Testosterone undecanoate - USA

On Jul 13, 2018, Federal Circuit upheld two patents covering testosterone replacement therapy (Aveed®) & rejected a generics maker’s argument that the patents were invalid for obviousness.

Endo Pharmaceuticals Solutions, Inc. holds NDA for Aveed®, a testosterone undecanoate (TU) intramuscular injection. Aveed® is a long-acting injectable testosterone replacement therapy for men suffering from physiologically low levels of testosterone, also known as hypogonadism. Custopharm Inc.’s predecessor-in-interest, Paddock Laboratories, LLC, submitted an ANDA to USFDA for approval of generic version of Aveed®.  Claim 2 of US 7,718,640 patent and claim 18 of US 8,338,395 patent which were the sole issues cover Aveed®’s formulation and injection regimen. Specifically, claim 2 of the ’640 patent covers a 750 mg dosage of TU in the composition & claim 18 of the ’395 patent covers a 750 mg dosage of TU & a vehicle containing castor oil (42% or less) and a co-solvent, benzyl benzoate.

The case proceeded to a bench trial on the sole issues of whether claim 2 of the ’640 patent and claim 18 of the ’395 patent would have been obvious to a skilled artisan in view of the prior art, which consisted primarily of three scientific articles: Behre, Nieschlag, and von Eckardstein (Articles). These Articles describe small clinical studies involving 1000 mg TU injections. The Articles report a composition of 250 mg/ml TU in castor oil. The parties agreed that the Articles do not disclose or describe the use of a co-solvent. District court found that the prior art did not disclose the 750 mg TU injection dosage, and that Custopharm had not shown, by clear and convincing evidence, that a skilled artisan would have been motivated to lower the dosage of TU from 1000 mg to 750 mg due to concerns patients were being overdosed. Further, the district court found that the Articles do not inherently disclose benzyl benzoate as a co-solvent or the particular ratio of solvent to co-solvent claimed by the patents-in-suits. Custopharm appealed.

During appeal, Custopharm contended that a skilled artisan would have recognized that these patients were being overdosed and would have been motivated to reduce the dose from 1000 mg to 750 mg by injecting patients with 3 ml instead of 4 ml of solution at a TU concentration of 250 mg/ml. Court however, rejected the arguments & found that Custopharm had not shown, by clear and convincing evidence, that a skilled artisan would have recognized that patients injected with 1000 mg TU were being overdosed. To meet its burden, Custopharm needed to do more than merely show that the prior art does not preclude lowering the dose of TU. Custopharm needed 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 which disclosed 300 to 1000 ng/dl ranges.

Regarding the vehicle formulation, Custopharm argued that the vehicle formulation was inherently disclosed because the Articles provide a detailed recitation of the TU injection composition’s pharmacokinetic performance, from which a skilled artisan could derive that the vehicle consisted of 40% castor oil and 60% benzyl benzoate. The district court reasonably found that this was not enough “to establish that the Articles barred the possibility of an alternative vehicle being used in the prior art compositions” to meet the rigorous standard of inherency. Because first, Custopharm has not demonstrated that a skilled artisan could extrapolate the vehicle formulation used in the Articles from pharmacokinetic performance data. Second, the prior art was replete with potential co-solvents such that a skilled artisan, reviewing the Articles, would not have necessarily recognized that the Articles’ authors used benzyl benzoate as a co-solvent for their reported clinical studies. Third, the cases Custopharm cited to support their inherency arguments are inapposite.

Thus, Federal Circuit concluded that the district court did not commit reversible error in finding that claim 2 of the ’640 patent and claim 18 of the ’395 patent were not proven to be obvious over the prior art.