  United States Court of Appeals
      for the Federal Circuit
                ______________________

NOVARTIS PHARMACEUTICALS CORPORATION,
             NOVARTIS AG,
            Plaintiffs-Appellees

                           v.

        WEST-WARD PHARMACEUTICALS
          INTERNATIONAL LIMITED,
              Defendant-Appellant
             ______________________

                      2018-1434
                ______________________

    Appeal from the United States District Court for the
District of Delaware in No. 1:15-cv-00474-RGA, Judge
Richard G. Andrews.
                ______________________

                 Decided: May 13, 2019
                ______________________

   CHRISTINA A. L. SCHWARZ, Venable LLP, New York,
NY, argued for plaintiffs-appellees. Also represented by
NICHOLAS N. KALLAS, SHANNON KEOUGH CLARK, LAURA
KATHERINE FISHWICK, SUSANNE FLANDERS, JARED LEVI
STRINGHAM.

    DAVID ZIMMER, Goodwin Procter LLP, Boston, MA, ar-
gued for defendant-appellant. Also represented by KEITH
A. ZULLOW, CINDY CHANG, STEVEN J. BERNSTEIN, MICHAEL
2                       NOVARTIS PHARM. v. WEST-WARD PHARM.




B. COTTLER, New York, NY; NATASHA ELISE DAUGHTREY,
Los Angeles, CA; WILLIAM M. JAY, Washington, DC.
                ______________________

    Before STOLL, PLAGER, and CLEVENGER, Circuit Judges.
STOLL, Circuit Judge.
    West-Ward Pharmaceuticals International Ltd (“West-
Ward”) 1 appeals the decision of the United States District
Court for the District of Delaware holding that claims 1–3
of U.S. Patent No. 8,410,131 would not have been obvious
in view of the prior art. We conclude that the district court
did not err in its nonobviousness determination and affirm.
                        BACKGROUND
     Novartis Pharmaceuticals Corp. and Novartis AG (col-
lectively, “Novartis”) own the ’131 patent, which claims
methods of using the compound everolimus to treat ad-
vanced renal cell carcinoma (“RCC”). Everolimus is the ac-
tive ingredient in Novartis’s Afinitor product. West-Ward’s
predecessor in interest filed an Abbreviated New Drug Ap-
plication (“ANDA”) seeking to manufacture and sell generic
versions of Afinitor, and Novartis filed this patent infringe-
ment suit in response. After a bench trial, the district court
ruled that West-Ward failed to prove by clear and convinc-
ing evidence that claims 1–3 of the ’131 patent are invalid
as obvious. Novartis Pharm. Corp. v. West-Ward Pharm.
Int’l Ltd., 287 F. Supp. 3d 505, 518 (D. Del. 2017) (“Deci-
sion”). West-Ward appeals the district court’s nonobvious-
ness ruling.




      1On January 9, 2019, appellant West-Ward filed an
amended certificate of interest notifying this court that it
is now known as Hikma Pharmaceuticals International
Ltd. We refer to appellant as West-Ward in this opinion.
NOVARTIS PHARM. v. WEST-WARD PHARM.                         3



           I. Advanced RCC and the ’131 Patent
    Advanced RCC is a cancer of the kidneys that has
spread to other parts of the body. As of February 19,
2001—the priority date of the ’131 patent—advanced RCC
carried a poor prognosis and was known to be unpredicta-
ble and difficult to treat. At that time, the only FDA-
approved drug for treating advanced RCC was the im-
munostimulant interleukin-2, which was associated with
poor response rates and toxicity in patients. Interferon al-
pha, another immunostimulant, was also administered to
some patients in practice and was likewise shown to have
poor response rates and toxicity. Numerous clinical trials
investigating a wide range of treatment strategies for ad-
vanced RCC failed. Various chemotherapies, hormonal
therapies, and immunotherapies had been unsuccessful.
The prior art explained that “[a]dvanced RCC is character-
ized by a high level of resistance to all treatment modalities
that have been studied.” J.A. 2058. Cancer drugs in gen-
eral had high failure rates for treatment of advanced RCC
in clinical trials, with more than 70% of cancer drugs fail-
ing during phase II, and a majority of cancer drugs failing
during phase III.
    The ’131 patent covers methods of administering the
compound everolimus to inhibit the growth of advanced
RCC tumors. Claims 1–3 are at issue here. Everolimus is
recited in claim 1 as formula I:
    1. A method for inhibiting growth of solid excretory
    system tumors in a subject, said method consisting
    of administering to said subject a therapeutically
    effective amount of a compound of formula I
4                      NOVARTIS PHARM. v. WEST-WARD PHARM.




    wherein
    R1 is CH3,
    R2 is —CH2—CH2—OH, and
    X is —O.
    2. The method of claim 1 wherein the solid excre-
    tory system tumor is an advanced solid excretory
    system tumor.
    3. The method of claim 1 wherein the solid excre-
    tory system tumor is a kidney tumor.
’131 patent col. 17 l. 43–col. 18 l. 29 (as amended by Certif-
icate of Correction).
                    II. mTOR Inhibitors
    Everolimus belongs to a class of compounds called
mTOR inhibitors. These compounds bind intracellularly to
and form a complex with the FK506 binding protein
(“FKBP-12”). This complex then binds to and inhibits the
NOVARTIS PHARM. v. WEST-WARD PHARM.                        5



activity of the mammalian target of rapamycin (mTOR) en-
zyme. By February 2001, the prior art disclosed that
(1) compounds called mTOR inhibitors produced effects,
such as inhibition of hypoxia-inducible factor 1 (“HIF-1”),
that were hypothesized to inhibit tumor growth; (2) evero-
limus was an mTOR inhibitor; and (3) temsirolimus, an-
other mTOR inhibitor, had shown responses in RCC
patients in phase I clinical trials. There was no data on the
efficacy of everolimus to treat any type of cancer, let alone
to treat advanced RCC.
     At the time of the priority date of the ’131 patent,
mTOR inhibitors were known in the art to have a variety
of beneficial properties. Rapamycin, the first mTOR inhib-
itor, was known to have antimicrobial, immunosuppres-
sive, and antitumor activities. Its poor solubility, however,
precluded its development as an anti-cancer agent.
Temsirolimus, another mTOR inhibitor and a derivative of
rapamycin, was also known to exhibit antitumor proper-
ties. Temsirolimus showed improved solubility over ra-
pamycin and demonstrated positive responses as an anti-
cancer agent in phase I clinical trials. Everolimus is struc-
turally similar to temsirolimus and is likewise a derivative
of rapamycin.
    It was also known in the prior art that advanced RCC
tumors are highly vascularized and require angiogenesis to
grow. Angiogenesis is the process through which new blood
vessels are formed. A prior art article written by Semenza 2
explained that primary tumors and metastases will not
grow beyond a certain size without establishing an ade-
quate blood supply. See J.A. 2113. By February 2001,
studies showed that tumor angiogenesis correlates with


    2   Gregg L. Semenza, Hypoxia, Clonal Selection, and
the Role of HIF-1 in Tumor Progression, 35 Critical Revs.
in Biochemistry & Molecular Biology 71, 71–103 (2000).
6                     NOVARTIS PHARM. v. WEST-WARD PHARM.




increased expression of vascular endothelial growth factor
(“VEGF”) and that, in turn, elevated VEGF expression cor-
relates with increased expression of HIF-1. See J.A. 2114,
2118–19. The prior art Zhong 1999 3 study reported ele-
vated HIF-1 expression in several types of tumor samples,
including in two RCC tumor samples. See J.A. 2187. By
the time of the priority date of the patent-in-suit, however,
HIF-1’s precise mechanism of action and role in tumor
growth were not yet fully understood. Semenza’s Figure 4
disclosed that multiple genes (p53, PTEN, VHL), multiple
pathways (RTKs, RAS, PI3K-AKT-FRAP, RAF-MEK-
ERK), and multiple downstream effects (relating to VEGF,
IGF-2, and glucose transporters) are associated with HIF-
1 expression. See J.A. 2128. While Semenza noted that
“[i]t is possible that inhibition of HIF-1 activity may con-
tribute significantly” to the anti-cancer effects of certain
HIF-1 inhibitors, including rapamycin, it cautioned that
the role of HIF-1 in RCC “requires further analysis.”
J.A. 2119, 2127.
    The prior art also provided some evidence linking HIF-
1 inhibition to mTOR activity, though the exact mechanism
of action was not established. The prior art Zhong 2000 4
study investigated the effects of modulating or modifying
the mTOR pathway (referred to as the FRAP pathway) in
human prostate cancer cell lines. The study reported that
treating cells with the mTOR inhibitor rapamycin


    3   Hua Zhong et al., Overexpression of Hypoxia-induc-
ible Factor 1α in Common Human Cancers and Their Me-
tastases, 59 Cancer Res. 5830, 5830–35 (1999).
    4   Hua Zhong et al., Modulation of Hypoxia-inducible
Factor 1α Expression by the Epidermal Growth Fac-
tor/Phosphatidylinositol     3-Kinase/PTEN/AKT/FRAP
Pathway in Human Prostate Cancer Cells: Implications for
Tumor Angiogenesis and Therapeutics, 60 Cancer Res.
1541, 1541–45 (2000).
NOVARTIS PHARM. v. WEST-WARD PHARM.                       7



inhibited the expression of HIF-1α, the regulated subunit
of HIF-1. See J.A. 2193. Zhong concluded that “HIF-1α-
dependent gene transcription . . . and the expression of a
HIF-1-regulated gene product . . . are modulated by the ac-
tivity of the PI3K/AKT/[mTOR] pathway in [prostate can-
cer] cells.” J.A. 2194. Zhong recognized that the effect of
the mTOR pathway “may provide a basis for therapeutic
efficacy,” but noted that additional studies are required to
determine the precise mechanism by which mTOR activity
modulates the expression of HIF-1α. J.A. 2196; see also
J.A. 2194.
                  III. Asserted Prior Art
    West-Ward argued before the district court that ’131
patent claims 1–3 would have been obvious over a temsiro-
limus reference (Hidalgo 2000 5 or Hutchinson 6) and an
everolimus patent (U.S. Patent No. 5,665,772 or U.S. Pa-
tent No. 6,004,973), in view of the general knowledge in the
art. We discuss each reference in turn.
     Hidalgo 2000 discusses the development of rapamycin
and temsirolimus (referred to as CCI-779) as anti-cancer
agents and the mechanisms of action underlying rapamy-
cin’s antitumor activity. The reference explains that block-
ing mTOR interferes with several intracellular pathways
(e.g., p70s6k, 4E-BP1/PHAS-1) involved in cell cycle pro-
gression, which leads to growth arrest in the G1 phase of
the cell cycle. See J.A. 2030. This interference is reported
to contribute to rapamycin’s inhibition of cancer cell
growth. See J.A. 2030. Hidalgo 2000 also includes sum-
maries of the preliminary results of two phase I


   5    Manuel Hidalgo & Eric K. Rowinsky, The Rapamy-
cin-sensitive Signal Transduction Pathway as a Target for
Cancer Therapy, 19 Oncogene 6680, 6680–86 (2000).
    6   Ezzie Hutchinson, CCI-779: A New Targeted Anti-
cancer Agent, 1 The Lancet 198, 198 (2000).
8                     NOVARTIS PHARM. v. WEST-WARD PHARM.




temsirolimus clinical trials. These phase I studies were de-
signed to determine the maximum tolerated dose of
temsirolimus in patients with a variety of solid tumors.
The studies show major tumor responses in RCC and cell
lung carcinoma patients, and minor tumor responses in pa-
tients having other tumor types. See J.A. 2031. They do
not disclose the number of RCC patients involved in the
studies and do not include any data on everolimus. Hidalgo
2000 notes that “[t]he fact that [temsirolimus] consistently
induced tumor regressions at relatively nontoxic doses in
the phase I studies is particularly noteworthy,” and that
disease-directed studies of temsirolimus would be initiated
following completion of the phase I studies. J.A. 2031. It
also recognized that, while the downstream signaling path-
ways of temsirolimus were “well characterized,” “a critical
issue is whether these downstream effects correlate with
the anti-tumor activity of [temsirolimus], particularly since
malignant cells can traverse the cell cycle and proliferate
despite” the effects of mTOR inhibition by rapamycin.
J.A. 2032. Hidalgo 2000 concludes that temsirolimus “in-
hibit[s] the proliferation of a broad range of human tumors
both in vitro and in vivo,” but notes that predicting “which
tumors will be particularly sensitive to [temsirolimus]” re-
mains a developmental challenge. J.A. 2032–33.
    Hutchinson discusses the clinical development of
temsirolimus and reviews the updated results from the
temsirolimus phase I studies disclosed in Hidalgo 2000. It
notes that temsirolimus had “shown promise in a series of
phase I studies.” J.A. 2038. One study observed twenty-
one patients with advanced solid tumors that were admin-
istered temsirolimus via intravenous infusion. It reported
that, out of sixteen observable patients, three with RCC
had a partial (one) or a minor response (two) to the treat-
ment. Another study observed 51 patients with advanced
solid tumors that were administered temsirolimus. It re-
ported minor responses in three RCC patients. Hutchinson
NOVARTIS PHARM. v. WEST-WARD PHARM.                          9



also discloses that two phase II clinical trials investigating
the use of temsirolimus were then underway, one of which
was investigating RCC in particular.
     The ’772 patent discloses several rapamycin deriva-
tives including everolimus, which is referred to as “40-O-
(2-Hydroxy)ethyl-rapamycin.” ’772 patent col. 2 l. 30. The
’772 patent teaches that the disclosed compounds “are par-
ticularly useful” for treating several conditions, including
organ transplant rejection, autoimmune diseases, asthma,
and proliferative disorders such as tumors. Id. at col. 3
l. 22–col. 4 l. 1. It also teaches that the disclosed com-
pounds bind to macrophilin-12 (another name for FKBP-
12), meaning that they inhibit mTOR activity. Id. at col. 6
ll. 1–3. It is undisputed that the ’772 patent does not dis-
close any preclinical or clinical data on the antitumor ac-
tivity of everolimus. It is also undisputed that the ’772
patent does not contain an explicit disclosure that everoli-
mus would be effective in treating advanced RCC.
    The ’973 patent also discloses everolimus, which is re-
ferred to as “40-O-(2-Hydroxy)ethyl rapamycin” and “com-
pound X.” ’973 patent col. 2 ll. 9–11. The ’973 patent
discloses everolimus oral formulations, dosage ranges, and
formulation techniques. Id. at col. 2 l. 25–col. 4 l. 59. It is
undisputed that the ’973 patent does not contain any pre-
clinical or clinical data showing any antitumor activity of
everolimus, and does not disclose that everolimus would be
effective in treating advanced RCC.
                   IV. Procedural History
    The ’131 patent covers Novartis’s Afinitor product.
West-Ward’s predecessor in interest filed ANDA
No. 207486, seeking to manufacture and sell generic ver-
sions of Afinitor. In response, Novartis filed the current
patent infringement suit. The parties stipulated that
West-Ward’s ANDA infringes claims 1–3 of the ’131 patent
and a bench trial proceeded on validity.
10                    NOVARTIS PHARM. v. WEST-WARD PHARM.




     West-Ward argued that administering a therapeuti-
cally effective amount of everolimus to treat advanced RCC
would have been obvious to a person of ordinary skill in the
art. According to West-Ward, knowledge in the art about
the molecular biology of advanced RCC, the antitumor ac-
tivity of mTOR inhibitors, phase I temsirolimus clinical
trial results, and safe dosing ranges for everolimus, would
have provided a person of ordinary skill with a reasonable
expectation of success of effectively treating advanced RCC
with everolimus. Specifically, West-Ward argued that the
’131 claims would have been obvious over either Hidalgo
2000 or Hutchinson in view of either the ’772 patent or the
’973 patent, further in view of the general knowledge in the
art.
     The district court rejected West-Ward’s arguments. It
found that West-Ward failed to prove that a person of skill
in the art would have been motivated to select everolimus.
The district court recognized that there was a need to find
an effective treatment for advanced RCC, there was a pref-
erence for oral treatments, temsirolimus showed promising
phase I clinical data, and everolimus and temsirolimus
shared certain properties.       Decision, 287 F. Supp. 3d
at 515–16. In light of these facts, the district court found
that a person of ordinary skill “would have been motivated
to pursue everolimus as one of several potential treatment
options for advanced solid tumors, including advanced
RCC.” Id. at 516. Despite this finding, however, the dis-
trict court continued its analysis of whether there would
have been a motivation to combine. It criticized West-
Ward’s expert Dr. Cho for limiting his review of the prior
art to only mTOR inhibitors and found that “the relevant
prior art would have included art relating to treatments
beyond mTOR inhibitors.” Id. at 515. It noted that there
were a variety of other treatments in development at the
time of the invention and that the knowledge gaps in the
molecular biology of advanced RCC would have led a
NOVARTIS PHARM. v. WEST-WARD PHARM.                        11



person of ordinary skill to search for art beyond those in-
volving mTOR modulation. The district court explained
that Dr. Cho’s narrow review allowed hindsight bias to in-
form his analysis. Even though the district court found
that there would have been a motivation to pursue everoli-
mus, it ultimately determined that West-Ward “failed to
prove by clear and convincing evidence that a POSA would
have been motivated to select everolimus.” Id. at 516.
     In addition, the district court determined that the as-
serted prior art would not have provided a person of ordi-
nary skill in the art with a reasonable expectation of
success in using everolimus to treat advanced RCC. Id. It
noted Dr. Cho’s admission that a person of skill in the art
would not have reasonably expected a drug to work based
only on phase I clinical trial results, or on the fact that a
drug had entered phase II clinical trials. Id. The district
court explained that the temsirolimus phase I data dis-
closed in Hutchinson had diminished weight because it re-
sulted from small sample sizes and because phase I clinical
trials are designed to determine safety, not efficacy. Id. It
further noted that everolimus and temsirolimus differed in
pharmacological properties relevant to treatment. These
differences, along with the high failure rate of cancer drugs
in phase II and III clinical trials, and the fact that the mo-
lecular pathways of advanced RCC were not fully under-
stood, all diminished the relevance of the temsirolimus
data. Based on these facts, the district court found that
West-Ward failed to establish by clear and convincing evi-
dence that a person of skill in the art would have reasona-
bly expected everolimus to effectively treat advanced RCC.
    The district court ultimately concluded that West-
Ward failed to show by clear and convincing evidence that
claims 1–3 of the ’131 patent are invalid as obvious. West-
Ward appeals the decision of the district court. We have
jurisdiction under 28 U.S.C. § 1295(a)(1).
12                     NOVARTIS PHARM. v. WEST-WARD PHARM.




                         DISCUSSION
                   I. Standard of Review
     “Following a bench trial on the issue of obviousness, we
review the court’s ultimate legal conclusions de novo and
the underlying factual findings for clear error.” Insite Vi-
sion Inc. v. Sandoz, Inc., 783 F.3d 853, 858 (Fed. Cir. 2015)
(quoting Tyco Healthcare Grp. LP v. Ethicon Endo-Surgery,
Inc., 774 F.3d 968, 974 (Fed. Cir. 2014)). “A factual finding
is clearly erroneous if, despite some supporting evidence,
we are left with the definite and firm conviction that a mis-
take has been made.” Ferring B.V. v. Watson Labs., Inc.-
Fla., 764 F.3d 1401, 1406 (Fed. Cir. 2014) (citing United
States v. U.S. Gypsum Co., 333 U.S. 364, 395 (1948)).
                       II. Obviousness
     A patent is invalid “if the differences between the sub-
ject matter sought to be patented and the prior art are such
that the subject matter as a whole would have been obvious
at the time the invention was made” to a person of ordinary
skill in the art to which said subject matter pertains.
35 U.S.C. § 103(a). 7 Obviousness is a question of law based
on underlying factual determinations including: (1) the
“level of ordinary skill in the pertinent art,” (2) the “scope
and content of the prior art,” (3) the “differences between
the prior art and the claims at issue,” and (4) “secondary
considerations” of non-obviousness such as “commercial
success, long-felt but unsolved needs, failure of others, etc.”
KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 406 (2007)



     7  Because the ’131 patent does not contain any claim
with an effective filing date on or after March 16, 2013, the
version of 35 U.S.C. § 103 that applies here is the one pre-
ceding the changes made by the America Invents Act. See
Leahy-Smith America Invents Act, Pub. L. No. 112-29, 125
Stat. 284, 293, § 3(n) (2011).
NOVARTIS PHARM. v. WEST-WARD PHARM.                       13



(quoting Graham v. John Deere Co., 383 U.S. 1, 17–18
(1966)).
     A party seeking to invalidate a patent based on obvi-
ousness must prove “by clear and convincing evidence that
a skilled artisan would have been motivated to combine the
teachings of the prior art references to achieve the claimed
invention, and that the skilled artisan would have had a
reasonable expectation of success in doing so.” Procter &
Gamble Co. v. Teva Pharm. USA, Inc., 566 F.3d 989, 994
(Fed. Cir. 2009) (quoting Pfizer, Inc. v. Apotex, Inc., 480
F.3d 1348, 1361 (Fed. Cir. 2007)). “The presence or absence
of a motivation to combine references in an obviousness de-
termination is a pure question of fact.” PAR Pharm., Inc.
v. TWI Pharm., Inc., 773 F.3d 1186, 1196 (Fed. Cir. 2014)
(quoting Alza Corp. v. Mylan Labs., Inc., 464 F.3d 1286,
1289 (Fed. Cir. 2006)). “The presence or absence of a rea-
sonable expectation of success is also a question of fact.”
Id.
    We hold that the district court erred in its analysis of
whether there was a motivation to combine. However, we
discern no clear error in the district court’s finding that a
person of ordinary skill would not have reasonably ex-
pected success in using everolimus to treat advanced RCC
as of February 2001. We thus agree with the district
court’s ultimate determination that the challenged claims
would not have been obvious. We address both prongs of
the obviousness inquiry below.
                 A. Motivation to Combine
     After reviewing the prior art, the district court found
that a person of ordinary skill “would have been motivated
to pursue everolimus as one of several potential treatment
options for advanced solid tumors, including advanced
RCC.” Decision, 287 F. Supp. 3d at 516. This finding
should have affirmatively answered whether there would
have been a motivation to combine. Yet, the district court
continued its analysis and found that West-Ward “failed to
14                    NOVARTIS PHARM. v. WEST-WARD PHARM.




prove by clear and convincing evidence that a POSA would
have been motivated to select everolimus.” Id. The district
court erred in applying this heightened standard. “[O]ur
case law does not require that a particular combination
must be the preferred, or the most desirable, combination
described in the prior art in order to provide motivation for
the current invention.” In re Fulton, 391 F.3d 1195, 1200
(Fed. Cir. 2004); see also Bayer Healthcare Pharm., Inc. v.
Watson Pharm., Inc., 713 F.3d 1369, 1376 (Fed. Cir. 2013).
It is thus improper to require West-Ward to prove that a
person of ordinary skill would have selected everolimus
over other prior art treatment methods.
     Citing Takeda Chemical Industries, Ltd. v. Alpha-
pharm Pty., Ltd., 492 F.3d 1350 (Fed. Cir. 2007), Novartis
argues that the district court did not err in concluding that
the prior art fails to provide motivation to select everoli-
mus. See Appellee Br. 58–59. As West-Ward correctly
notes, however, Takeda is a lead compound case. See Ap-
pellant Reply Br. 8 n.2. In lead compound cases, the court
first determines whether a person of ordinary skill in the
art “would have selected the asserted prior art compounds
as lead compounds, or starting points, for further develop-
ment efforts.” See Otsuka Pharm. Co. v. Sandoz, Inc.,
678 F.3d 1280, 1291–92 (Fed. Cir. 2012). This requires the
patent challenger to show by clear and convincing evidence
that a person of ordinary skill “would have had a reason to
select a proposed lead compound or compounds over other
compounds in the prior art.” Daiichi Sankyo Co. v. Matrix
Labs., Ltd., 619 F.3d 1346, 1354 (Fed. Cir. 2010) (emphasis
added). The court then determines “whether the prior art
would have supplied one of ordinary skill in the art with a
reason or motivation to modify a lead compound to make
the claimed compound with a reasonable expectation of
success.” Otsuka, 678 F.3d at 1292.
     We have applied a similar test in obviousness cases
where the prior art discloses a range and a claim limitation
falls within that range, focusing on “whether there would
NOVARTIS PHARM. v. WEST-WARD PHARM.                       15



have been a motivation to select the claimed composition
from the prior art ranges.” Allergan, Inc. v. Sandoz Inc.,
796 F.3d 1293, 1305 (Fed. Cir. 2015); see also Galderma
Labs., L.P. v. Tolmar, Inc., 737 F.3d 731, 737–38 (Fed. Cir.
2013) (“The relevant dispute in this case is thus not over
whether the prior art discloses all of the claim elements or
over the motivation to combine the prior art references. Ra-
ther, the dispute is whether there was motivation to select
the claimed 0.3% adapalene composition in the disclosed
range.”).
    The ’131 patent claims methods of using everolimus to
inhibit growth of solid tumors, including in patients having
advanced RCC. ’131 patent col. 17 l. 42–col. 18 l. 29. It
does not claim the everolimus compound itself, but rather
methods of using the compound. This case therefore does
not require lead compound analysis or analysis of whether
a particular dose in a range of prior art doses would have
been obvious. The district court, however, appeared to ap-
ply or conflate the standard for these types of cases by re-
quiring clear and convincing evidence that a person of
ordinary skill “would have been motivated to select everoli-
mus.” Decision, 287 F. Supp. 3d at 516 (emphasis added).
To the extent the district court required a showing that a
person of ordinary skill would have selected everolimus
over other prior art compounds, it erred. The proper in-
quiry is whether a person of ordinary skill would have been
motivated to modify the prior art disclosing use of temsiro-
limus to treat advanced RCC with the prior art disclosing
everolimus. This question was answered affirmatively
when the district court found that a person of ordinary skill
“would have been motivated to pursue everolimus as one of
several potential treatment options for advanced solid tu-
mors, including advanced RCC.” Id.
          B. Reasonable Expectation of Success
    West-Ward also challenges the district court’s finding
that a person of ordinary skill would not have had a
16                    NOVARTIS PHARM. v. WEST-WARD PHARM.




reasonable expectation of success in using everolimus to
treat advanced RCC. See Appellant Br. 40–41. It argues
that the district court erred by imposing “a heightened
standard under which it found no reasonable expectation
of success simply because there was not yet clinical proof
that everolimus would successfully treat advanced RCC.”
Id. at 41. By February 2001, the prior art disclosed that:
(1) RCC patients had shown responses to temsirolimus
treatment in phase I clinical trials (Hidalgo 2000,
Hutchinson), (2) everolimus was an mTOR inhibitor that
was available in oral formulations (’772 patent, ’973 pa-
tent), and (3) inhibiting mTOR in prostate cancer cells in-
hibits HIF-1, which was hypothesized to inhibit tumor-
promoting angiogenesis (Zhong 2000). According to West-
Ward, these disclosures would have provided a person of
ordinary skill with a reasonable expectation that inhibiting
mTOR would inhibit growth of advanced RCC, and the dis-
trict court clearly erred by finding otherwise. See id. at 49–
55.
     Novartis counters and points out that by Febru-
ary 2001, there were no clinical trial data on everolimus as
an anti-cancer agent, and no clinical trials for cancer had
been completed for mTOR inhibitors. See Appellee Br. 21.
It further argues that the district court correctly recognized
the limitations of the temsirolimus phase I data. Id. at 24.
It also notes the high failure rate of cancer drugs in phase
II and phase III clinical trials, the numerous failed at-
tempts to treat advanced RCC, and the pharmacological
differences between everolimus and temsirolimus. See id.
at 24–26. Novartis further argues that the district court
correctly found that the roles of HIF-1 and mTOR in the
molecular biology of advanced RCC were not completely
understood. See id. at 43–47.
    We conclude that the district court did not clearly err
in finding that West-Ward’s asserted prior art combina-
tion—Hidalgo 2000 or Hutchinson in view of the ’772 pa-
tent or ’973 patent in view of the knowledge in the art—
NOVARTIS PHARM. v. WEST-WARD PHARM.                        17



failed to provide clear and convincing evidence of a reason-
able expectation of success. In reaching this finding, the
district court relied on the prior art and expert testimony
to support subsidiary findings that (1) the temsirolimus
phase I data had diminished weight, (2) everolimus and
temsirolimus had different pharmacological properties,
and (3) the molecular biology of advanced RCC was not
completely understood. Decision, 287 F. Supp. 3d at 515–
17.
     The district court correctly recognized that the temsiro-
limus phase I data resulted from small sample sizes and
came from studies that were designed to test safety, not
efficacy. Id. It also noted that the studies disclosed in Hi-
dalgo 2000 and Hutchinson do not reveal the total number
of advanced RCC patients enrolled and that phase II data
was not yet available. Id. Further, it considered the testi-
mony of West-Ward’s expert Dr. Cho, who stated that a
person of ordinary skill “would not make a determination
or reasonable suggestion simply based in isolation upon
whether a drug enters phase II,” and who did not dispute
that more than seventy percent of oncology drugs failed at
phase II. Id. (citing J.A. 1072 at 202:7–15); J.A. 1072 at
202:7–20.
    The district court also considered evidence that evero-
limus and temsirolimus are pharmacologically different.
Decision, 287 F. Supp. 3d at 515–17. Novartis’s expert, Dr.
Burris, testified that the prior art, which disclosed that ra-
pamycin and everolimus had different binding affinities for
FKBP-12, would not have led a person of ordinary skill to
reasonably expect that rapamycin, temsirolimus, and
everolimus would all have the same antitumor efficacy.
See J.A. 1394–95 at 524:2–525:6. Dr. Burris further testi-
fied that everolimus and temsirolimus had different elimi-
nation half-lives and that a person of ordinary skill would
not have expected compounds with different half-lives to
have the same anti-tumor efficacy. See J.A. 1397–1400 at
18                    NOVARTIS PHARM. v. WEST-WARD PHARM.




527:4–530:17. The district court did not err in crediting Dr.
Burris’s testimony.
     In addition, the district court considered several prior
art references in finding that the roles of HIF-1 and mTOR
in the molecular biology of advanced RCC were not fully
understood as of February 2001.               See Decision,
287 F. Supp. 3d at 511–14. The district court cited Se-
menza, which showed that numerous pathways are impli-
cated in HIF-1 activation in human cancers. Id. at 512; see
J.A. 2128. Semenza states that “the role of HIF-1α expres-
sion in [RCC] requires further analysis.” J.A. 2119. The
district court also cited to Alexandre, 8 which noted that
“there is still much to learn on, firstly, the exact mecha-
nisms by which mTOR controls the G1/S transition and,
secondly, on any other cellular targets of rapamycin.” De-
cision, 287 F. Supp. 3d at 512 (quoting J.A. 1978). It fur-
ther recognized Zhong 2000, which cautioned that
“[a]dditional studies are required to determine whether
this process is modulated by PI3K/AKT/[mTOR] activity
and, if so, whether such modulation involves direct phos-
phorylation of HIF-1α.” Id. at 513; see also J.A. 2194. In
addition, the district court noted Sekulić, 9 which states
“[c]learly, additional experiments are required to establish
the relationship between deregulated PI3K-AKT activity
and rapamycin sensitivity in human cancer cells.” Deci-
sion, 287 F. Supp. 3d at 513 (quoting J.A. 2105).
    The district court’s finding is also consistent with rec-
ord evidence explaining that inhibiting mTOR does not


     8  Jérôme Alexandre et al., Rapamycin and CCI-779,
86 Bull. Cancer 808, 808–11 (1999).
    9   Aleksandar Sekulić et al., A Direct Linkage Be-
tween the Phosphoinositide 3-Kinase-AKT Signaling Path-
way and the Mammalian Target of Rapamycin in Mitogen-
stimulated and Transformed Cells, 60 Cancer Res. 3504,
3504–13 (2000).
NOVARTIS PHARM. v. WEST-WARD PHARM.                        19



necessarily result in tumor growth inhibition.          Hi-
dalgo 2000 states that “a critical issue is whether these
downstream effects [of mTOR inhibition] correlate with the
anti-tumor activity of [temsirolimus], particularly since
malignant cells can traverse the cell cycle and proliferate
despite the [downstream effects of mTOR inhibition] by ra-
pamycin.” J.A. 2032. Dr. Burris explained that in this
quote, Dr. Hidalgo was “pointing out that even when think-
ing that we were inhibiting the mTOR pathway, we could
still see tumor cells traverse, continue to grow and prolif-
erate.” J.A. 1337–38 at 467:19–468:2. In addition, Dr. Cho
testified that mTOR inhibition does not necessarily mean
that tumor growth will be inhibited. See J.A. 1108
at 238:19–24 (“Q: But you agree that a POSA would under-
stand that you can have mTOR inhibition and still see tu-
mor growth; right? A: A POSA would have been aware that
that is possible.”).
     We discern no clear error with the district court’s find-
ings. We also disagree with West-Ward’s contention that
the district court applied an erroneously heightened stand-
ard in its analysis. The district court reviewed the above
evidence, determined that the molecular biology of ad-
vanced RCC was not fully understood, recognized the limi-
tations in the temsirolimus phase I data, and found that
such data did not provide a person of ordinary skill with a
reasonable expectation of success. Decision, 287 F. Supp.
3d at 515–17. We hold that the district court did not err in
its determination and affirm its conclusion that claims 1–3
of the ’131 patent would not have been obvious in view of
the asserted prior art.
                        CONCLUSION
    We have considered West-Ward’s remaining argu-
ments and find them unpersuasive. While the district
court erred in its motivation to combine analysis, this error
is harmless as the district court did not clearly err in its
finding regarding reasonable expectation of success. For
20                    NOVARTIS PHARM. v. WEST-WARD PHARM.




the reasons above, we affirm the district court’s decision
that West-Ward failed to prove by clear and convincing ev-
idence that claims 1–3 of the ’131 patent are invalid as ob-
vious.
                       AFFIRMED
