Par Pharmaceutical, Inc. v. Twi Pharmaceuticals, Inc. , 773 F.3d 1186 ( 2014 )

United States Court of Appeals
for the Federal Circuit
______________________
PAR PHARMACEUTICAL, INC., AND
ALKERMES PHARMA IRELAND LIMITED,
Plaintiffs-Appellants,
v.
TWI PHARMACEUTICALS, INC.,
Defendant-Appellee.
______________________
2014-1391
______________________
Appeal from the United States District Court for the
District of Maryland in No. 1:11-cv-02466-CCB, Judge
Catherine C. Blake.
______________________
Decided: December 3, 2014
______________________
DANIEL G. BROWN, Latham & Watkins LLP, of New
York, New York, argued for plaintiffs-appellants. On the
brief for Par Pharmaceutical, Inc. were GREGORY G.
GARRE, JONATHAN Y. ELLIS and JENNIFER M. HALBLEIB, of
Washington, DC, and ROGER J. CHIN and GREGORY K.
SOBOLSKI, of San Francisco, California. On the brief for
Alkermes Pharma Ireland Limited were MARYELLEN
NOREIKA, JACK B. BLUMENFELD and JEREMY A. TIGAN,
Morris Nichols, Arsht & Tunnell LLP, of Wilmington,
Delaware. On the brief for both plaintiffs-appellants was
2 PAR PHARMACEUTICAL, INC. v. TWI PHARMACEUTICALS, INC.
JAMES PATRICK ULWICK, Kramon and Graham, P.A., of
Baltimore, Maryland.
DON J. MIZERK, Husch Blackwell LLP, of Chicago, Il-
linois, argued for defendant-appellee. With him on the
brief were STEVEN E. FELDMAN, DANIEL R. CHERRY, and
JOHN A. SHOLAR, JR.
______________________
Before O’MALLEY, WALLACH, and HUGHES, Circuit Judges.
O’MALLEY, Circuit Judge.
This patent case involves methods of use of nanosized
formulations of the drug megestrol acetate (“megestrol”).
After a bench trial, the U.S. District Court for the District
of Maryland found the asserted claims of U.S. Patent No.
7,101,576 (“’576 patent”) invalid as obvious. We vacate
the district court’s judgment of invalidity and remand for
further analysis because the district court incorrectly
applied our law on inherency in the context of obvious-
ness.
I.
The ’576 patent claims methods of using megestrol
nanoparticles to “increas[e] the body mass in a human
patient suffering from anorexia, cachexia, or loss of body
mass.” ’576 Patent col. 41 l. 63–col. 43 l. 8. Megestrol has
long been used to treat wasting, initially for cancer pa-
tients. In 1993, Bristol-Myers Squibb began marketing
an oral suspension of micronized megestrol, named Mega-
ce OS, specifically for the treatment of anorexia and
cachexia in AIDS patients. Megace OS proved to be a
commercial success, and other manufacturers submitted
Abbreviated New Drug Applications (“ANDAs”) under the
Hatch-Waxman Act to seek approval to market generic
versions of Megace OS.
PAR PHARMACEUTICAL, INC. v. TWI PHARMACEUTICALS, INC. 3
A.
Par Pharmaceutical (“Par”) 1 applied for and received
approval to market a generic micronized megestrol formu-
lation. Par, however, continued to experiment with
megestrol, including attempts at reformulating the drug
by reducing the particle size from the micrometer range to
the nanometer range. Par contracted with Alkermes
Pharma Ireland (“Alkermes”), née Elan Pharmaceuticals,
to use its “NanoCrystal” technology to formulate na-
nosized megestrol.
After Alkermes produced megestrol nanoparticles, Par
discovered that Megace OS demonstrated a strong food
effect. Patients taking Megace OS with a meal showed a
significantly higher rate and extent of absorption com-
pared with those patients who took Megace OS while in a
fasting state. The nanosized megestrol formulation,
however, showed a greatly reduced food effect. A reduc-
tion in the food effect would be especially vital for AIDS
patients undergoing wasting, as those patients often have
substantially reduced appetites.
The U.S. Patent and Trademark Office (“USPTO”)
rejected Par’s initial claims covering methods for use of
nanosized megestrol formulations as obvious in light of
prior art that discussed micronized megestrol formula-
tions and Elan’s NanoCrystal technology. To overcome
the rejection, Par amended its independent claims by
adding two “wherein” clauses that address the lack of a
food effect in the nanosized megestrol formulation (“food
1 The district court referred to the appellant, Par
Pharmaceutical, as “Par Pharmaceuticals” in its memo-
randum opinion. We will, consistent with the parties’
briefing, refer to the appellant as “Par Pharmaceutical”
throughout the opinion, including in citations to the
district court’s opinions.
4 PAR PHARMACEUTICAL, INC. v. TWI PHARMACEUTICALS, INC.
effect limitations”), and the USPTO granted the patent
with the amended claims. Claim 1 is instructive:
A method of increasing the body mass in a
human patient suffering from anorexia, ca-
chexia, or loss of body mass, comprising ad-
ministering to the human patient a
megestrol formulation, wherein:
(a) the megestrol acetate formulation is a
dose of about 40 mg to about 800 mg in
about a 5 mL dose of an oral suspension;
(b) the megestrol acetate formulation com-
prises megestrol particles having an ef-
fective average particle size of less than
about 2000 nm, and at least one surface
stabilizer associated with the surface of
the megestrol particles; and
(c) the administration is once daily;
wherein after a single administration in a
human subject of the formulation there is no
substantial difference in the Cmax of meges-
trol when the formulation is administered to
the subject in a fed versus a fasted state,
wherein fasted state is defined as the subject
having no food within at least the previous
10 hours, and wherein fed state is defined as
the subject having a high-calorie meal within
approximately 30 minutes of dosing.
The Food and Drug Administration (“FDA”) approved
Par’s New Drug Application for its megestrol nanoparticle
formulation, Megace ES. Megace ES was indicated for
use “without regard to meals,” unlike Megace OS, where,
“[t]he effect of food on bioavailability of MEGACE [OS]
has not been evaluated.” Joint Appendix (“JA”) 5957
PAR PHARMACEUTICAL, INC. v. TWI PHARMACEUTICALS, INC. 5
(Megace ES); JA5970 (Megace OS). Par claims that
Megace ES has generated more than $600M in net sales
since approval in 2005. Par, however, pled guilty to
charges of misbranding Megace ES because Par marketed
Megace ES without FDA approval as an effective weight-
gain method for geriatric patients and as having superior
clinical efficacy over Megace OS despite an absence of
clinical studies supporting that claim.
TWi Pharmaceuticals, Inc. (“TWi”) filed an ANDA
seeking approval to market a generic form of nanosized
megestrol. TWi provided Par with proper notice of its
ANDA and its Paragraph IV certification asserting that
the ’576 patent is invalid or would not be infringed by the
marketing of their nanosized megestrol formulation. In
response, Par filed suit on September 1, 2011, under 35
U.S.C. § 271(e)(2)(A) (2012), claiming that TWi infringed
claims 1–2, 4–5, 7, 10, 12–17, 19, 21, 24, and 26–31.
Claims 1 and 4 are the only independent claims asserted.
Dependent claims 2, 10, 21, 22, 23, and 24 add disease-
specific treatment limitations. Dependent claims 5, 7, 15,
19, and 29 add specific Cmax limitations. Dependent
claims 6 and 18 add specific Tmax limitations. Dependent
claims 8, 12, 13, 14, 15, 20, 25, 26, 27, and 28 add specific
absorption or blood plasma concentration limitations.
And dependent claims 16, 17, 30, and 31 add limitations
for specific surface stabilizers that help to prevent ag-
glomeration of the nanoparticles. TWi responded that: (1)
the claims are invalid as obvious under 35 U.S.C. § 103(2006); (2) the claims do not cover patentable subject
matter under § 101; (3) the claims are not enabled under
§ 112; and (4) Par does not have standing to assert its
claims. 2
2 The district court explicitly did not reach TWi’s
defenses of lack of patentable subject matter, enablement,
6 PAR PHARMACEUTICAL, INC. v. TWI PHARMACEUTICALS, INC.
B.
TWi bases its obviousness argument on multiple
pieces of prior art. 3 In a thorough opinion, the district
court described much of the prior art in detail. Par
Pharm., Inc. v. TWi Pharm., Inc., No. CCB-11-2466, 2014
WL 694976, at *5–12 (D. Md. Feb. 21, 2014) (“Post-Trial
Memorandum”). There are two general categories of prior
art at issue here: (1) analyses of the pharmacokinetic
properties of megestrol, and (2) discussions of the use of
nanoparticle technology in drug formulation. The prior
art, including the label for Megace OS, demonstrated that
micronized oral suspensions of megestrol were used in the
treatment of anorexia, cachexia, and unexplained weight
loss for AIDS patients. Id. at *5–9. Scientific studies
identified many of the clinical characteristics of meges-
trol. A study by Kathleen K. Graham et. al., Pharmaco-
logic Evaluation of Megestrol Acetate Oral Suspension in
Cachectic AIDS Patients, 7 J. Acquired Immune Deficien-
cy Syndromes 580–86 (1994) (“Graham”), analyzed the
pharmacokinetic parameters of AIDS patients treated
with micronized megestrol. Graham found a statistically
significant relationship between weight gain and the
percentage of a 24-hour period during which the patient’s
plasma concentration exceeded a threshold level of
300ng/mL. Post-Trial Memorandum, at *5. Graham
identified two patterns of megestrol elimination in nine
test subjects. Four patients had rapid absorption and
rapid elimination of the megestrol within the first 10
hours of dosage—two of these four patients showed a
weight gain, but on average, the group of four patients
or standing. Post-Trial Memorandum, at *1 n.1. TWi
does not raise these issues in this appeal.
3 The district court found that April 12, 2002 was
the effective filing date for the ’576 patent. Post-Trial
Memorandum, at *5. Par does not challenge this date.
PAR PHARMACEUTICAL, INC. v. TWI PHARMACEUTICALS, INC. 7
experienced no significant weight gain. The other five
patients, however, demonstrated prolonged absorption
and delayed elimination, resulting in a statistically-
significant weight gain. Id. at *5–6.
Other studies with micronized megestrol suspensions,
such as Jamie H. Von Roenn et. al., Megestrol Acetate in
Patients with AIDS-related Cachexia, 121 Annals of
Internal Med. 393–98 (1994) (“Von Roenn”), and Michelle
H. Oster et al., Megestrol Acetate in Patients with AIDS
and Cachexia, 121 Annals of Internal Med. 400–08 (1994)
(“Oster”), also confirmed dose-dependent weight gains in
the test subjects. Post-Trial Memorandum, at *5. These
studies all found significant interpatient variability in
weight gain, but the authors merely speculated as to the
underlying cause of the weight gain. Id. at *6. Finally, A.
Farinha et. al., Improved Bioavailability of a Micronized
Megestrol Acetate Tablet Formulation in Humans, 26
Drug Dev. & Industrial Pharmacy 567–70 (2000)
(“Farinha”), using a solid tablet dosage form of megestrol,
concluded that micronized megestrol showed improved
bioavailability over prior, larger megestrol formulations.
Post-Trial Memorandum, at *6.
Several pieces of prior art disclosed the use of nano-
particle technology in drug formulation. United States
Patent No. 5,145,684 (“’684 patent”), U.S. Patent No.
5,399,363 (“’363 patent”), and European Patent No.
0577215B1 (collectively, “Liversidge patents”) discussed
the use of the NanoCrystal technology for manufacture of
drug particles less than either 1000nm or 400nm in size.
The Liversidge patents stated that drug nanoparticles
with surface modifiers are stable in liquid suspensions,
and the technology could be implemented with many
poorly soluble drug substances. Id. at *10–11. The ’363
patent, in particular, listed megestrol as one of many
preferred anticancer agents for use with the patented
technology. Id. at *11. During the prosecution of the ’684
patent, the inventors disclosed that nanoparticle formula-
8 PAR PHARMACEUTICAL, INC. v. TWI PHARMACEUTICALS, INC.
tions of steroid A and danazol 4 demonstrated substantial
increases in bioavailability, implying that the nanoparti-
cle technology could lead to “decreased fed-fasted variabil-
ity and more rapid onset of action.” Id. Elan’s website
and marketing materials also indicated that the Nano-
Crystal technology “touted the potential to increase
bioavailability, reduce fed-fasted effects, allow higher dose
loading with smaller dose volume, decrease time to thera-
peutic levels, and reduce viscosity in poorly soluble
drugs.” Id. R.H. Müller et al, Nanosuspensions as Par-
ticulate Drug Formulations in Therapy: Rationale for
Development and What We Can Expect for the Future, 47
Advanced Drug Delivery Rev. 3–19 (2001) (“Müller”), also
noted the increased bioavailability and decreased food
effect that results from nanosizing drug particles. Post-
Trial Memorandum, at *11.
C.
TWi moved for summary judgment of invalidity and
noninfringement, and Par cross-moved for summary
judgment on TWi’s collateral estoppel and anticipation
arguments, and to strike TWi’s defenses as untimely. As
an initial matter, the district court adopted Par’s pro-
posed construction of “no substantial difference” to mean
a difference that “would be understood . . . to incorporate
4 Steroid A, danazol, and megestrol are all Bio-
pharmaceutics Classification System (“BCS”) Class II
drugs. The prior art taught that Class II drugs have
similar absorption profiles and often demonstrate fed-
fasted effects. Jennifer B. Dressman & Christos Reppas,
In Vitro-In Vivo Correlations for Lipophilic, Poorly Water-
Soluble Drugs, 11 Eur. J. of Pharmaceutical Sci. S73-80
(2000); David Fleisher et al., Drug, Meal and Formulation
Interactions Influencing Drug Absorption After Oral
Administration: Clinical Implications, 36 Clinical Phar-
macokinetics 233–54 (1999).
PAR PHARMACEUTICAL, INC. v. TWI PHARMACEUTICALS, INC. 9
a ‘clinically useful reduced food effect’ in light of the prior
art’s unexpectedly significant food effect . . . .” Par
Pharm., Inc. v. TWi Pharm., Inc., No. CCB-11-2466, 2013
WL 3777028, at *4–5 (D. Md. July 17, 2013). The district
court then: (1) denied summary judgment pursuant to
TWi’s collateral estoppel argument regarding a related
Board of Patent Appeals and Interferences decision, id. at
*8–9; (2) denied summary judgment as to TWi’s argument
that claim 4 failed to meet the written description re-
quirement in 35 U.S.C. § 112, id. at *9–10; (3) denied
summary judgment on TWi’s claim that the ’363 patent
anticipated all asserted claims of the ’576 patent, id. at
*10–12; and (4) denied summary judgment with respect to
TWi’s argument that the asserted claims were invalid as
obvious, id. at *12–13. The district court specifically
denied summary judgment on obviousness because “[t]his
issue essentially turns on a series of factual disputes that
are not resolvable on summary judgment,” such as the
scope of the prior art disclosures, the existence of a moti-
vation to combine, and considerations of objective indicia
of nonobviousness. Id. After the district court’s denial of
summary judgment, TWi stipulated that its generic
nanosized megestrol product would infringe the asserted
claims of the ’576 patent.
D.
After a five day bench trial, the district court conclud-
ed that the ’576 patent was invalid as obvious. Post-Trial
Memorandum, at *13–21. The court determined that,
although TWi showed megestrol acetate was a known
BCS Class II drug with poor bioavailability, TWi failed to
prove that Megace OS had a known bioavailability prob-
lem or a known food effect in the prior art. Id. at *7–9.
Regardless, TWi proved that all elements of the claimed
invention were disclosed in the prior art. Id. at *12–13.
Importantly, even though the prior art did not explicitly
disclose the food effect differences as claimed, the district
court concluded that “[t]he claimed pharmacokinetic
10 PAR PHARMACEUTICAL, INC. v. TWI PHARMACEUTICALS, INC.
parameters with respect to a food effect . . . are inherent
properties of the obvious nanoparticulate formulation.”
Id. at *13. The reduced food effect was thus “an inherent
result” of nanosized megestrol “even if it was previously
not known in the prior art that a food effect existed.” Id.The district court also found a sufficient motivation to
combine the prior art references. Id. at *14–16. Although
TWi failed to demonstrate that a food effect for Mega-
ce OS was known in the art, the district court concluded
that the known high viscosity and high interpatient
variability of Megace OS would have motivated “a person
skilled in the art to create a method of treatment using
nanoparticles.” Id. at *14. Par’s expert, Dr. Fleckenstein,
admitted that Megace OS “was known to be highly vis-
cous and that this created difficulties in the patient
population.” Id. The district court also pointed to various
studies, such as Farinha, Oster, and Graham, that noted
serious concerns regarding interpatient variability with
Megace OS. Id. at *15. Further, the district court found
that Graham did not teach away from combining mi-
cronized megestrol with nanoparticle technology. Id. at
*17. In the district court’s view, Graham merely “cau-
tion[ed] a person skilled in the art that rapid absorption
with rapid elimination and low blood plasma concentra-
tions may cause Megace OS to be ineffective,” but did not
say that nanoparticles, which “were known to increase
absorption levels and were associated with longer dose
retention,” would lead to deleterious results. Id. The
district court rejected Par’s claims that nanoparticle
technology was so “new, untested, and unpredictable” that
a person of skill in the art would not have a reasonable
expectation of success. Id. at *18. To the contrary, the
district court determined that the “expected benefits of
nanoparticles were widely touted by 2002” and the tech-
nique was noted for its “simplicity.” Id.The district court also considered objective indicia of
nonobviousness, including evidence of unexpected results
PAR PHARMACEUTICAL, INC. v. TWI PHARMACEUTICALS, INC. 11
and long-felt need. 5 Id. at *19. For unexpected results,
the district court found that the evidence of unexpected
results was not particularly convincing, id. at *19 n.20,
and, regardless, concluded that alternate motivations of
viscosity and interpatient variability limited the im-
portance of unexpected results with regards to the food
effect. Id. at *19. The district court also determined that
Par’s claims of a long-felt but unmet need for a more
efficacious method to treat wasting in AIDS patients
could not overcome the strong evidence of obviousness.
Id. Thus, the district court concluded that, even in light
of objective evidence of nonobviousness, the asserted
claims of the ’576 patent were invalid as obvious. Id. at
*21.
Par filed a timely Notice of Appeal, and we have
jurisdiction over the appeal under 28 U.S.C. § 1295(a)(1)
(2012).
II.
Under § 103, a patent may not issue “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 (2006). 6
Obviousness is a question of law based on underlying
5 Par also claimed copying and commercial success,
Post-Trial Memorandum, at *20, but did not dispute the
district court’s analysis of those issues on appeal.
6 Pursuant to § 3(n)(1) of the America Invents Act
(“AIA”), Pub. L. No. 112-29, amended § 103 applies to
patent applications with claims having an effective filing
date on or after March 16, 2013. Because the application
for the ’576 patent was filed before that date, we apply the
pre-AIA version of § 103.
12 PAR PHARMACEUTICAL, INC. v. TWI PHARMACEUTICALS, INC.
factual determinations, including: (1) the scope and
content of prior art; (2) differences between prior art and
claims; (3) the level of ordinary skill in the art; and (4)
objective indicia of nonobviousness. Graham v. John
Deere Co., 383 U.S. 1, 17–18 (1966). A party asserting
that a patent is obvious “must ‘demonstrate by clear and
convincing evidence that a skilled artisan would have had
reason to combine the teaching of the prior art references
to achieve the claimed invention, and that the skilled
artisan would have had a reasonable expectation of suc-
cess from doing so.’” In re Cyclobenzaprine Hydrochloride
Extended-Release Capsule Patent Litig., 676 F.3d 1063,
1068–69 (Fed. Cir. 2012) (quoting Procter & Gamble Co. v.
Teva Pharm. USA, Inc., 566 F.3d 989, 994 (Fed. Cir.
2009)); see also Microsoft Corp. v. i4i Ltd. P’ship, __ U.S.
__, 131 S. Ct. 2238, 2242 (2011) (confirming that an
invalidity defense must meet the clear-and-convincing
evidence standard of proof). Our obviousness inquiry
“must be expansive and flexible.” In re Cyclobenzaprine,
676 F.3d at 1068 (citing KSR Int’l Co. v. Teleflex, Inc., 550
U.S. 398, 415, 419 (2007)).
We review the district court’s determination of obvi-
ousness de novo, but review the court’s underlying factual
findings for clear error. Alcon Research, Ltd. v. Apotex
Inc., 687 F.3d 1362, 1365 (Fed. Cir. 2012). “The burden of
overcoming the district court’s factual findings is, as it
should be, a heavy one.” Polaroid Corp. v. Eastman
Kodak Co., 789 F.2d 1556, 1559 (Fed. Cir. 1986). We
retain, however, “plenary review to determine whether, as
a legal matter, the evidence satisfies the clear-and-
convincing standard of proof.” In re Cyclobenzaprine, 676
F.3d at 1069.
III.
We first must determine whether TWi carried its
burden to prove that all claimed limitations are disclosed
in the prior art. Medichem, S.A. v. Rolabo, S.L., 437 F.3d
PAR PHARMACEUTICAL, INC. v. TWI PHARMACEUTICALS, INC. 13
1157, 1164 (Fed. Cir. 2006) (stating that we consider
motivation to combine and reasonable expectation of
success only “if all the elements of an invention are found
in a combination of prior art references”). Both Par and
TWi appear to agree that essentially all of the substantive
limitations in the independent claims are present in the
various prior art references identified by the district
court. The point of contention is whether the specific food
effect limitations are also disclosed in the prior art. See,
e.g., ’576 Patent col. 42 l. 66–col. 43 l. 3 (“wherein after a
single administration in a human subject of the formula-
tion there is no substantial difference in the Cmax of
megestrol when the formulation is administered to the
subject in a fed versus a fasted state”). Both TWi and the
district court claim that these limitations are an inherent
property of the formulation disclosed by the obvious
combination of prior art elements.
We do not find any clear error in the district court’s
conclusion that TWi failed to prove by clear and convinc-
ing evidence that a food effect for micronized megestrol
was known in the art. Post-Trial Memorandum, at *6–10.
The prior art references failed to mention any food effect
related to megestrol treatments. Certain references
disclosed that BCS Class II drugs in general could demon-
strate a food effect, but these references failed to identify
megestrol as a Class II drug that presented such an effect.
The district court also correctly noted that, if there was a
known food effect with megestrol, it would have been
illogical to administer megestrol to patients in a fasting
state, when the compound would be less effective, in
clinical studies such as Graham. Id. at *8 (“If the Gra-
ham investigators knew the drug was more effective when
taken with food as TWi alleges, it does not make sense
that they would purposefully make it less effective by
having patients take it in a fasted state.”) Thus, the
district court did not clearly err in concluding that there
14 PAR PHARMACEUTICAL, INC. v. TWI PHARMACEUTICALS, INC.
was no known food effect for megestrol in the prior art as
of April 12, 2002.
Because the prior art failed to disclose a known food
effect in megestrol, both TWi and the district court rely on
the doctrine of inherency to disclose the food effect limita-
tion. Id. at *13 (“The claimed pharmacokinetic properties
with respect to a food effect, however, are inherent prop-
erties of the obvious nanoparticulate formulation claimed
by the ’576 patent . . . .”). We conclude that the district
court erred in its inherency analysis under our precedent.
“The inherent teaching of a prior art reference” is a
“question of fact.” In re Napier, 55 F.3d 610, 613 (Fed.
Cir. 1995). We have recognized that inherency may
supply a missing claim limitation in an obviousness
analysis. See, e.g., Santarus, Inc. v. Par Pharm., Inc., 694
F.3d 1344, 1354 (Fed. Cir. 2012); Alcon, 687 F.3d at 1369;
In re Kao, 639 F.3d 1057, 1070 (Fed. Cir. 2011); In re
Kubin, 561 F.3d 1351, 1357 (Fed. Cir. 2009); cf. Ansonia
Brass & Copper Co. v. Elec. Supply Co., 144 U.S. 11(1892) (“[N]othing is better settled in this court than that
the application of an old process to a new and analogous
purpose does not involve invention, even if the new result
had not before been contemplated.”). We have, however,
also explained that the use of inherency, a doctrine origi-
nally rooted in anticipation, must be carefully circum-
scribed in the context of obviousness. See, e.g., In re
Rijckaert, 9 F.3d 1531, 1533–34 (Fed. Cir. 1993) (“The
mere fact that a certain thing may result from a given set
of circumstances is not sufficient [to establish inherency].”
(internal quotation omitted)); In re Oelrich, 666 F.2d 578,
581 (C.C.P.A. 1981) (“[M]ere recitation of a newly discov-
ered function or property, inherently possessed by things
in the prior art, does not distinguish a claim drawn to
those things from the prior art.”); Application of Shetty,
566 F.2d 81, 86 (C.C.P.A. 1977) (“‘[T]he inherency of an
advantage and its obviousness are entirely different
questions . . . . Obviousness cannot be predicated on what
PAR PHARMACEUTICAL, INC. v. TWI PHARMACEUTICALS, INC. 15
is unknown.’” (quoting In re Spormann, 363 F.2d 444, 448
(C.C.P.A. 1966))). In Oelrich, we quoted Hansgirg v.
Kemmer, 102 F.2d 212, 214 (C.C.P.A. 1939), to describe
inherency in an obviousness analysis:
Inherency, however, may not be established by
probabilities or possibilities. The mere fact that a
certain thing may result from a given set of cir-
cumstances is not sufficient. If, however, the dis-
closure is sufficient to show that the natural result
flowing from the operation as taught would result
in the performance of the questioned function, it
seems to be well settled that the disclosure should
be regarded as sufficient.
In re Oelrich, 666 F.2d at 581 (emphasis added) (citations
and quotation marks omitted). Thus, our early precedent,
and that of our predecessor court, established that the
concept of inherency must be limited when applied to
obviousness, and is present only when the limitation at
issue is the “natural result” of the combination of prior art
elements. Id.
Our recent precedent does not diminish this conclu-
sion. In both Alcon and Kubin, we found that the patent
itself defined the limitation at issue as a “property that is
necessarily present.” Alcon, 687 F.3d at 1369; Kubin, 561
F.3d at 1357–58 (“Even if no prior art of record explicitly
discusses the [limitation], the . . . application itself in-
structs that [the limitation] is not an additional require-
ment imposed by the claims on the [claimed invention],
but rather a property necessarily present in the [claimed
invention].”). In Kao, we stated that the claimed limita-
tion was an “inherent property” of a formulation that
“adds nothing of patentable consequence,” thus it was
inherently disclosed by the prior art formulation. 639
F.3d at 1070. Further, in Santarus, we correctly identi-
fied that “an obvious formulation cannot become nonobvi-
ous simply by administering it to a patient and claiming
16 PAR PHARMACEUTICAL, INC. v. TWI PHARMACEUTICALS, INC.
the resulting serum concentrations.” 694 F.3d at 1354;
see also id. (“To hold otherwise would allow any formula-
tion—no matter how obvious—to become patentable
merely by testing and claiming an inherent property.”).
Importantly, though, neither party disputed that the
blood serum concentrations claimed in Santarus were
expected in light of the dosages disclosed in the prior art.
Id.
A party must, therefore, meet a high standard in
order to rely on inherency to establish the existence of a
claim limitation in the prior art in an obviousness analy-
sis—the limitation at issue necessarily must be present,
or the natural result of the combination of elements
explicitly disclosed by the prior art. The district court,
however, did not require that TWi present evidence
sufficient to prove inherency under this standard. Dr.
Beach, TWi’s expert, testified that an improvement in
bioavailability “necessarily results in a decrease in any
food effect,” and TWi presented evidence that a reduction
in particle size improves bioavailability. Post-Trial Mem-
orandum, at *13. Therefore, per the district court, the
reduced particle size would, ipso facto, lead to a reduced
food effect.
The district court’s analysis, however, ignores the
claim limitations at issue. Claim 1, for example, requires
“no substantial difference in Cmax” between the fed and
fasted states. ’576 Patent col. 42 l. 66–col. 43 l. 3. Claim
4 requires that the “difference in Cmax” between the fed
and fasted states be within an enumerated percentage
difference. ’576 Patent col. 43 ll. 27–40. The district
court’s broad diktats regarding the effect of particle size
on bioavailability and food effect are not commensurate
with the actual limitations at issue. While it may be true
that a reduction in particle size naturally results in some
improvement in the food effect, the district court failed to
conclude that the reduction in particle size naturally
results in “no substantial difference” in the food effect. In
PAR PHARMACEUTICAL, INC. v. TWI PHARMACEUTICALS, INC. 17
re Oelrich, 666 F.2d at 581 (“Inherency, however, may not
be established by probabilities or possibilities. The mere
fact that a certain thing may result from a given set of
circumstances is not sufficient.” (quoting Hansgirg, 102
F.2d at 214)).
Although the district court applied the incorrect
standard for inherency in its obviousness analysis, we
cannot, on the record before the court, conclude that TWi
failed to present evidence sufficient to demonstrate that
the claimed food effect limitations necessarily are present
in the prior art combinations. There are simply no find-
ings of fact addressing that question, and we decline to
make such findings in the first instance. We therefore
vacate the district court’s inherency analysis and remand
for the district court to determine if TWi has presented
clear and convincing evidence that demonstrates the food
effect as claimed is necessarily present in the prior art
combination.
IV.
Although the district court erred in its inherency
analysis, we agree with its analysis of the motivation to
combine and reasonable expectation of success. After
determining that claimed elements are present in the
prior art,
[P]roper analysis under § 103 requires, inter alia,
consideration of two factors: (1) whether the prior
art would have suggested to those of ordinary skill
in the art that they should make the claimed
composition or device, or carry out the claimed
process; and (2) whether the prior art would also
have revealed that in so making or carrying out,
those of ordinary skill would have a reasonable
expectation of success.
Medichem, 437 F.3d at 1164 (quoting Verlander v. Garner,
348 F.3d 1359, 1363 (Fed. Cir. 2003)). “The presence or
18 PAR PHARMACEUTICAL, INC. v. TWI PHARMACEUTICALS, INC.
absence of a motivation to combine references in an
obviousness determination is a pure question of fact.”
Alza Corp. v. Mylan Labs., Inc., 464 F.3d 1286, 1289 (Fed.
Cir. 2006) (quoting In re Gartside, 203 F.3d 1305, 1316
(Fed. Cir. 2000)). The presence or absence of a reasonable
expectation of success is also a question of fact. Id.“What a reference teaches and whether it teaches toward
or away from the claimed invention are questions of fact.”
Winner Int’l Royalty Corp. v. Wang, 202 F.3d 1340, 1349
(Fed. Cir. 2000) (quoting In re Bell, 991 F.2d 781, 784
(Fed. Cir. 1993)).
A.
Par argues that there is no motivation to combine
because a person of ordinary skill in the art at the time of
the invention would not have known of a food effect for
Megace OS. Thus, Par asserts a person of ordinary skill
in the art would not have been motivated to combine
nanoparticle technology with micronized megestrol to
abrogate a food effect. Par’s argument, however, ignores
that we are not limited to the same motivation that may
have motivated the inventors. Alcon, 687 F.3d at 1369
(“We have repeatedly held that the motivation to modify a
prior art reference to arrive at the claimed invention need
not be the same motivation that the patentee had.”). We
have explained that “that “[m]otivation to combine may be
found in many different places and forms.” Allergan, Inc.
v. Sandoz, Inc., 726 F.3d 1286, 1292 (Fed. Cir. 2013); see
also Alza, 464 F.3d at 1294 (stating that the motivation to
combine does not have to be explicitly stated in the prior
art, and can be supported by testimony of an expert
witness regarding knowledge of a person of skill in the art
at the time of invention). In particular, as the food effect
was not known in the art at the time of the invention, it is
not clear how the food effect could have even motivated
the named inventors to attempt to nanosize megestrol.
Thus, the district court did not err in looking to motiva-
tions beyond the food effect.
PAR PHARMACEUTICAL, INC. v. TWI PHARMACEUTICALS, INC. 19
The district court also did not err in finding alternate
motivations due to the viscosity and interpatient variabil-
ity problems with micronized megestrol. The district
court pointed to testimony by Dr. Fleckenstein, Par’s own
expert, who stated that Megace OS “was known to be
highly viscous and that this created difficulties in the
patient population because AIDS patients have difficulty
swallowing viscous materials.” Post-Trial Memorandum,
at *14. TWi demonstrated that Megace OS treatments
required relatively large volumes of a viscous liquid
suspension, making patient compliance difficult. Id. The
district court also found that it was known in the art that
the NanoCrystal technology could significantly reduce the
viscosity in highly viscous drug formulations. Id.For interpatient variability, Par does not appear to
dispute that prior art studies, such as Graham and
Farinha, identified significant interpatient variability in
weight gain with use of micronized megestrol. Based on
these findings of interpatient variability, a person of skill
in the art would have known that reduction of particle
size to microsized Megace OS improved bioavailability for
megestrol. Id. at *15. TWi also presented evidence that
improved bioavailability in BCS Class II drugs, such as
danazol and steroid A, reduced interpatient variability.
Id. Thus, interpatient variability would have been a valid
motivation for a person of skill in the art to seek to im-
prove the bioavailability of megestrol by using NanoCrys-
tal technology. Par argues that, even if these studies
identified an interpatient variability problem, the re-
searchers postulated that the cause of the variability was
due to subject-specific aspects of AIDS, for example how
HIV interacts with the gastrointestinal tract, and not due
to the megestrol formulation. These statements were not,
however, conclusive determinations of a cause, but mere
speculation. Par also argues that there were better
methods available to address the viscosity and interpa-
tient variability concerns with Megace OS. Our prece-
20 PAR PHARMACEUTICAL, INC. v. TWI PHARMACEUTICALS, INC.
dent, however, does not require that the motivation be the
best option, only that it be a suitable option from which
the prior art did not teach away. See Galderma Labs.,
L.P. v. Tolmar, Inc., 737 F.3d 731, 738 (Fed. Cir. 2013);
Bayer Healthcare Pharm., Inc. v. Watson Pharm., Inc.,
713 F.3d 1369, 1376 (Fed. Cir. 2013). There is no ques-
tion, based on the disclosures in the prior art, that the
NanoCrystal technology presented a suitable option for
reducing interpatient variability and viscosity in meges-
trol formulations.
The district court thus did not err in finding a motiva-
tion to combine megestrol with nanoparticle technology
due to the known viscosity and interpatient variability
problems with micronized megestrol.
B.
Par also claims that TWi failed to demonstrate a
reasonable expectation of success because nanoparticle
technology in 2002 was “new, untested, and unpredicta-
ble.” Post-Trial Memorandum, at *18. The district court
disagreed, concluding that “a person skilled in the art in
2002 would have believed making nanoparticles was not
extremely difficult, could successfully be implemented
with a wide variety of drugs, and would result in reduced
interpatient variability, improved bioavailability, reduced
viscosity and reduced dosing volumes.” Id. We see no
clear error in the district court’s conclusion.
The prior art, such as Elan’s marketing materials and
Müller, made clear that the use of nanoparticle technolo-
gy in formulation chemistry had become fairly reliable
and showed consistent results regarding bioavailability,
viscosity, and interpatient variability. The Liversidge
patents discussed the successful use of nanoparticle
technology with other BCS Class II drugs, such as
danazol and steroid A. The prior art also identified that
one of the key benefits of the nanoparticle technology was
its simplicity. The reasonable expectation of success
PAR PHARMACEUTICAL, INC. v. TWI PHARMACEUTICALS, INC. 21
requirement for obviousness does not necessitate an
absolute certainty for success. In re O’Farrell, 853 F.2d
894, 903–04 (Fed. Cir. 1988). Thus, we conclude that the
district court did not err in finding that TWi proved a
reasonable likelihood of success in combining megestrol
with nanoparticle technology.
C.
Par further argues that the Graham reference teaches
away from combining megestrol with nanoparticle tech-
nology. Par claims that Graham specifically teaches away
from combining megestrol with a technique that would
lead to quicker absorption and elimination of megestrol.
Graham determined that patients with rapid absorption
and release of megestrol exhibited, on average, no signifi-
cant weight gain, while patients with better megestrol
retention showed a significant weight gain. Par argues
that nanoparticle technology increases absorption and
elimination rates, so Graham teaches away from the
combination of this technique with megestrol.
A prior art reference teaches away when it “suggests
that the line of development flowing from the reference’s
disclosure is unlikely to be productive of the result sought
by the applicant.” Santarus, 694 F.3d at 1354 (quoting
Medichem, 437 F.3d at 1165); see also Kubin, 561 F.3d at
1357 (“A reference may be said to teach away when a
person of ordinary skill, upon reading the reference,
would be discouraged from following the path set out in
the reference, or would be led in a direction divergent
from the path that was taken by the applicant.” (quoting
In re Gurley, 27 F.3d 551, 553 (Fed. Cir. 1994)). We find
that the district court did not err in concluding that
Graham does not teach away from combining megestrol
with the NanoCrystal technology. Graham merely “cau-
tion[ed] a person skilled in the art that rapid absorption
with rapid elimination and low blood plasma concentra-
tions may cause Megace OS to be ineffective.” Post-Trial
22 PAR PHARMACEUTICAL, INC. v. TWI PHARMACEUTICALS, INC.
Memorandum, at *17. Graham never mentioned nano-
particle technology, and never stated that further size
reductions would lead to more rapid elimination of meges-
trol. Par also fails to point to any prior art reference that
indicated that nanoparticle technology led to faster elimi-
nation or lower blood plasma concentrations of BCS Class
II drug products. Absent evidence that nanoparticles
invariably led to faster elimination of drug products from
circulation, the district court did not clearly err in finding
that Graham does not teach away.
V.
Par also presented evidence of objective indicia of
nonobviousness. Par first objects to the fact that the
district court turned to these indicia only after concluding
that “TWi has proved by clear and convincing evidence a
prima facie case of obviousness.” Post-Trial Memoran-
dum, at *12. We are unpersuaded that the legal frame-
work employed by the district court was improper. It is
true that we have frequently noted that there is no formal
burden-shifting framework associated with an obvious-
ness analysis before a district court. See, e.g., In re Cyclo-
benzaprine, 676 F.3d at 1075 (“The district court erred,
however, by making its finding that the patents in suit
were obvious before it considered the objective considera-
tions and by shifting the burden of persuasion to [the
patentee].”); see also i4i Ltd., 131 S. Ct. at 2246–48 (rec-
ognizing that the presumption of patent validity in 35
U.S.C. § 282 does not act as merely a procedural burden-
shifting device). The trial court should not “defer exami-
nation of the objective considerations until after the fact
finder makes an obviousness finding,” In re Cycloben-
zaprine, 676 F.3d at 1075–76 (citing Stratoflex, Inc. v.
Aeroquip Corp., 713 F.2d 1530, 1538–39 (Fed. Cir. 1983)),
and “consideration of the objective indicia is part of the
whole obviousness analysis, not just an afterthought.”
Leo Pharm. Prods., Ltd. v. Rea, 726 F.3d 1346, 1358 (Fed.
Cir. 2013). Despite the phrasing employed, however, we
PAR PHARMACEUTICAL, INC. v. TWI PHARMACEUTICALS, INC. 23
do not believe the district court erred in its analysis of the
objective indicia of nonobviousness—it is clear that the
district court did consider the objective indicia before
reaching its ultimate obviousness conclusion, which is
what our precedent counsels.
Par has appealed the district court’s analysis of
unexpected results and long-felt need. Par claims that
the reduced food effect and the increased weight gain for
patients treated with nanosized megestrol formulations
were unexpected results. The district court, focusing on
the alternate motivations of decreased viscosity and
decreased interpatient variability, found that “[t]he fact
that the use of nanotechnology may have surprisingly
solved [the food effect] problem[] as well does not under-
mine” the district court’s motivation to combine analysis.
Post-Trial Memorandum, at *19. Par argues that the
district court has categorically excluded its purported
unexpected results solely because those results do not
flow directly from the alternate motivations. We disagree.
“Unexpected results are useful to show the ‘improved
properties provided by the claimed compositions are much
greater than would have been predicted.’” Leo Pharm.,
726 F.3d at 1358 (quoting In re Soni, 54 F.3d 746, 751
(Fed. Cir. 1995)). We have previously held that unex-
pected results do not have to derive explicitly from the
motivation to combine to be relevant. See, e.g., Allergan,
726 F.3d at 1293; Ortho-McNeil Pharm., Inc. v. Mylan
Labs., Inc., 520 F.3d 1358, 1365 (Fed. Cir. 2008). We do
not read the district court’s opinion to have categorically
excluded the unexpected results from its obviousness
analysis. See Post-Trial Memorandum, at *19 (citing
Allergan, 726 F.3d at 1293, for the proposition that “un-
expected results with respect to one property did not
overcome the . . . showing of obviousness where there were
other issues providing motivation to combine” (emphasis
added)). It appears that the district court correctly took
into consideration the relevance of the unexpected results
24 PAR PHARMACEUTICAL, INC. v. TWI PHARMACEUTICALS, INC.
in weighing the importance of those results. The district
court concluded that, even if we assume that the results
here were unexpected, given the nature of those results,
they were insufficient to alter the court’s obviousness
conclusion. See Post-Trial Memorandum, at *19 & n.20.
In reviewing the district court’s conclusion regarding the
ultimate persuasiveness of the evidence of unexpected
results, we agree with the district court that this evi-
dence, while not categorically excluded, was not entitled
to substantial weight when factored into the overall
obviousness analysis. It is true that unexpected results
can, in appropriate circumstances, be sufficient standing
alone to preclude a finding of obviousness. See Procter &
Gamble, 566 F.3d at 994 (“If a patent challenger makes a
prima facie showing of obviousness, the owner may rebut
based on ‘unexpected results’ by demonstrating ‘that the
claimed invention exhibits some superior property or
advantage that a person of ordinary skill in the relevant
art would have found surprising or unexpected.’” (quoting
Soni, 54 F.3d at 750)). Whether that is true, however,
will necessarily turn on the precise nature of those results
and the strength of other evidence weighing in favor of an
obviousness determination.
Finally, Par claims there was a long-standing need for
more effective treatment of wasting in AIDS patients. A
pilot study by Dr. Christine Wanke comparing the effec-
tiveness of Megace ES and Megace OS in AIDS patients, 7
as well as Dr. Wanke’s trial testimony, purportedly
demonstrates that patients taking Megace ES had “signif-
icantly greater weight gain.” Post-Trial Memorandum, at
*19. According to Par, this evidence confirms that na-
7 Christine Wanke et al., Safety and Efficacy of Two
Preparations of Megestrol Acetate in HIV-Infected Indi-
viduals with Weight Loss in Africa, India, and the United
States, 7 J. Applied Res. 206–16 (2007).
PAR PHARMACEUTICAL, INC. v. TWI PHARMACEUTICALS, INC. 25
nosized megestrol meets this long-felt need. The district
court disagreed. The district court found that only de-
pendent claims 2, 10, 21, and 24 are limited to treatment
of weight loss in AIDS patients, and the Wanke evidence
is only commensurate with the scope of those claims. Id.Further, even for those four dependent claims, Dr. Wanke
merely concluded that “the use of the [Megace ES] formu-
lation may be preferable to [Megace OS].” Id. The dis-
trict court found this equivocal statement to be
insufficient for Megace ES to establish a long-felt need.
We agree, and find that the district court did not clearly
err in its analysis of long-felt need.
VI.
Although we agree with the district court’s analysis
and conclusions on motivation to combine, reasonable
expectation of success, and objective indicia of nonobvi-
ousness, we vacate the district court’s judgment that
the ’576 patent is obvious, and remand for further analy-
sis of the food effect limitation consistent with our prece-
dent on inherency. The district court should also consider
TWi’s other grounds for invalidity, such as enablement, if
necessary. 8
VACATED AND REMANDED
8 The pending motion to dissolve the injunction
pending appeal is denied as moot.