PAR PHARMACEUTICAL, INC., AND ALKERMES PHARMA IRELAND LIMITED, Plaintiffs-Appellants,
TWI PHARMACEUTICALS, INC., Defendant-Appellee
Appeal from the United States District Court for the District of Maryland in No. 1:11-cv-02466-CCB, Judge Catherine C. Blake.
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 JAMES PATRICK ULWICK, Kramon and Graham, P.A., of Baltimore, Maryland.
DON J. MIZERK, Husch Blackwell LLP, of Chicago, Illinois, 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 obviousness.
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 patients. In 1993, Bristol-Myers Squibb began marketing an oral suspension of micronized megestrol,
named Megace 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 (" Par" ) applied for and received approval to market a generic micronized megestrol formulation. 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" ), né e Elan Pharmaceuticals, to use its " NanoCrystal" technology to formulate nanosized 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 compared with those patients who took Megace OS while in a fasting state. The nanosized megestrol formulation, however, showed a greatly reduced food effect. A reduction 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 formulations 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, cachexia, or loss of body mass, comprising administering 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 comprises megestrol particles having an effective 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 megestrol 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 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 agglomeration of the nanoparticles. TWi responded ...