The United States Court of Appeals for the Federal Circuit (“Federal Circuit”) upheld the district court’s finding of nonobviousness of a patent owned by Sanofi relating to methods of administering a pharmaceutical composition.  This November 9, 2017 Federal Circuit decision (Sanofi v. Watson Labs.), reiterates that a reasonable probability, rather than a mere possibility, of success is necessary to demonstrate that a patent claim is obvious.  This decision also demonstrates the importance of introducing proof of what one of ordinary skill in the art would expect in light of the prior art.  Despite some damaging statements in prior art literature that certain results were “expected,” Sanofi managed to defend the validity of its patent by showing, through expert testimony, that the statement was a statement of a hypothesis rather than an assertion of fact.  Obviousness is based on underlying factual determinations and litigants need to develop the record regarding the expectation of success to support their position, both in the district court and on appeal.

Background

The patents owned by Sanofi are directed to pharmaceutical compositions containing dronedarone and methods of reducing hospitalization by administering dronedarone to patients having specified characteristics.  Sanofi’s subsidiary, Sanofi-Aventis U.S., LLC (collectively, “Sanofi”), received approval in mid-2009 for a new drug application for 400 mg tablets of dronedarone, sold as Multaq®.  Both patents are listed in the Orange Book as patents claiming either Multaq® or a method of using Multaq®.  Sanofi filed the application that established the priority date for the patent on its dronedarone composition in June 1998.  FDA approval occurred after considerable research investigating the effects of dronedarone on heart patients, work which led to the method patent.

Sanofi sued Watson Laboratories Inc. and Sandoz Inc. (collectively, “defendants”) in the United States District Court for the District of Delaware.  Both defendants had filed abbreviated drug applications with the FDA to market generic versions of Multaq®.  Both firms certified, under 21 U.S.C. § 355(j)(2)(A)(vii)(IV), their beliefs that the patents were not valid and were not infringed.  Upon receiving notice of the paragraph IV certifications, Sanofi sued the defendants for infringement under 35 U.S.C. § 271(e)(2)(a).  After a three-day bench trial, the district court held that defendants’ sale of their proposed generic drugs, with their proposed labels, would induce physicians to infringe all but one of the asserted claims of the method patent and that the composition patent was infringed.  The district court also held that the defendants did not prove that any of the asserted claims of the method patent were obvious.  Validity of the composition patent was apparently no longer at issue.

The Federal Circuit upheld the nonobviousness determination, finding that the district court had used the correct legal standard and that its findings that the defendants had not proven a reasonable expectation of success by clear and convincing evidence were not clearly erroneous.  The prior art included a 2007 publication describing two identical large-scale clinical trials undertaken in November 2001 (“Euridis”) and September 2003 (“Adonis”). In both trials, dronedarone was administered to patients who were at the time in normal sinus rhythm, but had earlier experienced an episode of atrial fibrillation or flutter.  The trials were designed to address the issue of whether dronedarone “reduced the incidence of a first recurrence, as well as a symptomatic first reoccurrence, within 12 months after randomization” and “significantly reduced the ventricular rate during the recurrence of arrhythmia.” The 2007 publication also noted that the researchers conducted a “post hoc analysis” of a particular clinical benefit that the trials were not designed to address: the effect of dronedarone on rates of hospitalization or death.  The post hoc analysis showed that dronedarone significantly reduced the rate of hospitalization or death.

Another clinical study to investigate the safety of dronedarone (“Andromeda”) was started in 2002.  The study was designed to test the effects of dronedarone on patients with symptomatic heart failure and severe left ventricular systolic dysfunction. The study was terminated early because it appeared that dronedarone was actually increasing mortality from heart failure.

In 2006, the European Medicines Agency, discussing the first two trials, stated that “the clinical relevance needs further consideration” and as of 2007, the literature stated that the efficacy and safety of dronedarone had not yet been determined.  Between June 2005 and March 2008, Sanofi conducted another large scale clinical trial (“ATHENA”) designed to address the potential for clinical benefits of dronedarone that researchers had identified in their post-hoc analysis after the EURIDIS and ADONIS trials.  The results of the ATHENA trial postdated the critical date of February 2008.  ATHENA involved administration of dronedarone to patients who had a recent history of atrial fibrillation and/or flutter and at least one of several specified characteristics believed to be associated with cardiovascular risk.  The study assessed differences in cardiovascular hospitalization or death rates between patients given dronedarone and patients given a placebo.  The study produced positive effects for dronedarone.

The prior art asserted against the method patent did not include the results of the ATHENA study, but included a January 2008 article describing the study’s rationale and design. The article noted that “dronedarone appears to be a promising new antiarrhythmic compound for treatment of [atrial fibrillation]” but “was associated with increased mortality in patients with a recent history of decompensated heart failure,” a finding that “reemphasizes the need for a large dronedarone outcomes study in a typical population of elderly [atrial fibrillation] patients.” The article explained that ATHENA was the first randomized clinical study that used an end point of mortality and rehospitalization for cardiovascular reasons, as opposed to time for first reoccurrence. The article then included the following sentence: “Since it was shown that dronedarone is not only capable of maintaining [sinus rhythm] in many patients, but also of controlling heart rate in case of [atrial fibrillation] relapses, it is expected that treatment with this compound will result in a significant reduction in the need of rehospitalization for cardiovascular reasons” (emphasis added).

The Federal Circuit Decision

According to the Federal Circuit, the statement regarding the “expected” result was a “centerpiece” of the obviousness challenge to the method patent (which claimed methods of reducing cardiovascular hospitalization by administering dronedarone to patients meeting conditions mirroring those stated in the ATHENA trial). The defendants induced infringement by marketing generic dronedarone, which had the same label as the patented version.

Obviousness under 35 U.S.C. § 103 is a question of law based on underlying questions of fact.  Defendants had the burden to establish that, as of the priority date, “a person of ordinary skill in the art would have had a reasonable expectation that the processes claimed would succeed in their (claimed) aims, a factual issue.” The Federal Circuit addressed defendants’ argument that the district court applied too high a standard for proving a reasonable expectation of success.  The district court found that the claims were not obvious based on its factual finding that, in light of all the evidence, a person of ordinary skill in the art “would not have had a reasonable expectation that dronedarone would reduce the risk of cardiovascular hospitalization and hospitalization for [atrial fibrillation] in patients with paroxysmal or persistent [atrial fibrillation] and the associated risk factors of the ATHENA patient population.”  Given that express finding, the district court “did not expressly or by necessary implication demand known certainty as to the objective of reduced hospitalization.”  Nothing in the decision indicated that the district court improperly used a higher standard.

Defendants also argued that the district court’s finding under that standard was “clearly erroneous,” a contention rejected by the Federal Circuit. Although the original pair of studies “showed some positive results,” they were not designed to investigate reduced hospitalization, let alone do so for the patient population covered by the patent claims.  While a post-hoc analysis suggested a potential reduced hospitalization benefit, the literature at the time indicated that the benefit was a “potential,” and the ANDROMEDA study showed dangers of dronedarone severe enough to have spurred early termination of the study.  A 2007 article characterized the safety and efficacy data as “confusing and severely challenged.”

The main evidence relied upon by defendants was the January 2008 article in which the benefit of reduced hospitalization was described as “expected.”  An evidentiary dispute existed about how that statement would be understood by a person of ordinary skill in the art.  Defense experts testified that the statement “would be taken as a concrete assertion of fact about what the authors expected, and perhaps what a relevant skilled artisan should expect.”  Sanofi’s expert testified that in the context of the article, “the statement would be understood as nothing more than a statement of the hypothesis being tested in ATHENA.” The district court credited Sanofi’s expert and gave a reasoned explanation supporting its finding.

Further, the Federal Circuit found that the district court did not clearly err in finding that a skilled artisan would not have relied on the post hoc analysis based on the two initial trials. Record evidence demonstrated the unreliability of post hoc analysis in general, and Sanofi’s expert testified that a person of ordinary skill in the art would not “draw an expectation” about dronedarone from the post-hoc analysis, especially in light of conflicting results from various clinical trials.  The Federal Circuit therefore determined that the district court did not commit clear error in finding 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 [arterial fibrillation] in the ATHENA patient population” and that defendants had failed to prove obviousness by clear and convincing evidence.

This decision demonstrates that litigants need to develop the record, including introducing expert evidence showing what a reasonable person of ordinary skill in the art would expect, when trying to establish whether a patent is obvious.