Everolimus - USA

On Dec. 14, 2017, Judge Richard G. Andrews of district of Delaware issued a trial opinion in Everolimus (Afinitor) case & found method of treatment patents valid in Hatch-Waxman litigation.

Plaintiffs brought this patent infringement action against Roxane Laboratories, Inc. Roxane (now West-Ward) filed Abbreviated New Drug Application ("ANDA") No. 207486, seeking to engage in the commercial manufacture, use, and sale of generic versions of Novartis's Afinitor product. The parties have stipulated that this ANDA infringes claims 1-3 of U.S. Patent No. 8,410,131 ("the '131 patent") and claim 1 of U.S. Patent No. 9,006,224 ("the '224 patent"). The Court held a bench trial on September 13-15, 2017. Defendant argues that the asserted claims of the '131 and '224 patents are invalid as obvious. Asserted claims 1-3 of the '131 patent require administering a therapeutically effective amount of everolimus to inhibit the growth of solid excretory system tumors, including advanced solid excretory system tumors and kidney tumors. Asserted claim 1 of the '224 patent relates to method for treating pancreatic neuroendocrine tumors wherein the tumors are advanced tumors after failure of cytotoxic chemotherapy. At issue in this case are methods for using everolimus to treat advanced renal cell carcinoma ("RCC") and advanced pancreatic neuroendocrine tumors ("PNETs").

VALIDITY OF THE '131 PATENT:

Defendant contended that administration of a therapeutically effective amount of everolimus to treat advanced RCC would have been obvious to a POSA. The essence of Defendant's obviousness argument was that knowledge in the art about the biology of advanced RCC, mTOR3 inhibitors, and safe dosing ranges of everolimus, alongside phase I temsirolimus clinical trial results in advanced RCC, would have given a POSA a reasonable expectation of success of effectively treating advanced RCC with everolimus, as both everolimus and temsirolimus are mTOR inhibitors. Defendant asserted that "the prior art established a strong scientific rationale for using an mTOR inhibitor to treat advanced RCC”. Plaintiffs countered that many different agents were under investigation for the treatment of advanced RCC, and that the relative success of immunotherapies would have motivated a POSA to investigate immunostimulants rather than immunosuppressants like everolimus.

The prior art disclosed general antiproliferative properties of everolimus, and that oral administration of everolimus was safe and tolerable in treating renal and liver transplant patients. Defendant's expert, Dr. Cho, opines that a POSA would have been motivated to administer therapeutically effective amounts of everolimus to inhibit the progression of advanced RCC with a reasonable expectation of success. According to Dr. Cho, the claimed invention would have been obvious over the teachings of Hidalgo 2000 or Hutchinson in combination with the '973 patent or the '772 patent, in view of the general knowledge in the art. Plaintiffs assert that because Dr. Cho restricted his review and analysis to art regarding mTOR inhibitors, he failed to consider the full scope of the relevant prior art, and Defendant has failed to prove obviousness because it has failed to prove a motivation to select everolimus over other compounds.

Court found that the relevant prior art would have included art relating to treatments beyond mTOR inhibitors. Against the backdrop of a strong desire to find an effective advanced RCC treatment and the general preference for orally-administered cancer treatments, promising temsirolimus phase I data, and shared properties of temsirolimus and everolimus, a POSA would have been motivated to pursue everolimus as one of several potential treatment options for advanced solid tumors, including advanced RCC. But even if a POSA would have been motivated to select everolimus to treat advanced RCC, court found that the asserted combinations would not have provided a POSA a reasonable expectation of success in using everolimus to treat advanced RCC. Here, no prior art reference disclosed the use of everolimus to treat advanced RCC. The prior art does not disclose all elements of the asserted claims. Thus considering the evidence as a whole, Defendant has not shown by clear and convincing evidence that claims 1-3 of the '131 patent are invalid as obvious.

VALIDITY OF THE '224 PATENT:

Defendant contended that administration of a therapeutically effective amount of everolimus as a monotherapy to treat patients with advanced PNETs after the failure of cytotoxic chemotherapy would have been obvious to a POSA. The essence of Defendant's obviousness argument was that the prior art teaches that mTOR inhibitors were demonstrated to be safe and effective to treat advanced PNETs in phase II and preclinical models, including after the failure of cytotoxic chemotherapy, and that everolimus would have been an obvious substitute for temsirolimus because both drugs are mTOR inhibitors with shared properties. Defendant's expert, Dr. Yu, opined that a POSA would have been motivated to administer a therapeutically effective amount of everolimus as a monotherapy to treat advanced PNETs after the failure of cytotoxic chemotherapy. Dr. Yu stated that a POSA would have been motivated to combine the prior art references Duran, Dancey, and Tabemero because they all deal with using mTOR inhibitors to treat cancer.

Court held that given the incomplete knowledge of the molecular biology of PNETs and the mTOR pathway, along with the high number of potential therapeutic targets both within and outside the mTOR pathway, I find that Defendant has failed to establish by clear and convincing evidence a motivation to select everolimus. Even if Defendant had established such a motivation, however, Defendant has failed to prove by clear and convincing evidence that any one of the asserted prior art combinations would give a POSA a reasonable expectation of success of administering a therapeutically effective amount of everolimus as a monotherapy to treat advanced PNETs after the failure of cytotoxic chemotherapy.

CONCLUSION: Defendant failed to prove by clear and convincing evidence that the asserted claims of the '131 and '224 patents are invalid as obvious.