Sanofi v. Watson Laboratories Inc. , 875 F.3d 636 ( 2017 )

United States Court of Appeals
for the Federal Circuit
______________________
SANOFI, SANOFI-AVENTIS U.S., LLC,
Plaintiffs-Appellees
v.
WATSON LABORATORIES INC., SANDOZ INC.,
Defendants-Appellants
______________________
2016-2722, 2016-2726
______________________
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.
______________________
Decided: November 9, 2017
______________________
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.
2 SANOFI v. WATSON LABORATORIES INC.
NATALIE CHRISTINE CLAYTON, Alston & Bird LLP,
New York, NY, for defendant-appellant Watson Laborato-
ries, Inc. Also represented by CHRISTOPHER L. MCARDLE,
YI WEN WU.
______________________
Before PROST, Chief Judge, WALLACH, and TARANTO,
Circuit Judges.
TARANTO, Circuit Judge.
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 administer-
ing dronedarone to patients having specified characteris-
tics. 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 Admin-
istration. 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).
SANOFI v. WATSON LABORATORIES INC. 3
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 contain-
ing polysorbate surfactants. Id. at 699–704. The district
court then entered a final judgment rejecting the obvious-
ness 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 un-
der 28 U.S.C. § 1295(a)(1). We affirm.
I
A
In June 1998, Sanofi filed the application that estab-
lished 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 invalid-
ity of the ’167 patent claims at issue all pre-dates Febru-
ary 11, 2008, one year before the priority date.
4 SANOFI v. WATSON LABORATORIES INC.
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 Fibrilla-
tion 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 experi-
enced 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 monitor-
ing, 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 con-
ducted 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 report-
ed: “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
SANOFI v. WATSON LABORATORIES INC. 5
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 meas-
ure 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 hospitaliza-
tion 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 Phar-
macotherapy 599, 602 (2007). ANDROMEDA was de-
signed to test the effects of dronedarone on patients with
symptomatic heart failure and severe left ventricular
6 SANOFI v. WATSON LABORATORIES INC.
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 rele-
vance 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 ancil-
lary analysis and needs further confirmation, in particu-
lar 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 consid-
ered 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
SANOFI v. WATSON LABORATORIES INC. 7
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 charac-
teristics 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 Cardiovas-
cular 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 in-
clude 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 Hospital-
ization or Death from Any Cause in Patients with Atrial
Fibrillation/Atrial Flutter, 19 J. Cardiovascular Electro-
physiology 69 (2008) (internal acronym-supporting capi-
talization 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 decompen-
sated 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 droneda-
8 SANOFI v. WATSON LABORATORIES INC.
rone,” 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 direct-
ly related to” atrial fibrillation such as time to first recur-
rence. 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 sig-
nificant reduction in the need of rehospitalization
for cardiovascular reasons.
Id. The second part of that sentence became a centerpiece
of the obviousness challenge in this case.
B
The ’167 patent claims methods of reducing cardio-
vascular hospitalization by administering dronedarone to
patients meeting conditions mirroring those stated in the
in the ATHENA trial. Claim 1 is representative:
A method of decreasing a risk of cardiovascular
hospitalization in a patient, said method compris-
ing administering to said patient an effective
amount of dronedarone or a pharmaceutically ac-
ceptable salt thereof, twice a day with a morning
and an evening meal, wherein said patient does
not have severe heart failure, (i) wherein severe
heart failure is indicated by: a) NYHA Class IV
heart failure or b) hospitalization for heart failure
within the last month; and (ii) wherein said pa-
tient has a history of, or current, paroxysmal or
persistent non-permanent atrial fibrillation or
flutter; and (iii) wherein the patient has at least
SANOFI v. WATSON LABORATORIES INC. 9
one cardiovascular risk factor selected from the
group consisting of:
i. an age greater than or equal to 75;
ii. hypertension;
iii. diabetes;
iv. a history of cerebral stroke or of sys-
temic embolism;
v. a left atrial diameter greater than or
equal to 50 mm; and
vi. a left ventricular ejection fraction less
than 40%.
’167 patent, col. 28, line 64 through col. 29, line 15.
C
The extensive information (the “label”) that Sanofi in-
cludes along with its Multaq® product—which Watson
and Sandoz propose to use for their generic versions
without any change material to this case, J.A. 7784,
7797–801—relies on the key studies described above. See
J.A. 7609, 7623–27. Section 1 of the label, as revised in
March 2014, is titled “Indications and Usage.” It pro-
vides:
Multaq® is indicated to reduce the risk of hospital-
ization for atrial fibrillation in patients in sinus
rhythm with a history of paroxysmal or persistent
atrial fibrillation (AF) [see Clinical Studies (14)].
J.A. 7609 (emphasis and brackets in original). That
sentence says that Multaq® is indicated for use in certain
patients and refers to section 14 on “Clinical Studies” for
identification of those patients. Section 14 primarily
describes the ATHENA study (section 14.1), but also
contains a short description of the EURIDIS and ADONIS
studies (section 14.2). And it refers to two studies that
10 SANOFI v. WATSON LABORATORIES INC.
had to be terminated early because of negative results in
their patient pools: the ANDROMEDA study (section
14.3) and the PALLAS study (section 14.4). 1 J.A. 7623–
27.
Both Watson and Sandoz plan to market their generic
versions of Multaq® with the same labeling, including
sections 1 and 14. J.A. 7643, 7784; see AstraZeneca LP v.
Apotex, Inc., 633 F.3d 1042, 1045–46 (Fed. Cir. 2010)
(explaining that, in general, an applicant for an abbrevi-
ated new drug application must “show that ‘the labeling
proposed for the new drug is the same as the labeling
approved for the listed drug.’” (quoting 21 U.S.C. §
355(j)(2)(A)(v))).
II
Watson and Sandoz challenge the district court’s in-
ducement finding as to the ’167 patent, the district court’s
rejection of their obviousness challenge to that patent,
and the district court’s rejection of their prosecution-
disclaimer argument for limiting the scope of the ’800
patent claims.
A
Under 35 U.S.C. § 271(b), “[w]hoever actively induces
infringement of a patent shall be liable as an infringer.”
Here, the district court found, the inducing act will be the
marketing by Watson and Sandoz of their generic
dronedarone drugs with the label described above. And
the induced act will be the administration of dronedarone
by medical providers to patients meeting the criteria set
forth in the ’167 patent claims.
“In contrast to direct infringement, liability for induc-
ing infringement attaches only if the defendant knew of
1 The details of the PALLAS study are not im-
portant for purposes of this appeal.
SANOFI v. WATSON LABORATORIES INC. 11
the patent and that ‘the induced acts constitute patent
infringement.’” Commil USA, LLC v. Cisco Sys., Inc., 135
S. Ct. 1920, 1926 (2015) (quoting Global-Tech Appliances,
Inc. v. SEB S.A., 563 U.S. 754, 766 (2011) (stating that
“we now hold that induced infringement under § 271(b)
requires knowledge that the induced acts constitute
infringement”)). Neither of those two knowledge re-
quirements is disputed here. If and when Watson and
Sandoz receive FDA approval and market dronedarone
with the label at issue, they will know of the ’167 patent
(they already do) and that a medical provider’s admin-
istration of the drug to the claimed class of patients is an
act of infringement (which Watson and Sandoz do not
dispute).
The dispute in this case involves an aspect of the con-
nection between the marketing and the medical providers’
infringement that is different from the two knowledge
requirements and is inherent in the word “induce” as it
has been understood in this area. The Supreme Court
stated the following in Global-Tech:
The term “induce” means “[t]o lead on; to influ-
ence; to prevail on; to move by persuasion or in-
fluence.” Webster’s New International Dictionary
1269 (2d ed. 1945). The addition of the adverb ‘ac-
tively’ suggests that the inducement must involve
the taking of affirmative steps to bring about the
desired result, see id., at 27.
563 U.S. at 760 (brackets in original). The purposeful-
causation connotation of that language is reinforced by
the Court’s statement: “When a person actively induces
another to take some action, the inducer obviously knows
the action that he or she wishes to bring about.” Id.
Further reinforcement is found in the Supreme
Court’s discussion of inducement of copyright infringe-
ment in Metro-Goldwyn-Mayer Studios Inc. v. Grokster
Ltd., 545 U.S. 913, 936–37 (2005), which the Court in
12 SANOFI v. WATSON LABORATORIES INC.
Global-Tech cited in discussing patent infringement, see
563 U.S. at 763. In Grokster, the Court explained that
inducement is present where “‘active steps . . . taken to
encourage direct infringement,’ such as advertising an
infringing use or instructing how to engage in an infring-
ing use, show an affirmative intent that the product be
used to infringe.” 545 U.S. at 936 (citation omitted). The
Court cited, for support, this court’s decision in Water
Techs. Corp. v. Calco, Ltd., which focused on intent and
noted that intent is a factual determination that may rest
on circumstantial evidence. 850 F.2d 660, 668 (Fed. Cir.
1988). The Supreme Court in Grokster held: “one who
distributes a device with the object of promoting its use to
infringe copyright, as shown by clear expression or other
affirmative steps taken to foster infringement, is liable for
the resulting acts of infringement by third parties.” 545
U.S. at 936–37.
This court has accordingly explained that, for a court
to find induced infringement, “[i]t must be established
that the defendant possessed specific intent to encourage
another’s infringement.” DSU Med. Corp. v. JMS Co.,
471 F.3d 1293, 1306 (Fed. Cir. 2006) (en banc in relevant
part) (quoting Manville Sales Corp. v. Paramount Sys.,
Inc., 917 F.2d 544, 553 (Fed.Cir.1990)); see ACCO Brands,
Inc. v. ABA Locks Mfrs. Co., 501 F.3d 1307, 1312 (Fed.
Cir. 2007). The court has articulated certain necessary
conditions: the plaintiff must show “that the alleged
infringer’s actions induced infringing acts and that he
knew or should have known his actions would induce
actual infringements.” DSU Med., 471 F.3d at 1306
(emphasis omitted) (quoting Manville, 917 F.2d at 553).
And the court has repeatedly explained that, for the
finder of fact to find the required intent to encourage,
“[w]hile proof of intent is necessary, direct evidence is not
required; rather, circumstantial evidence may suffice.”
Id. (quoting Water Techs., 850 F.2d at 668); see Ricoh Co.
v. Quanta Computer Inc., 550 F.3d 1325, 1342 (Fed. Cir.
SANOFI v. WATSON LABORATORIES INC. 13
2008) (similar). When proof of intent to encourage de-
pends on the label accompanying the marketing of a drug,
“[t]he label must encourage, recommend, or promote
infringement.” Takeda Pharm. USA, Inc. v. West-Ward
Pharm. Corp., 785 F.3d 625, 631 (Fed. Cir. 2015) (cita-
tions omitted).
In this case, the district court relied on those stand-
ards. Sanofi, 204 F. Supp. 3d at 673. And, applying those
standards, the court found that Sanofi had proven inten-
tional encouragement of infringement of the independent
claims. Id. at 677 (“Sanofi has proven that Defendants’
proposed labels demonstrate specific intent to encourage
physicians to infringe independent claims 1 and 8 of the
’167 patent and will lead to such infringement . . . .”); see
id. (finding the “proposed labels encourage physicians to
prescribe dronedarone to patients with at least one of the
cardiovascular risk factors claimed in the ’167 patent”;
Watson and Sandoz “kn[o]w that their proposed labels
would actually cause physicians to prescribe dronedarone
to patients with the cardiovascular risk factors
claimed” and that “such a use would infringe the ’167
patent”). Watson and Sandoz, in this court, make no
separate argument about any dependent claim except
claim 4, which they discuss in one paragraph. Appellants’
Br. 37. But they do not suggest, and we see no sound
basis for a conclusion, that the district court made any
lesser findings for claim 4. See id. at 682–84 (finding
inducement for claims 4 and 10, but not claim 5).
We review the district court’s finding of inducement
based on encouragement and inferred intent for clear
error. See AstraZeneca LP v. Apotex, Inc., 633 F.3d 1042,
1056 (Fed. Cir. 2010). We find no such error. The label
itself has a short “Indications and Usage” section, one
sentence long. It states what dronedarone is indicated
for: it “is indicated to reduce the risk of hospitalization for
atrial fibrillation.” J.A. 7609; see J.A. 7784. And it states
which patients are covered by this indication: “patients in
14 SANOFI v. WATSON LABORATORIES INC.
sinus rhythm with a history of paroxysmal or persistent
atrial fibrillation (AF) [see Clinical Studies (14)].” J.A.
7609; see J.A. 7784. The reference to the Clinical Studies
section (14) of the label expressly directs the reader to
that section for elaboration of the class of patients for
whom the drug is indicated to achieve the stated objec-
tive, i.e., reduced hospitalization. Section 14 leads with
and features a subsection on the ATHENA study, which
sets forth the positive results, relating to reduced hospi-
talization, for patients having the risk factors written into
the ’167 patent. And it is only the ATHENA subsection—
not any of the three other brief subsections—that identi-
fies a class of patients as having been shown to achieve
reduced hospitalization from use of dronedarone. The
EURIDIS/ADONIS subsection says nothing about reduced
hospitalization; and the ANDROMEDA and PALLAS
subsections are negative warnings, describing studies
that had to be terminated early because of adverse re-
sults. See J.A. 7626–27, J.A. 7800–801. The label thus
directs medical providers to information identifying the
desired benefit for only patients with the patent-claimed
risk factors. 2
There was considerable testimony that this label en-
courages—and would be known by Watson and Sandoz to
encourage—administration of the drug to those patients,
thereby causing infringement. Approximately 77% of
Multaq® prescriptions have actually been written for
2 As to claim 4, the district court made findings,
which are not clearly erroneous, that the label’s descrip-
tion of the ATHENA study as covering patients already
receiving “conventional therapy” embraced the taking of
diuretics as claimed in claim 4. Administration of diuret-
ics is just such a conventional therapy—one received, in
fact, by more than half of the patients in the ATHENA
study. Sanofi, 204 F. Supp. 3d at 682–83.
SANOFI v. WATSON LABORATORIES INC. 15
patients with the claimed risk factors. Sanofi, 204 F.
Supp. 3d at 677, 684; see J.A. 8069. Moreover, Dr. Kim,
an expert for Sanofi, testified that a person of ordinary
skill in the art would read the drug label and understand
that the only FDA-approved use of dronedarone came out
of the ATHENA trial, J.A. 177–79, and that a physician
would find “clear encouragement” from the label to use
dronedarone in a manner that infringes the ’167 patent,
J.A. 174, especially in light of label’s description of the
ANDROMEDA study, which warns of the safety concerns
of using dronedarone on patients other than those for
whom the ATHENA trial showed reduced hospitalization,
J.A. 175–76. See also J.A. 302–304 (Dr. Reiffel, expert for
Sanofi, discussing physicians’ reluctance to use droneda-
rone in a manner that has not yet been proven successful,
given the drug’s poor performance in the ANDROMEDA
trial and the inconsistent clinical history of antiarrhyth-
mic drugs in general). Dr. Zusman, who testified for
Watson and Sandoz, agreed that persons of skill in the art
“look[] to drug labels, in part, ‘for information about the
use of the drug in special or specific populations,’ and that
it is important for the [person of skill] to look at the
label’s indications section to see if a drug ‘is indicated for
administration to patients of certain characteristics with
a certain intent.’” Sanofi, 204 F. Supp. 3d at 678 (quoting
J.A. 196–97). On the record in this case, the district court
could draw the required inducement inferences.
Watson and Sandoz contend that, because Multaq®
has substantial noninfringing uses not forbidden by the
proposed labels, Sanofi, 204 F. Supp. 3d at 684, the dis-
trict court could not permissibly find intent to encourage
an infringing use. But there is no legal or logical basis for
the suggested limitation on inducement. Section 271(b),
on inducement, does not contain the “substantial nonin-
fringing use” restriction of section 271(c), on contributory
infringement. And the core holding of Grokster, a copy-
right decision that drew expressly on patent and other
16 SANOFI v. WATSON LABORATORIES INC.
inducement law, is precisely that a person can be liable
for inducing an infringing use of a product even if the
product has substantial noninfringing uses (like the peer-
to-peer software product at issue there, which was capa-
ble of infringing and non-infringing uses). 545 U.S. at
934–37. There is no basis for a different inducement rule
for drug labels.
The content of the label in this case permits the infer-
ence of specific intent to encourage the infringing use. As
noted above, inducement law permits the required factual
inferences about intended effects to rest on circumstantial
evidence in appropriate circumstances. Moreover, in
AstraZeneca v. Apotex, the court upheld an inducement
finding without the kind of explicit limiting commands
that Watson and Sandoz suggest a label must contain.
633 F.3d at 1058–60. In Eli Lilly & Co. v. Teva Parenter-
al Medicines, Inc., the court stated that “[d]epending on
the clarity of the [drug label’s] instructions, the decision
to continue seeking FDA approval of those instructions
may be sufficient evidence of specific intent to induce
infringement.” 845 F.3d 1357, 1368−69 (Fed. Cir. 2017)
(internal citations omitted). Unlike in Takeda, the infer-
ence in the present case is based on interpreting the
label’s express statement of indications of use and the
internally referred-to elaboration of those indications. See
785 F.3d at 625. And this case is not like Vita-Mix Corp
v. Basic Holding, Inc., in which the defendant, in its (non-
pharmaceutical) product instructions, encouraged a non-
infringing use in a way that showed an intent to discour-
age infringement. 581 F.3d 1317, 1328–29 (Fed. Cir.
2009). The evidence in this case supports the finding of
intentional encouragement of infringing use and, there-
fore, of inducement.
B
Obviousness under 35 U.S.C. § 103 is a question of
law based on underlying questions of fact. Allergan, Inc.
SANOFI v. WATSON LABORATORIES INC. 17
v. Sandoz Inc., 726 F.3d 1286, 1290 (Fed. Cir. 2013). 3
Watson and Sandoz accept the legal framework under
which they had to establish that, as of February 2008, 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. Cumber-
land Pharm. Inc. v. Mylan Institutional LLC, 846 F.3d
1213, 1221–23 (Fed. Cir. 2017); PharmaStem Therapeu-
tics, Inc. v. ViaCell, Inc., 491 F.3d 1342, 1360 (Fed. Cir.
2007). On appeal, Watson and Sandoz make no argument
as to obviousness independent of their challenge to the
district court’s finding of no such expectation. We reject
the contention that the district court adopted an incorrect
legal standard on the issue, and we are unpersuaded that
the district court was clearly erroneous in determining
that Watson and Sandoz failed to prove the required
reasonable expectation. Based on those conclusions, we
affirm the nonobviousness judgment.
Watson and Sandoz initially argue that the district
court committed legal error by applying too high a stand-
ard for proving a reasonable expectation of success. We
disagree.
The district court held that the claims of the ’167 pa-
tent were not proved to be obvious based on its factual
finding that, in light of all the evidence, “a [person of
ordinary skill in the art] in 2008 would not have had a
reasonable expectation that dronedarone would reduce
the risk of cardiovascular hospitalization and hospitaliza-
tion for [atrial fibrillation] in patients with paroxysmal or
persistent [atrial fibrillation] and the associated risk
factors of the ATHENA patient population.” Sanofi, 204
3 Given the filing date of the ’167 patent, this case
is governed by the version of section 103 in force preced-
ing the changes by the Leahy-Smith America Invents Act,
Pub. L. No. 112-29, 125 Stat. 284, 293 (2011).
18 SANOFI v. WATSON LABORATORIES INC.
F. Supp. 3d at 691. In making that finding, the court
invoked the language of “reasonable expectation” repeat-
edly. Id. at 686, 687, 688, 689, 691, 693, 696, 696 n.7; see
also id. at 693 (crediting Sanofi’s expert testimony that
the EURIDIS/ADONIS post-hoc analysis did not support
“any sort of scientifically reasonable likelihood that
dronedarone would successfully reduce the risk of cardio-
vascular hospitalization in patients with persistent or
paroxysmal [atrial fibrillation] and the associated risk
factors”).
Contrary to the contention of Watson and Sandoz, the
court did not expressly or by necessary implication de-
mand known certainty as to the objective of reduced
hospitalization. No such demand is implicit in the court’s
finding that the Hohnloser 2008 “it is expected” statement
was not a “concrete” factual assertion, id. at 688, 692, but
instead a mere “hypothesis,” id. at 688, 692. Nor did the
court demand certainty when it simply described the
proposed information for ATHENA enrollees as present-
ing the EURIDIS/ADONIS data “in less than certain
terms,” id. at 693, as one piece of evidence supporting the
court’s determination to credit Sanofi’s expert testimony
that there was no “scientifically reasonable likelihood” of
the claimed hospitalization reduction based on the
EURIDIS/ADONIS post-hoc analysis, id. Watson and
Sandoz have not shown that the court demanded some
degree of or foundation for the required expectation that
is contrary to any refinement we have adopted to elabo-
rate on the “reasonable expectation” standard. The court
used and applied the terminology from our decisions that
Watson and Sandoz accept.
Watson and Sandoz’s appeal on obviousness thus ul-
timately rests on the contention that the district court’s
finding under the standard was clearly erroneous. We
conclude that it was not. Although the evidence might
well have supported the opposite finding, we cannot
conclude that the district court clearly erred in its finding
SANOFI v. WATSON LABORATORIES INC. 19
that Watson and Sandoz did not carry their burden of
showing that a person of ordinary skill in the art in
February 2008 would have had a reasonable expectation
that dronedarone would succeed in reducing cardiovascu-
lar hospitalization in the ATHENA patient population.
We have described the key publications available to
the relevant community of skilled artisans before Febru-
ary 2008. The EURIDIS/ADONIS pair of studies showed
some positive results in the time to recurrence of atrial
fibrillation and in ventricular rates, but they were not
designed to investigate reduced hospitalization, let alone
to do so for the patient population covered by the patent
claims at issue. A post-hoc analysis of the results sug-
gested a potential reduced-hospitalization benefit, but
publications in 2005 and 2006 indicated that the suggest-
ed benefit was a “potential,” no more. Meanwhile, the
ANDROMEDA study showed dangers of dronedarone
severe enough to have spurred early termination of the
study. A 2006 European Medicines Agency report doubt-
ed the presence of clinical benefits and deemed the effica-
cy/safety ratio to be “negative.” A 2007 article
characterized the safety and efficacy data as confusing
and severely challenged.
In light of that body of publications, Watson and
Sandoz relied heavily on the final publication of rele-
vance, the January 2008 article by Dr. Hohnloser and his
colleagues, in which they described the benefit of reduced
hospitalization as “expected.” Hohnloser 2008 at 72 (“it is
expected that treatment with this compound will result in
a significant reduction in the need of rehospitalizations
for cardiovascular reasons”). But there was an eviden-
tiary dispute about how that statement would be under-
stood by a person of ordinary skill in the art. 4 Dr.
4 The district court found that the person of ordi-
nary skill in the art “was a clinician with a medical degree
20 SANOFI v. WATSON LABORATORIES INC.
Zusman, for Watson and Sandoz, testified that the state-
ment would be taken as a concrete assertion of fact about
what the authors expected, and perhaps what a relevant
skilled artisan should expect. J.A. 209. But Dr. Reiffel,
for Sanofi, testified that, in this context, the statement
would be understood as nothing more than a statement of
the hypothesis being tested in ATHENA. J.A. 351. The
district court credited Dr. Reiffel’s testimony, explaining
why. Sanofi, 204 F. Supp. 3d at 692–95. We have been
furnished no basis on which to say, in light of the other
evidence in the case, that the district court clearly erred
in doing so. See Senju Pharm. Co. v. Lupin Ltd., 780 F.3d
1337, 1351 (Fed. Cir. 2015) (stressing need for exceptional
evidentiary reasons for appellate court not to defer to trial
court’s determination to credit expert testimony about
what prior art taught). This is not a case like Phar-
maStem, in which the expert testimony about prior-art
references was rejected because the testimony could not
“be reconciled with statements made by the inventors in
the [patent] specification and with the prior art references
themselves.” 491 F.3d at 1361; id. at 1361–63.
Watson and Sandoz also point to the post-hoc analysis
based on the EURIDIS and ADONIS trials. But the
district court did not clearly err in finding that a relevant
skilled artisan would not have relied on that analysis to
form a reasonable expectation of reduced hospitalizations
in the claimed populations. Sanofi, 204 F. Supp. 3d at
690–91. The record contains evidence about the unrelia-
bility of post-hoc analyses generally. Rothwell, Subgroup
who was board certified either in cardiology or electro-
physiology and had at least two years of clinical experi-
ence after fellowship, and because of such fellowship,
would have had some knowledge of the design, implemen-
tation, and analysis of clinical studies.” Sanofi, 204 F.
Supp. 3d at 686. That finding is not challenged on appeal.
SANOFI v. WATSON LABORATORIES INC. 21
Analysis in Randomised Controlled Trials: Importance,
Indications, and Interpretation (2006) (explaining that
“[p]ost hoc observations are not automatically invalid . . .
but they should be regarded as unreliable unless they can
be replicated”). And Sanofi’s expert Dr. Reiffel testified
that a person of ordinary skill in the art would not “draw
an expectation” about dronedarone from the post-hoc
analysis in this case specifically. J.A. 348–52. He cited
differences in the respective patient populations as well
as the “discordant results” between the EURIDIS and
ADONIS trials as to hospitalization/death reduction
versus time of recurrence of atrial fibrillation. Id. at 349.
And he testified that a person of ordinary skill in the art
would be especially skeptical about what to draw from the
particular post-hoc analysis relating to dronedarone here
due to the safety concerns that arose after the failed
ANDROMEDA trial. J.A. 352.
Finally, Watson and Sandoz presented evidence that
Sanofi sent to some hospitals that participated in the
ATHENA trial a document called “Written Subject Infor-
mation,” proposed to be given to ATHENA enrollees, that
contained predictions about the benefits of dronedarone.
J.A. 7444 (JTX-55, proposed Written Subject Information,
containing the language, “it is expected, that dronedarone
improves the outcome in atrial fibrillation and atrial
flutter patients by reducing the admissions to hospital
and by prolonging the time in normal heart rhythm”); J.A.
7977 (DTX-24, same). But there was no evidence that the
documents containing “it is expected” language were ever
actually given to patients in the ATHENA trial. 5 To the
5 The district court referred to the Written Subject
Information (DTX-24) as “provided to ATHENA trial
patients.” Sanofi, 204 F. Supp. 3d at 689 (citing DTX-24
and Tr. 236–37 (J.A. 210–11)). The cited evidence says
only that the document was what was “proposed” to be
22 SANOFI v. WATSON LABORATORIES INC.
contrary, experts for both Sanofi and Watson/Sandoz
stated that the Institutional Review Boards at their
hospitals altered the benefits language from the Written
Subject Information. J.A. 236 (Dr. Zusman, expert for
Watson and Sandoz, testifying that the Written Subject
Information actually given to patients at Massachusetts
General Hospital, JTX-218, was changed by the Institu-
tional Review Board to tell enrollees that, as to the effect
of placebo versus dronedarone on “the long-term outcome
of your disease,” “there is no clear evidence that this will
be a positive or negative difference” “based on the current-
ly available information”); J.A. 373 (Dr. Reiffel, expert for
Sanofi, testifying that the Institutional Review Board at
his hospital changed the wording proposed by Sanofi
before distributing the Written Subject Information to
patients); JTX-218 (Massachusetts General Hospital
form, not containing “it is expected” language, but saying,
in addition to the above-quoted statements: “It is possible
that you may receive no benefit from this research
study. . . . Your participation in this study might be a
direct benefit to you and could help in the development of
new treatments for the benefit of future patients.”). The
initially proposed enrollee-information “it is expected”
language cannot show that the district court’s finding
regarding reasonable expectation is clearly erroneous
when, as far as the record shows, that language was not
actually given to enrollees and, indeed, was deleted by
Institutional Review Boards (which, we must presume,
were concerned about overstatements to lay patients in
securing informed consent). 6
given to ATHENA enrollees. We do not read the court’s
language as finding more than what the cited evidence
supports.
6 We note that a longstanding “Federal Policy for
the Protection of Human Subjects,” where applicable,
SANOFI v. WATSON LABORATORIES INC. 23
We conclude 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 AF in the
ATHENA patient population” and that Watson and
Sandoz had failed to prove obviousness by clear and
convincing evidence. Sanofi, 204 F. Supp. 3d at 696.
C
In seeking to reverse the finding of infringement of
the ’800 patent, Watson and Sandoz raise just one issue.
They argue that the district court erred by failing to limit
the claims of the ’800 patent to exclude polysorbate sur-
factants. They point to the fact that, while prosecuting
the parent application, which issued as U.S. Patent No.
7,323,493, Sanofi amended the sole independent claims
(hence all claims) so as expressly to exclude pharmaceuti-
cal compositions with a “polysorbate surfactant” from the
claims of the ’493 patent. Based on that amendment,
Watson and Sandoz contend that Sanofi made a “prosecu-
tion disclaimer” that also limits the scope of the claims of
the ’800 patent, despite the absence of any limiting lan-
guage in the ’800 patent’s claims. We review the district
court’s rejection of this prosecution-disclaimer argument
de novo. Shire Dev., LLC v. Watson Pharms., Inc., 787
F.3d 1359, 1365 (Fed. Cir. 2015). We agree with the
district court.
requires investigators to obtain informed consent from
human subjects of research and generally requires, as a
basic element of informed consent, that the information
given to prospective subjects include “[a] description of
any benefits to the subject or to others which may reason-
ably be expected from the research.” 45 C.F.R.
§ 46.116(a)(3).
24 SANOFI v. WATSON LABORATORIES INC.
A prosecution disclaimer occurs “when a patentee, ei-
ther through argument or amendment, surrenders claim
scope during the course of prosecution.” Heuft Sys-
temtechnik GmbH v. Indus. Dynamics Co., Ltd., 282 F.
App’x 836, 839 (Fed. Cir. 2008). But “[w]hen the purport-
ed disclaimers are directed to specific claim terms that
have been omitted or materially altered in subsequent
applications (rather than to the invention itself), those
disclaimers do not apply.” Saunders Grp., Inc. v. Com-
fortrac, Inc., 492 F.3d 1326, 1333 (Fed. Cir. 2007). “In
general, a prosecution disclaimer will only apply to a
subsequent patent if that patent contains the same claim
limitation as its predecessor.” Regents of Univ. of Minn. v.
AGA Med. Corp., 717 F.3d 929, 943 (Fed Cir. 2013).
In this case, all that Sanofi did, in prosecuting the ap-
plication that issued as the ’493 patent, was to write an
express limitation into the claims: “provided that the
pharmaceutical composition does not contain a polysorb-
ate surfactant.” See Sanofi, 204 F. Supp. 3d at 701. That
language does not appear in the ’800 patent claims at
issue. As the district court noted, Sanofi did not argue
during prosecution that the unamended claim language of
the ’493 patent, or the disclosed invention generally,
excluded polysorbate surfactants. Id. at 702–03. In these
circumstances, the process in this case fit a familiar
pattern: an applicant adopts an explicit claim-narrowing
limitation to achieve immediate issuance of a patent
containing the narrowed claims and postpones to the
prosecution of a continuation application further argu-
ments about claims that lack the narrowing limitation.
Without more than exists here, that process does not
imply a disclaimer as to claims, when later issued in the
continuation, that lack the first patent’s express narrow-
ing limitation.
We therefore affirm the district court’s ruling that the
scope of the claims of the ’800 patent should not be lim-
ited so as to exclude polysorbate surfactants.
SANOFI v. WATSON LABORATORIES INC. 25
III
For the foregoing reasons, we affirm the district
court’s judgment.
AFFIRMED