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.
Prost, Chief Judge, Wallach, and Taranto, Circuit Judges.
TARANTO, CIRCUIT JUDGE.
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®.
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. §
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.
and Sandoz appeal. We have jurisdiction under 28 U.S.C.
§ 1295(a)(1). We affirm.
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.
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.
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.
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.
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.
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).
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.
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).
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 ...