Par Pharmaceutical, Inc., & Alkermes Pharma Ireland Ltd. v. TWi Pharmaceuticals, Inc., No. 2014-1391 (Fed. Cir. Dec. 3, 2014) (O'Malley, J.).Click Here for a copy of the opinion.
Megace OS, marketed by Bristol-Myers Squibb, is an oral suspension of micronized megestrol (megestrol acetate) used for increasing body mass in patients suffering from anorexia and cachexia in AIDS and cancer patients. Par received FDA approval to market a generic version of Megace OS. Par also discovered that Megace OS showed a strong food effect. It demonstrated greater drug absorption when given with a meal than when fasting. However, a nanosized megestrol formulation showed a greatly reduced food effect. The difference in drug absorption between fed and fasted states is much less. Par obtained U.S. Pat. No. 7,101,576 covering methods for using nanosized megestrol to increase body mass, wherein "there is no substantial difference in the Cmax of megestrol" in a subject between fasted and fed states. The FDA approved Par's New Drug Application for its megestrol nanoparticle formulation, which was marketed as Megestrol ES. Unlike Megace OS, Megace ES was indicated for use without regard to meals.
TWi filed an ANDA seeking approval to market a generic form of nanosized megestrol and made a Paragraph IV certification asserting invalidity and non-infringement of the '576 patent. Par then sued TWi for infringement of the '576 patent. After a bench trial, the district court held the '576 patent invalid as inherently obvious. The court based its decision on evidence that reducing particle size could improve bioavailability and on expert testimony indicating that an improvement in bioavaibility necessarily decreases any food effect. The food effect of megestrol was not explicit in the prior art, but was found to be an inherent result of an obvious reduction in particle size, even if it was not previously known that a food effect existed for megestrol or Megace OS.
The Federal Circuit disagreed with the district court's inherency analysis. To rely on inherency as applied to obviousness, a party must meet the "high standard" of establishing that a challenged claim limitation "necessarily must be present" or is the "natural result" of the combination of explicitly disclosed prior art elements. "The mere fact that a certain thing may result from a given set of circumstances is not sufficient." Here, a reduction in particle size may naturally result in some improvement in the food effect. Nevertheless, the claims require more than a decrease in food effect. They require "no substantial difference in Cmax" between fasted and fed states. "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." Because the district court ignored the claim limitations at issue, its inherency finding was erroneous.
Par argued there was no motivation to combine the megestrol and nanoparticle technology, there was evidence of a "teach away" and that the evidence of unexpected results was inadequate. The Federal Circuit affirmed on these points. A motivation to combine references is not limited to the same motivation that drove the original inventors. The district court did not err in looking to motivations beyond the food effect, such as viscosity and interpatient variability problems with micronized megestrol. In addition, Federal Circuit law "does not require that the motivation be the best option, only that it be a suitable option." The district court was also correct in finding a reasonable likelihood of success in combining megestrol with nanoparticle technology, which "does not necessitate an absolute certainty for success." There was no "teach away" because the reference never mentioned nanoparticle technology nor indicated that particle size reduction would lead to more rapid elimination of megestrol.
Finally, the Federal Circuit held that the district court correctly considered the relevance of the unexpected results and appropriately weighed those results. The district court also correctly determined that an expert's equivocal statement that "the use of [nanosized] formulation may be preferable to Megace OS" was insufficient to establish a long-felt need.
The Court ruled: "Although we agree with the district court's analysis and conclusions on motivation to combine, reasonable expectation of success, and objective indicia of nonobviousness, we vacate the district court's judgment that the '576 patent is obvious, and remand for further analysis of the food effect limitation consistent with our precedent on inherency. The district court should also consider TWi's other grounds for invalidity, such as enablement, if necessary."
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