  United States Court of Appeals
      for the Federal Circuit
                  ______________________

  NEPTUNE GENERICS, LLC, FRESENIUS KABI
               USA, LLC,
               Appellants

                                 v.

               ELI LILLY & COMPANY,
                       Appellee
                ______________________

                   2018-1257, 2018-1258
                  ______________________

    Appeals from the United States Patent and Trademark
Office, Patent Trial and Appeal Board in Nos. IPR2016-
00237, IPR2016-00240, IPR2016-01190, IPR2016-01191,
IPR2016-01335,       IPR2016-01337,      IPR2016-01341,
IPR2016-01343.

          --------------------------------------------------

 MYLAN LABORATORIES LIMITED, FRESENIUS
            KABI USA, LLC,
               Appellants

                                 v.

               ELI LILLY & COMPANY,
                       Appellee
                ______________________

                   2018-1288, 2018-1290
2              NEPTUNE GENERICS, LLC v. ELI LILLY & COMPANY




                  ______________________

    Appeals from the United States Patent and Trademark
Office, Patent Trial and Appeal Board in Nos. IPR2016-
00318, IPR2016-01340, IPR2016-01393, IPR2016-01429.
                 ______________________

                  Decided: April 26, 2019
                  ______________________

     SARAH ELIZABETH SPIRES, Skiermont Derby LLP, Dal-
las, TX, argued for all appellants. Appellant Neptune Ge-
nerics, LLC also represented by PAUL SKIERMONT; MIEKE
K. MALMBERG, Los Angeles, CA; JOSHUA HARLAN HARRIS,
Neptune Generics, LLC, Chicago, IL.

   MICHAEL B. COTTLER, Goodwin Procter LLP, New York,
NY, for appellant Fresenius Kabi USA, LLC.

    THOMAS J. PARKER, Alston & Bird LLP, New York, NY,
for appellant Mylan Laboratories Limited. Also repre-
sented by CHARLES ABRAHAM NAGGAR, STEPHEN YANG.

   ADAM LAWRENCE PERLMAN, Williams & Connolly LLP,
Washington, DC, argued for appellee. Also represented by
GALINA I. FOMENKOVA, DOV PHILIP GROSSMAN, DAVID M.
KRINSKY, ANDREW P. LEMENS, CHARLES MCCLOUD; JAMES
PATRICK LEEDS, Eli Lilly and Company, Indianapolis, IN.
                ______________________

    Before MOORE, WALLACH, and HUGHES, Circuit Judges.
MOORE, Circuit Judge.
    Neptune Generics, LLC, Fresenius Kabi USA, LLC,
and Mylan Laboratories Ltd. (“Petitioners”) appeal the Pa-
tent Trial and Appeals Board’s inter partes review (“IPR”)
decisions holding Petitioners did not establish that claims
1–22 of U.S. Patent No. 7,772,209 are unpatentable for
NEPTUNE GENERICS, LLC v. ELI LILLY & COMPANY                 3



obviousness. Because the Board did not err in its obvious-
ness analysis, substantial evidence supports its underlying
fact findings, and subject matter eligibility is not properly
before the court in an appeal from an IPR decision, we af-
firm.
                        BACKGROUND
    The ’209 patent is owned by Eli Lilly & Co. and relates
to administering folic acid and a methylmalonic acid
(“MMA”) lowering agent, such as vitamin B12, before ad-
ministering pemetrexed disodium, a chemotherapy agent,
in order to reduce the toxic effects of pemetrexed, an anti-
folate. ’209 patent at 1:19–21, 57–61. Antifolates inhibit
enzymes used in making the components of DNA and RNA,
slowing the ability of cells to divide. Id. at 1:36–38. How-
ever, antifolates have toxic effects, which can be life threat-
ening. E.g., id. at 1:11–12; 1:62–2:4.
     The two independent claims in the patent are method
of treatment claims. They recite:
    1. A method for administering pemetrexed diso-
    dium to a patient in need thereof comprising ad-
    ministering an effective amount of folic acid and an
    effective amount of a methylmalonic acid lowering
    agent followed by administering an effective
    amount of pemetrexed disodium, wherein
        the methylmalonic acid lowering agent is
        selected from the group consisting of vita-
        min B12, hydroxycobalamin, cyano-10-
        chlorocobalamin, aquocobalamin perchlo-
        rate, aquo-10-cobalamin perchlorate, az-
        idocobalamin, cobalamin, cyanocobalamin,
        or chlorocobalamin.
    12. An improved method for administering
    pemetrexed disodium to a patient in need of chemo-
    therapeutic treatment, wherein the improvement
    comprises:
4             NEPTUNE GENERICS, LLC v. ELI LILLY & COMPANY




        a) administration of between about 350 μg
        and about 1000 μg of folic acid prior to the
        first administration of pemetrexed diso-
        dium;
        b) administration of about 500 μg to about
        1500 μg of vitamin B12, prior to the first
        administration of pemetrexed disodium;
        and
        c) administration of pemetrexed disodium.
     The Board considered three petitions for IPR, each of
which alleged the claims would have been obvious. In
IPR2016-00318, Petitioners alleged claims 1–22 would
have been obvious over a 1999 article by Hilary Calvert,
titled “An Overview of Folate Metabolism: Features Rele-
vant to the Actions and Toxicities of Antifolate Anticancer
Agents”; a 1998 abstract by C. Niyikiza, et. al., titled “MTA
(LY231514): Relationship of vitamin metabolite profile,
drug exposure, and other patient characteristics to tox-
icity” (“Niyikiza I”); a 1998 article by John F. Worzalla, et
al., titled “Role of Folic Acid in Modulating the Toxicity and
Efficacy of the Multitargeted Antifolate, LY231514”; Euro-
pean Patent Application 0 595 005 A1 (“EP005”); and U.S.
Patent No. 5,217,974. In IPR2016-00237, Petitioner al-
leged the claims would have been obvious over Niyikiza I,
the ’974 patent, and EP005. In IPR2016-00240, Petitioners
alleged the claims would have been obvious over a 1999 ar-
ticle by James J. Rusthoven, et al., titled “Multitargeted
Antifolate LY231514 As First-Line Chemotherapy for Pa-
tients with Advanced Non-Small-Cell Lung Cancer: A
Phase II Study,” and EP005.
    The Board concluded in each case that the claims were
not established to be unpatentable for obviousness. It
found that it was known in the prior art that pretreatment
with folic acid reduces the toxicity associated with admin-
istration of an antifolate, like pemetrexed, but there was
not a reason to pretreat with vitamin B12 along with folic
NEPTUNE GENERICS, LLC v. ELI LILLY & COMPANY               5



acid before administering pemetrexed to treat cancer. It
also found that the skepticism of others, particularly the
FDA, supported a conclusion of nonobviousness. Because
the Board concluded the independent claims would not
have been obvious, it did not consider the additional limi-
tations of the dependent claims.
   Petitioners appeal.     We have jurisdiction under
28 U.S.C. § 1295(a)(4)(A).
                        DISCUSSION
    We review the Board’s legal determinations de novo
and its underlying factual findings for substantial evi-
dence. Belden Inc. v. Berk-Tek LLC, 805 F.3d 1064, 1073
(Fed. Cir. 2015). Obviousness is a question of law based on
underlying facts. Id. Motivation to combine is a question
of fact. Intelligent Bio-Sys., Inc. v. Illumina Cambridge
Ltd., 821 F.3d 1359, 1366 (Fed. Cir. 2016).
     On appeal, the parties focus on three references: Ni-
yikiza I, EP005, and another abstract by C. Niyikiza, et al.,
titled “Relationship of Vitamin Metabolite Profile to Tox-
icity,” (“Niyikiza II”). The lead author on Niyikiza I and II
is also the sole named inventor of the ’209 patent.
             Pretreatment with Vitamin B12
     The Board found that that a skilled artisan would not
have been motivated to administer an MMA lowering
agent, such as vitamin B12, in addition to folic acid. On
appeal, Petitioners argue that in making this finding, the
Board did not consider EP005 for all that it teaches. Spe-
cifically, Petitioners point to EP005’s disclosure of the ad-
ministration of folic acid and vitamin B12 to lower
homocysteine levels for all purposes. We disagree and hold
that substantial evidence supports the Board’s findings.
    The Board’s findings are based on the prior art’s disclo-
sure of the relationships between various biochemicals and
toxicity. The Board found that deficiencies in both vitamin
6             NEPTUNE GENERICS, LLC v. ELI LILLY & COMPANY




B12 and folate can lead to elevated levels of the biomarker
homocysteine. In contrast, it found that elevated levels of
MMA are correlated only with vitamin B12 deficiencies and
not folate deficiencies. J.A. 61. Therefore, in patients with
a vitamin B12 deficiency, but not a folate deficiency, both
MMA levels and homocysteine levels would be elevated,
while in patients with just a folate deficiency homocysteine
levels would be elevated, but MMA levels would not be el-
evated. The Board further found that while elevated levels
of homocysteine were known to be predictive of pemetrexed
toxicity, elevated levels of MMA were understood to not be
a predictor of pemetrexed toxicity. Because elevated MMA
levels are not predictive of toxicity, but do correlate with
vitamin B12 deficiency, the Board credited the testimony
of Lilly’s expert Dr. Bruce Chabner that a skilled artisan
would have understood that there was no observed correla-
tion between vitamin B12 deficiency and pemetrexed-in-
duced toxicity. J.A. 62–63.
     Each step of the Board’s analysis is supported by sub-
stantial evidence. In finding that elevated MMA levels cor-
related with vitamin B12 deficiency but not folate
deficiency, the Board considered the disclosures in a prior
art article by David G. Savage, et al., which found that in
patients with vitamin B12 deficiency 94.8% of MMA levels
and 95.9% of homocysteine levels were elevated, but in pa-
tients with folate deficiencies, only 12.2% of MMA levels
were elevated while 91% of homocysteine levels were.
J.A. 61 (citing J.A. 7698). These findings are further sup-
ported by additional prior art and are consistent with the
testimony of Petitioner’s expert Dr. Ron Schiff. J.A. 60–61
(citing J.A. 4404).
     The Board’s finding that while elevated levels of homo-
cysteine were known to be predictive of pemetrexed tox-
icity, elevated levels of MMA were understood to not be a
predictor of pemetrexed toxicity is also supported by sub-
stantial evidence. Niyikiza I discloses that elevated levels
of homocysteine are predictive of pemetrexed toxicity,
NEPTUNE GENERICS, LLC v. ELI LILLY & COMPANY                7



J.A. 4148, and the Board credited Dr. Chabner’s testimony
that a skilled artisan would have read Niyikiza II to mean
that elevated MMA levels were not a predictor of
pemetrexed-induced toxicity, J.A. 62–63 (citing J.A. 9084).
The Board further credited Dr. Chabner’s testimony that
given the link between vitamin B12 deficiency and elevated
MMA levels, and the lack of a correlation between elevated
MMA levels and pemetrexed-induced toxicity, a skilled ar-
tisan would have understood “there was no correlation ob-
served between vitamin B12 deficiency and pemetrexed-
induced toxicity.” J.A. 62 (quoting J.A. 9084). Because vit-
amin B12 deficiencies are linked to both elevated levels of
MMA and homocysteine, the mere fact that homocysteine
is correlated with toxicity does not mean that vitamin B12
levels are linked with toxicity. In short, this evidence indi-
cates that pemetrexed-inducted toxicity correlated with fo-
late deficiencies, but not vitamin B12 deficiencies.
    Collectively, this constitutes substantial evidence in
support of the Board’s finding that the art did not provide
a motivation for a skilled artisan to administer an MMA
lowering agent, such as vitamin B12, in addition to folic
acid. In contrast, the Board found that there would have
been a motivation to pretreat with folate, which was a
known way to reduce the toxicity associated with admin-
istration of an antifolate, like pemetrexed. J.A. 50.
     Petitioners argue that EP005 teaches the administra-
tion of folic acid and vitamin B12 to lower homocysteine
levels for all purposes. Therefore, they argue, a skilled ar-
tisan would have been motivated to pretreat with vitamin
B12. This is, at heart, a challenge to the Board’s factual
findings, and the Board’s position is supported by substan-
tial evidence. Admittedly, EP005 states that it “is applica-
ble to the lowering of total homocysteine blood levels if
elevated by any known cause.” J.A. 4409. However, as the
Board found, EP005 is concerned with the cardiovascular
effects associated with elevated homocysteine levels, does
not discuss antifolates generally, and only generally
8             NEPTUNE GENERICS, LLC v. ELI LILLY & COMPANY




mentions certain cancers. J.A. 67 (citing J.A. 4407). More-
over, the Board found that the levels of homocysteine asso-
ciated with elevated pemetrexed toxicity risk were not
“elevated” as that term is defined in EP005. J.A. 68–69.
This is consistent with the plain language of EP005 and the
testimony of Dr. Schiff. J.A. 4417, 7308–09. Likewise,
while EP005 also states that methotrexate, an antifolate
drug like pemetrexed, “induce[s] elevated homocysteine
levels,” J.A. 4409, the Board noted that, in contrast, Ni-
yikiza II explained that pemetrexed did not increase homo-
cysteine levels, J.A. 67, 4148. Given the contrast between
the specific, directly applicable teachings of Niyikiza II and
the tangential, general statements of EP005, substantial
evidence supports the Board’s finding that EP005 did not
provide information as to how pretreatment with folic acid
and vitamin B12 would impact toxicity effects. J.A. 69.
    Petitioners attempt to evade the substantial evidence
standard of review by manufacturing legal error. Among
other things, they argue the Board legally erred in its treat-
ment of EP005 and in requiring the art to directly link vit-
amin B12 deficiency with pemetrexed toxicity. The Board
extensively discussed EP005 both individually and in the
context of the prior art, and we see no error in its analysis.
Likewise, we see nothing in the Board’s opinion that re-
quired the art directly link vitamin B12 deficiency with
pemetrexed toxicity.
               Lilly’s Statements to the FDA
     During clinical trials of pemetrexed, Lilly engaged in
various communications with the FDA. Petitioners argue
that the Board erred in not considering these statements
and precluding Lilly from taking contrary positions in the
IPR. In particular, they argue that in its communications
with the FDA, Lilly “inform[ed] the FDA that the prior art
suggested that pretreating with folic acid and B12 was a
no-risk, predictable way to lower pemetrexed-induced fa-
talities by lowering pretreatment homocysteine levels.”
NEPTUNE GENERICS, LLC v. ELI LILLY & COMPANY               9



Appellants’ Br. 33. It argues that even if these communi-
cations are not in the prior art, they reflect the background
knowledge of a skilled artisan and are indicators of the
level of ordinary skill in the art.
     The level of skill in the art and the scope and content
of the prior art are fact questions we review for substantial
evidence. Arctic Cat Inc. v. Bombardier Recreational
Prods. Inc., 876 F.3d 1350, 1358 (Fed. Cir. 2017). While, a
patent owner’s own disclosures to the FDA may be consid-
ered in assessing the state of the prior art, In re Copaxone
Consol. Cases, 906 F.3d 1013, 1030 (Fed. Cir. 2018), a fact
finder must not allow its analysis to be distorted by hind-
sight bias, KSR Int’l Co. v. Teleflex, 550 U.S. 398, 421
(2007).
    Here, the statements Petitioners argue established the
state of the art were made in December 1999, more than
five months after the critical date. As the Board found, the
views Lilly expressed about the prior art references in its
communications are made through the lens of what they
had invented. J.A. 81. Therefore, it declined to read the
other prior art references in view of these communications.
In doing so, the Board did not err.
                        Skepticism
    Evidence of industry skepticism is a question of fact
that weighs in favor of non-obviousness. WBIP, LLC v.
Kohler Co., 829 F.3d 1317, 1335 (Fed. Cir. 2016). The
Board found that evidence of skepticism of others, particu-
larly the FDA, supported a conclusion of nonobviousness.
J.A. 87. During Lilly’s clinical trials for pemetrexed, a
number of fatalities occurred. In response, Lilly recom-
mended supplementation with folic acid and vitamin B12.
The FDA responded that the “medical officer does not sup-
port adding vitamins to the ongoing . . . trial.” J.A. 8748
(capitalization changed). In other communications with
Lilly it stated that the information provided to it “does not
10            NEPTUNE GENERICS, LLC v. ELI LILLY & COMPANY




appear to support the addition of vitamins,” J.A. 8750, and
“the addition of vitamins . . . is risky,” J.A. 8687.
     Petitioners argue that the Board legally erred in hold-
ing this evidence sufficient to support a finding of skepti-
cism because, despite the FDA’s concerns, it allowed the
trial to continue. It argues skepticism must be premised
on whether it is “technically infeasible,” “unworkable,” or
“impossible” that the claimed subject matter would work
for its intended purpose. Appellants’ Br. 51. This position
is not consistent with our caselaw, which recognizes a
range of third-party opinion that can constitute skepticism.
See, e.g., Circuit Check Inc. v. QXQ Inc., 795 F.3d 1331,
1337 (Fed. Cir. 2015) (holding testimony that third parties
were “worried” or “surprised” was sufficient to establish
skepticism). The FDA’s concerns in this case fall well
within that range. While evidence that third parties
thought the invention was impossible might be entitled to
more weight, that does not mean the Board erred in giving
weight to the skepticism evidence here. Accordingly, the
Board did not err in finding that skepticism supported a
conclusion of nonobviousness.
                    Dependent Claims
     Petitioners argue the nonobviousness determination
should be reversed for the dependent claims as well. Given
our affirmance as to the independent claims, we likewise
affirm as to the dependent claims.
                     Patent Eligibility
    Finally, Petitioners argue the claims are not directed
to patentable subject matter. It argues this issue is
properly raised because eligibility is a question of law and
in this appeal there are no factual issues that must be de-
cided. We do not agree. Congress expressly limited the
scope of inter partes review to a subset of grounds that can
be raised under 35 U.S.C. §§ 102 & 103. 35 U.S.C. § 311(b)
(stating that in an “inter partes review,” a petitioner is
NEPTUNE GENERICS, LLC v. ELI LILLY & COMPANY            11



limited to only grounds that “could be raised under section
102 or 103”). The ground of patent eligibility arises under
§ 101. Accordingly, we may not address it on appeal of an
IPR.
                       CONCLUSION
   We have considered Petitioners’ remaining arguments
and find them unpersuasive. Accordingly, we affirm.
                      AFFIRMED
