When is an “expected” result not truly expected?

Sanofi Aventis (“Sanofi”) continues to successfully protect Multaq® (dronedarone) tablets from generic competition, this time receiving a positive decision from the Federal Circuit Court of Appeals in Sanofi v. Watson Labs., 2017 U.S. App. LEXIS 22438 (Fed. Cir. 2017). Sanofi’s method of using dronedarone tablets to decrease cardiovascular hospitalizations was deemed non-obvious even though post-hoc analyses of earlier studies had suggested a reduction in hospitalizations, and prior art had explicitly stated:

“it is expected that treatment with this compound will result in a significant reduction in the need of rehospitalizations for cardiovascular reasons.”

The case demonstrates what drug innovators and medical doctors have known for years: drug development is a risky venture.  Companies make their best educated guesses when designing clinical trials, but until that trial is performed and the results un-blinded, it is extremely difficult to predict whether a new method of treatment will actually work.

Readers of this blog will recall a blog we wrote on a related patent owned by Sanofi; we named the patent a “subset” patent.  Similar to that patent, the patent in this case, U.S. Patent No. 8,410,167 (“the ‘167 patent”), claims:

“A method of decreasing … cardiovascular hospitalization … comprising administering … dronedarone … twice a day … wherein said patient does not have severe heart failure, … said patient has … paroxysmal or persistent non-permanent atrial fibrillation or flutter; and … at least one cardiovascular risk factor …”

One of the main issues in this case was a prior art statement that “it is expected that treatment with this compound will [reduce] re-hospitalizations for cardiovascular reasons,” and whether this statement proved the patent was obvious because it proved a “reasonable expectation of success.” While it seems that the statement should have been fatal to the patent, Sanofi was able to overcome the statement through some excellent lawyering, and by proving that the statement was based on post-hoc analyses of two earlier studies, the EURIDIS and ADONIS studies, which had not studied hospitalization rates as a primary endpoint.  As the Federal Circuit explained:

“The EURIDIS/ADONIS pair of studies … were not designed to investigate reduced hospitalization, [the endpoint claimed in the ‘167 patent,] let alone to do so for the patient population covered by the patent claims at issue. A post-hoc analysis of the results suggested a potential reduced-hospitalization benefit, but publications in 2005 and 2006 indicated that the suggested benefit was a ‘potential,’ no more.”

Citing a 2006 article that discussed the limitations of post-hoc analyses, and statements the European Medicines Agency (EMA”) made when reviewing the drug, Sanofi was able to prove that the “‘it is expected’ statement was not a ‘concrete’ factual assertion,” and that “in this context, the statement would be understood as nothing more than a statement of the hypothesis being tested in [the clinical trial].”  The 2006 article explained that “[p]ost hoc observations are not automatically invalid . . . but they should be regarded as unreliable unless they can be replicated”. Rothwell, Subgroup Analysis in Randomised Controlled Trials: Importance, Indications, and Interpretation (2006).  The 2006 EMA report “doubted the presence of clinical benefits and deemed the efficacy/safety ratio to be ‘negative.’”

Based on all of this evidence the Federal Circuit affirmed the Trial Court’s conclusion that:

“a person of ordinary skill in the art ‘would have been at best cautiously optimistic that dronedarone could reduce the risk of cardiovascular hospitalization and hospitalization for [atrial fibrillation] in the [claimed] patient population.’”

END RESULT: The innovator’s hard work, risk, and investment were protected; the validity of the patent was affirmed.