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Sanofi v. Watson Laboratories Inc.

United States Court of Appeals, Federal Circuit

November 9, 2017

SANOFI, SANOFI-AVENTIS U.S., LLC, Plaintiffs-Appellees

         Appeals from the United States District Court for the District of Delaware in Nos. 1:14-cv-00264-RGA, 1:14-cv-00265-RGA, 1:14-cv-00292-RGA, 1:14-cv-00293-RGA, 1:14-cv-00294-RGA, 1:14-cv-00424-RGA, 1:14-cv-00875-RGA, 1:14-cv-01434-RGA, Judge Richard G. Andrews.

          William E. Solander, Fitzpatrick, Cella, Harper & Scinto, New York, NY, argued for plaintiffs-appellees. Also represented by Anna Elizabeth Dwyer, Zachary Garrett, Daniel John Minion, James R. Tyminski, Jr.

          Maureen L. Rurka, Winston & Strawn LLP, Chicago, IL, argued for defendant-appellants. Defendant-appellant Sandoz Inc. also represented by Tyler Johannes, Julia Mano Johnson.

          Natalie Christine Clayton, Alston & Bird LLP, New York, NY, for defendant-appellant Watson Laboratories, Inc. Also represented by Christopher L. McArdle, Yi Wen Wu.

          Before Prost, Chief Judge, Wallach, and Taranto, Circuit Judges.


         Sanofi owns U.S. Patent Nos. 8, 318, 800 and 8, 410, 167, which describe and claim compositions and uses of the cardiovascular (specifically, antiarrhythmic) drug dronedarone. The '800 patent, which expires in 2019, claims pharmaceutical compositions containing dronedarone. The '167 patent, which expires in 2029, claims methods of reducing hospitalization by administering dronedarone to patients having specified characteristics. Sanofi's subsidiary, Sanofi-Aventis U.S., LLC, received approval in mid-2009 for New Drug Application No. 022425 for 400 mg tablets of dronedarone, sold as Multaq®. Both the '800 and the '167 patents are listed in the Food and Drug Administration's publication Approved Drug Products with Therapeutic Equivalence Evaluations (the "Orange Book") as patents claiming either Multaq® or a method of using Multaq®.

         Watson Laboratories Inc. and Sandoz Inc., hoping to market generic versions of Multaq®, filed abbreviated new drug applications with the Food and Drug Administration. Both firms certified, under 21 U.S.C. § 355(j)(2)(A)(vii)(IV), their beliefs that the '167 and '800 patents were invalid and/or that the manufacture, use, and sale of the proposed generic drugs would not infringe either patent. Upon receiving notice of the paragraph IV certifications, the two Sanofi firms, which we will simply call "Sanofi, " sued Watson and Sandoz for infringement of the two patents under 35 U.S.C. § 271(e)(2)(A).

         After a three-day bench trial, the district court ruled in crucial respects for Sanofi. Sanofi v. Glenmark Pharm. Inc., USA, 204 F.Supp.3d 665, 704-705 (D. Del. 2016). As to the '167 patent, the court made the following rulings of relevance here: Sanofi proved that Watson's and Sandoz's sale of their proposed generic drugs, with their proposed labels, would induce physicians to infringe all but one of the asserted claims, id. at 673-84; and Watson and Sandoz did not prove that any of the asserted claims were invalid for obviousness, id. at 685-96. As to the '800 patent, the district court, rejecting the non-infringement argument made by Watson and Sandoz, concluded that the asserted claims do not exclude compositions containing polysorbate surfactants. Id. at 699-704. The district court then entered a final judgment rejecting the obviousness challenge to claims 1-6, 8-13, and 16 of the '167 patent; finding inducement of infringement, by both defendants, of all of those claims except claim 5; and finding infringement by both defendants of claims 1-3, 5-9, and 12-15 of the '800 patent and by Watson of claims 10 and 11 as well.

         Watson and Sandoz appeal. We have jurisdiction under 28 U.S.C. § 1295(a)(1). We affirm.



         In June 1998, Sanofi filed the application that established the priority date for the '800 patent on its droneda-rone composition. But Sanofi did not receive FDA approval for Multaq® until mid-2009, after considerable work investigating the effects of dronedarone on heart patients. That work led to the '167 patent, which, it is undisputed here, has a priority date of February 11, 2009. J.A. 34. The prior art asserted here as a basis for invalidity of the '167 patent claims at issue all pre-dates February 11, 2008, one year before the priority date.

         Between November 2001 and September 2003, Sanofi conducted two materially identical large-scale clinical trials, and the methods and results were described in a 2007 publication. See Bramah N. Singh et al., Droneda-rone for Maintenance of Sinus Rhythm in Atrial Fibrillation or Flutter, 357 New Eng. J. Med. 987 (2007). The EURIDIS trial drew its patients from Europe; the ADONIS trial drew its patients from North and South America, Australia, and Africa. Id. at 987. In both, 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. Id. at 988.

         What was primarily being measured (the "primary end point" for which the study was designed) was simply "the time to the first recurrence of atrial fibrillation or flutter." Id. at 987; see id. at 989. The studies also were set up to record "ventricular rates during the recurrence of atrial fibrillation, " id. at 990, and certain symptoms (palpitations, dizziness, fatigue, chest pain, and dyspnea) when accompanied by atrial fibrillation during monitoring, id. at 989. The 2007 Singh publication described the results regarding the issues the trials were designed to address: "dronedarone reduced the incidence of a first recurrence, as well as a symptomatic first recurrence, within 12 months after randomization" and "significantly reduced the ventricular rate during the recurrence of arrhythmia." Id. at 995.

         The 2007 Singh publication also noted that, once the data from the trials was collected, the researchers conducted a "post hoc analysis" of a particular clinical-benefit issue that the trials were not designed to address: the effect of dronedarone on rates of hospitalization or death. Id. at 993. As to that issue, the 2007 publication reported: "in a post hoc analysis, dronedarone significantly reduced the rate of hospitalization or death." Id. at 995. The figures showed some differences between the two studies regarding hospitalization/death reduction, with the European trial (EURIDIS) showing greater reduction than the non-European trial (ADONIS), whereas the opposite difference existed regarding the primary measure of time to first recurrence. Id. at 993-94.

         Dr. Singh and his co-author Dr. Hohnloser-the latter of whom was central to Sanofi's dronedarone studies-had already briefly reported the post-hoc analysis in public. They stated, in an abstract, that they had conducted the post-hoc analysis in order to evaluate "the potential clinical benefit of [dronedarone] at reducing hospitalizetion or death" and were planning a new study to assess that potential. Stefan H. Hohnloser & Bramah N. Singh, Dronedarone Significantly Decreases the Combined End-point of Hospitalization and Death in Patients with Atrial Fibrillation, 112 Circulation II-327, II-327-28, Abstract 1637 (2005) (Abstracts from Scientific Sessions 2005 in the Journal of the American Heart Association). In early 2006, Internal Medicine News, describing the Scientific Session presentation by Dr. Hohnloser that is apparently reflected in the 2005 abstract, noted the "potential major clinical benefit" of reduced hospitalization or death and that "Dr. Hohnloser stressed that 'potential' needs to be emphasized because this was a posthoc analysis." Bruce Jancin, Dronedarone Cut Morbidity, Deaths in Atrial Fib, Internal Med. News, Mar. 15, 2006.

         Meanwhile, in June 2002, even as the EURIDIS and ADONIS trials were underway, Sanofi conducted a trial to investigate safety: the ANDROMEDA trial- "Antiarrhythmic Trial with Dronedarone in Moderate-to-Severe Congestive Heart Failure Evaluating Morbidity Decrease." See Krista M. Dale & C. Michael White, Dronedarone: An Amiodarone Analog for the Treatment of Atrial Fibrillation and Atrial Flutter, 41 Annals of Pharmacotherapy 599, 602 (2007). ANDROMEDA was designed to test the effects of dronedarone on patients with symptomatic heart failure and severe left ventricular systolic dysfunction; although atrial fibrillation was not a criterion for patient entry into the study, atrial fibrillation "patients commonly have underlying heart disease and 40% of the ANDROMEDA patients actually had" atrial fibrillation. Sanofi, 204 F.Supp.3d at 686-87. As was explained in publications before February 2008, the results of the ANDROMEDA trial, as they came in, led Sanofi to terminate the study early: it appeared that dronedarone was actually increasing mortality from heart failure. Id.; see Dale & White, at 602; Mohammad J. Tafreshi & Joie Rowles, A Review of the Investigational Antiarrhythmic Agent Dronedarone, 12 J. Cardiovascular Pharmacology & Therapeutics 15, 24 (2007); European Medicines Agency, Withdrawal Public Assessment Report Of the Marketing Authorisation Application for Multaq (Dronedarone), EMEA/H/C/676 at 22-23 (October 2006) (EMEA 2006 Report).

         In 2006, the European Medicines Agency, discussing EURIDIS and ADONIS, stated that "the clinical relevance needs further consideration." EMEA 2006 Report, at 20. It further noted that "[a] reduction in time to death and hospitalisation was noted but this reflects an ancillary analysis and needs further confirmation, in particular in the context of the negative effects seen in the ANDROMEDA." Id. at 19. The Report concluded: "At the moment, the ratio between efficacy and safety is considered negative." Id. at 24. The 2007 Tafreshi & Rowles article, for its part, stated: "The efficacy and safety of dronedarone have not yet been determined. . . . The existing clinical data of dronedarone, both in terms of safety and efficacy, have been confusing and severely challenged so far." Tafreshi & Rowles, at 24.

         Those assessments were made while Sanofi was con-ducting-between June 2005 and March 2008-the large-scale clinical trial, called ATHENA, that was designed to address the potential for clinical benefits of dronedarone that the EURIDIS/ADONIS researchers had identified in their post-hoc analysis. The results of the ATHENA study post-date 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 (secondarily, in hospitalization or death regardless of cause) between patients given dronedarone and patients given a placebo. J.A. 7846-48. The study produced positive results for dronedarone. See Stefan H. Hohnloser, Effect of Dronedarone on Cardiovascular Events in Atrial Fibrillation, 360 New Eng. J. Med. 668 (2009). Those results led to the filings that resulted in the '167 patent and to the FDA's approval of Multaq®. J.A. 177 (Tr. 101), 194 (Tr. 169).

         Although the pre-February 2008 prior art does not include the results of the ATHENA study, it does include an article published by Dr. Hohnloser and his colleagues in January 2008, which describes the rationale and design of the ATHENA study. Stefan H. Hohnloser, Rationale and Design of ATHENA: A Placebo-Controlled, Double-Blind, Parallel Arm Trial to Assess the Efficacy of Dronedarone 400 mg Bid for the Prevention of Cardiovascular Hospitalization or Death from Any Cause in Patients with Atrial Fibrillation/Atrial Flutter, 19 J. Cardiovascular Electro-physiology 69 (2008) (internal acronym-supporting capitalization and highlighting omitted) (Hohnloser 2008). The article notes 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 (ANDROMEDA), " a "finding [that] reemphasizes the need for a large dronedarone outcomes study in a typical population of elderly [atrial fibrillation] patients." Id. at 72. It declares that "ATHENA is the pivotal outcome study for the development of dronedarone, " explaining that ATHENA is the first randomized clinical study that uses "exclusively the combined end-point of all-cause mortality and rehospitalization for cardiovascular causes, " as opposed to an "endpoint directly related to" atrial fibrillation such as time to first recurrence. Id. The article then includes 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.

Id. The second part of that sentence became a centerpiece of the obviousness challenge in ...

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