The US Court of Appeals for the Federal Circuit upheld a district court finding that the patent challenger failed to prove that patents directed to a testosterone replacement injection therapy were valid and non-obvious. Endo Pharmaceuticals Solutions, Inc. v. Custopharm Inc., Case No. 17-1719 (Fed. Cir. July 13, 2018) (Chen, J).

Endo Pharmaceuticals holds the new drug application for Aveed, a long-acting injectable testosterone undecanoate (TU) formulation. Bayer Intellectual Property and Bayer Pharma own the two patents listed in the Orange Book for Aveed. In 2014, Custopharm’s predecessor in interest, Paddock Laboratories, submitted an abbreviated new drug application and a Paragraph IV certification. Endo and Bayer subsequently sued Custopharm for patent infringement.

The claims of the Orange Book-listed patents require three primary elements:

  • 750 mg of TU
  • A vehicle comprising 40 percent castor oil and 60 percent benzyl benzoate (the ‘395 patent only required a co-solvent rather than benzyl benzoate specifically)
  • Administration at an initial interval of two injections four weeks apart and maintenance injections at 10-week intervals thereafter (this limitation applied to the asserted claim of one of the listed patents only)

Custopharm argued that the asserted claims were obvious based on three prior art references (collectively, the articles). The articles taught administration of 1000 mg of TU at a concentration of 250 mg/ml in castor oil. The articles, however, did not describe the use of a co-solvent, although it was known in the art in 2007 that the vehicle formulation used in the articles was 40 percent castor oil and 60 percent benzyl benzoate. 

The district court found that Custopharm had not met its burden of proving that the disputed claims would have been obvious because (1) one would not have been motivated to lower the dosage of TU from 1000 mg to 750 mg, as required by the patent claims; (2) the articles did not inherently disclose benzyl benzoate as a co-solvent; and (3) the articles did not disclose the specific injection schedule of the ‘395 patent. Custopharm appealed.

On appeal, Custopharm argued that a skilled artisan would have been motivated to lower the dose of TU from 1000 mg (as disclosed in the articles) to 750 mg (as required by the patent claims), because under the American Association of Clinical Endocrinologists (AACE) Guidelines, four of 14 patients in one of these clinical studies were being overdosed. The district court found this evidence insufficient because under US Food and Drug Administration (FDA) guidelines, only one of these patients would have been considered overdosed, and it found that FDA guidelines are more prevalently applied than AACE guidelines. The Federal Circuit found no error in the district court’s determination that Custopharm failed to affirmatively demonstrate that a skilled artisan would have been motivated to lower the dose of TU despite no clear evidence of overdosing under the FDA guidelines. The Federal Circuit also found that Custopharm’s overdose theory improperly assumed that the only solution to overdosed patients was to reduce the dosage rather than extending the injection intervals.

Custopharm also argued that the vehicle formulation was “necessarily present” in the articles because (1) it was later revealed to be the actual formulation the authors of the articles used in their reported clinical studies, and (2) the articles provided a detailed recitation of the TU injection composition’s pharmacokinetic performance, and from this information the skilled artisan would have derived the claimed vehicle formulation of 60 percent castor oil and 40 percent benzyl benzoate. The Federal Circuit disagreed. With respect to prior art in an obviousness analysis, “[o]bviousness cannot be predicated on what is unknown.” While the inherent characteristic does not have to be recognized or appreciated by a skilled artisan, it must be either necessarily present or the natural result of the combination of elements explicitly disclosed by the prior art. Here, the Court found that the pharmacokinetic performance data was not enough to establish that the articles barred the possibility of alternative vehicles being used in the prior art compositions. 

The Federal Circuit also found no errors in the district court’s finding that the articles did not disclose the claimed injection schedule. Custopharm argued that once a skilled artisan recognized that patients were being overdosed, the claimed injection schedule would be the result of routine treatment of individual patients and would thus be obvious. The Court found this argument unpersuasive, because (1) it was predicated on Custopharm’s overdose theory, which had already been rejected, and (2) read together, the cited art did not contemplate a two-phase dosing regimen with initial loading doses followed by maintenance doses.

Practice Note: This case highlights the difficulty in establishing obviousness based on an inherent characteristic in a prior art reference. To support such an inherency argument, it is important at trial to establish a clear factual record that demonstrates what is disclosed in the prior art reference that would prove that the inherent-undisclosed claim element was necessarily present.