  United States Court of Appeals
      for the Federal Circuit
                ______________________

  NOVARTIS AG, MITSUBISHI PHARMA CORP.,
                 Appellants

                          v.

  TORRENT PHARMACEUTICALS LIMITED,
APOTEX INC., MYLAN PHARMACEUTICALS INC.,
                    Appellees
             ______________________

                      2016-1352
                ______________________

    Appeal from the United States Patent and Trademark
Office, Patent Trial and Appeal Board in Nos. IPR2014-
00784, IPR2015-00518.
                 ______________________

                Decided: April 12, 2017
                ______________________

   ROBERT TRENCHARD, Gibson, Dunn & Crutcher LLP,
New York, NY, argued for appellants. Appellant Novartis
AG also represented by JANE M. LOVE; MICHAEL A. VALEK,
Dallas, TX; ALEXANDER N. HARRIS, San Francisco, CA.

    JOSEPH M. O'MALLEY, JR., Paul Hastings LLP, New
York, NY, for appellant Mitsubishi Pharma Corp. Also
represented by ERIC WILLIAM DITTMANN.
2                 NOVARTIS AG   v. TORRENT PHARMACEUTICALS



    TERESA STANEK REA, Crowell & Moring, LLP, Wash-
ington, DC, argued for appellees. Appellee Apotex Inc.
also represented by VINCENT JOHN GALLUZZO; JONATHAN
M. LINDSAY, Irvine, CA.

   MICHAEL K. LEVY, Andrews Kurth Kenyon LLP, New
York, NY, for appellee Torrent Pharmaceuticals Limited.

    SHANNON BLOODWORTH, Perkins Coie, LLP, Washing-
ton, DC, for appellee Mylan Pharmaceuticals Inc. Also
represented by BRANDON MICHAEL WHITE; DAN L.
BAGATELL, Hanover, NH.
                ______________________

     Before TARANTO, CHEN, and STOLL, Circuit Judges.
CHEN, Circuit Judge.
     This is an appeal from the Final Written Decision of
the United States Patent and Trademark Office, Patent
Trial and Appeal Board (Board) in two consolidated inter
partes review (IPR) proceedings of U.S. Patent No.
8,324,283 (the ’283 patent), owned by Novartis AG and
Mistubishi Tanabe Pharma Corp. (collectively, Novartis).
The Board instituted IPRs on all claims of the ’283 patent
based on petitions filed by Torrent Pharmaceuticals
Limited, Apotex, Inc. and Mylan Pharmaceuticals Inc.
(collectively, Petitioners). After reviewing the claims,
receiving extensive briefing, and hearing oral argument,
the Board found all original claims of the ’283 patent and
Novartis’ proposed substitute claims unpatentable as
obvious. See Torrent Pharm. Ltd. v. Novartis AG, Nos.
IPR2014-00784, IPR2015-00518, 2015 WL 5719630
(PTAB Sept. 24, 2015) (Final Written Decision). Novartis
raises a series of challenges to the Board’s analysis of the
evidence and ultimate determination of unpatentability.
For the reasons stated below, we affirm.
NOVARTIS AG   v. TORRENT PHARMACEUTICALS                    3



                       BACKGROUND
                              I.
    The ’283 patent relates to a solid pharmaceutical
composition suitable for oral administration, comprising a
sphingosine-1 phosphate (S1P) receptor agonist and a
sugar alcohol, which the patent explains is useful for the
treatment of certain autoimmune diseases such as multi-
ple sclerosis. ’283 patent, col. 1, lines 11–14, 33–35; col.
12, lines 19–49. According to the specification, S1P
receptor agonists generally exhibit properties that make
formulations suitable for oral administration of a solid
composition difficult to create. However, “solid composi-
tions comprising a sugar alcohol provide formulations
which are particularly well suited to the oral administra-
tion of S1P receptor agonists.” See id. at col. 1, lines 36–
39. They also “provide a convenient means of systemic
administration of S1P receptor agonists, do not suffer
from the disadvantages of liquid formulations for injection
or oral use, and have good physiocochemical and storage
properties.” Id. at col. 1, lines 39–43. In such a composi-
tion, the S1P receptor agonist is the active ingredient and
the sugar alcohol acts as an excipient—the substance
formulated alongside the active ingredient as a diluent,
carrier, filler and/or bulking agent for the composition.
See id. at col. 9, lines 53–54.
    The ’283 patent states that there are multiple known
S1P receptor agonists appropriate for use in the claimed
invention, set forth in the specification as formulas I–XIII.
Id. at col. 1, line 51 to col. 8, line 4. The ’283 patent also
states that a “particularly preferred S1P receptor agonist
of formula I is FTY720, i.e., 2-amino-2-[2-(4-octylphenyl)
ethyl]propane-1,3-diol in free form or in a pharmaceutical-
ly acceptable salt form . . . .” Id. at col. 8, lines 23–26.
FTY720 is also known as fingolimod. The ’283 patent
further discloses that the specific sugar alcohol used in
the claimed composition “may suitably be mannitol,”
4                 NOVARTIS AG   v. TORRENT PHARMACEUTICALS



because of its non-hygroscopic properties (i.e., it is not
likely to absorb moisture, which is beneficial in manufac-
turing solid oral pills). Id. at col. 9, lines 53–54.
   Claims 1 and 19 of the ’283 patent are the only inde-
pendent claims and are illustrative of the claimed subject
matter:
    1. A solid pharmaceutical composition suitable for
    oral administration, comprising:
        (a) a S1P receptor agonist which is select-
        ed     from      2-amino-2-[2-(4-octylpheny
        l)ethyl]propane-1,3-diol, 2-amino-2-[4-(3-
        benzyloxyphenoxy)-2-chloropheny
        l]propyl-1,3-propane-diol, 2-amino-2-[4-(3-
        benzyloxyphenylthio)-2-
        chlorophenyl]propyl-1,3-propane-diol, or 2-
        amino-2-[4-(3-benzyloxyphenylthio)-2-
        chlorophenyl]-2-ethyl-1,3-propane-diol,
        and its phosphates or a pharmaceutically
        acceptable salt thereof; and
        (b) a sugar alcohol.
    19. A solid pharmaceutical composition suitable
    for oral administration, comprising mannitol and
    2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol
    or a pharmaceutically acceptable salt thereof.
Id. at col. 17, lines 2–11; col. 18, lines 7–10. Thus, claim 1
is directed towards a solid oral composition comprised of
the combination of one of a handful of S1P receptor ago-
nists and any sugar alcohol, whereas claim 19 is directed
towards the specific combination of fingolimod and man-
nitol in a solid oral composition.
    The dependent claims are directed towards various re-
finements of the composition, including for example, the
addition of a lubricant:
NOVARTIS AG   v. TORRENT PHARMACEUTICALS                   5



    20. A composition according to claim 19, further
    comprising a lubricant.
Id. at col. 18, lines 11–12. Other claims are directed
towards adjusting the respective amount of ingredients:
    22. A composition according to claim 19, wherein
    the           compound              2-amino-2-[2-(4-
    octylphenyl)ethyl]propane-1,3-diol, or a pharma-
    ceutically acceptable salt thereof, is present in an
    amount of 0.5 to 5% by weight, based on the total
    weight of the composition.
    23. A composition according to claim 19, wherein
    mannitol is present in an amount of 90 to 99.5%
    by weight, based on the total weight of the compo-
    sition.
Id. at col. 18, lines 15–22.
    While the application leading to the ’283 patent was
pending at the Patent Office, Novartis applied to the U.S.
Food and Drug Administration (FDA) for approval to sell
a fingolimod-mannitol pill to treat multiple sclerosis
under the “Gilenya” brand name. The FDA approved
Gilenya for the treatment of multiple sclerosis in 2010.
                               II.
    On May 27, 2014, Torrent filed a petition to institute
an inter partes review of claims 1–32 of the ’283 patent.
Torrent’s petition presented three separate patentability
challenges:
    1. claims 1–32 are unpatentable as obvious over
    the combination of U.S. Patent No. 6,004,565
    (Chiba) and Pharmaceutics: The Science of Dosage
    Form Design (Aulton); and
    2. claims 1–4, 7, 8, 19, 22 and 32 are unpatenta-
    ble as anticipated by U.S. Patent No. 6,277,888
    (Sakai); and
6                 NOVARTIS AG   v. TORRENT PHARMACEUTICALS



    3. claims 1–32 are unpatentable as obvious over
    Chiba and Sakai.
    Chiba teaches the use of immunosuppressive com-
pounds with fingolimod as the preferred species. J.A.
18442. 1 Chiba also teaches that these immunosuppres-
sive compounds are useful for treating “autoimmune
diseases such as . . . multiple sclerosis,” among other
diseases and conditions. J.A. 18443. Chiba goes on to
disclose oral administration of fingolimod, including
“admix[ing] with [a] carrier, excipient, diluent, and so on
and formulat[ion] into . . . capsules [or] tablets . . . for
administering to patients.” J.A. 18444. In discussing the
preparation of these capsules and tablets for oral admin-
istration of fingolimod, Chiba teaches that “pharmaceuti-
cally or physiologically acceptable carriers or excipients
for use with the . . . compounds noted herein are known in
the art or can be readily found by methods and tests
known in the art.” J.A. 18446. In other words, Chiba
teaches a solid oral composition of fingolimod combined
with a generic excipient.
    Aulton teaches the use of tablets and capsules to ad-
minister drugs orally. J.A. 19041. It specifically teaches
that “[t]he successful formulation of a stable and effective
solid dosage form depends on the careful selection of the
excipients which are added to facilitate administration,
promote the consistent release and bioavailability of the
drug and protect it from degradation.” J.A. 19066–167.
Aulton recommends mannitol as a common diluent used
in “[t]ableting by the wet granulation process,” which
Aulton describes as “the most widely used method for
pharmaceutical materials.” J.A. 19074–77. Aulton de-
scribes mannitol as “expensive,” but “commonly used” as
an excipient in solid oral compositions. J.A. 19077.


    1    Citations to “J.A. ____” refer to the Joint Appendix
filed by the parties.
NOVARTIS AG   v. TORRENT PHARMACEUTICALS                  7



    Sakai describes a pharmaceutical composition con-
taining fingolimod as an active ingredient. J.A. 18421.
More particularly, Sakai discloses that the composition
can be formulated into a liquid preparation, or can be a
solid lyophilized (freeze-dried) product. J.A. 18421–22.
Sakai further discloses that the addition of a saccharide,
such as sugar alcohol, to the composition can result in a
less irritating resulting liquid solution. J.A. 18421. Sakai
discloses a list of eight exemplary saccharides, including
mannitol. J.A. 18422. The saccharide, such as mannitol,
can be dissolved in the liquid for dissolution, or alterna-
tively may be contained in the lyophilized product along
with the active ingredient. J.A. 18422. Sakai teaches
that this liquid pharmaceutical composition can be used
for immunosuppression in connection with organ or bone
marrow transplantation, autoimmune diseases, or allergic
diseases. Id. In short, Sakai teaches the specific combi-
nation of fingolimod and mannitol for a liquid formula-
tion.
                            III.
    On December 1, 2014, the Board granted in part Tor-
rent’s petition and instituted trial to review patentability
of the challenged claims in IPR2014-00784. Specifically,
the Board instituted on the first ground, the combination
of Chiba and Aulton, but declined to institute on grounds
two or three. The Board found that Chiba discloses the
use of fingolimod in a solid formulation for oral admin-
istration when combined with conventional excipients. It
then found that Aulton teaches the use of mannitol as a
conventional excipient that a person of skill in the art
would have looked to when formulating a solid composi-
tion with fingolimod.
    The Board found Sakai to be an improper anticipatory
reference because the reference does not describe a solid
composition suitable for oral administration. It then
rejected the grounds predicated on the combination of
8                 NOVARTIS AG   v. TORRENT PHARMACEUTICALS



Chiba and Sakai for similar reasons, noting that, unlike
Aulton, “Sakai does not identify mannitol as a ‘conven-
tional excipient’ in solid pharmaceutical compositions,
and Sakai’s stated reasons for using mannitol in liquid
pharmaceutical compositions are inapplicable to its
potential use in connection with solid pharmaceutical
compositions.” J.A. 72.
    Apotex and Mylan thereafter filed a separate petition
seeking to institute an IPR of claims 1–32 of the ’283
patent based on the already-instituted Chiba/Aulton
grounds and requested joinder with the Torrent proceed-
ings. On February 17, 2015, the Board instituted trial in
this follow-on proceeding in IPR2015-00518 and joined it
with the Torrent proceeding.
     After briefing and oral argument, the Board issued its
Final Written Decision in the consolidated proceeding.
The Board concluded that Chiba and Aulton collectively
teach each limitation of claims 1–32 of the ’283 patent. It
first addressed claim 19, directed towards the specific
combination of fingolimod and mannitol. The Board
found that Chiba and Aulton together strongly suggested
the claimed two-ingredient combination:
    First, Chiba teaches that a person of ordinary
    skill in the art would have been able to identify or
    easily determine excipients that would have been
    compatible with fingolimod . . . (“pharmaceutically
    or physiologically acceptable carriers or excipients
    for use with the . . . compounds noted herein are
    known in the art or can be readily found by meth-
    ods and tests known in the art”). Second, Aulton
    teaches that mannitol is not only a known diluent
    for direct compression manufacturing, but also
    commonly used in wet granulation, which Aulton
    teaches is “the most widely used method for
    pharmaceutical materials.” . . . This combination
    of teachings already strongly suggests that man-
NOVARTIS AG   v. TORRENT PHARMACEUTICALS                   9



   nitol likely would have been a target of investiga-
   tion for a person of ordinary skill in the art inter-
   ested in finding an excipient compatible with
   fingolimod . . . .
Final Written Decision, 2015 WL 5719630, at *8. After
finding that the two references themselves strongly
suggested the claimed invention, the Board expressly
found “additional evidence of the reason to combine
fingolimod and mannitol.” Id. First, the Board noted that
Sakai “directly instructs that the two ingredients should
be combined.” Id. Although Novartis argued in its briefs
below that Sakai’s teaching is narrowly limited to liquid-
phase pharmaceutical compositions, as opposed to the
claimed solid oral dosage forms, the Board observed that
Novartis’ own expert, Dr. Stephen Byrn, had written an
article describing how “solution studies can be very help-
ful” in understanding drug degradations in the solid state.
Id. Despite Novartis’ attempt to minimize the article’s
meaning, the Board concluded that “a suggestion to
combine ingredients in the liquid phase would have been
relevant to the determination of a person of ordinary skill
in the art to combine the same ingredients in the solid
phase.” Id.
    Acknowledging that it had denied instituting the IPR
based on Sakai alone (per § 102) or in combination with
Chiba (per § 103), the Board distinguished its final deci-
sion’s usage of Sakai, explaining that its final decision
simply relied on Sakai as a background reference that
offered additional motivation evidence to combine Chiba
with Aulton. The Board explained that even though
Sakai did not “teach that mannitol is a conventional
excipient for use in solid pharmaceutical compositions,”
id., the record evidence relating to Dr. Byrn’s article,
which was debated by the parties, supported a finding
that “Sakai’s teaching would have been relevant to the
decision on which excipient to use in formulating a solid
oral dosage form of fingolimod.” Id.
10                 NOVARTIS AG   v. TORRENT PHARMACEUTICALS



    The Board went on to find that several additional
background references in the proceeding demonstrate
that mannitol provides advantages when used as a dilu-
ent in tableting, further supporting a reason to combine.
The Board concluded its motivation to combine analysis:
     Given (1) the knowledge in the art that mannitol
     provided advantages in formulating tablets gen-
     erally, (2) Chiba’s teaching that a person of ordi-
     nary skill in the art would have been able to
     identify or easily determine excipients that would
     have been compatible with fingolimod, (3) Aulton’s
     teaching that mannitol was a diluent commonly
     used in the most common form of pharmaceutical
     manufacture, (4) Sakai’s teaching that mannitol
     and fingolimod should be combined in the liquid
     phase, and (5) Dr. Byrn’s statement that liquid-
     phase compatibility was relevant to the prediction
     of solid-phase compatibility, we conclude that Pe-
     titioners have shown a reason to combine the
     teachings of Chiba and Aulton.
Id. at *9.
    The Board next turned to the objective indicia of non-
obviousness. First, it found that independent claims 1
and 19 were “not commensurate in scope” with the pur-
ported unexpected result of fingolimod’s low concentration
stability when combined with mannitol, because the
independent claims are “not limited to any particular dose
or dose range of fingolimod.” Id. at *10. Therefore, the
Board concluded, “even if the stability of the mannitol-
fingolimod combination at low doses was unexpected, it is
insufficient to support a legally significant finding of
unexpected results.” Id. at *11. The Board also rejected
Novartis’ long-felt but unsolved need, industry praise, and
commercial success arguments because all of Novartis’
proffered evidence was directed solely toward the fact that
NOVARTIS AG   v. TORRENT PHARMACEUTICALS                11



Gilenya was a solid oral multiple sclerosis treatment,
which was already known in the prior art.
    The Board then analyzed the dependent claims in
turn. Relevant to this appeal, the Board turned to de-
pendent claims 8, 10, 22, and 23, and proposed amended
claims 40, 42, 54, and 55, directed towards concentrations
with low percentages of fingolimod by weight. The Board
found that “Petitioners provide evidence that the selection
of the relative amounts of the constituents of the claimed
formulation is the result of routine optimization.” Id. at
*16. It further noted, “[w]e have not been directed to any
evidence of record contradicting this evidence, so we find
that a person of ordinary skill in the art familiar with
Chiba and Aulton would have been able and motivated to
optimize the amount of fingolimod . . .” Id.
    In conclusion, the Board held every claim unpatenta-
ble as obvious and denied Novartis’ motion to amend for
essentially the same reasons it rejected the original
claims. Appellants timely appealed. We have jurisdiction
under 28 U.S.C. § 1295(a)(4)(A).
                        DISCUSSION
     We review Board decisions using the standard set
forth in the Administrative Procedure Act (APA), 5 U.S.C.
§ 706. In re Sullivan, 362 F.3d 1324, 1326 (Fed. Cir.
2004) (citing Dickinson v. Zurko, 527 U.S. 150, 154
(1999)); see also Belden Inc. v. Berk–Tek LLC, 805 F.3d
1064, 1080 (Fed. Cir. 2015). Under the APA, we must
“hold unlawful and set aside agency action . . . not in
accordance with law [or] . . . without observance of proce-
dure required by law.” 5 U.S.C. § 706.
    We review the Board’s legal conclusions de novo but
review for substantial evidence any underlying factual
determinations. See Nike, Inc. v. Adidas AG, 812 F.3d
1326, 1332 (Fed. Cir. 2016); In re Giannelli, 739 F.3d
1375, 1378–79 (Fed. Cir. 2014). Substantial evidence is
12                NOVARTIS AG   v. TORRENT PHARMACEUTICALS



“such relevant evidence as a reasonable mind might
accept as adequate to support a conclusion.” Consol.
Edison Co. v. NLRB, 305 U.S. 197, 229 (1938); see In re
Applied Materials, Inc., 692 F.3d 1289, 1294 (Fed. Cir.
2012).
    On appeal, Novartis first contends that the Board vio-
lated the APA when it relied on Sakai in the Final Writ-
ten Decision without affording Novartis proper notice and
a chance to be heard. Novartis goes on to argue that the
Board also erred on the merits, specifically in its analysis
of the motivation to combine evidence and in its treat-
ment of the alleged objective indicia of nonobviousness.
                   I.     APA Due Process
    We first turn to Novartis’ argument that the Board
violated the requirements of notice and an opportunity to
respond found in the APA when it used the Sakai refer-
ence as part of its motivation to combine analysis in the
Final Written Decision. According to Novartis, the Board
ruled Sakai entirely out of the case in the Institution
Decision, and on that basis, denied institution of the two
proposed grounds based on Sakai. Novartis contends that
it relied on that ruling and consequently submitted a
“vastly different” record than it would have if it had
known Sakai was still a live issue.
    In a formal adjudication, such as an IPR, the APA im-
poses certain procedural requirements on the agency.
The Patent and Trademark Office, including the Board,
must provide the patent owner with timely notice of “the
matters of fact and law asserted,” and an opportunity to
submit facts and argument. 5 U.S.C. §§ 554(b)–(c), 557(c);
Dell Inc. v. Acceleron, LLC, 818 F.3d 1293, 1301 (Fed. Cir.
2016). The notice and opportunity to be heard provisions
of the APA have been applied “to mean that ‘an agency
may not change theories in midstream without giving
respondents reasonable notice of the change’ and ‘the
opportunity to present argument under the new theory.’”
NOVARTIS AG   v. TORRENT PHARMACEUTICALS                  13



Belden, 805 F.3d at 1080 (quoting Rodale Press, Inc. v.
FTC, 407 F.2d 1252, 1256–57 (D.C. Cir. 1968)). In this
case we conclude that the relevant APA provisions were
satisfied.
                             A.
    We first disagree with Novartis that the Board ruled
Sakai out of the case entirely in the Institution Decision.
In the Institution Decision, the Board declined to read
Sakai as an anticipatory reference or primary obviousness
reference because Sakai does not disclose “mannitol as a
‘conventional excipient’ in solid pharmaceutical composi-
tions, and Sakai’s stated reasons for using mannitol in
liquid pharmaceutical compositions are inapplicable to its
potential use in connection with solid pharmaceutical
compositions.” J.A. 72. In other words, although Sakai
discloses the combination of fingolimod and mannitol, it
does not expressly disclose the combination in a solid
pharmaceutical composition nor does its teaching of a
liquid composition necessarily translate to a solid oral
composition.
     This conclusion, however, is not contrary to the
Board’s discussion of Sakai in the Final Written Decision
that Sakai’s teachings would have nevertheless been
relevant to one of skill in the art in deciding which excipi-
ents to use in formulating a solid oral dosage form of
fingolimod. Having already found that Chiba and Aulton
strongly suggest the combination of fingolimod and man-
nitol in a solid oral composition, the Board found that
Sakai merely reinforced its finding that the person of
ordinary skill in the art would have expected mannitol to
be compatible with fingolimod because Sakai discloses a
stable combination of these two ingredients suitable for
long-term preservation. The Board’s discussion of Sakai
in the Final Written Decision was not inconsistent with
its review of Sakai in the Institution Decision.
14                NOVARTIS AG   v. TORRENT PHARMACEUTICALS



                            B.
    We also reject as unfounded Novartis’ complaints of
“surprise” and contention that, following the Institution
Decision, the parties “paid Sakai scant attention in sub-
sequent proceedings.” The parties debated Sakai at
length throughout the proceeding and in the same context
that it was discussed by the Board in the Final Written
Decision.
    As an initial matter, we note that in addition to as-
serting Sakai as a primary reference, Torrent’s petition
also argued that several references, including Sakai,
further support the motivation to combine the teachings
of Chiba and Aulton. Specifically, Torrent argued in
connection with the combination of Chiba and Aulton that
“Sakai (Ex. 1005) reinforced the expectation to the ordi-
narily-skilled artisan that mannitol would have been
compatible with FTY720 [fingolimod] because Sakai
discloses pharmaceutical injectable compositions contain-
ing FTY720 [fingolimod] and mannitol in solution, as well
as lyophilized product meant for long-term preservation
in vials containing FTY720 [fingolimod] and mannitol.”
J.A. 6832. And in support of their petition, Apotex and
Mylan also explained that Sakai would direct the person
of ordinary skill in the art to the combined teachings of
Chiba with Aulton. It reiterated the argument raised in
the Torrent petition that the ordinarily skilled artisan
would have naturally considered mannitol because of its
known compatibility with fingolimod, again citing Sakai’s
disclosure of a stable composition comprised of these two
ingredients.
    Following institution of the Apotex/Mylan proceeding
and joinder with the Torrent proceeding, the relevance of
Sakai’s compatibility-disclosure to support a motivation to
combine Chiba and Aulton was an ongoing, debated issue
that Novartis addressed directly, on multiple occasions.
In its Patent Owner’s Response, Novartis specifically
NOVARTIS AG   v. TORRENT PHARMACEUTICALS                  15



argued that Petitioners’ reliance on Sakai’s stability-
disclosure in connection with the motivation to combine
inquiry lacked merit because Sakai is relevant only to
liquid compositions. Petitioners continued to press the
issue in their Reply, contending that Sakai “would have
provided a [person of skill in the art] with a reasonable
expectation that mannitol is compatible with fingolimod.”
J.A. 7782.
    Furthermore, both Petitioners’ expert and Novartis’
expert went into significant detail in their post-institution
declarations discussing Sakai and its applicability to the
motivation to combine inquiry. Novartis’ counsel then
questioned Petitioners’ expert at length about Sakai. And
Novartis’ submitted Observations on Cross Examination
repeatedly explained why Sakai did not support Petition-
ers’ motivation to combine argument. At the hearing,
both parties submitted demonstrative slides dedicated to
Sakai and spent considerable attention discussing Sakai’s
relevance as a background reference supporting the
motivation to utilize mannitol with fingolimod in an oral
formulation. Based on this record, it is quite clear that
Novartis had more than sufficient notice and opportunity
to be heard on Sakai’s potential relevance, and in fact
actively and repeatedly attempted to distinguish Sakai to
defeat the very argument relied on by the Board in the
Final Written Decision.
    In sum, we reject Novartis’ contention to this court
that it believed Sakai was not at issue in the proceeding. 2
For this reason we reject Novartis’ APA challenge.



    2   Indeed, had Novartis believed the Board eliminat-
ed Sakai from the proceeding, it had various procedural
mechanisms at its disposal to respond to any perceived
impropriety with Petitioners’ continued reliance on the
reference. In particular, Novartis could have moved to
16                NOVARTIS AG   v. TORRENT PHARMACEUTICALS



                            C.
    Finding no APA violation for the reasons discussed
above, we nevertheless also reject Novartis’ characteriza-
tion of Sakai as the “missing link” in the Board’s obvious-
ness analysis. Contrary to Novartis’ contention, Sakai
was discussed by the Board as one of several independent
grounds supporting the motivation to combine fingolimod
and mannitol in a solid oral composition. In finding a
motivation to combine, the Board explained that the
teachings of Chiba and Aulton alone “already strongly



exclude the Sakai reference. See Genzyme Therapeutic
Prods. v. Biomarin Pharm. Inc., 825 F.3d 1360, 1368 (Fed.
Cir. 2016). We find meritless Novartis’ argument that it
did in fact move to exclude Sakai from the proceeding.
See     Oral    Arg.   at     53:30–53:51:    available   at
http://oralarguments.cafc.uscourts.gov/default.aspx?fl=20
16-1352.mp3. Although not provided in the Joint Appen-
dix, Novartis’ counsel invited the court to review its
motion to exclude. That invitation, unfortunately, led the
court on a road to nowhere. In its motion, Novartis moved
to exclude over fifty exhibits, including Sakai, all identi-
fied by exhibit number only and listed in one long string
cite, based on one conclusory sentence: “Petitioners rely
on numerous exhibits that are incomplete and/or irrele-
vant to the sole issue for review identified by the Board –
i.e., (non)obviousness of the ’283 Patent in light of Chiba
over Aulton).” Patent Owner’s Motion to Exclude at 20,
Paper No. 73. This superficial treatment amounts to little
more than a request that the Board peruse the cited
evidence and piece together a coherent argument on
Novartis’ behalf. It is far from sufficient to raise a mean-
ingful challenge to any of the several dozen exhibits, let
alone to sensitize the Board to the complained-of use of
Sakai in particular.
NOVARTIS AG   v. TORRENT PHARMACEUTICALS                17



suggests that mannitol likely would have been a target of
investigation for a person of ordinary skill in the art
interested in finding an excipient compatible with fin-
golimod.” Final Written Decision, 2015 WL 5719630, at
*8.
     Nevertheless, the Board continued to bolster its anal-
ysis with “additional evidence of the reason to combine
fingolimod and mannitol.” Id. And Sakai’s teaching to
combine fingolimod and mannitol was just one of those
additional reasons. The Board further explained that
“[i]n addition to the direct teaching in Sakai that manni-
tol and fingolimod should be combined, several documents
that would have been known to a person of ordinary skill
in the art teach that mannitol provides advantages when
used as a diluent in tableting.” Id. at *9. The Board went
on to explain that these references—all unchallenged on
appeal—describe known advantages of using mannitol as
an excipient in solid oral compositions that “provide a
strong reason to combine Chiba’s teaching of a solid oral
dosage form of fingolimod and Aulton’s teaching of manni-
tol as an excipient for making solid oral dosage forms.”
Id. These additional references are also substantial
evidence supporting the Board’s motivation to combine
conclusion, independent of Sakai. This is not a case
where Sakai provided the linchpin of the Board’s analysis,
as Novartis contends.
    For all these reasons, we find no violation of the APA
with respect to the Board’s discussion of Sakai in the
Final Written Decision.
                     II.   OBVIOUSNESS
   We turn to Novartis’ remaining challenges to the
Board’s obviousness analysis.
   Obviousness is a mixed question of fact and law. The
Board’s ultimate conclusion that the claims are not obvi-
ous is a legal determination subject to de novo review,
18                NOVARTIS AG   v. TORRENT PHARMACEUTICALS



however, the subsidiary factual findings are reviewed for
substantial evidence. In re Gartside, 203 F.3d 1305, 1316
(Fed. Cir. 2000). Motivation to combine is one of those
underlying factual issues. Id. (“The presence or absence
of a motivation to combine references in an obviousness
determination is a pure question of fact.”). Whether
objective indicia support a finding of nonobviousness is
also a factual question. Merck & Cie v. Gnosis S.P.A., 808
F.3d 829, 833 (Fed. Cir. 2015).
                  A. Motivation to Combine
     Novartis argues that the Board further erred in its
motivation to combine analysis because it failed to read
the prior art as a whole and overlooked critical evidence of
mannitol’s known disadvantages as an excipient for solid
compositions. In particular, Novartis argues that it
pointed out mannitol’s negative properties, including
difficulty to manufacture, the existence of impurities, and
expense. Because the Board did not expressly state that
it was weighing all of these negatives against mannitol’s
positives, Novartis contends that the Board’s motivation
to combine analysis was legally flawed. In support of its
contention, Novartis directs the court to Medichem, S.A.
v. Rolabo, S.L., 437 F.3d 1157 (Fed. Cir. 2006). In Medi-
chem, this court explained that “[w]here the prior art
contains ‘apparently conflicting’ teachings (i.e., where
some references teach the combination and others teach
away from it) each reference must be considered ‘for its
power to suggest solutions to an artisan of ordinary skill .
. . consider[ing] the degree to which one reference might
accurately discredit another.’” Id. at 1165 (quoting In re
Young, 927 F.2d 588, 591 (Fed. Cir. 1991)).
    Contrary to Novartis’ contention, the record reflects
that the Board considered Novartis’ arguments regarding
motivation to combine, weighed them against the compet-
ing evidence and argument, and concluded that despite
Novartis’ contentions, one of skill in the art would have
NOVARTIS AG   v. TORRENT PHARMACEUTICALS                 19



been motivated to combine fingolimod with mannitol in a
solid composition. Indeed, the Board expressly discussed
one of mannitol’s negative properties in the Final Written
Decision—its expense—but noted that, despite this poten-
tially discouraging characteristic, it was still “commonly
used.” Final Written Decision, 2015 WL 5719630, at *5.
And it went on to cite the portion of the Patent Owner’s
Response discussing the arguments Novartis highlights
on appeal when rejecting Novartis’ teaching-away argu-
ment.
     Moreover, the Board’s consideration of mannitol’s
negative properties in the Final Written Decision was at
least commensurate with Novartis’ presentation of those
issues to the Board in its Patent Owner Response. In a
lengthy brief, Novartis’ discussion was relegated to one
passing, unsupported sentence, stating that “[w]hile
mannitol has some positive properties, it also has nega-
tive ones, including expense, poor machinability and
possible impurities.” J.A. 7354. Novartis did not direct
the Board to the expert declarations it now highlights on
appeal, nor did it direct the Board to any record evidence
at all. And there is no indication in the record that No-
vartis elsewhere meaningfully advanced these suggested
negatives or developed them in such a fashion as to
necessarily overcome the numerous advantages of manni-
tol identified by Petitioners and discussed in the Final
Written Decision. Thus, we are not persuaded that No-
vartis presented its arguments against the use of manni-
tol in such a way that it would be appropriate to find fault
in the Board’s arguably limited treatment of those argu-
ments in the Final Written Decision.
     This court’s discussion in Medichem does not change
our conclusion. Although the court there stated that prior
art must be considered as a whole and the disadvantages
of a reference must be considered in addition to the bene-
fits, 437 F.3d at 1165, there is no requirement that the
Board expressly discuss each and every negative and
20                NOVARTIS AG   v. TORRENT PHARMACEUTICALS



positive piece of evidence lurking in the record to evaluate
a cursory argument. In addition, this court has said on
multiple occasions that failure to explicitly discuss every
issue or every piece of evidence does not alone establish
that the tribunal did not consider it. See, e.g., Carolina
Tobacco Co. v. Bureau of Customs & Border Prot., 402
F.3d 1345, 1350 (Fed. Cir. 2005) (“[T]he failure of Cus-
toms to explicitly discuss the six factors when it initially
increased Carolina’s bond does not establish that it did
not consider them.”); Lab. Corp. of Am. Holdings v. Chi-
ron Corp., 384 F.3d 1326, 1332 (Fed. Cir. 2004) (stating
that a district court’s failure to discuss an issue does not
necessarily establish that the court did not consider it);
Charles G. Williams Const., Inc. v. White, 326 F.3d, 1376,
1380 (Fed. Cir. 2003) (“The Board’s failure to discuss the
evidence upon which Williams relies does not mean that it
did not consider it”). The Board is “not require[d] . . . to
address every argument raised by a party or explain
every possible reason supporting its conclusion.” Synop-
sys, Inc. v. Mentor Graphics Corp., 814 F.3d 1309, 1322
(Fed. Cir. 2016). Here, given that the Board cited to the
relevant pages of Novartis’ Patent Owner Response, we
find no reason to assume the Board failed to consider
mannitol’s cited negatives simply because they were not
recited at length in the Board’s Final Written Decision.
    Having dispatched Novartis’ numerous procedural ar-
guments, we ask finally whether substantial evidence
supports the Board’s finding on the motivation to combine
Chiba and Aulton. Here, we conclude that substantial
evidence supports the Board’s finding that, despite man-
nitol’s potentially negative characteristics, it was never-
theless a valid consideration as an excipient for solid oral
pharmaceuticals and a person of skill in the art would
have been motivated to combine fingolimod and mannitol
in the manner claimed by the ’283 patent. Indeed, the
Board cites to multiple pieces of evidence establishing
mannitol as one of a handful of excipients used in solid
NOVARTIS AG   v. TORRENT PHARMACEUTICALS                21



oral compositions and its primacy as a non-hygroscopic
and compressible diluent which makes it particularly
valuable in tableting.
    We, therefore, find no legal error in the Board’s
treatment of the motivation to combine evidence nor do
we find a lack of substantial evidence supporting its
conclusion.
           B. Objective Indicia of Nonboviousness
    Novartis next argues that the Board erred in its as-
sessment of the various objective indicia of nonobvious-
ness. We address each argument in turn.
                  i.    Unexpected Results
    According to Novartis, the Board erred when it
grouped several dependent claims with their independent
claims when considering Novartis’ unexpected results
evidence. Novartis argues that it presented persuasive
evidence to the Board that the combination of fingolimod
and mannitol solved the problem of fingolimod’s unex-
pected low dose instability. The Board rejected that
argument with respect to independent claims 1 and 19
because those claims contain no dosage limitation, and
therefore, the unexpected results evidence was not com-
mensurate in scope with the claims. Novartis does not
appeal that Board finding as it relates to claims 1 and 19.
Instead, Novartis argues that the Board should have
reassessed the unexpected results argument when it
found unpatentable dependent claims 8, 10, 22, and 23,
and proposed amended claims 40, 42, 54, and 55. 3 In
Novartis’ view, these claims recite the “low dosage” limi-
tation lacking in claims 1 and 19.



   3    Proposed amended claims 40, 42, 54, and 55 are
identical to, and would have replaced, original claims 8,
10, 22, and 23, respectively.
22                NOVARTIS AG   v. TORRENT PHARMACEUTICALS



    At the outset, we note that the argument raised to the
Board below was quite different than Novartis’ character-
ization of that argument on appeal. In appeals from the
Board, “we have before us a comprehensive record that
contains the arguments and evidence presented by the
parties and our review of the Board’s decision is confined
to the four corners of that record.” In re Watts, 354 F.3d
1362, 1367 (Fed. Cir. 2004) (internal quotation marks and
citation omitted). Thus, we must first determine whether
Novartis preserved this argument for appeal. While the
court “retains case-by-case discretion over whether to
apply waiver,” Harris Corp. v. Ericsson Inc., 417 F.3d
1241, 1251 (Fed. Cir. 2005) (citations omitted), we have
held that a party waives an argument that it “failed to
present to the Board” because it deprives the court of “the
benefit of the Board’s informed judgment,” Watts, 354
F.3d at 1367–68. We turn our attention to the unexpected
results argument Novartis actually presented to the
Board.
    The undeniable focus of Novartis’ arguments
throughout the proceeding, including its Patent Owner’s
Response, was the patentability of the combination of
fingolimod and mannitol, as broadly recited in claim 19.
The Argument section of the Patent Owner’s Response
alerts the Board in the very first paragraph that Novartis’
arguments are directed to claim 19. What follows in the
Patent Owners’ Response is Novartis’ explanation for why
there was no ex ante reason to combine fingolimod with
mannitol or to reasonably expect success in the combina-
tion—untethered from any specific dosage or concentra-
tion limitation and with no discussion of any dependent
claims.
    Novartis’ objective indicia argument under the head-
ing “Objective Indicia Prove the Fingolimod-Mannitol
Invention” is similarly generic. Novartis there contends
that the objective indicia “overwhelmingly prove the
patentability of the fingolimod-mannitol formula.” J.A.
NOVARTIS AG   v. TORRENT PHARMACEUTICALS                 23



7362. Given the reference to the fingolimod-mannitol
formula only and the failure to identify any specific claim,
this section is simply a continuation of Novartis’ defense
of claim 19. And turning to the unexpected results section
in particular, we see the entirety of Novartis’ argument in
a few short sentences:
   First, mannitol unexpectedly is stable with fin-
   golimod throughout the full dosage range. Excipi-
   ent stability normally does not vary with dose
   proportions. Drs. Kent and Kibbe each confirmed
   that fact in their depositions. [Citing deposition
   transcripts]. So do Dr. Byrn, Dr. Pudipeddi, and
   Mr. Oomura. [Citing declarations]. Petitioners do
   not address this unexpected result at all.
J.A. 7363 (emphasis added). Novartis did not identify the
dependent claims at issue now or discuss specific dosages
or concentrations at all. Nor do any of the supporting
citations. The only fair characterization of Novartis’
argument is that the combination of fingolimod and
mannitol was unexpectedly stable irrespective of concen-
tration, i.e., “throughout the dosage range.” Id. Novartis’
Motion to Amend likewise fails to present any separate
argument for proposed amended claims 40, 42, 54, and 55.
    We thus find no fault in the Board’s observation that
Novartis offered no separate argument with respect to
dependent claims 8, 10, 22, and 23, or proposed amended
claims 40, 42, 54, and 55. The sole focus of the proceed-
ing, including Novartis’ unexpected results argument, was
on claim 19. Novartis even conceded at oral argument
that the focus of its unexpected results argument was
that fingolimod was unexpectedly stable across the entire
dosage range. Oral Arg. at 48:40–48:49 and 53:00–53:08,
available                                               at
http://oralarguments.cafc.uscourts.gov/default.aspx?fl=20
16-1352.mp3. We find no evidence that Novartis distinct-
ly argued an unexpected result specific to the dependent
24                NOVARTIS AG   v. TORRENT PHARMACEUTICALS



claims Novartis now raises on appeal. That argument is
therefore waived.
                        ii.     Nexus
     Novartis next argues that the Board erred as a matter
of law in its analysis of the “nexus” requirement with
respect to the objective evidence of nonobviousness.
Before the Board, Novartis contended that its drug,
Gilenya, enjoyed commercial success, industry praise, and
met a long-felt but previously unsolved need, due to
Gilenya being the first commercially available solid oral
treatment for multiple sclerosis. On appeal, Novartis
complains that the Board wrongly discounted this evi-
dence in light of the disclosure of solid oral multiple
sclerosis drug formulas in prior art references, which, in
the Board’s view, precluded Novartis’ argued for basis for
a nexus between the ’283 patent’s invention and the
objective indicia—even though none of those drugs were
available to the market until after the ’283 patent was
filed. Distilled down, Novartis argues that, as a matter of
law, a feature that is known in the art but not actually
available to the market—i.e., in commerce—cannot be
used to disprove Novartis’ attempts to establish a nexus
based on that claimed feature.
    We disagree. None of the cases cited by Novartis, or
any that we are aware of, stand for such a sweeping
proposition. For objective indicia evidence to be accorded
substantial weight, we require that a nexus must exist
“between the evidence and the merits of the claimed
invention.” Wyers v. Master Lock Co., 616 F.3d 1231,
1246 (Fed. Cir. 2010). 4 “Where the offered secondary



     4  This is not a case where Novartis argues that the
required nexus may be presumed and the presumption
was disregarded by the Board. Moreover, any presump-
tion of nexus is nevertheless rebuttable by evidence that
NOVARTIS AG   v. TORRENT PHARMACEUTICALS                25



consideration actually results from something other than
what is both claimed and novel in the claim, there is no
nexus to the merits of the claimed invention.” In re Kao,
639 F.3d 1057, 1068 (Fed. Cir. 2011); see also Tokai Corp.
v. Easton Enters., Inc., 632 F.3d 1358, 1369 (Fed. Cir.
2011) (“If commercial success is due to an element in the
prior art, no nexus exists.”); Ormco Corp. v. Align Tech.,
Inc., 463 F.3d 1299, 1312 (2006) (“[I]f the feature that
creates the commercial success was known in the prior
art, the success is not pertinent.”).
     In evaluating whether the requisite nexus exists, the
identified objective indicia must be directed to what was
not known in the prior art—including patents and publi-
cations—which may well be the novel combination or
arrangement of known individual elements. See KSR Int’l
Co. v. Teleflex Inc., 550 U.S. 398, 418–19 (2007); Veritas
Techs. LLC v. Veeam Software Corp., 835 F.3d 1406,
1414-15 (Fed. Cir. 2016). Our opinion in Asyst Technolo-
gies, Inc. v. Emtrak, Inc., 544 F.3d 1310 (Fed. Cir. 2008),
is instructive. In Asyst, the trial court concluded that
patent owner Asyst failed to link the objective indicia to
the claimed invention because the proffered evidence
lacked a nexus to any feature of the invention’s commer-
cial embodiments that was not already disclosed in a prior
art patent—the Hesser patent. 544 F.3d at 1316. The
court found “even though commercial embodiments of
[Asyst’s] ’421 invention may have enjoyed commercial
success, Asyst’s failure to link that commercial success to
the features of its invention that were not disclosed in
[the] Hesser [patent] undermines the probative force of
the evidence pertaining to the success of Asyst’s [] prod-



the proffered objective evidence was due to extraneous
factors other than the merits of the claimed invention.
See, e.g., WBIP, LLC v. Kohler Co., 829 F.3d 1317, 1329
(Fed. Cir. 2016).
26                NOVARTIS AG   v. TORRENT PHARMACEUTICALS



ucts.” Id. We explained, “[w]hile the evidence shows that
the overall system drew praise as a solution to a felt need,
there was no evidence that the success of the commercial
embodiment of the ’421 patent was attributable to the
substitution of a multiplexer for a bus, which was the only
material difference between [the] Hesser [patent] and the
patented invention.” Id.
    Here, Novartis’ nexus argument for its objective indi-
cia evidence is based solely on a single premise—Gilenya
being the first commercially-available solid oral multiple
sclerosis treatment. The treatment of multiple sclerosis
with a solid oral composition, however, was indisputably
known in the prior art. The Board found evidence that
Chiba itself suggested treating multiple sclerosis using a
solid oral form of fingolimod. And at least two other solid
oral multiple sclerosis treatments were disclosed in the
prior art literature before the ’283 patent’s priority date.
The fact that Gilenya was the first to receive FDA ap-
proval for commercial marketing does not overcome the
fact that solid multiple sclerosis compositions were al-
ready known. Thus, we agree with the Board that Novar-
tis’ proffered evidence is not probative of the
nonobviousness inquiry. 5



     5  Novartis raises an additional challenge to the
Board’s analysis of Novartis’ commercial success evidence
in particular. Having concluded that Novartis failed to
establish a sufficient nexus between its proffered com-
mercial success and the claims, the Board continued,
“setting aside the issue of whether commercial success of
Gilenya should be probative of nonobviousness, we are not
convinced that Patent Owners have carried their thresh-
old burden to show ‘significant sales in a relevant mar-
ket.’” Final Written Decision, 2015 WL 5719630, at *14.
The Board then proceeded to dismiss Novartis’ commer-
cial success argument due to its concerns with Novartis’
NOVARTIS AG   v. TORRENT PHARMACEUTICALS                27



                       CONCLUSION
    For the foregoing reasons, we affirm the Board’s deci-
sion. We have considered all of Novartis’ remaining
arguments but conclude that they are without merit.
                       AFFIRMED
                          COSTS
   No costs.




assessment of the relevant market and the completeness
of its market share data. Because we agree with the
Board that Novartis failed to establish a nexus between
the claims and all purported evidence of nonobvious-
ness—including commercial success—we need not and do
not reach the Board’s additional grounds for rejecting this
evidence.
