Everolimus – USA

On May 13, 2019, Federal Circuit affirmed district court’s decision that method of treatment claims of Afinitor® patent are not invalid as obvious.

Novartis own US 8,410,131 (expiring on May 01, 2026 with PED), which claims methods of using the compound everolimus to treat advanced renal cell carcinoma (“RCC”). West-Ward filed ANDA seeking to manufacture and sell generic versions of Afinitor, and Novartis filed this patent infringement suit in response. After a bench trial, the district court ruled that West-Ward failed to prove by clear and convincing evidence that claims 1–3 of the ’131 patent are invalid as obvious. West-Ward appealed.

Claim 1 reads:

1. A method for inhibiting growth of solid excretory system tumors in a subject, said method consisting of administering to said subject a therapeutically effective amount of a compound of formula I (Everolimus).

West-Ward argued before the district court that claims 1–3 would have been obvious over a temsirolimus reference Hidalgo 20005 (discloses phase I development  of rapamycin and temsirolimus) or Hutchinson (discloses updated results of phase I studies) and an everolimus patent (U.S. Patent No. 5,665,772 or U.S. Patent No. 6,004,973), in view of the general knowledge in the art. According to West-Ward, knowledge in the art about the molecular biology of advanced RCC, the antitumor activity of mTOR inhibitors, phase I temsirolimus clinical trial results, and safe dosing ranges for everolimus, would have provided a person of ordinary skill with a reasonable expectation of success of effectively treating advanced RCC with everolimus. The district court found that a person of ordinary skill “would have been motivated to pursue everolimus as one of several potential treatment options for advanced solid tumors, including advanced RCC.” However, it ultimately determined that West-Ward “failed to prove by clear and convincing evidence that a POSA would have been motivated to select everolimus.” District court noted that there were a variety of other treatments in development at the time of the invention and that the knowledge gaps in the molecular biology of advanced RCC would have led a person of ordinary skill to search for art beyond those involving mTOR modulations.

In addition, the district court determined that the asserted prior art would not have provided a person of ordinary skill in the art with a reasonable expectation of success in using everolimus to treat advanced RCC. The district court explained that the temsirolimus phase I data disclosed in Hutchinson had diminished weight because it resulted from small sample sizes and because phase I clinical trials are designed to determine safety, not efficacy. It further noted that everolimus and temsirolimus differed in pharmacological properties relevant to treatment. These differences, along with the high failure rate of cancer drugs in phase II and III clinical trials, and the fact that the molecular pathways of advanced RCC were not fully understood, all diminished the relevance of the temsirolimus data. Based on these facts, the district court found that West-Ward failed to establish by clear and convincing evidence that a person of skill in the art would have reasonably expected everolimus to effectively treat advanced RCC.

Federal Circuit upon appeal said that district court erred in its analysis of “motivation to combine”. However, there was no clear error in the district court’s finding that a person of ordinary skill would not have “reasonably expected success” in using everolimus to treat advanced RCC as of February 2001.

With respect to motivation to combine, Federal Circuit said that after reviewing the prior art, the district court found that a person of ordinary skill “would have been motivated to pursue everolimus as one of several potential treatment options for advanced solid tumors, including advanced RCC.” Yet, the district court continued its analysis and found that West-Ward “failed to prove by clear and convincing evidence that a POSA would have been motivated to select everolimus.” The district court erred in applying this heightened standard. “[O]ur case law does not require that a particular combination must be the preferred, or the most desirable, combination described in the prior art in order to provide motivation for the current invention.”[In re Fulton, 391 F.3d 1195, 1200 (Fed. Cir. 2004); see also Bayer Healthcare Pharm., Inc. v. Watson Pharm., Inc., 713 F.3d 1369, 1376 (Fed. Cir. 2013)]. Novartis argued that the district court did not err in concluding that the prior art fails to provide motivation to select everolimus. But Federal Circuit said that this is not a lead compound analysis. The ’131 patent claims methods of using everolimus to inhibit growth of solid tumors, including in patients having advanced RCC. The district court, however, appeared to apply or conflate the standard for these types of cases by requiring clear and convincing evidence that a person of ordinary skill “would have been motivated to select everolimus.” The proper inquiry should be whether a person of ordinary skill would have been motivated to modify the prior art disclosing use of temsirolimus to treat advanced RCC with the prior art disclosing everolimus.

With respect to Reasonable Expectation of Success, West-ward argued that the district court erred by imposing “a heightened standard under which it found no reasonable expectation of success simply because there was not yet clinical proof that everolimus would successfully treat advanced RCC.” Federal Circuit sided with district court & saw no clear error on this issue. Federal Circuit said that the district court correctly recognized that the temsirolimus phase I data resulted from small sample sizes and came from studies that were designed to test safety, not efficacy. Further, it considered the testimony of West-Ward’s expert Dr. Cho, who stated that a person of ordinary skill “would not make a determination or reasonable suggestion simply based in isolation upon whether a drug enters phase II,” and who did not dispute that more than seventy percent of oncology drugs failed at phase II. The district court also considered evidence that everolimus and temsirolimus are pharmacologically different. In addition, the district court considered several prior art references in finding that the roles of HIF-1 and mTOR in the molecular biology of advanced RCC were not fully understood as of February 2001.

Thus, federal Circuit affirmed district court & held that claims 1–3 of the ’131 patent would not have been obvious in view of the asserted prior art.