  United States Court of Appeals
      for the Federal Circuit
                ______________________

        INTELLIGENT BIO-SYSTEMS, INC.,
                  Appellant

                           v.

           ILLUMINA CAMBRIDGE LTD.,
                      Appellee
               ______________________

                      2015-1693
                ______________________

    Appeal from the United States Patent and Trademark
Office, Patent Trial and Appeal Board in No. IPR2013-
00517.
                 ______________________

                 Decided: May 9, 2016
                ______________________

    ROBERT R. BARON, JR., Ballard Spahr LLP, Philadel-
phia, PA, argued for appellant. Also represented by MARC
S. SEGAL; SCOTT DAVID MARTY, Atlanta, GA.

    WILLIAM R. ZIMMERMAN, Knobbe, Martens, Olson &
Bear, LLP, Washington, DC, argued for appellee. Also
represented by JONATHAN EDWARD BACHAND; BRENTON R.
BABCOCK, JOSEPH S. CIANFRANI, SHEILA N. SWAROOP,
Irvine, CA; NATHANAEL LUMAN, KERRY S. TAYLOR, San
Diego, CA.
                ______________________
2                           INTELLIGENT BIO-SYSTEMS, INC. v.
                                  ILLUMINA CAMBRIDGE LTD.


Before O’MALLEY, WALLACH, and HUGHES, Circuit Judges.
O’MALLEY, Circuit Judge.
     Illumina Cambridge Ltd. (“Illumina”) owns U.S. Pa-
tent No. 7,566,537 (“the ’537 patent”), which is directed to
a method of labeling nucleotides in a deoxyribonucleic
acid (“DNA”) strand. Intelligent Bio-Systems, Inc. (“IBS”)
filed a revised petition to the Patent Trial and Appeal
Board (“Board”) requesting inter partes review of claims
1–6 and 8 of the ’537 patent on August 30, 2013. The
Board instituted review of the challenged claims on the
basis that they were invalid as obvious under 35 U.S.C.
§ 103 in view of certain prior art references. In its Final
Written Decision, issued February 11, 2015, the Board
found that IBS failed to satisfy its burden of demonstrat-
ing the obviousness of the challenged claims by a prepon-
derance of the evidence. IBS appeals. Because we find
that the Board’s judgment was supported by substantial
evidence, we affirm.
                       BACKGROUND
                      A. Technology
     By way of background, DNA is comprised of two
strands of nucleotides, which bind to each other to form a
double helix structure. “A nucleotide is made up of a
sugar molecule, a phosphate, and a ‘base.’ It is the
‘base’—adenine (A), cytosine (C), guanine (G), or thymine
(T)—that provides the code for the genetic information in
DNA.” Appellant Br. 4. The bases of two nucleotide
strands pair predictably: A with T, and G with C. In this
way, if one knows the identity of a nucleotide in one
strand, the identity of the corresponding nucleotide in the
other strand is easily inferred. Identification of the
sequence of nucleotides in DNA is important, as “the
sequence of nucleotides in DNA determines the traits of
living organisms.” Id.
INTELLIGENT BIO-SYSTEMS, INC.   v.                        3
ILLUMINA CAMBRIDGE LTD.


     The invention of the ’537 patent “relates to labelled
nucleotides.” ’537 patent, col. 1 l. 14. The labels, used to
identify the nucleotides, are removable and are intended
for “use in polynucleotide sequencing methods.” Id. at col.
1 ll. 14–16. The polynucleotide sequencing method at
issue is the so-called sequencing by synthesis (“SBS”)
method. SBS “is a process used to identify the sequence
of nucleotides in DNA by synthesizing a single strand of
DNA using nucleotides that are complementary to the
nucleotides in a sample single strand of DNA.” Appellee
Br. 3.
    The claimed method in the ’537 patent is directed to
labelling nucleotide bases to determine their identity.
The 3′-OH (“three prime hydroxyl”) position of the sugar
components of the labeled nucleotides are further modi-
fied with a blocking group (also referred to as a protecting
group). The blocking group (or protecting group) attached
to the sugar molecule “prevent[s] the natural linking
process between nucleotides.” Appellant Br. 4. By stop-
ping the linking process, one can detect the label on the
nucleotide base and determine its identity (A, C, G, or T).
The blocking group is cleavable, which allows the linking
process to continue after the label is detected.
    The SBS method starts with a single strand of un-
known nucleotides and adds complementary nucleotides
one-by-one to form the complete, double-helix structure.
“The protecting group allows the polymerase to incorpo-
rate only one nucleotide at a time into the complementary
strand.” Intelligent Bio-Sys., Inc. v. Illumina Cambridge
Ltd., IPR2013-00517, 2015 WL 996355, at *3 (PTAB Feb.
11, 2015) (Final Written Decision of the Board). “By
incorporating such modified nucleotides one-by-one into a
growing DNA chain, researchers are able to first detect
the label to determine the base of each nucleotide, before
another nucleotide (with its own label attached to its own
base) is added.” Appellant Br. 4–5. The identity of the
attached label is determined “by any suitable method,
4                           INTELLIGENT BIO-SYSTEMS, INC. v.
                                  ILLUMINA CAMBRIDGE LTD.


including fluorescence spectroscopy or by other optical
means.” ’537 patent, col. 5 ll. 21–23.
    The claims require that “the protecting group com-
prises an azido group.” Id. at col. 19 ll. 58–59 (claim 1).
According to Illumina, “the inventors of the ’537 patent
were the first to identify the azidomethyl group (CH2N3)
as a protecting group that would meet the rigorous re-
quirements of SBS.” Appellee Br. 9.
    Claim 1, the only independent claim under review, is
reproduced below:
    1. A method of labeling a nucleic acid molecule,
    the method comprising incorporating into the nu-
    cleic acid molecule a nucleotide or nucleoside mol-
    ecule, wherein the nucleotide or nucleoside
    molecule has a base that is linked to a detectable
    label via a cleavable linker and the nucleotide or
    nucleoside molecule has a ribose or deoxyribose
    sugar moiety, wherein the ribose or deoxyribose
    sugar moiety comprises a protecting group at-
    tached via the 2′ or 3′ oxygen atom, and said pro-
    tecting group can be modified or removed to expose
    a 3′ OH group and the protecting group comprises
    an azido group.

Id. at col. 19 ll. 49–59 (emphases added).
                       B. Prior Art
    There are three articles of prior art at issue in this
appeal: (1) Roger Tsien et al., WO 91/06678 (May 16,
1991) (“Tsien”); (2) Jingyue Ju et al., U.S. Patent No.
6,664,079 (Dec. 16, 2003) (“Ju”); and (3) Zavgorodny et al.,
1-Alkylthioalkylation of Nucleoside Hydroxyl Functions
and Its Synthetic Applications: A New Versatile Method in
Nucleoside Chemistry, 32 TETRAHEDRON LETTERS 7593
(1991) (“Zavgorodny”). IBS argued to the Board that Ju
in combination with Zavgorodny or Tsien in combination
with Zavgorodny render the patent invalid as obvious
INTELLIGENT BIO-SYSTEMS, INC.   v.                       5
ILLUMINA CAMBRIDGE LTD.


pursuant to 35 U.S.C. § 103. 1 IBS relied on Tsien and Ju
for similar purposes.
    In its Decision to Institute, the Board determined that
both Ju and Tsien “describe[] a process of labeling, and
ultimately sequencing, a nucleic acid molecule” by a
polymerase. J.A. 166, 169. Both Ju and Tsien disclose a
method of sequencing unknown DNA involving the SBS
method, including the labeling of nucleotides for detection
and the use of a protecting group at the 3′-OH position of
the nucleotide. Neither Ju nor Tsien disclose a protecting
group that comprises an azido group, however.
    Regarding Zavgorodny, the Board found that it teach-
es that an “azidomethyl moiety is a suitable protecting
group for the 3′ OH position of nucleosides, precisely the
position requiring protecting in Ju’s [or Tsien’s] process,
as well as the fact that the azidomethyl group is cleavable
from the nucleoside under specific and mild conditions.”
J.A. 167, 172. As Zavgorodny notes, the “[a]zidomethyl
group is of special interest, since it can be removed under
very specific and mild conditions, viz. with tri-
phenylphosphine in aqueous pyridine at 20 °C.” J.A. 861.
    Of particular importance to this appeal, Tsien teaches
that one of “[t]he criteria for the successful use of 3′-



   1     The Board also instituted proceedings on the com-
bination of Tsien and Zavgorodny with James M. Prober
et al., A System for Rapid DNA Sequencing with Fluores-
cent Chain-Terminating Dideoxynucleotides, 238 SCIENCE
336 (1987), but IBS does not appeal the Board’s conclu-
sion that it failed to show “by a preponderance of the
evidence that claim 3 of the ’537 patent would have been
obvious over the combination of Tsien, Zavgorodny, and
Prober.” Intelligent Bio-Sys., Inc., 2015 WL 996355, at
*13.
6                           INTELLIGENT BIO-SYSTEMS, INC. v.
                                  ILLUMINA CAMBRIDGE LTD.


blocking groups” is “the availability of mild conditions for
rapid and quantitative deblocking.” J.A. 1010 (emphasis
added). In order for the deblocking (i.e., the removal of
the protecting group) to be quantitative, it must take
place at 100% or near-100% efficiency. Appellant Br. 26
n.10; Appellee Br. 6. Ju similarly notes as a “fundamen-
tal requirement” that “the tag and the [protecting] group
capping the 3′-OH need to be removed with high yield to
allow the incorporation and detection of the next nucleo-
tide.” J.A. 742, col. 21 ll. 3–16 (emphasis added).
                 C. The Board’s Decision
    In its Final Written Decision, the Board construed
claim 1 to “encompass[] the use of any protecting group
attached via the 2′ or 3′ oxygen atom of a [sugar] moiety,
in which the protecting group can be modified or removed
to expose a 3′ OH group.” Intelligent Bio-Sys., Inc., 2015
WL 996355, at *4. It also noted that its construction of
“claim 1 does not require removal of the protecting group
to allow subsequent nucleotide incorporation.” Id. The
parties did not dispute that construction below and do not
dispute it here.
    The Board then considered whether the combination
of Tsien and Zavgorodny rendered claims 1–6 and 8 of the
’537 patent invalid as obvious. Based on the teachings of
Tsien and Zavgorodny, IBS argued “that an ordinary
artisan, ‘to improve the efficiency, reliability, and robust-
ness of the sequencing by synthesis method taught in
Tsien, would have been motivated to use other protecting
groups that meet the criteria of Tsien, such as the az-
idomethyl group taught by Zavgorodny.’” Id. (citation
omitted). In addition to contending that an ordinary
artisan would be motivated to combine these references,
IBS separately asserted that an ordinary artisan would
have a reasonable expectation of success in meeting the
limitations of the claimed invention by combining Tsien
and Zavgorodny. See id. at *5 (“[B]ecause an ordinary
INTELLIGENT BIO-SYSTEMS, INC.   v.                         7
ILLUMINA CAMBRIDGE LTD.


artisan would have recognized that Zavgorodny’s az-
idomethyl group met Tsien’s criteria for a suitable 3′ OH
protecting group, the artisan ‘would have expected to
succeed in combining the teachings of Tsien and Zavgo-
rodny to carry out’” the claimed invention.) (quoting IBS’s
Petition, J.A. 146). In its Petition, IBS first addressed
whether there was a motivation to combine Tsien or Ju
with Zavgorodny and then separately addressed whether
an ordinary artisan would have a reasonable expectation
of success in meeting the limitations of the claimed inven-
tion. J.A. 144–47.
    Illumina disagreed with IBS, and argued that an or-
dinary artisan would not expect the azidomethyl group of
Zavgorodny to meet the specific criteria of Tsien or Ju. In
particular, Tsien requires “quantitative and rapid remov-
al” of the protecting group, which it understands “to mean
essentially 100% removal.” Intelligent Bio-Sys., Inc., 2015
WL 996355, at *5. Prior art of record, however, “demon-
strates that an ordinary artisan would have expected
Zavgorodny’s azidomethyl group to be removed at a much
lower efficiency than required by Tsien’s methods.” Id.
That prior art reference is known as Loubinoux. See J.A.
971–87 (Bernard Loubinoux et al., Protection of Phenols
by the Azidomethylene Group Application to the Synthesis
of Unstable Phenols, 44 TETRAHEDRON 6055 (1988)).
Loubinoux reports a 60–80% removal efficiency for az-
idomethyl groups from phenols using triphenylphosphine.
Intelligent Bio-Sys., Inc., 2015 WL 996355, at *7, *10, *12;
J.A. 974–75. 60–80% removal is not quantitative removal
within the meaning of Tsien or Ju.
    Ultimately, the Board credited Illumina’s argument
that, given Loubinoux, IBS “has not shown, by a prepon-
derance of the evidence, that an ordinary artisan would
have considered it obvious to use Zavgorodny’s azidome-
thyl group as the 3′ hydroxyl protecting group in Tsien’s
processes.” Id. at *5. See also id. at *12 (finding similarly
that IBS failed to establish “that an ordinary artisan
8                           INTELLIGENT BIO-SYSTEMS, INC. v.
                                  ILLUMINA CAMBRIDGE LTD.


would have considered it obvious to use Zavgorodny’s
azidomethyl protecting group in the processes described
in Ju”).
    In discussing the legal requirements of obviousness,
the Board particularly pointed out the requirement for a
reasonable expectation of success:
    [A] conclusion of obviousness requires a reasona-
    ble expectation of success:
       When there is a design need or market
       pressure to solve a problem and there are
       a finite number of identified, predictable
       solutions, a person of ordinary skill has
       good reason to pursue the known options
       within his or her technical grasp. If this
       leads to the anticipated success, it is likely
       the product not of innovation but of ordi-
       nary skill and common sense. In that in-
       stance the fact that a combination was
       obvious to try might show that it was ob-
       vious under § 103.
    [KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 421
    (2007)] (emphases added).
    As the Court of Appeals for the Federal Circuit
    has explained, “[a]lthough predictability is a
    touchstone of obviousness, the ‘predictable result’
    discussed in KSR refers not only to the expecta-
    tion that prior art elements are capable of being
    physically combined, but also that the combina-
    tion would have worked for its intended purpose.”
    Depuy Spine, Inc v. Medtronic Sofamor Danek,
    Inc., 567 F.3d 1314, 1326 (Fed. Cir. 2009) (cita-
    tions omitted).
Id. at *6. The Board further described Tsien and Zavgo-
rodny, stressing that “the Petition does not point to any
specific evidence explaining why an ordinary artisan
INTELLIGENT BIO-SYSTEMS, INC.   v.                        9
ILLUMINA CAMBRIDGE LTD.


would have expected Zavgorodny’s azidomethyl protecting
group to meet” the quantitative deblocking requirement of
Tsien. Id. at *7. And as Loubinoux “discloses that re-
moval of an azidomethyl protecting group from a phenolic
hydroxyl . . . resulted in deprotected phenols ‘as pure
products at a yield between 60 and 80%,’” id. (citing
Loubinoux, J.A. 975), IBS’s “Petition did not provide a
specific or credible explanation why an ordinary artisan
would have expected Zavgorodny’s azidomethyl protecting
group to meet Tsien’s quantitative deblocking require-
ment under conditions suitable for use in Tsien’s sequenc-
ing methods,” id. at *8. 2
     Although the Board’s precise legal underpinnings are
difficult to discern, it appears to have relied on IBS’s
failure to demonstrate (1) a motivation to combine the
relevant references, (2) that a person of ordinary skill
would have a reasonable expectation of success of develop-
ing the claimed invention, or (3) both. The Board’s opin-
ion conflates these legal issues but its ultimate conclusion
is clear. IBS failed to demonstrate that the challenged
claims were obvious under the prior art at issue.
    In reaching its decision, the Board refused to consider
IBS’s reply brief and accompanying expert declaration
because it found that IBS’s reply was improper under two
regulations: first under 37 C.F.R. § 42.23(b), which pro-
vides that a “reply may only respond to arguments raised
in the corresponding opposition or patent owner re-
sponse,” and then under 37 C.F.R. § 42.6(a)(3), which
states that “[a]rguments must not be incorporated by



   2   The Board similarly found that IBS failed to show
by a preponderance of the evidence that the claims of the
’537 patent were obvious over Ju in combination with
Zavgorodny under the same reasoning. Id. at *10–12.
10                         INTELLIGENT BIO-SYSTEMS, INC. v.
                                 ILLUMINA CAMBRIDGE LTD.


reference from one document into another document.” See
Intelligent Bio-Sys., Inc., 2015 WL 996355, at *8–9.
    According to the Board, IBS ran afoul of § 42.23(b) by
presenting a new argument for the first time in its reply
brief. “[T]he Reply presents new issues by changing the
unpatentability rationale from express reliance on Zavgo-
rodny’s deprotecting conditions, to asserting that those
conditions would have been obvious to modify, as well as
presenting new evidence to support the new rationale and
explain the modifications to Zavgorodny.” Id. at *9.
    The reply, moreover, was accompanied by an expert
declaration. According to the Board, the expert declara-
tion “expands on the assertions in the Reply by presenting
a number of additional new arguments explaining why
quantitative deblocking would have been expected, and
cites a number of non-patent literature references which
were not relied upon to support unpatentability in the
Petition.” Id. That expert declaration, the Board found,
contains “in-depth explanations and supporting documen-
tary evidence” not contained in the reply itself. Id. In
this way, the Board found, IBS ran afoul of § 42.6(a)(3) by
improperly incorporating by reference arguments and
evidence from the expert declaration into the reply brief.
     IBS now challenges the Board’s conclusion that IBS
failed to demonstrate the challenged claims were obvious
by a preponderance of the evidence. IBS also argues the
Board abused its discretion to the extent it found IBS’s
reply brief improper.
    We have jurisdiction       pursuant   to   28   U.S.C.
§ 1295(a)(4)(A).
                       DISCUSSION
    Obviousness is a mixed question of fact and law. Alt-
hough the Board’s ultimate conclusion that the claims are
not obvious is a legal determination subject to de novo
review, the subsidiary factual findings are reviewed for
INTELLIGENT BIO-SYSTEMS, INC.   v.                       11
ILLUMINA CAMBRIDGE LTD.


substantial evidence. In re Gartside, 203 F.3d 1305, 1312,
1316 (Fed. Cir. 2000). “Substantial evidence is more than
a mere scintilla.” Consol. Edison Co. v. N.L.R.B., 305 U.S.
197, 229 (1938).      Substantial evidence review asks
“whether a reasonable fact finder could have arrived at
the agency’s decision” and requires examination of the
“record as a whole, taking into account evidence that both
justifies and detracts from an agency’s decision.” In re
Gartside, 203 F.3d at 1312.
     “The presence or absence of a motivation to combine
references in an obviousness determination is a pure
question of fact.” Par Pharm., Inc. v. TWI Pharm., Inc.,
773 F.3d 1186, 1196 (Fed. Cir. 2014) (citations omitted).
“The presence or absence of a reasonable expectation of
success is also a question of fact.” Id. Accordingly, the
substantial evidence standard of review applies to the
Board’s resolution of these factual determinations. The
Court can review de novo, however, whether the Board
“fail[ed] to consider the appropriate scope of
the . . . patent’s claimed invention in evaluating the
reasonable expectation of success.” Allergan, Inc. v.
Apotex Inc., 754 F.3d 952, 966 (Fed. Cir. 2014).
    Decisions related to compliance with the Board’s pro-
cedures are reviewed for an abuse of discretion. Bilstad v.
Wakalopulos, 386 F.3d 1116, 1121 (Fed. Cir. 2004). “An
abuse of discretion is found if the decision: (1) is clearly
unreasonable, 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 Board could rationally base its
decision.” Id. Accordingly, the Board’s determinations
that IBS exceeded the scope of a proper reply in violation
of 37 C.F.R. § 42.23(b) and improperly incorporated
arguments by reference from another document in viola-
tion of 37 C.F.R. § 42.6(a)(3) are reviewed for an abuse of
discretion.
12                          INTELLIGENT BIO-SYSTEMS, INC. v.
                                  ILLUMINA CAMBRIDGE LTD.


          A. Motivation to Combine/Reasonable
                 Expectation of Success
    The Board found that Zavgorodny would not be “obvi-
ous to use” with Tsien or Ju because its azidomethyl
group would not be removed quantitatively (at or near
100%). Intelligent Bio-Sys., Inc., 2015 WL 996355, at *5,
*12. IBS argues that, “[b]ecause the claims do not require
quantitative cleavage, the Board erred by imposing such a
requirement through the reasonable expectation of suc-
cess analysis.” Appellant Br. 38. To the extent the
Board’s decision is based on the “reasonable expectation of
success” requirement, we agree.
    The reasonable expectation of success requirement re-
fers to the likelihood of success in combining references to
meet the limitations of the claimed invention. “[F]ailure
to consider the appropriate scope of the . . . patent’s
claimed invention in evaluating the reasonable expecta-
tion of success . . . constitutes a legal error that [is] re-
view[ed] without deference.” Allergan, 754 F.3d at 966
(emphasis added). Under the Board’s uncontested con-
struction, “claim 1 does not require removal of the protect-
ing group to allow subsequent nucleotide incorporation,”
let alone quantitative removal. Intelligent Bio-Sys., Inc.,
2015 WL 996355, at *4. Accordingly, it is of no moment
that Zavgorodny’s protecting group would not be removed
quantitatively in Tsien or Ju’s sequencing method—
removal is simply not required by the claim of the ’537
patent. The Board seemed to believe that the “reasonable
expectation of success” inquiry looked to whether one
would reasonably expect the prior art references to oper-
ate as those references intended once combined. That is
not the correct inquiry—one must have a motivation to
combine accompanied by a reasonable expectation of
achieving what is claimed in the patent-at-issue. The
Board’s reliance on the absence of a reasonable expecta-
tion of success was, thus, improper. See id. at *5–6 (citing
KSR, 550 U.S. at 421 to support the proposition “that a
INTELLIGENT BIO-SYSTEMS, INC.   v.                        13
ILLUMINA CAMBRIDGE LTD.


conclusion of obviousness requires a reasonable expecta-
tion of success”).

    Yet this court “sit[s] to review judgments, not opin-
ions.” Stratoflex, Inc. v. Aeroquip Corp., 713 F.2d 1530,
1540 (Fed. Cir. 1983). And while the Board conflated two
different legal concepts—reasonable expectation of suc-
cess and motivation to combine—it nevertheless made
sufficient factual findings to support its judgment that the
claims at issue are not invalid. It was IBS’s burden to
demonstrate both “that a skilled artisan would have been
motivated to combine the teachings of the prior art refer-
ences to achieve the claimed invention, and that the
skilled artisan would have had a reasonable expectation
of success in doing so.” Kinetic Concepts, Inc. v. Smith &
Nephew, Inc. 688 F.3d 1342, 1360 (Fed. Cir. 2012) (quot-
ing Procter & Gamble Co. v. Teva Pharm. USA, Inc., 566
F.3d 989, 994 (Fed. Cir. 2009) (internal quotation marks
omitted)); In re Cyclobenzaprine Hydrochloride Extended–
Release Capsule Patent Litig., 676 F.3d 1063, 1068–69
(Fed. Cir. 2012). Despite the loose language employed by
the Board, its factual findings support its conclusion that
the claims are not invalid.
    IBS argued in its revised initial petition to the Board
that the combination of Tsien or Ju with Zavgorodny was
based entirely on a shared purpose: SBS. IBS argued that
an ordinary artisan would have a motivation to combine
Tsien or Ju with Zavgorodny: “[O]ne of ordinary skill in
the art, in order to improve the efficiency, reliability, and
robustness of the sequencing by synthesis method taught in
Tsien, would have been motivated to use other protecting
groups that meet the criteria of Tsien, such as the az-
idomethyl group taught by Zavgorodny.” J.A. 145 (em-
phasis added). This argument follows immediately after
IBS lists the “criteria for the successful use of 3′-blocking
groups,” which includes “quantitative deblocking.” J.A.
144.
14                          INTELLIGENT BIO-SYSTEMS, INC. v.
                                  ILLUMINA CAMBRIDGE LTD.


    The Board, therefore, was justified in finding that,
“despite having acknowledged the quantitative deblocking
requirement in Tsien (Pet. 37), the Petition did not pro-
vide a specific or credible explanation why an ordinary
artisan would have expected Zavgorodny’s azidomethyl
protecting group to meet Tsien’s quantitative deblocking
requirement under conditions suitable for use in Tsien’s
sequencing methods.” Intelligent Bio-Sys., Inc., 2015 WL
996355, at *8. While this shortcoming is irrelevant to a
finding that there was no reasonable expectation of suc-
cess in meeting the claims of the ’537 patent, which do not
require quantitative deblocking at all, it is central to a
finding of no motivation to combine. This is because the
petitioner’s sole argument for why one of skill in the art
would be motivated to combine Zavgorodny’s azidomethyl
group with Tsien’s SBS method was because it would
meet Tsien’s quantitative deblocking requirement. “When
an obviousness determination relies on the combination of
two or more references, there must be some suggestion or
motivation to combine the references.” WMS Gaming,
Inc. v. Int’l Game Tech., 184 F.3d 1339, 1355 (Fed. Cir.
1999); see also Dome Patent L.P. v. Lee, 799 F.3d 1372,
1380 (Fed. Cir. 2015) (“If all elements of a claim are found
in the prior art, as is the case here, the factfinder must
further consider the factual questions of whether a person
of ordinary skill in the art would be motivated to combine
those references, and whether in making that combina-
tion, a person of ordinary skill would have had a reasona-
ble expectation of success.”).
    There is, moreover, substantial evidence to support a
finding that a person of ordinary skill would not have had
reason to combine Tsien or Ju with Zavgorodny to achieve
the claimed invention. In its decision the Board acknowl-
edged two background references presented by Illumina:
Loubinoux, which teaches that azidomethyl methyl
groups are removed from phenols with modest efficiency
(60-80% yield), and Greene & Wuts, which teaches that
INTELLIGENT BIO-SYSTEMS, INC.   v.                         15
ILLUMINA CAMBRIDGE LTD.


removal of an azidomethyl methyl group from the 3′
hydroxyl position of a deoxyribonucleotide moiety is likely
to proceed with even lower efficiency.        Intelligent Bio-
Sys., Inc., 2015 WL 996355, at *7–8 (citing Loubinoux
(J.A. 974–75) and Theodora W. Greene & Peter G.M.
Wuts, Protective Groups in Organic Synthesis 246–92 (3d
ed. 1999) (J.A. 863–970)). These references support a
conclusion that the claimed efficiency that allegedly
motivated the combination would not be achieved and
that a person of ordinary skill in this field would not have
been motivated to use the azidomethyl group of Zavgo-
rodny as a “protecting group [that] can be modified or
removed to expose a 3′ [hydroxyl] group” of a nucleic acid
molecule, as the claim requires. This is so because the
azidomethyl group would have been expected to perform
inefficiently in that role.
    IBS submitted an initial petition that articulated a set
of rationales for why the challenged claims were invalid,
including why a person of ordinary skill would be moti-
vated to combine the prior art references at issue. IBS
made a clear argument as to why a person of ordinary
skill would be motivated to combine the prior art refer-
ences at issue and Illumina demonstrated the error in
that argument, which the Board credited. This factual
finding by the Board is supported by substantial evidence.
The Board did not err in finding that the grounds of
invalidity described in IBS’s petition were not established.
              B. IBS’s Improper Reply Brief
    IBS also argues that “the Board must consider wheth-
er it is within the skill of the ordinary artisan to modify
the cleavage conditions to satisfy the alleged cleavage
requirements.” Appellant Br. 44. The Board did not
consider this argument, however, because it was raised
for the first time in IBS’s reply brief and expert declara-
tion.
16                          INTELLIGENT BIO-SYSTEMS, INC. v.
                                  ILLUMINA CAMBRIDGE LTD.


     It is of the utmost importance that petitioners in the
IPR proceedings adhere to the requirement that the
initial petition identify “with particularity” the “evidence
that supports the grounds for the challenge to each
claim.” 35 U.S.C. § 312(a)(3). “All arguments for the
relief requested in a motion must be made in the motion.
A reply may only respond to arguments raised in the
corresponding opposition or patent owner response.” 37
C.F.R. § 42.23(b). Once the Board identifies new issues
presented for the first time in reply, neither this court nor
the Board must parse the reply brief to determine which,
if any, parts of that brief are responsive and which are
improper. As the Board noted, “it will not attempt to sort
proper from improper portions of the reply.” Office Patent
Trial Practice Guide, 77 Fed. Reg. 48,756, 48,767 (Aug.
14, 2012).
     IBS argued in its petition that “Zavgorodny teaches
the desired property [in Tsien] that the azidomethyl group
‘can be removed under very specific and mild conditions.’”
J.A. 145–46 (quoting Zavgorodny, J.A. 861). Illumina
presented evidence in its response that, “an ordinary
artisan would not have considered Zavgorodny’s condi-
tions suitably mild for Tsien’s sequencing purposes.” Id.
IBS’s reply then argued, for the first time, “that an ordi-
nary artisan would have considered it obvious to use
deprotecting conditions other than those described in
Zavgorodny.” Id. But IBS chose which grounds of inva-
lidity to assert in its petition and it chose not to assert
this new one. Unlike district court litigation—where
parties have greater freedom to revise and develop their
arguments over time and in response to newly discovered
material—the expedited nature of IPRs bring with it an
obligation for petitioners to make their case in their
petition to institute. While the Board’s requirements are
strict ones, they are requirements of which petitioners are
aware when they seek to institute an IPR.
INTELLIGENT BIO-SYSTEMS, INC.   v.                       17
ILLUMINA CAMBRIDGE LTD.


     IBS supported its new theory of invalidity by refer-
ence to new evidence, citing “a number of non-patent
literature references which were not relied upon to sup-
port unpatentability in the Petition.” Id. at *9. See Office
Patent Trial Practice Guide, 77 Fed. Reg. at 48,767 (“Ex-
amples of indications that a new issue has been raised in
a reply include new evidence necessary to make out a
prima facie case for the . . . unpatentability of an origi-
nal . . . claim, and new evidence that could have been
presented in a prior filing.”). In these circumstances, we
find that the Board did not err in refusing the reply brief
as improper under 37 C.F.R. § 42.23(b) because IBS relied
on an entirely new rationale to explain why one of skill in
the art would have been motivated to combine Tsien or Ju
with a modification of Zavgorodny.
    Because we conclude that the reply brief and accom-
panying declaration exceeded the scope of the reply under
§ 42.23(b), and, therefore, that the Board did not abuse its
discretion in excluding those documents, we need not
resolve whether the reply brief complied with 37 C.F.R.
§ 42.6(a)(3), which states that “[a]rguments must not be
incorporated by reference from one document into another
document.”      See Intelligent Bio-Sys., Inc., 2015 WL
996355, at *9. Nor do we review the Board’s conclusion
that, even if proper, the arguments contained in the reply
brief are unpersuasive for the same reason it found the
arguments in the petition unpersuasive. Id. at *10.
                       CONCLUSION
    We find the Board’s conclusion that IBS failed to
demonstrate by a preponderance of the evidence that the
challenged claims of the ’537 patent are invalid as obvious
over the combination of Tsien and Zavgorodny or Ju and
Zavgorodny is supported by substantial evidence. Be-
cause the Board correctly determined that IBS failed to
carry its burden to establish obviousness of the challenged
claims, and because the Board did not abuse its discretion
18                        INTELLIGENT BIO-SYSTEMS, INC. v.
                                ILLUMINA CAMBRIDGE LTD.


in finding that IBS’s reply brief and accompanying decla-
ration were improper, we need not address IBS’s other
arguments. Accordingly, we affirm the Board.
                      AFFIRMED
