         NOTE: This disposition is nonprecedential.


   United States Court of Appeals
       for the Federal Circuit
                     ______________________

              ILLUMINA CAMBRIDGE LTD.,
                      Appellant

                                  v.

          INTELLIGENT BIO-SYSTEMS, INC.,
                       Appellee
                ______________________

                           2015-1123
                     ______________________

    Appeal from the United States Patent and Trademark
Office, Patent Trial and Appeal Board in No. IPR2013-
00128.
      ------------------------------------------------------------------

              ILLUMINA CAMBRIDGE LTD.,
                      Appellant

                                  v.

          INTELLIGENT BIO-SYSTEMS, INC.,
                       Appellee
                ______________________

                           2015-1243
                     ______________________
2     ILLUMINA CAMBRIDGE LTD.   v. INTELLIGENT BIO-SYSTEMS



    Appeal from the United States Patent and Trademark
Office, Patent Trial and Appeal Board in No. IPR2013-
00266.
                 ______________________

               Decided: January 29, 2016
                ______________________

    WILLIAM R. ZIMMERMAN, Knobbe, Martens, Olson &
Bear, LLP, Washington, DC, argued for appellant. Also
represented by JONATHAN EDWARD BACHAND; BRENTON R.
BABCOCK, Irvine, CA; NATHANAEL LUMAN, KERRY S.
TAYLOR, San Diego, CA.

    ROBERT R. BARON, JR., Ballard Spahr LLP, Philadel-
phia, PA, argued for appellee. Also represented by MARC
S. SEGAL; JOHN L. CUDDIHY, Washington, DC; SCOTT
DAVID MARTY, Atlanta, GA.
                ______________________

    Before LOURIE, BRYSON, and STOLL, Circuit Judges.
LOURIE, Circuit Judge.
    Illumina Cambridge Ltd. (“Illumina”) appeals from
the final written decisions of the United States Patent
and Trademark Office, Patent Trial and Appeal Board
(“the Board”) cancelling all challenged claims of its
U.S. Patents 7,057,026 (“the ’026 patent”) and 8,158,346
(“the ’346 patent”) and denying entry of substitute claims
in two inter partes review proceedings. Intelligent Bio-
Systems, Inc. v. Illumina Cambridge Ltd., IPR2013-
00128, Paper No. 92 (P.T.A.B. July 25, 2014); Intelligent
Bio-Systems, Inc. v. Illumina Cambridge Ltd., IPR2013-
00266, Paper No. 73 (P.T.A.B. Oct. 28, 2014). Because the
Board did not err in determining that Illumina failed to
show that the proposed substitute claims are patentable
over the prior art of record, and thus did not err in deny-
ing in part the motions to amend, we affirm.
ILLUMINA CAMBRIDGE LTD.   v. INTELLIGENT BIO-SYSTEMS      3



                       BACKGROUND
    Illumina owns the ’026 and ’346 patents, which are
both directed to DNA sequencing by synthesis (“SBS”)
with non-natural nucleotides. As the name implies, SBS
allows one to determine the composition of a target DNA
sequence by synthesizing new copies of the DNA. Briefly,
the synthesis process involves splitting the double helix of
a target DNA molecule into two strands and then incorpo-
rating complementary labeled nucleotides onto each
strand to create two double helices. Non-natural nucleo-
tides contain a non-natural base, i.e., a modified purine or
pyrimidine base.
    The ’026 patent is directed to nucleotide compositions
of matter, while the ’346 patent relates to methods of
using such nucleotides. As the issues relating to the
patentability of the claims of both of these patents are
essentially the same, we evaluate both of them here in
one opinion and decision.
    An exemplary non-natural nucleotide of the two pa-
tents, pictured below, has a deoxyribose ring, with a
protecting group attached at the 3′-OH position and a
label connected to the non-natural base (here,
deazapurine) by a linker (here, containing a disulfide
linkage). According to the ’026 and ’346 patents, the
linker and the protecting group for the claimed non-
natural nucleotides are cleavable under identical condi-
tions.
ILLUMINA CAMBRIDGE LTD.   v. INTELLIGENT BIO-SYSTEMS       5



phase” with the other strands, i.e., its sequence will no
longer match the others in any future steps. In contrast,
if a linker for a label fails to be cleaved, the strand will
still be in phase despite its incorrect or mixed signals;
moreover, the linker will likely be cleaved, and the signal
corrected, in subsequent cycles.
    In 2012, a third party filed suit against Illumina, as-
serting several DNA sequencing patents for which Intelli-
gent Bio-Systems, Inc. (“Intelligent Bio-Systems”) is the
exclusive licensee. In its answer, Illumina counter-
claimed that Intelligent Bio-Systems infringed Illumina’s
’026 and ’346 patents. Intelligent Bio-Systems then filed
petitions for inter partes review at the Board, challenging
claims 1–8 of the ’026 patent and claims 1, 2, 4, 11, 12, 17,
18, and 19 of the ’346 patent. The district court case was
stayed pending resolution of these and several other
related inter partes review proceedings.
     The Board instituted review of both the ’026 and ’346
patents on the grounds of anticipation and obviousness.
2015-1123 Joint App. (“1123-J.A.”) 332–350; 2015-1243
Joint App. (“1243-J.A.”) 208–221. Instead of submitting
responses to the institution decisions, Illumina filed
motions to amend, requesting cancellation of all chal-
lenged claims of both patents, and entry of substitute
claims 9–12 for the ’026 patent (“’026-substitute claims”),
1123-J.A. 501–503, and claims 20–26 for the ’346 patent
(“’346-substitute claims”), 1243-J.A. 278–279. Noting that
the cancellation requests were not contingent on the
original claims being found unpatentable, the Board
granted Illumina’s motions in part, cancelling all of the
challenged claims of both patents. 1123-J.A. 29–30; 1243-
J.A. 23.
    The Board then examined the proposed substitute
claims for the ’026 patent. Representative proposed
substitute claim 9 for the ’026 patent reads as follows,
with Illumina’s annotations for replacing claim 1:
6     ILLUMINA CAMBRIDGE LTD.   v. INTELLIGENT BIO-SYSTEMS



    9. A nucleotide triphosphate or nucleoside mole-
    cule, having a 7-deazapurine base that is linked to
    a detectable label via a cleavable linker, wherein
    the cleavable linker is attached to the 7-position of
    the 7-deazapurine base and wherein the cleavable
    linker contains a disulfide linkage, and wherein
    the nucleotide triphosphate molecule has a ribose
    or deoxyribose sugar moiety comprising a protect-
    ing group attached via the 2′ or 3′ oxygen atom,
    and the disulfide linkage of the cleavable linker
    and the protecting group are cleavable under
    identical conditions.
1123-J.A. 30. The Board found only one new limitation
that is different from the original claims: that the cleava-
ble linker “contains a disulfide linkage.” 1123-J.A. 30.
    Starting with the premise that the obviousness of us-
ing a disulfide linkage was the main issue to be decided,
the Board found that all of the claim limitations were
described in the prior art. 1123-J.A. 37–39. The Board
also found that the prior art provided a reason to use a
disulfide linkage to attach a label to a base of a nucleo-
tide, including for DNA sequencing, and with a reasona-
ble expectation of success. 1123-J.A. 40–42. Because the
proposed substitute claims do not require a disulfide
linkage between the protecting group and the 3′-OH, the
Board rejected Illumina’s argument that the prior art’s
requirement of greater than 90% cleavage efficiency for a
protecting group also applied to the claimed disulfide
linkage. 1123-J.A. 42–44. Even so, the Board also found
that one of skill in the art would have expected to achieve
more than 90% cleavage efficiency of the disulfide bond by
routine experimentation. 1123-J.A. 44–50. The Board
determined that Illumina had not met its burden of
showing that one of skill in the art would not have had a
reasonable expectation of success, viz., that identical
conditions could not be selected in which the disulfide
linkage is cleavable with less than 90% efficiency and the
ILLUMINA CAMBRIDGE LTD.   v. INTELLIGENT BIO-SYSTEMS     7



protecting group is cleavable with greater than 90%
efficiency.
     The Board also rejected Illumina’s proffered evidence
of unexpected results of high cleavage efficiency of disul-
fide linkages. The Board found that Illumina did not
provide a proper comparison to the closest prior art, and
failed to provide evidence that the results were due to the
claimed subject matter, not the experimental conditions
or the latent properties of the bond. 1123-J.A. 52–54.
The Board thus concluded that Illumina had not met its
burden of showing that the proposed ’026-substitute
claims are patentable over the prior art of record. 1123-
J.A. 54. The Board noted that such a showing is required
in order to establish that the patent owner is entitled to
the relief requested, i.e., to amend the patent with the
proposed substitute claims. 1123-J.A. 29, 31 (citing 35
U.S.C. § 316; 37 C.F.R. § 42.20(c)).
    The Board separately also examined the proposed
substitute claims for the ’346 patent, which recite meth-
ods comprising providing, similarly, a nucleotide with a
linker containing a disulfide linkage for attaching a label
to the base, and removing the label and the protecting
group from the nucleotide under a single set of chemical
cleavage conditions. 1243-J.A. 23–24. The Board again
found only one new limitation as compared to the original
claims: that the cleavable linker “contains a disulfide
linkage.” 1243-J.A. 24. For virtually the same reasons as
for the ’026-substitute claims, the Board concluded that
Illumina had not met its burden of showing that the
proposed ’346-substitute claims are patentable. 1243-J.A.
26–48.
    The Board therefore denied in part Illumina’s motions
to amend both patents by entering the proposed substi-
tute claims. Illumina timely appealed from the Board’s
final written decisions. We have jurisdiction pursuant to
28 U.S.C. § 1295(a)(4).
8     ILLUMINA CAMBRIDGE LTD.   v. INTELLIGENT BIO-SYSTEMS



                       DISCUSSION
    We review the Board’s legal conclusions de novo, In re
Elsner, 381 F.3d 1125, 1127 (Fed. Cir. 2004), and the
Board’s factual findings underlying those determinations
for substantial evidence, In re Gartside, 203 F.3d 1305,
1315 (Fed. Cir. 2000). “Substantial evidence . . . means
such relevant evidence as a reasonable mind might accept
as adequate to support a conclusion.” Consol. Edison Co.
v. NLRB, 305 U.S. 197, 217 (1938).
    Obviousness is a question of law based on underlying
factual findings, including what a reference teaches and
whether there would have been sufficient motivation to
combine the prior art. In re Baxter Int’l, Inc., 678 F.3d
1357, 1361 (Fed. Cir. 2012); Rapoport v. Dement, 254 F.3d
1053, 1060–61 (Fed. Cir. 2001); In re Gartside, 203 F.3d at
1316. For a motion to amend during an inter partes
review proceeding, the patentee bears the burden of
showing that its proposed substitute claims are patenta-
ble over the prior art of record. Microsoft Corp. v. Proxy-
conn, Inc., 789 F.3d 1292, 1306–08 (Fed. Cir. 2015);
Prolitec, Inc. v. ScentAir Techs., Inc., 807 F.3d 1353,
1363–64 (Fed. Cir. 2015).
     Illumina argues that the Board improperly limited its
analysis to the disulfide linkage limitation, rather than
also considering the combination of the additional limita-
tions. Illumina contends that the ’026-substitute claims
added limitations of both (i) the linker containing a disul-
fide linkage and (ii) the disulfide linkage being cleavable
under identical conditions as the protecting group. Simi-
larly, the ’346-substitute claims added limitations of both
(i) the linker containing a disulfide linkage and (ii) the
disulfide linkage and the protecting group being removed
under a single set of chemical conditions. Although each
limitation may have been independently disclosed in the
prior art, Illumina asserts that the Board only found a
motivation to use a linker with a disulfide linkage in SBS
ILLUMINA CAMBRIDGE LTD.   v. INTELLIGENT BIO-SYSTEMS       9



methods, which was insufficient to find the full scope of
the claimed subject matter obvious. Illumina reasons
that because the prior art teaches both that SBS requires
greater than 90% deblocking efficiency, and that cleaving
disulfide linkages was variable and inefficient, one of skill
in the art would not have been motivated to combine the
prior art for SBS methods. Worse yet, Illumina argues,
the Board improperly imposed a heightened standard of
nonobviousness by requiring proof that it would have
been impossible to combine the prior art to arrive at the
substitute claims, e.g., impossible to achieve higher cleav-
age efficiency yields for disulfide linkages. Illumina also
asserts that the Board improperly discounted its evidence
of unexpected results, which showed not simply high
cleavage efficiency of the disulfide linkage, but superior
SBS results using the claimed nucleotides.
    Intelligent Bio-Systems responds that Illumina failed
to carry its burden of showing that the proposed substi-
tute claims were patentable over the prior art of record.
Because the Board had already decided in its Decisions to
Institute that the prior art taught all of the limitations in
the original claims, Intelligent Bio-Systems contends, the
only additional limitation in the proposed claims was the
disulfide linker, and thus the Board only needed to ad-
dress the prior art relating to the successful use of disul-
fide linkers in DNA sequencing. Intelligent Bio-Systems
characterizes Illumina’s arguments as using the variable
cleavage efficiency of a disulfide linkage as a proxy for the
greater than 90% cleavage efficiency of a protecting group
required by the prior art; however, Intelligent Bio-
Systems notes, the Board found that the claims do not
require that they cleave at the same efficiency. Intelli-
gent Bio-Systems also asserts that the Board did not err
in finding that Illumina’s evidence of unexpected results
was insufficient to meet its burden of showing nonobvi-
ousness.
10    ILLUMINA CAMBRIDGE LTD.   v. INTELLIGENT BIO-SYSTEMS



    We agree with Intelligent Bio-Systems that the Board
did not err in focusing on the prior art regarding disulfide
linkages. For the proposed substitute claims in the
context of inter partes review proceedings, Illumina bore
the burden of proving patentability over the prior art of
record; here, specifically, Illumina had to show that the
substitute claims would not have been obvious in view of,
inter alia, prior art raised during the review proceedings
and prior art from the patent’s original prosecution histo-
ry. See Prolitec v. ScentAir Techs., 807 F.3d at 1363–64.
Because none of the original claims comprised the limita-
tion of the linker containing a disulfide linkage, the Board
chose to primarily address prior art relevant to that
limitation to determine whether Illumina had proven that
the addition rendered the claims as a whole nonobvious.
    The Board did not analyze the obviousness of using a
disulfide linkage in SBS in isolation, however; the original
claims provided a backdrop for the Board to find that one
of skill in the art would have reasonably expected to
succeed in using a linker with a disulfide linkage as
claimed. The prior art taught the use of linkers contain-
ing disulfide linkages for attaching a label to a nucleotide,
as well as the desirability of simultaneously removing
labels and protecting groups, in DNA sequencing meth-
ods. One of skill in the art would have been motivated to
use a commercially available linker to attach a label to a
nucleotide that also could be removed when removing the
protecting group, and thus would have been motivated to
modify SBS prior art with a disulfide linkage as claimed.
The heightened standard that Illumina decries is instead
properly Illumina’s burden to show nonobviousness, proof
that one of skill in the art would not have a reasonable
expectation of success in using a disulfide linkage. Illu-
mina simply failed to sufficiently elucidate grounds upon
which the use of a disulfide linkage for SBS, particularly
such a linkage cleavable under the same conditions as a
ILLUMINA CAMBRIDGE LTD.   v. INTELLIGENT BIO-SYSTEMS    11



protecting group, would not have been obvious in view of
the prior art.
     Importantly, Illumina’s arguments rely on the idea
that one of skill in the art would not have used a linker
with a disulfide linkage—for a desired combination in
which the label and protecting group would be cleaved in
identical conditions—because disulfide linkages did not
appear to have sufficiently high cleavage efficiency to
match the supposed minimum cleavage efficiency of
protecting groups for SBS. The proposed substitute
claims do not require that the linker and the protecting
group be cleaved at the same efficiency rates, however,
only that they are cleavable under the same conditions.
The Board alluded to this by finding that Illumina had
not met its burden to show that identical conditions could
not have been selected; the implication being that nonob-
viousness might have been supported by evidence that
one of skill in the art would not have expected there to be
any set of conditions in which a disulfide linkage has
lower cleavage efficiency than a protecting group and is
still suitable for SBS.
    Although Illumina provided an expert declaration
stating that the prior art did not provide an expectation
that disulfide cleavage conditions would cleave a protect-
ing group with greater than 90% efficiency, the claims
also do not require that the protecting group be cleaved at
greater than 90% efficiency, much less that the linker also
be cleaved at such efficiency. Nor do the claims limit the
protecting group to one also involving a disulfide bond,
which would inherently link its efficiency rate to the
cleavage efficiency of the linker. We are not persuaded by
Illumina’s argument that one of skill in the art would not
have been motivated to use a disulfide linkage as claimed,
because the prior art does not expressly disclose greater
than 90% cleavage efficiency of disulfide linkages.
12    ILLUMINA CAMBRIDGE LTD.   v. INTELLIGENT BIO-SYSTEMS



     Regardless, the Board found that even if that cleavage
efficiency were required of the linker, Illumina had not
met its burden to show that one of skill in the art would
not have reasonably expected to achieve greater than 90%
efficiency. The prior art taught that one of skill in the art
could reasonably have expected to increase the cleavage
efficiency of disulfide linkages by simple experimentation.
Moreover, as the Board noted, it was not critical for the
prior art to achieve higher cleavage efficiency of disulfide
bonds. The lack of prior art disclosures of actually achiev-
ing higher efficiency yields does not render the teachings
about increasing efficiency irrelevant; obviousness is not a
question of novelty. See EWP Corp. v. Reliance Universal
Inc., 755 F.2d 898, 907 (Fed. Cir. 1985) (“A reference must
be considered for everything it teaches by way of technolo-
gy and is not limited to the particular invention it is
describing and attempting to protect.”). Expert testimony
in the record also supports the Board’s finding that one of
skill in the art would have reasonably expected to achieve
increased efficiency for a disulfide linkage. Substantial
evidence thus supports the Board’s findings that several
prior art references taught the additional limitations of
the proposed substitute claims and that one of skill in the
art would have had a reasonable expectation of success in
combining the prior art to obtain the claimed invention.
    The Board also did not err in finding that Illumina’s
evidence of unexpected results relative to the prior art
was insufficient. Illumina failed to show that the unex-
pected results obtained were due to the claimed nucleo-
tide rather than differences from the prior art, e.g., the
cleavage reagent used or other experimental conditions,
or a latent property of the disulfide linkage. The Board
therefore did not err in finding that Illumina had not met
its burden to prove that the substitute claims were pa-
tentable over the prior art.
ILLUMINA CAMBRIDGE LTD.   v. INTELLIGENT BIO-SYSTEMS   13



                      CONCLUSION
    We have considered the remaining arguments and
conclude that they are without merit. Because substan-
tial evidence supports the Board’s determination that
Illumina failed to meet its burden in showing that the
proposed substitute claims in both patents are patentable
over the prior art of record, we affirm.
                      AFFIRMED
