Ertapenem – USA

On Oct. 26, 2017, Federal circuit affirmed the Delaware court’s decision of obviousness in Invanz® case.

Merck Sharp & Dohme Corp. appealed from the decision of the United States District Court for the District of Delaware concluding, after a bench trial, that claims 21–34 (“the asserted claims”) of U.S. Patent 6,486,150 are invalid under 35 U.S.C. § 103. Merck owns the ’150 patent, which is directed to a process for preparing a stable formulation of ertapenem. Ertapenem is known to be unstable because of two degradation reactions—hydrolysis of the lactam nitrogen and dimerization via the pyrrolidine nitrogen. The method of the ’150 patent claims a manufacturing process for a final formulation of the antibiotic that purportedly minimizes both dimerization and hydrolysis degradation pathways. On May 29, 2014, Hospira, Inc. notified Merck that it had filed an abbreviated new drug application (“ANDA”), seeking approval to engage in the commercial manufacture, use, or sale of generic versions of Merck’s Invanz® product, the principal component of which is the carbon dioxide adduct of ertapenem. In response, Merck sued Hospira for infringement of two patents—the ’150 patent and U.S. Patent 5,952,323 (OB listed).

The district court concluded that the asserted claims of the ’323 patent were not invalid and were infringed and that the asserted claims of the ’150 patent would also be infringed, but were invalid as obvious over the ’323 patent and PCT publication WO 98/18800. The district court found that, while none of the three steps of claim 21 of the ’150 patent was individually taught by the prior art, the “recipe” for the final formulation was disclosed and the three steps leading to that formulation were nothing more than conventional manufacturing steps that would have been obvious from the disclosures and thus were the product of routine experimentation. The court found that both references expressly taught that the formation of the carbon dioxide adduct is pH-dependent and requires a pH range of about 6.0 to about 9.0; sodium hydroxide could be used to adjust the pH; and the carbon dioxide adduct could be produced using “standard lyophilization techniques.” The district court reviewed Merck’s objective evidence and concluded that commercial success and copying by others were shown, but that the objective evidence could not overcome the “strong prima facie case of obviousness” established by Hospira.

On appeal from a bench trial, Federal circuit reviewed the district court’s conclusions of law de novo and its findings of fact for clear error. On appeal, Merck argued that the district court erred in finding that the claims would have been obvious over either the ’323 patent or Almarsson because it is undisputed that none of the claimed steps is disclosed in the prior art. Merck contended that the court erred in relying solely on the “knowledge, creativity, and common sense” of a skilled artisan because “common sense” is properly invoked to provide a motivation to combine, not to supply a missing claim limitation. Furthermore, Merck said, the prior art focused solely on degradation by dimerization, not hydrolysis. In that way, Merck argued, the prior art taught away from the claimed invention because pH values favorable for reducing dimerization result in increased hydrolysis, and vice versa. Hospira responded that the district court properly evaluated the claims as a whole and determined that they recite nothing more than an obvious implementation of the disclosures of the ’323 patent and Almarsson. Hospira contended that claim 21 recites three broad, general processing steps that constitute nothing more than the routine way a skilled artisan would have implemented the teachings of the ’323 patent. Finally, Hospira maintained that the prior art taught that the carbon dioxide adduct could be obtained by “standard lyophilization techniques,” and claim 21 does not require any specific lyophilization conditions.

Federal circuit agreed with Hospira & held that the district court did not err in finding that the claimed process would have been obvious at the time the invention was made. The court found that both references expressly taught minimizing dimerization by forming the carbon dioxide adduct of ertapenem at pH 6.0–9.0, that sodium hydroxide could be used to adjust the pH, and that the final adduct was to be obtained using “standard lyophilization techniques.” The court also found that, while the claimed temperature range was not explicitly taught in the prior art, it was understood that degradation is minimized at low temperatures, so one of ordinary skill would have wanted to keep the temperature as low as possible without freezing. The only elements of that process that were not expressly disclosed in the prior art are—namely, the order of the steps, the simultaneous addition of base, the specific temperature range, and a final moisture content of less than 10%. But, as the court found, those are all experimental details that one of ordinary skill would have utilized via routine experimentation, armed with the principles disclosed in the prior art. Thus, Federal circuit concluded that the district court did not err in its conclusion of obviousness & therefore affirmed the decision of the district court.