United States District Court, D. Delaware
NOVARTIS PHARMACEUTICALS CORPORATION and NOVARTIS AG, Plaintiffs;
WEST-WARD PHARMACEUTICALS INTERNATIONAL LIMITED, Defendant.
M. Silver, MCCARTER & ENGLISH, LLP, Wilmington, DE;
Nicholas N. Kallas, Charlotte Jacobsen, Christina L. Schwarz,
Susanne Flanders, Jared Stringham, and Laura Fishwick,
FITZPATRICK, CELLA, HARPER & SCINTO, New York, NY.
Attorneys for Plaintiffs.
E. Moore and Bindu A. Palapura, POTTER ANDERSON & CORROON
LLP, Wilmington, DE; Keith A. Zullow, Michael B. Cottier,
Natasha Daughtrey, Cindy Chang, and Steven J. Bernstein,
GOODWIN PROCTER LLP, New York, NY. Attorneys for Defendant.
ANDREWS, U.S. DISTRICT JUDGE.
brought this patent infringement action against Roxane
Laboratories, Inc. in 2015. (D.I. 1). Roxane (now West-Ward)
filed Abbreviated New Drug Application ("ANDA") No.
207486, seeking to engage in the commercial manufacture, use,
and sale of generic versions of Novartis's Afinitor
product. (D.I. 68-1 at 7-8). The parties have stipulated that
this ANDA infringes claims 1-3 of U.S. Patent No. 8, 410, 131
("the '131 patent") and claim 1 of U.S. Patent
No. 9, 006, 224 ("the '224 patent"). (D.I. 66
at ¶¶ 3-4).
issue in this case are methods for using everolimus to treat
advanced renal cell carcinoma ("RCC") and advanced
pancreatic neuroendocrine tumors ("PNETs").
Everolimus, which has the formula
40-O-(2-hydroxyethyl)-rapamycin, is a derivative of rapamycin
and is the active ingredient in Novartis's Afinitor
product. Everolimus itself is claimed in U.S. Patent No. 5,
665, 772 ("the '772 patent"), which is not at
issue in this case.
has long been known to have beneficial medicinal properties,
such as immunosuppressive activity and anticancer activity.
(Trial Transcript ("Tr.") 74:11-16). Despite these
beneficial properties, rapamycin is recognized as having
limited utility in pharmaceutical applications as it has low
bioavailability, high toxicity, and poor solubility.
('772 patent at 1:36-40; Tr. 74:16-21). Rapamycin
derivatives such as everolimus, however, have been shown to
have better stability and bioavailability, making them more
desirable for pharmaceutical preparations. ('772 patent
at 1:41-45). Ternsirolimus, another rapamycin derivative, was
a subject of active investigation to treat various cancers as
of the priority date. (Tr. 58:12-19).
Court held a bench trial on September 13-15, 2017. Defendant
argues that the asserted claims of the '131 and '224
patents are invalid as obvious. The '131 patent is
directed to the use of rapamycin derivatives to treat solid
tumors. ('131 patent at Abstract). Asserted claims 1-3 of
the '131 patent require administering a therapeutically
effective amount of everolimus to inhibit the growth of solid
excretory system tumors, including advanced solid excretory
system tumors and kidney tumors. (Id. at claims
1-3). Claims 1-3 of the '131 patent read as follows:
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
is -CH2-CH2-OH, and
method of claim 1 wherein the solid excretory system tumor is
an advanced solid excretory system tumor.
method of claim 1 wherein the solid excretory system tumor is
a kidney tumor.
at claims 1-3).
'224 patent is directed to treating endocrine tumors with
an mTOR inhibitor as a monotherapy or in combination with
another drug. ('224 patent at Abstract). Asserted claim 1
of the '224 patent reads as follows:
1. A method for treating pancreatic neuroendocrine tumors,
comprising administering to a human subject in need thereof a
therapeutically effective amount of
40-O-(2-hydroxyethyl)-rapamycin as a monotherapy and wherein
the tumors are advanced tumors after failure of cytotoxic
(Id. at claim 1).
patent claim is invalid as obvious under 35 U.S.C. § 103
"if the differences between the subject 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 having ordinary skill in the
art to which said subject matter pertains." 35 U.S.C.
§ 103; see also KSR Int'l Co. v. Teleflex
Inc., 550 U.S. 398, 406-07 (2007). The determination of
obviousness is a question of law with underlying factual
findings. See Kinetic Concepts, Inc. v. Smith &
Nephew, Inc., 688 F.3d 1342, 1360 (Fed. Cir. 2012).
"The underlying factual inquiries include (1) the scope
and content of the prior art; (2) the differences between the
prior art and the claims at issue; (3) the level of ordinary
skill in the art; and (4) any relevant secondary
considerations .. .." Western Union Co. v. MoneyGram
Payment Sys., Inc., 626 F.3d 1361, 1369 (Fed. Cir. 2010)
(citing Graham v. John Deere Co., 383 U.S. 1, 17-18
is required to consider secondary considerations, or
objective indicia of nonobviousness, before reaching an
obviousness determination, as a "check against hindsight
bias." See In re Cyclobenzaprine Hydrochloride
Extended-Release Capsule Patent Litig., 676 F.3d 1063,
1077-79 (Fed. Cir. 2012). Relevant secondary considerations
include commercial success, long felt but unsolved needs,
failure of others, praise, unexpected results, and copying,
among others. Graham, 383 U.S. at 17-18; Ruiz v.
A.B. Chance Co., 234 F.3d 654, 662-63 (Fed. Cir. 2000);
Tex. Instruments, Inc. v. U.S. Int'l Trade Comm
'n, 988 F.2d 1165, 1178 (Fed. Cir. 1993). Secondary
considerations of nonobviousness are important because they
"serve as insurance against the insidious attraction of
the siren hindsight...." W.L. Gore &Assocs.,
Inc. v. Garlock, Inc., 721 F.2d 1540, 1553 (Fed. Cir.
patentee is not required to present evidence of secondary
considerations. See Prometheus Labs., Inc. v. Roxane
Labs., Inc., 805 F.3d 1092, 1101-02 (Fed. Cir. 2015).
There must be enough evidence, however, for a finding that a
given secondary consideration, if presented, exists by a
preponderance of the evidence. See Apple Inc. v. Samsung
Elec. Co., Ltd., 839 F.3d 1034, 1053 (Fed. Cir. 2016)
(en banc). If there is, then the probative value of each
secondary consideration will be considered in light of the
evidence produced. That does not mean, though, that the
burden of persuasion on the ultimate question of obviousness
transfers to the proponent of the secondary consideration.
Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1359
(Fed. Cir. 2007). That burden stays always with the patent
challenger. Id. at 1359-60.
asserting that a patent is invalid as obvious must "show
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." Id. at 1361. That
"expectation of success need only be reasonable, not
absolute." Id. at 1364. "Whether an
ordinarily skilled artisan would have reasonably expected
success ... is measured as of the date of the invention . .
.." Amgen Inc. v. F. Hoffman-La Roche Ltd, 580
F.3d 1340, 1362 (Fed. Cir. 2009).
VALIDITY OF THE '131 PATENT
Findings of Fact
person of ordinary skill in the art ("POSA") has a
medical degree and/or Ph.D. in biology, biochemistry,
pharmaceutical sciences, molecular biology, cancer biology,
or other biological sciences, and, if necessary, collaborates
with others having skills and expertise in areas such as
pharmacology, drug formulation, and biochemistry.
priority date for claims 1-3 of the '131 patent is
February 19, 2001. (D.I. 68-1 at 3).
Hidalgo 2000, Hutchinson, the '772 patent, and U.S.
Patent No. 6, 004, 973 ("the '973 patent") are
Hidalgo 2000 or Hutchinson and the '772 patent or the
'973 patent, in view of what was known in the art, do not
teach a POSA the administration of a therapeutically
effective amount of everolimus to inhibit the growth of solid
excretory system tumors.
Administration of a therapeutically effective amount of
everolimus to treat advanced RCC would not have been obvious
to a POSA.
Conclusions of Law
contends that administration of a therapeutically effective
amount of everolimus to treat advanced RCC would have been
obvious to a POSA. (D.I. 91 at 29). The essence of
Defendant's obviousness argument is that knowledge in the
art about the biology of advanced RCC, mTOR inhibitors, and
safe dosing ranges of everolimus, alongside phase I
temsirolimus clinical trial results in advanced RCC, would
have given a POSA a reasonable expectation of success of
effectively treating advanced RCC with everolimus, as both
everolimus and temsirolimus are mTOR inhibitors.
(Id. at 14). Therefore, according to Defendant, the
invention as a whole would have been obvious to a POSA.
Scope and Content of the Prior Art
asserts that "the prior art established a strong
scientific rationale for using an mTOR inhibitor to treat
advanced RCC." (Id. at 30). Plaintiffs counter
that many different agents were under investigation for the
treatment of advanced RCC, and that the relative success of
immunotherapies would have motivated a POSA to investigate
immunostimulants rather than immunosuppressants like
everolimus. (D.I. 93 at 13; see, e.g., JTX-30 at pp.
869-75; PTX-79 at pp. 43-45).
February 2001, clinical trials for advanced RCC treatments
included immunotherapies (PTX-79 at p. 43-45), chemotherapy
combinations (PTX-127 at p. 2425), and agents targeting
growth factors (JTX-5 at p. 361). Temsirolimus was also in
clinical trials to treat cancer at that time, but no mTOR
inhibitor had been approved to treat any type of cancer (Tr.
463:6-15, 591:9-592:3), and no clinical data existed for
everolimus as an antitumor agent (id. at
188:23-189:3, 464:22-24). Advanced RCC was difficult to treat
(id. at 69:15-70:4), as demonstrated by clinical
trial failures in immunotherapies and chemotherapy
combinations (id. at 590:7-20). Despite these
failures, scientists continued to develop and to test
chemotherapy combination treatments for advanced RCC because
they were active against a variety of cancers and many
combinations were available. (D.I. 93 at 14; Tr.
461:2-462:8). Scientists continued to pursue immunotherapy
treatments for advanced RCC because they had demonstrated the
greatest success to date, with FDA approval for interleukin 2
("IL-2"). (D.I. 93 at 13; Tr. 69:15-18, 431:7- II,
437:10-20). As of February 2001, there were no completed
clinical trials of mTOR inhibitors for treatment of advanced
RCC. (Tr. 595:13-24). The prior art also disclosed high
failure rates of cancer drugs during clinical trials: more
than 70% of cancer drugs failed during phase II, and a
majority of cancer drugs failed during phase III.
(Id. at 202:17-20, 518:18-23). I conclude that in
February 2001, (1) a failure of a particular agent for
treatment of advanced RCC would not have dissuaded a POSA
from pursuing as a whole the class of agents to which the
failed agent belonged, and (2) as a class of drugs, mTOR
inhibitors represented a relatively new line of research for
treatment of advanced RCC.
asserts that the molecular biology of advanced RCC would have
motivated a POSA to pursue treatment using mTOR inhibitors.
(D.I. 91 at 24-28, 41; D.I. 92 at 15-16). According to Dr.
Cho, the prior art established that in renal cell cancer, von
Hippel-Lindau ("VHL") tumor suppressor gene
function loss leads to the accumulation of hypoxia-inducible
factor 1 ("HIF-1"), resulting in over-secretion of
vascular endothelial growth factor ("VEGF"), which
in turn leads to increased angiogenesis and cancer growth.
(Tr. 127:7-128:2, 129:12-23).
prior art's mixed results in studies investigating the
molecular biology of advanced RCC had not explained the
biology as clearly as Dr. Cho stated. As of February 2001,
advanced RCC tumors were known to be highly vascularized
(id. at 129:14-18), and several studies had
demonstrated that a majority (55-60%) of clear cell RCC
patients had VHL tumor suppressor gene mutations
(id. at 132:4-133:13; JTX-11 at p. 793). It was also
known that HIF-1 played a role in regulating VEGF gene
expression, VHL gene inactivation was associated with VEGF
gene expression, and VEGF gene expression correlated with
blood vessel density in many tumor types. (JTX-29 at p. 76).
The prior art also linked VHL-defective RCC cell lines to
HIF-1 activation, hypothesizing that HIF-1 activation
"may underlie the angiogenic phenotype of VHL-associated
tumors, " but also cautioning that HIF-1 activation may
not be a "sufficient explanation for oncogenesis."
(JTX-20 at pp. 271, 274). Immunohistochemical studies
spanning multiple types of cancer cells had demonstrated
HIF-1 a overexpression in only one of the two samples of
human advanced RCC cells studied. (Tr. 137:11-138:21; JTX-36
at pp. 5831-32, 5834).
prior art also implicated multiple pathways in HIF-1
activation in human cancer (JTX-29 at p. 90 Fig. 4), and
noted inconsistent results for HIF-la expression across RCC
biopsies and RCC cell lines (id. at p. 81).
Reviewing studies of HIF-1 in human cancer, the Semenza paper
was optimistic about the future "potential efficacy of
combination therapy utilizing an angiogenesis inhibitor and a
HIF-1 inhibitor" (id. at p. 89 (citations
omitted)), but concluded that "the role of HIF-la
expression in [RCC] requires further analysis"
(id. at p. 81; accord JTX-7 at p. 809
("However, there is still much to learn on, firstly, the
exact mechanisms by which mTOR controls the Gl/S transition
and, secondly, on any other cellular targets of
rapamycin.")). Therefore, although the prior art
provided a working hypothesis for the molecular biology of
advanced RCC, it revealed multiple potential targets in the
mTOR pathway, and scientists acknowledged that the precise
role of HIF-1 in the molecular biology of advanced RCC was
not completely understood.
as of the priority date, some evidence existed to support the
hypothesis that HIF-la overexpression was related to the mTOR
pathway, but the precise mechanism of action underlying that
relationship was not clear. (See, e.g., JTX-37 at p.
1543). The Zhong 2000 study examined human prostate cancer
cell lines and concluded that "HIF-la-dependent gene
transcription and the expression of HIF-1-regulated gene
product are modulated by the activity of the PI3K/AKT/FRAP
pathway" in prostate cancer cells. (Id. at p.
1543; see also Id. at p. 1545). From this, the
authors further concluded that increased HIF-la expression
can be induced by both genetic mutations and physiological
stimulation, and that HIF-1 expression "may play a major
role in promoting angiogenesis and metabolic adaptation in
[prostate cancer] and other common solid tumors."
(Id. at p. 1545). The authors demonstrated
correlations between treatment with either rapamycin or a
phosphoinositide 3-kinase ("PI3K") inhibitor and
reduced HIF-la expression and VEGF secretion in the prostate
cancer cell lines. (Tr. 140:8-20; JTX-37 at pp. 1543, 1544).
Based on these results and prior data, the authors
hypothesized that "pharmacological inhibition of HIF-1
activity may represent a useful treatment strategy, "
and that "the effect of PI3K/AKT/FRAP pathway inhibitors
on HIF-la expression may provide a basis for therapeutic
efficacy." (JTX-37 at p. 1545).
Zhong 2000 authors cautioned, however, that additional
studies would be required to determine the precise mechanism
of action of the PBK/protein kinase B
("AKT")/FKBP12 rapamycin-associated protein
("FRAP") pathway as it related to HIF-la
expression. (Id. at p. 1543; accord JTX-27
at p. 3512 ("Clearly, additional experiments are
required to establish the relationship between deregulated
PI3K-AKT activity and rapamycin sensitivity in human cancer
cells."); JTX-29 at p. 91 ("[T]he accelerating pace
of discovery [regarding the role of HIF-1 in cancer biology]
hopefully will provide sufficient momentum for the transition
from basic science to clinical application in the near
Defendant asserts that the prior art established a clear
preference for an orally-administered cancer treatment. (D.I.
91 at 28 (citing JTX-10 at Abstract (identifying
pharmacoeconomic principles, patient preference, and improved
quality of life as driving the pursuit of oral formulations,
and noting bioavailability and patient compliance concerns as
limitations to oral chemotherapy formulations))). Plaintiffs
disagree, arguing that "whether a drug [c]an be
administered intravenously or by subcutaneous injection or by
orally is not one of the important points for both physicians
and patients in choosing a therapy." (Tr. 477:13-17).
Whereas Plaintiffs' argument rests on their expert's
experience, Defendant's argument finds support in the
prior art. I agree with Defendant that the prior art
established a general preference for orally-administered
light of the preference for oral cancer treatments, the
molecular biology of advanced RCC, and the prior art relating
to mTOR inhibitors, Defendant argues a POSA would have been
motivated to pursue everolimus to treat advanced RCC with a
reasonable expectation of success. (D.I. 91 at 29). The prior
art disclosed general antiproliferative properties of
everolimus, and that oral administration of everolimus was
safe and tolerable in treating renal and liver transplant
patients. (JTX-19 at p. 160; JTX-22 at p. 694). According to
Dr. Cho, since everolimus and rapamycin both target the mTOR
pathway, a POSA would reasonably expect everolimus to have
the same antiproliferative effect in advanced RCC patients
that rapamycin had in prostate cancer cells. (D.I. 91 at 27;
Tr. 139:20-140:1). This assertion is undermined, however, by
Dr. Cho's admission that a POSA would not generalize
results of a particular treatment across different cancer
models. (Tr. 203:16-22). Additionally, although they are
related compounds, rapamycin, temsirolimus, and everolimus
differ in various pharmacological properties such as their
binding affinities for FKBP-12 (id. at 523:18-524:4
(citing JTX-25 at p. 38)), elimination half-lives (Tr.
526:24-527:20 (citing JTX-22 at p. 703)), and the correlation
between dose and drug duration in the bloodstream (Tr.
526:1-22 (citing JTX-22 at p. 702)). Therefore, the prior art
at most would have identified an oral formulation of
everolimus as one of many potential treatment options for
the background prior art disclosed a variety of approaches
under development to treat advanced RCC, including the use of
temsirolimus, an mTOR inhibitor, which was in the early
stages of clinical development. It cautioned, however, that
the role of HIF-1 and the mTOR pathway in the molecular
biology of advanced RCC was not completely understood, and
that cancer treatments generally demonstrated high failure
rates at phase II and phase III clinical trials. The prior
art also taught a preference for oral formulations for cancer