*2 O’M ALLEY , 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 trеatment 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.
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 discovеred 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 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 dаily; wherein after a single administration in a human subject of the formulation there is no substantial difference in the C max 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 (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 diseasе- specific treatment limitations. Dependent claims 5, 7, 15, 19, and 29 add specific C max limitations. Dependent claims 6 and 18 add specific T max 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]
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. 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. 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., Mеgestrol 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. at *11. During the prosecution of the ’684 patent, the inventors disclosed that nanoparticle formula- . 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.” 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 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. 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 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 оf 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 nanopartiсles, 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. 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 . 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. 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
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 Cаpsule 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
,
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.
,
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 . 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 сombination 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 C max 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. at *8 (“If the Gra- ham investigators knew the drug was more effective when taken with food as TWi alleges, it does not make sensе 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 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. 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,
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
,
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
,
The district court’s analysis, however, ignores the
claim limitations at issue. Claim 1, for example, requires
“no substantial difference in C
max
” between the fed and
fasted states. ’576 Patent col. 42 l. 66–col. 43 l. 3. Claim
4 requires that the “difference in C
max
” 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 aсtual 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
, . 17
re Oelrich
,
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 havе a reasonable expectation of success.
Medichem
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 miсronized 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.
,
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 rеduce 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. 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- 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 сlear 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 , , . 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
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.
,
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 exсluded 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
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
,
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. Aсcording to Par, this evidence confirms that na- . 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
Notes
[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.
[2] The district court explicitly did not reach TWi’s defenses of lack of patentable subject matter, enablement,
[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).
[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.
[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).
[8] The pending motion to dissolve the injunction pending appeal is denied as moot.