Dr.
Trainor’s testimony that the chemistry for creating a
nucleotide analogue with the claimed features was
complex, and a PHOSITA could not have reasonably
expected to be successful in devising an appropriate
chemical procedure. Id. at 45–46; see also J.A. 3827.
   Illumina responds “that every step of the synthetic
process would have been understood to be within the level
of ordinary skill [in the art],” and that Dr. Trainer
conceded this to be the case. Appellee’s Br. 39. It cites
the testimony of Dr. Trainer in which he admits to be
within the PHOSITA’s skill level: the use of “a starting
deazaguanine with a 7-iodide for linker attachment;”
“attaching a cleavable alkynylamino linker to the 7-iodo
position;” and “attaching a fluorescent label to the
alkynylamino linker.” Id. at 39–40. Tsien references
Prober as disclosing a method that would be applicable to
the synthesis of both ddNTPs and dNTPs. J.A. 3029–30.
24                  TRS. OF COLUMBIA UNIV. V. ILLUMINA, INC.

Most significantly, the ’869 patent explains a “7 deaza-
alkynylamino-dGTP[6] is prepared using well-established
procedures,” and does not provide additional guidance
with respect to chemical procedures. ’869 patent col. 23 ll.
37–38 (emphasis added).          Taken together, these
disclosures constitute substantial evidence supporting the
PTAB’s finding that a PHOSITA would have had a
reasonable expectation of success in achieving the claimed
invention.
III. Secondary Considerations Do Not Weigh Strongly in
               Favor of Nonobviousness
   Both parties present arguments with respect to
secondary considerations. Illumina argues simultaneous
invention supports its position that the claimed invention
was obvious.     Columbia University asserts copying,
attempted licensing, commercial success, and unexpected
results support the nonobviousness of the claimed
invention.
A. Simultaneous Invention Weighs Modestly in Favor of
                    Obviousness
    “Independently made, simultaneous inventions, made
within a comparatively short space of time, are persuasive
evidence that the claimed apparatus was the product only
of ordinary mechanical or engineering skill.” George M.
Martin Co. v. Alliance Mach. Sys. Int’l LLC, 618 F.3d
1294, 1305 (Fed. Cir. 2010) (internal quotation marks and
citation omitted). Illumina asserts two entities, Solexa
and Amersham, each separately conceived of an SBS
approach as early as December 2001, i.e., before Dr. Ju’s
patent applications were published, containing the novel
features of Dr. Ju’s patent claims.” Appellee’s Br. 47.

     6 The     notation     “dGTP”     refers   to     a
deoxyribonucleoside triphosphate in which guanine is the
base.
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    Columbia University first responds that the activities
of Solexa and Amersham “are not prior art.” Reply Br. 6.
This response reflects confusion over the difference
between simultaneous invention on the one hand and
anticipation and obviousness on the other.               If
simultaneous invention were only relevant where the
object of the simultaneous invention constituted prior art,
it would be analyzed under 35 U.S.C. § 102 and as part of
the second Graham factor (i.e., as part of a determination
of the “differences between the prior art and the claims at
issue”) under 35 U.S.C. § 103. Graham, 383 U.S. at 17.
As a secondary consideration, however—which falls under
the fourth Graham factor—simultaneous invention is
relevant when it occurs within a short space of time from
the date of invention, and “is strong evidence of what
constitutes the level of ordinary skill in the art.”
Ecolochem v. S. Cal. Edison Co., 227 F.3d 1361, 1379
(Fed. Cir. 2000). Unlike the ultimate determination of
obviousness, which requires courts to answer the
hypothetical question of whether an invention “would
have been obvious,” 35 U.S.C. § 103, simultaneous
invention demonstrates what others in the field actually
accomplished.
    The tendency of simultaneous invention to weigh in
favor of obviousness would, of course, be negated if the
purported simultaneous invention was not made
independently of the claimed invention. Perhaps with
this in mind, Columbia University asserts the Solexa
patent was filed “months after features of Dr. Ju’s SBS
method were disclosed in a public National Science
Foundation Grant Announcement.”             Reply Br. 6–7.
However, Columbia University asserts that at the time of
Solexa’s disclosure, “Solexa . . . thought that a nucleotide
with the requisite combination of features was
patentable.” Id. It makes a similar assertion with respect
to Amersham. Id. In so asserting, Columbia University
undermines its own argument: If Solexa and Amersham
26                  TRS. OF COLUMBIA UNIV. V. ILLUMINA, INC.

had copied their purported simultaneous inventions from
the grant announcement, they would have had no basis to
believe their simultaneous inventions were patentable.
    Columbia University also argues Amersham’s
activities did not constitute simultaneous invention
because the chemical configuration it described was
“useless as a chain terminator.” Reply Br. 7. It points out
that Illumina did not present its simultaneous invention
argument to the PTAB. Because the record is not fully
developed, the evidence of simultaneous invention as a
whole weighs only modestly in favor of obviousness.
      B. Copying Does Not Favor Nonobviousness
    Columbia University asserts “Manteia, a company
whose intellectual property was later acquired by
Illumina’s predecessor-in-interest Solexa, copied Dr. Ju’s
invention” as reflected in a 2003 presentation.
Appellant’s Br. 12. The 2003 presentation cites Dr. Ju’s
publication. See J.A. 3894. Illumina responds that the
asserted copying is irrelevant because the only elements
shown to be copied were disclosed in Tsien, Dower, and
Stemple, and that the presentation does not disclose a
deazapurine and therefore does not reflect copying of the
claimed invention. Appellee’s Br. 57.
    Illumina further responds that Solexa did not copy
Dr. Ju’s invention, citing a December 2001 patent
application filed by Solexa that discloses “a base that is
linked to a detectable label via a cleavable linker,” and a
removable “protecting group” at the 3’ position that “is
intended to prevent nucleotide incorporation.” J.A. 3750,
3755; see also Appellee’s Br. 11–14, 58. The PTAB
considered Columbia University’s evidence of copying and
did not find it persuasive. J.A. 29. Because the record is
inconclusive as to whether any party in fact copied Dr.
Ju’s invention, because the PTAB did not make an explicit
factual finding in this regard, and because it is unclear
whether the asserted actions represent copying or
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independent invention, the asserted copying does not
weigh in favor of nonobviousness.
  C. Attempted Licensing Weighs Modestly in Favor of
                   Nonobviousness
    Columbia University cites several emails from
Illumina showing an interest in “collaborating with Dr. Ju
from Columbia University on his reversible terminators,”
and stating “Professor Jingyue Ju purportedly has solved
the reversible terminator cleavable dye label issue.” J.A.
3993–95. Although these emails demonstrate an interest
in Dr. Ju’s work, none of the emails mentions the ’698,
’575, or ’869 patents or clearly indicates the subject
matter sought to be licensed fell within the claims of those
patents. In re GPAC, 57 F.3d 1573, 1580 (Fed. Cir. 1995)
(“Because, in affidavits reciting the licensing history of
the ’111 patent, GPAC did not establish which claim(s) of
the patent the licensing program incorporates, GPAC has
not shown that licensing . . . arose out of recognition and
acceptance of the subject matter claimed in the ’111
patent.”). This factor therefore provides only modest
evidence of nonobviousness.
D. Commercial Success Does Not Favor Nonobviousness
    Commercial success of a product embodying an
invention tends to show nonobviousness when “the
commercial success . . . results from the claimed
invention” and is “due to the merits of the claimed
invention beyond what was readily available in the prior
art.” J.T. Eaton & Co. v. Atl. Paste & Glue Co., 106 F.3d
1563, 1571 (Fed. Cir. 1997). “When a patentee can
demonstrate commercial success, usually shown by
significant sales in a relevant market, and that the
successful product is the invention disclosed and claimed
in the patent, it is presumed that the commercial success
is due to the patented invention.” Id.
28                  TRS. OF COLUMBIA UNIV. V. ILLUMINA, INC.

    Columbia University asserts Illumina’s sales were
significant and embody the claims of the ’698, ’869, and
’575 patents. Appellant’s Br. 59 (citing J.A. 3879–85);
Appellant’s Br. (-1548) 57; Appellant’s Br. (-1550) 57.
Illumina responds that “the very features proclaimed by
Columbia [University] to be the reason for Illumina’s
commercial success (attachment of the label to the base
via a cleavable linker) were already known in Tsien,
Dower, and Stemple,” and that Columbia University did
not assert the deazapurine contributed to commercial
success. Appellee’s Br. 54.
     Commercial success does not favor nonobviousness.
“[I]f the feature that creates the commercial success was
known in the prior art, the success is not pertinent.”
Ormco Corp. v. Align Tech., Inc., 463 F.3d 1299, 1312
(Fed. Cir. 2006). Here, each of the features claimed to be
responsible for the commercial success of the invention
was disclosed in a single prior art reference, Tsien.
    In addition, Columbia University does not itself sell
its patented invention.         Although reliance on a
defendant’s or third party’s sale of a patented invention to
demonstrate commercial success may be probative of
nonobviousness in some cases, it is not particularly
helpful in the present matter because it is unclear
whether any success was attributable to developments in
the field that led to simultaneous invention (which would
tend to show the invention was obvious) or to copying
(which would tend to show the invention was nonobvious).
 E. Unexpected Results Do Not Favor Nonobviousness
    Evidence of “some superior property or advantage
that a person of ordinary skill in the relevant art would
have found surprising or unexpected” tends to indicate
nonobviousness. In re Soni, 54 F.3d 746, 750 (Fed. Cir.
1995).   Columbia University asserts, as evidence of
unexpected results, Dr. Trainor’s testimony that the
claimed nucleotides are unexpectedly better than
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pyrosequencing. Appellant’s Br. 53; see also J.A. 30.
According to the ’698 patent, pyrosequencing is a “widely
used” process that “employs four natural nucleotides . . .
for sequencing DNA by synthesis” and “is based on the
pyrophosphate (PPi) released during the DNA polymerase
reaction, the quantitative conversion of pyrophosphate to
adenosine triphosphate (ATP) by sulfurylase, and the
subsequent production of visible light by firefly
luciferase.” ’698 patent col. 2 ll. 19–28.
    Unexpected results “‘must be shown to be unexpected
compared with the closest prior art.’” Kao Corp. v.
Unilever U.S., Inc., 441 F.3d 963, 970 (Fed. Cir. 2006)
(quoting In re Baxter Travenol Labs., 952 F.2d 388, 392
(Fed. Cir. 1991)). The PTAB found pyrosequencing was
not the closest prior art. Columbia University argues
pyrosequencing was the closest prior art because it was
“the only commercial embodiment of SBS at the time of
Dr. Ju’s invention.” Appellant’s Br. 63. However, there is
no requirement that the closest prior art be
commercialized. See In re Merchant, 575 F.2d 865, 869
(CCPA 1978) (“In In re Wright . . . , failure of a particular
reference to constitute the commercial standard did not
diminish its position as the closest prior art.”) (internal
quotation marks and citation omitted); see also In re
Chupp, 816 F.2d 643, 644 (Fed. Cir. 1987) (“To rebut the
prima facie case of obviousness, Chupp submitted a
declaration discussing the results of tests comparing the
herbicidal activity of the claimed compound with that of
the closest prior art compounds and with two commercial
herbicides . . . .  It is undisputed that the claimed
compound gave superior results . . . .”) (emphases added).
Evidence of unexpected results in comparison to
pyrosequencing      is   therefore     not    probative    of
nonobviousness.
30                   TRS. OF COLUMBIA UNIV. V. ILLUMINA, INC.

     IV. The PTAB Did Not Err in Determining Certain
           Challenged Claims Were Anticipated
    “Anticipation is a question of fact that we review for
clear error . . . .” Forest Labs., Inc. v. Ivax Pharm., Inc.,
501 F.3d 1263, 1268 (Fed. Cir. 2007). In Appeal 2014-
1548, Columbia University argues the PTAB erred in
rejecting claims 12, 13, 17, 20–26, 28, 29, 31, and 33 as
anticipated because “the references are non-enabling” and
do not “‘disclose all elements of the claim within the four
corners of the document . . . arranged as in the claim.’”
Appellant’s Br. (-1548) 64 (quoting Net MoneyIN, Inc. v.
VeriSign, Inc., 545 F.3d 1359, 1369 (Fed. Cir. 2008)).
(Columbia University makes a similar argument with
respect to claims 1–3 of the ’575 patent. See Appellant’s
Br. (-1550) 64.) Specifically, it identifies as elements
common to the listed claims, “a [1] 3’-OH-capped
nucleotide, [2] base-label, and [3] cleavable linker.”
Appellant’s Br. (-1548) 64. Tsien explains an approach in
which:
     a [1] 3’-blocked dNTP analogue containing a [2]
     label such as a fluorescent group [is] coupled to a
     remote position such as the base. This dNTP can
     be incorporated . . . according to the methods
     described below.
     One method involves the use of a fluorescent tag
     attached to the base moiety. . . .
     In another type of remote labeling the . . . label
     can be attached to the dNTP through a spacer or
     tether. The [3] tether can be cleavable if
     desired . . . .
J.A. 3028–29 (emphases added).
    It is true Tsien provides that elements 1 and 2 may be
combined with either a label that is directly attached to
the base or one that is attached via a cleavable or non-
TRS. OF COLUMBIA UNIV. V. ILLUMINA, INC.                31

cleavable tether. However, “when a genus is so limited
that a person of ordinary skill in the art can at once
envisage each member of this limited class, . . . a
reference describing the genus anticipates every species
within the genus.” Abbvie Inc. v. Mathilda & Terrence
Kennedy Inst. of Rheumatology Trust, 764 F.3d 1366, 1379
(Fed. Cir. 2014) (internal quotation marks and citation
omitted). This court agrees with the PTAB that an
embodiment comprising a 3’-OH-capped nucleotide, base-
label, and cleavable linker could be “envisaged clearly by
one of ordinary skill in the art upon reading the Tsien
disclosure.” J.A. (-1548) 10.
    Columbia University also argues Tsien does not
“enable[] a skilled artisan to make a base-labeled,
3’-OH-capped nucleotide without undue experimentation,”
because “[t]he references do not teach the necessary
synthetic chemistry.” Appellant’s Br. (-1548) 64–65. In
Appeal 2014-1550, Columbia University similarly argues
“Tsien does not enable a skilled artisan to make a base-
labeled, 3’-OH-capped nucleotide [as claimed in claims 1–
3 of the ’575 patent] without undue experimentation.”
Appellant’s Br. (-1550) 67.       However, as already
explained, if novel and nonobvious chemistry was needed
to practice the claimed inventions, Dr. Ju would have
been obligated to disclose this chemistry in the patent.
See 35 U.S.C. § 112(1) (2000). 7
    The PTAB’s denial of a procedural motion is reviewed
for abuse of discretion. See Bilstad v. Wakalopulos, 386 F.
3d 1116, 1121 (Fed. Cir. 2004). The PTAB abuses its
discretion when its decision: “(1) is clearly unreasonable,

    7   Section 112 has since been amended. See AIA
§ 4(c), 125 Stat. at 296.          However, because the
applications that led to the ’698, ’869, and ’575 patents
were filed before Sept. 16, 2012, the pre-AIA § 112
applies. See AIA § 4(e), 125 Stat. at 297.
32                   TRS. OF COLUMBIA UNIV. V. ILLUMINA, INC.

arbitrary, or fanciful; (2) is based on an erroneous
conclusion of law; (3) rests on clearly erroneous fact
finding; or (4) involves a record that contains no evidence
on which the [PTAB] could rationally base its decision.”
Id.
    In Appeal 2014-1548, Columbia University argues the
PTAB’s denial of its motion to amend its claims was
erroneous, and that the error was not harmless:
     Columbia’s amendments would have rewritten
     claim 15 in independent form and added the
     deazapurine limitation to the other challenged
     claims. . . .
     The [PTAB’s] failure to enter Columbia’s
     amendment led it to address the critical dispute
     over the scope of Tsien’s and Stemple’s disclosures
     first in the context of anticipation, where the
     issues were (in the [PTAB’s] mistaken view)
     uncontested. When the [PTAB] turned to the
     obviousness of claims 15 and 16, it had already
     decided that Tsien and Stemple disclosed a
     nucleotide with a 3’-OH cap and a label attached
     to the base by a cleavable linker, and it asked
     whether adding a deazapurine was obvious.
Appellant’s Br. (-1548) 62–63.         Columbia University
makes a similar argument with respect to claims 1–3 of
the ’575 patent. See Appellant’s Br. (-1550) 60–63.
Because the PTAB did not clearly err in its determination
of what Tsien teaches, Columbia University’s argument
based on its contrary assertion does not establish
patentability over the prior art, and is therefore rejected.
See Microsoft Corp. v. Proxyconn, Inc., No. 2014-1542,
2015 WL 3747257, at *13 (Fed. Cir. June 16, 2015)
(explaining that motions to amend may properly be
denied where the patentee has failed to establish
patentability over the prior art of record).
TRS. OF COLUMBIA UNIV. V. ILLUMINA, INC.               33

                        CONCLUSION
    For these reasons, the decisions of the PTAB are
                       AFFIRMED