Par Pharms., Inc. v. TWi Pharms., Inc.

Because combining nanotechnology with megestrol acetate would have been obvious to someone skilled in the art—due to the viscosity and inter-patient variability associated with the micronized formulation— patent-in-suit was invalid.

Spring 2014

Robins Kaplan GENERICally Speaking: A Hatch-Waxman Litigation Bulletin

Case Name: Par Pharms., Inc. v. TWi Pharms., Inc., Civ. No. 11-2466-CCB, 2014 U.S. Dist. LEXIS 21704 (D. Md. Feb. 21, 2014) (Blake, J.)

Drug Product and Patent(s)-in-Suit: Megace ES® (megestrol acetate); U.S. Pat. No. 7,101,576 (“the ’576 patent”)

Nature of the Case and Issue(s) Presented: In 1993 BMS began marketing Megace OS®, an oral suspension of micronized megestrol acetate. The drug was used to treat anorexia and cachexia in AIDS patients. It was commercially successful, and the FDA approved five generic equivalents, one of which was filed by Par. By 2005, Par had captured the majority of the generic Magace OS market.

As a result of further experimentation it was determined that reformulating Megace OS to reduce particle size increased bioavailability when the patient had an empty stomach.  This was an especially noteworthy improvement because the patients who typically were prescribed the drug often exhibited poor appetite.  The ’576 patent covered this improvement and issued in 2006, as did Par’s NDA for Megace ES.

TWi filed an ANDA seeking FDA approval to manufacture and market a generic version of Megace ES, which included a Paragraph IV certification against the ’576 patent. Par filed suit. The parties stipulated to infringement of the asserted claims, and the only issues left for trial were TWi’s defense that the ‘576 patent was invalid due to obviousness, and whether Par had standing to bring suit as a co-plaintiff. The court found in favor of TWi.

Why TWi Prevailed: The court first found that TWi proffered sufficient evidence to establish a prima facie case of obviousness. The prior art clearly identified the use of an oral suspension of megestrol acetate for increasing body mass in HIV/AIDS patients suffering from anorexia, cachexia, or unexplained weight loss. There was also disclosure of the claimed dose ranges, from 40 mg to 800 mg. The prior art disclosed each of the claimed therapeutic blood level concentrations, as well as the use of nanoparticulates in pharmaceutical compositions for oral administration. Par argued that the prior art failed to disclose the differences in blood concentration between individuals in fed and fasting states. But the court rejected this argument finding that the claimed pharmacokinetic parameters with respect to a food effect were merely an inherent property of the nanoparticulate formulation. The court held that TWi had proven by clear and convincing evidence that combining nanotechnology with megestrol acetate would have been obvious to someone skilled in the art because of the viscosity and inter-patient variability associated with the micronized formulation. Based on the prior art, it was likely that reducing particle size would improve bioavailability across all administrations, thus any food effect would inherently be reduced.

Next, the court next addressed the specific motivations to combine. Although TWi was not able to establish the food effect associated with Megace OS and the extent of its bioavailability problem, it did prove that it was known that Megace OS was viscous and required more dosing, and that absorption levels varied greatly among patients. The court found that both of these problems provided sufficient motivation for a person skilled in the art to create a method of treatment using nanoparticles. TWi proved that the problems known to exist with respect to Megace OS were its viscosity, dose volume, and its varied efficacy in patients, and that each was known to be affected by a drug's particle size. The benefits of reducing particle size were known with respect to all known problems. Although nanotechnology may have been relatively new and untested, the prior art nanotechnology patents provided a clear method for creating stable nanoparticles.

The court also rejected Par’s argument that the prior art taught away from combining Megace OS and nanoparticulate technology. Although cautioning a person skilled in the art that rapid absorption with rapid elimination and low blood-plasma concentrations could have caused Megace OS to be ineffective, the prior-art reference cited by Par did not discredit a nanoparticulate formulation or teach that it would not have worked for its intended treatment. The court also rejected Par’s argument that nanotechnology was new, untested and unpredictable, and that there was no reasonable likelihood of success in created in the claimed invention. Instead, the court noted that the available evidence indicated 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, particularly steroids, and would result in reduced interpatient variability, improved bioavailability, reduced viscosity and reduced dosing volumes.

The court next considered Par’s evidence of secondary considerations of non-obviousness. TWi provided clear and convincing evidence that there were motivations in the art other than fed-fasted variability and that the need for increased weight gain to use nanotechnology with the existing method, and that the technology’s ability to reduce interpatient variability and viscosity were known. The court rejected Par’s argument that its brand drug met a long-felt need because it relied on a study that merely stated that Magace ES may be preferable to Megace OS. A statement that one drug may be preferable to another was not strong enough to support Par’s argument.  The court quickly rejected Par’s argument regarding copying because in the context of most ANDA litigation, the generic manufacturer is required by law to establish bioequivalence with respect to the branded drug. Last, the court found Par’s evidence of commercial success unconvincing. The court found that Par failed to demonstrate that there was a nexus between the novel features of the invention and its sales.  Additionally the court noted that although Megace ES® captured 23 percent of the market at its peak, such still implied that it failed to capture the remaining 75% of the market.  The court also noted a decline in market share to 19% even after Par had spent over $70 million in advertising on the drug.

Because the court’s ruling on the obviousness issue was dispositive, it did not reach the issue of whether Par had standing to assert the patent.

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