Court Opinion

ID: 4115314
Source: CourtListenerOpinion
Date Created: 2017-01-12 16:01:28.449265+00
Date Added: 2024-06-11T07:45:45.286017
License: Public Domain

United States Court of Appeals
      for the Federal Circuit
                 ______________________

             ELI LILLY AND COMPANY,
                   Plaintiff-Appellee

                            v.

   TEVA PARENTERAL MEDICINES, INC., APP
  PHARMACEUTICALS LLC, PLIVA HRVATSKA
  D.O.O., TEVA PHARMACEUTICALS USA, INC.,
           BARR LABORATORIES, INC.,
               Defendants-Appellants
              ______________________

                       2015-2067
                 ______________________

   Appeal from the United States District Court for the
Southern District of Indiana in No. 1:10-cv-01376-TWP-
DKL, Judge Tanya Walton Pratt.
                ______________________

               Decided: January 12, 2017
                ______________________

    ADAM LAWRENCE PERLMAN, Williams & Connolly LLP,
Washington, DC, argued for plaintiff-appellee. Also repre-
sented by DOV PHILIP GROSSMAN, BRUCE GENDERSON,
DAVID M. KRINSKY, ALLISON JONES RUSHING, ELLEN E.
OBERWETTER.

   WILLIAM M. JAY, Goodwin Procter LLP, Washington,
DC, argued for defendants-appellants. Also represented
by DARYL L. WIESEN, ELAINE BLAIS, EMILY L. RAPALINO,
2       ELI LILLY AND COMPANY   v. TEVA PARENTERAL MEDICINES

HENRY C. DINGER, Boston, MA; BRIAN JOSEPH PREW,
MICHAEL B. COTTLER, NATASHA ELISE DAUGHTREY, New
York, NY.

   CHRISTINA JORDAN MCCULLOUGH, Perkins Coie, LLP,
Seattle, WA, for amicus curiae Generic Pharmaceutical
Association. Also represented by SHANNON BLOODWORTH,
Washington, DC.

    KEVIN SCOTT PRUSSIA, Wilmer Cutler Pickering Hale
and Dorr LLP, Boston, MA, for amicus curiae Pharmaceu-
tical Research and Manufacturers of America. Also repre-
sented by SAMEER AHMED; JAMIE WISZ, Washington, DC.

    DAVID S. FORMAN, Osha Liang LLP, Alexandria, VA,
for amicus curiae Biotechnology Innovation Organization.
Also represented by HANSJORG SAUER, Biotechnology
Innovation Organization, Washington, DC.
                 ______________________

    Before PROST, Chief Judge, NEWMAN and DYK, Circuit
                          Judges.
PROST, Chief Judge.
    Eli Lilly & Co. (“Eli Lilly”) is the owner of U.S. Patent
No. 7,772,209 (“’209 patent”). It filed this consolidated
Hatch-Waxman suit against Teva Parenteral Medicines,
Inc.; APP Pharmaceuticals LLC; Pliva Hrvatska D.O.O.;
Teva Pharmaceuticals USA, Inc.; and Barr Laboratories,
Inc. (collectively, “Defendants”) to prevent Defendants
from launching a generic version of a chemotherapy drug
with accompanying product literature that would alleged-
ly infringe methods of treatment claimed by the ’209
patent. The United States District Court for the Southern
District of Indiana held two bench trials, one on infringe-
ment and one on invalidity. The district court found that
no single actor performs all steps of the asserted claims
because the actions of both physicians and patients are
ELI LILLY AND COMPANY   v. TEVA PARENTERAL MEDICINES       3

required. Nonetheless, under Akamai Technologies, Inc.
v. Limelight Networks, Inc. (Akamai V), 797 F.3d 1020,
1022 (Fed. Cir. 2015) (en banc) (per curiam), cert. denied,
136 S. Ct. 1661 (2016), the court found direct infringe-
ment attributable to physicians and held Defendants
liable for inducing that infringement. The court also
determined that the asserted claims were not invalid for,
inter alia, indefiniteness, obviousness, or obviousness-
type double patenting.
    For the reasons below, we affirm.
                        BACKGROUND
    The ’209 patent, which issued in 2010, relates to
methods of administering the chemotherapy drug
pemetrexed disodium (“pemetrexed”) after pretreatment
with two common vitamins—folic acid and vitamin B12.
Pemetrexed is an antifolate that kills cancer cells by
inhibiting the function of folates, a class of nutrients
necessary for cell reproduction. The purpose of the dual
vitamin pretreatments is to reduce the toxicity of
pemetrexed in patients. Eli Lilly markets pemetrexed
under the brand name ALIMTA®, and the drug is used to
treat certain types of lung cancer and mesothelioma.
     Around 2008–2009, Defendants notified Eli Lilly that
they had submitted Abbreviated New Drug Applications
(“ANDAs”) seeking approval by the Food and Drug Ad-
ministration (“FDA”) to market generic versions of
ALIMTA®. After the ’209 patent issued, Defendants sent
Eli Lilly additional notices regarding their ANDAs, in-
cluding notices that they had filed Paragraph IV certifica-
tions under 21 U.S.C. § 355(j)(2)(A)(vii)(IV), declaring that
the ’209 patent was invalid, unenforceable, or would not
be infringed. Eli Lilly subsequently brought this consoli-
dated action against Defendants for infringement under
35 U.S.C. § 271(e)(2). Specifically, Eli Lilly alleged that
Defendants’ generic drugs would be administered with
folic acid and vitamin B12 pretreatments and, thus, result
4      ELI LILLY AND COMPANY   v. TEVA PARENTERAL MEDICINES

in infringement of the ’209 patent. Defendants raised
noninfringement and invalidity defenses.
    Eli Lilly asserted claims 9, 10, 12, 14, 15, 18, 19, and
21 of the ’209 patent at trial. Importantly, all of the
asserted claims require patient pretreatment by “admin-
istering” or “administration of” folic acid. Claims 9 and 10
depend from claim 1, which recites:
        1. A method of administering pemetrexed
    disodium to a patient in need thereof comprising
    administering an effective amount of folic acid and
    an effective amount of a methylmalonic acid low-
    ering agent followed by administering an effective
    amount of pemetrexed disodium, wherein
        the methylmalonic acid lowering agent is se-
    lected from the group consisting of vitamin B12,
    hydroxycobalamin,       cyano-10-chlorocobalamin,
    aquocobalamin perchlorate, aquo-10-cobalamin
    perchlorate, azidocobalamin, cobalamin, cyanoco-
    balamin, or chlorocobalamin.
’209 patent col. 10 ll. 55–65 (emphasis added). The addi-
tional limitations of claims 9 and 10 restrict the dose of
folic acid to particular ranges. Id. at col. 11 ll. 19–22.
    Asserted claim 12 is independent and recites:
        12. An improved method for administering
    pemetrexed disodium to a patient in need of
    chemotherapeutic treatment, wherein the im-
    provement comprises:
       a) administration of between about 350 μg
          and about 1000 μg of folic acid prior to the
          first administration of pemetrexed disodi-
          um;
       b) administration of about 500 μg to about
          1500 μg of vitamin B12, prior to the first
ELI LILLY AND COMPANY   v. TEVA PARENTERAL MEDICINES      5

           administration of pemetrexed disodium;
           and
       c) administration of pemetrexed disodium.
Id. at col. 11 l. 25–col. 12 l. 4 (emphasis added). Asserted
claims 14, 15, 18, 19, and 21 depend from claim 12 and
further limit the dose, schedule, or route of folic acid or
vitamin B12 administration. Id. at col. 12 ll. 7–11, col. 12
ll. 16–20, col. 12 ll. 24–27.
    The parties agree for purposes of this appeal that no
single actor performs all steps of the asserted claims;
rather, the steps are divided between physicians and
patients. Though physicians administer vitamin B12 and
pemetrexed, patients self-administer folic acid with
guidance from physicians. Eli Lilly’s theory of infringe-
ment therefore requires establishing liability for divided
infringement—an area of law that this court was actively
reconsidering during the pendency of this case.
    In June 2013, Defendants conditionally conceded in-
duced infringement under then-current law set forth in
Akamai Technologies, Inc. v. Limelight Networks, Inc.
(Akamai II), 692 F.3d 1301 (Fed. Cir. 2012) (en banc) (per
curiam), rev’d, 134 S. Ct. 2111 (2014). 1 At the time, the
Akamai II decision was the subject of a petition to the
Supreme Court for a writ of certiorari. The parties’
stipulation included a provision reserving Defendants’
right to litigate infringement if the Supreme Court re-
versed or vacated Akamai II.
    Eli Lilly and Defendants proceeded with a bench trial
on invalidity, after which the district court held that the
asserted claims were not invalid for, inter alia, obvious-

   1    Akamai II held that “induced infringement can be
found even if there is no single party who would be liable
for direct infringement.” 692 F.3d at 1317–18.
6       ELI LILLY AND COMPANY   v. TEVA PARENTERAL MEDICINES

ness or obviousness-type double patenting. The court had
also previously rejected Defendants’ contention that the
asserted claims were invalid for indefiniteness of the term
“vitamin B12.” Defendants filed an appeal on invalidity,
which was docketed in this court as Case No. 14-1455.
While that appeal was pending, the Supreme Court
reversed Akamai II, holding that liability for inducement
cannot be found without direct infringement, and remand-
ing for this court to possibly reconsider the standards for
direct infringement. Limelight Networks, Inc. v. Akamai
Techs., Inc. (Akamai III), 134 S. Ct. 2111 (2014). In view
of that development, the parties in this case filed a joint
motion to remand the matter to the district court for the
limited purpose of litigating infringement. We granted
the motion.
    The district court held a second bench trial in May
2015 and concluded in a decision issued on August 25,
2015 that Defendants would induce infringement of the
’209 patent. As explained in further detail below, the
court applied our intervening Akamai V decision, which
had broadened the circumstances in which others’ acts
may be attributed to a single actor to support direct-
infringement liability in cases of divided infringement. 2
See Akamai V, 797 F.3d at 1022. The court accordingly
entered final judgment against Defendants, barring them

    2   Following remand from the Supreme Court, a
panel of this court initially found that the accused in-
fringer in Akamai was not liable for direct infringement,
Akamai Techs., Inc. v. Limelight Networks, Inc. (Akamai
IV), 786 F.3d 899 (Fed. Cir. 2015), as had the first panel
in the case, Akamai Techs., Inc. v. Limelight Networks,
Inc. (Akamai I), 629 F.3d 1311 (Fed. Cir. 2010). We later
vacated Akamai IV and took the case en banc, which
resulted in the Akamai V decision.
ELI LILLY AND COMPANY   v. TEVA PARENTERAL MEDICINES     7

from launching their generic products before the expira-
tion of the ’209 patent.
   Defendants timely appealed.       We have jurisdiction
under 28 U.S.C. § 1295(a)(1).
                        DISCUSSION
    Defendants appeal the district court’s finding of in-
duced infringement, as well as the court’s decision that
the asserted claims are not invalid for indefiniteness,
obviousness, or obviousness-type double patenting. We
will address each of these issues in turn.
                              I
    Pursuant to 35 U.S.C. § 271(b), “[w]hoever actively
induces infringement of a patent shall be liable as an
infringer.” 3 Importantly, liability for induced infringe-
ment under § 271(b) “must be predicated on direct in-
fringement.” Akamai III, 134 S. Ct. at 2117. The
patentee must also show that the alleged infringer pos-
sessed the requisite intent to induce infringement, which
we have held requires that the alleged infringer “knew or
should have known his actions would induce actual in-
fringements.” DSU Med. Corp. v. JMS Co., 471 F.3d
1293, 1304 (Fed. Cir. 2006) (en banc in relevant part)
(internal quotation marks omitted). A patentee seeking
relief under § 271(e)(2) bears the burden of proving in-
fringement by a preponderance of the evidence. Warner-
Lambert Co. v. Apotex Corp., 316 F.3d 1348, 1366 (Fed.
Cir. 2003).
    “Infringement is a question of fact that, after a bench
trial, we review for clear error.” Alza Corp. v. Mylan
Labs, Inc., 464 F.3d 1286, 1289 (Fed. Cir. 2006). Reversal

   3    Section 271 was not amended by the Leahy-Smith
America Invents Act (“AIA”), Pub. L. No. 112–29, 125
Stat. 284 (2011).
8      ELI LILLY AND COMPANY   v. TEVA PARENTERAL MEDICINES

for clear error is appropriate “only when this court is left
with a definite and firm conviction that the district court
was in error.” Id.
    The district court relied in part on Defendants’ pro-
posed product labeling as evidence of infringement. For
purposes of this case, the parties have agreed that De-
fendants’ product labeling would be materially the same
as the ALIMTA® product labeling, which consists of two
documents: the Physician Prescribing Information and
the Patient Information. Both documents include instruc-
tions regarding the administration of folic acid—the step
that the district court found would be performed by pa-
tients but attributable to physicians. For example, the
Physician Prescribing Information provides, among other
things:
    “Instruct patients to initiate folic acid 400 [μg] to 1000
    [μg] orally once daily beginning 7 days before the first
    dose of [pemetrexed] . . . .” J.A. 11256.
    “Instruct patients on the need for folic acid and vita-
    min B12 supplementation to reduce treatment-related
    hematologic and gastrointestinal toxicity . . . .” J.A.
    11278.
The Patient Information includes similar information:
    “To lower your chances of side effects of [pemetrexed],
    you must also take folic acid . . . prior to and during
    your treatment with [pemetrexed].” J.A. 11253 (em-
    phasis omitted).
    “It is very important to take folic acid and vitamin B12
    during your treatment with [pemetrexed] to lower
    your chances of harmful side effects. You must start
    taking 400–1000 micrograms of folic acid every day
    for at least 5 days out of the 7 days before your first
    dose of [pemetrexed]. . . .” Id. (emphasis omitted).
ELI LILLY AND COMPANY   v. TEVA PARENTERAL MEDICINES        9

                              A
     Where, as here, no single actor performs all steps of a
method claim, direct infringement only occurs if “the acts
of one are attributable to the other such that a single
entity is responsible for the infringement.” Akamai V,
797 F.3d at 1022. The performance of method steps is
attributable to a single entity in two types of circum-
stances: when that entity “directs or controls” others’
performance, or when the actors “form a joint enterprise.”
Id. Eli Lilly did not pursue a joint enterprise theory, so
the question of direct infringement before us is whether
physicians direct or control their patients’ administration
of folic acid. 4
    In Akamai V, we held that directing or controlling
others’ performance includes circumstances in which an
actor: (1) “conditions participation in an activity or receipt
of a benefit” upon others’ performance of one or more
steps of a patented method, and (2) “establishes the man-
ner or timing of that performance.” Id. at 1023 (emphases
added). In addition to this two-prong test, we observed
that, “[i]n the future, other factual scenarios may arise
which warrant attributing others’ performance of method
steps to a single actor. Going forward, principles of at-
tribution are to be considered in the context of the partic-
ular facts presented.” Id.

    4    Before the district court, Eli Lilly also asserted
theories of direct infringement that did not rely on show-
ing physicians’ direction or control of patient action,
arguing that: (1) as a matter of claim construction, physi-
cians “administer” folic acid; and (2) under the doctrine of
equivalents, physicians’ actions are equivalent to putting
folic acid into patients’ bodies. The district court did not
reach those issues. Although Eli Lilly asks us to reach
them in the alternative, we need not do so in light of our
decision to affirm the district court under Akamai V.
10     ELI LILLY AND COMPANY   v. TEVA PARENTERAL MEDICINES

    Here, the district court decided that “the factual cir-
cumstances [we]re sufficiently analogous to those in
Akamai [V] to support a finding of direct infringement by
physicians.” Eli Lilly & Co. v. Teva Parenteral Meds., Inc.
(Eli Lilly III), 126 F. Supp. 3d 1037, 1041 (S.D. Ind. 2015).
The court observed initially that taking folic acid in the
manner recited by the asserted claims is a “critical” and
“necessary” step to “reduc[e] . . . potentially life-
threatening toxicities caused by pemetrexed,” i.e., to
“receive the benefit of the patented method.” Id. at 1042.
Regarding the first Akamai V prong, the court found,
based on the product labeling, that “taking folic acid in
the manner specified is a condition of the patient’s partic-
ipation in pemetrexed treatment.” Id. Regarding the
second prong, the court found that physicians would
“prescrib[e] an exact dose of folic acid and direct[] that it
be ingested daily.” Id. at 1043. The court therefore held
that, under Akamai V, the performance of all steps of the
asserted claims would be attributable to physicians.
                             1
    With respect to the first prong—conditioning partici-
pation in an activity or receipt of a benefit upon perfor-
mance of one or more method steps—Defendants argue at
the outset that the district court did not make a relevant
finding because it misidentified the benefit that would be
conditioned as the “benefit of the patented method, i.e., a
reduction of potentially life-threatening toxicities caused
by pemetrexed.” Appellants’ Opening Br. 21–22. We
agree that a reduction in toxicities is not a benefit that
physicians can condition (as it follows from folic acid
pretreatment) and that the relevant benefit that may be
conditioned on folic acid administration is pemetrexed
treatment.     But the court’s discussion of reducing
pemetrexed toxicities in relation to its direction-or-control
analysis was not erroneous. A reduction in pemetrexed
toxicities is relevant only if pemetrexed treatment is
administered, and it provides a reason why physicians
ELI LILLY AND COMPANY   v. TEVA PARENTERAL MEDICINES     11

would condition the receipt of pemetrexed treatment on
folic acid administration. The court recognized this
relationship and correctly identified pemetrexed treat-
ment as the benefit to be conditioned: “What is relevant is
whether the physician sufficiently directs or controls the
acts of the patients in such a manner as to condition
participation in an activity or receipt of a benefit—in this
case, treatment with pemetrexed in the manner that
reduces toxicities—upon the performance of a step of the
patented method and establishes the manner and timing
of the performance.” Eli Lilly III, 126 F. Supp. 3d at 1042
(emphasis added); see also id. (“[T]aking folic acid in the
manner specified is a condition of the patient’s participa-
tion in pemetrexed treatment.” (emphasis added)).
    The district court’s finding that physicians “condition”
pemetrexed treatment on the administration of folic acid
is supported by the record evidence. The Physician Pre-
scribing Information, which is “directed to the physician,”
J.A. 2181, explains that folic acid is a “[r]equirement for
[p]remedication” in order “to reduce the severity of hema-
tologic and gastrointestinal toxicity of [pemetrexed].” J.A.
11258. Consistent with the importance of folic acid pre-
treatment, the product labeling repeatedly states that
physicians should “[i]nstruct patients” to take folic acid
and includes information about folic acid dosage ranges
and schedules. J.A. 11256; see also J.A. 11255, 11278.
The Patient Information also informs patients that physi-
cians may withhold pemetrexed treatment: “You will have
regular blood tests before and during your treatment with
[pemetrexed]. Your doctor may adjust your dose of
[pemetrexed] or delay treatment based on the results of
your blood test and on your general condition.” J.A.
11253 (emphasis added).
    Furthermore, Eli Lilly’s expert, Dr. Chabner, testified
that it is “the physician’s responsibility to initiate the
supplementation” of folic acid. J.A. 2181. He explained
that the product labeling shows that taking folic acid is
12     ELI LILLY AND COMPANY   v. TEVA PARENTERAL MEDICINES

“an absolute requirement” before pemetrexed treatment
because “it wouldn’t be safe to take the drug without the
vitamin supplementation. . . . [I]t must be done this way.”
J.A. 2192; see also J.A. 2195 (“[I]t’s an absolute require-
ment.”), 2246 (“I think it’s that important.”). He further
testified that if a physician realizes that a patient did not
follow his or her instructions to take folic acid, then the
“doctor will not give the pemetrexed.” J.A. 2218. Even
Defendants’ expert, Dr. Schulz, acknowledged that it is
“standard practice”—both his personally and physicians’
generally—that a patient “must have taken their required
folic acid in order to have the pemetrexed administered.”
J.A. 2329–40; see also J.A. 2304 (“I would withhold the
pemetrexed therapy until [the patient] had initiated or
resumed their folic acid treatment . . . [s]o as to avoid the
toxicities associated with pemetrexed without vitamin
replacement.”). Dr. Schulz agreed that he was “not aware
of any reputable institution or doctor . . . who, when they
think the patient hasn’t taken the required folic acid”
would go ahead and administer pemetrexed. J.A. 2330–
31.
    The record is thus replete with evidence that physi-
cians delineate the step of folic acid administration that
patients must perform if they wish to receive pemetrexed
treatment.
    Defendants argue that mere guidance or instruction is
insufficient to show “conditioning” under Akamai V. But
the evidence regarding the critical nature of folic acid
pretreatment and physicians’ practices support a finding
that physicians cross the line from merely guiding or
instructing patients to take folic acid to conditioning
pemetrexed treatment on their administration of folic
acid. If a patient does not take folic acid as instructed, a
physician, in his or her discretion, need not provide
pemetrexed treatment based on the patient’s failure to
perform the step of folic acid administration. Defendants
also complain that there is no evidence that physicians go
ELI LILLY AND COMPANY   v. TEVA PARENTERAL MEDICINES       13

further to “verify compliance” with their instructions or to
“threaten” denial of pemetrexed treatment. Appellants’
Opening Br. 22. Conditioning, however, does not neces-
sarily require double-checking another’s performance or
making threats.
    We also reject Defendants’ argument that an actor
can only condition the performance of a step “by imposing
a legal obligation to do so, by interposing that step as an
unavoidable technological prerequisite to participation,
or, as in [Akamai V], both.” Id. In Akamai V, we found
“conditioning” based on evidence that the defendant
required all of its customers to sign a standard contract
delineating the steps that customers had to perform to
use the defendant’s service. 797 F.3d at 1024. But we did
not limit “conditioning” to legal obligations or technologi-
cal prerequisites. 5 We cautioned that “principles of
attribution are to be considered in the context of the
particular facts presented” and even expressly held that
§ 271(a) infringement “is not limited solely to principal-
agent relationships, contractual arrangements, and joint
enterprise.” Id. at 1023.
    The product labeling, combined with the testimony
discussed above, provide sufficient evidence that physi-
cians condition pemetrexed treatment on folic acid pre-
treatment.

    5   As Eli Lilly points out, nor did we rely on legal ob-
ligations or technological prerequisites to reach our deci-
sion in Akamai V. The standard contract in that case was
not significant for imposing potential civil liability but for
“delineat[ing] the steps” that customers would have to
perform “if [they] wish[ed] to use [defendant’s] product.”
Akamai V, 797 F.3d at 1024. And we did not focus on
whether a customer’s failure to perform certain steps
might have made it technologically impossible for other
steps to occur. Id.
14       ELI LILLY AND COMPANY   v. TEVA PARENTERAL MEDICINES

                               2
     With respect to the second prong—establishing the
manner or timing of performance—Defendants argue that
the product labeling “gives patients wide berth to select
the dose . . . , the dosage form . . . , and the timing . . . of
folic acid self-administration.” Appellants’ Opening Br.
23. Eli Lilly submits that expert testimony and product
labeling demonstrate that “physicians prescribe or specify
a dose of folic acid, specify that patients must ingest the
folic acid daily during a particular span of days, and
withhold pemetrexed if patients do not follow orders.”
Appellee’s Br. 25. We agree with Eli Lilly.
    The product labeling is again informative. For in-
stance, the Physician Prescription Information instructs
physicians not only to tell patients to take folic acid
orally, but also to take “400 [μg] to 1000 [μg] [of folic acid]
once daily beginning 7 days before the first dose of
[pemetrexed],” accompanied with warnings about the
consequences of non-compliance. J.A. 11256. That
dosage range and schedule overlaps with all of the assert-
ed claims’ dosage ranges and schedules. 6 In addition, Dr.
Chabner testified that “it’s the doctor” who “decides how
much [folic acid] the patient will take and when the
patient takes it.” J.A. 2197. In view of the record evi-

     6   Asserted claims 9, 12, 14, and 15 recite adminis-
tering “about 350 μg to about 1000 μg” of folic acid. ’209
patent col. 11 ll. 19–20, col. 11 l. 25–col. 12 l. 4, col. 12
ll. 7–11. Asserted claims 10, 18, and 19 recite administer-
ing “350 μg to 600 μg” of folic acid. Id. at col. 11 ll. 21–23,
col. 12 ll. 16–20. Asserted claim 21 recites either of those
folic acid dosage ranges. Id. at col. 12 ll. 24–27. Asserted
claim 19 further recites a schedule for folic acid admin-
istration “wherein folic acid is administered 1 to 3 weeks
prior to the first administration of the pemetrexed.” Id. at
col. 12 ll. 18–20.
ELI LILLY AND COMPANY   v. TEVA PARENTERAL MEDICINES     15

dence, the court’s finding that physicians establish the
manner and timing of patients’ folic acid intake is not
clearly erroneous. Even if, as Defendants argue, patients
are able to seek additional outside assistance regarding
folic acid administration, such guidance is beyond what is
required here to establish the manner or timing of per-
formance and is therefore immaterial.
    We therefore see no reversible error in the district
court’s finding that physicians condition patient partici-
pation in an activity or receipt of a benefit (pemetrexed
treatment) on folic acid administration and also establish
the manner or timing of performance. Our holding today
does not assume that patient action is attributable to a
prescribing physician solely because they have a physi-
cian-patient relationship. We leave to another day what
other scenarios also satisfy the “direction or control”
requirement. The two-prong test that we set forth in
Akamai V is applicable to the facts of this case and re-
solves the existence of underlying direct infringement.
                             B
    Although we conclude that the two-prong Akamai V
test is met here, this does not end our inquiry. “The mere
existence of direct infringement by physicians, while
necessary to find liability for induced infringement, is not
sufficient for inducement.” Takeda Pharm. USA, Inc. v.
West-Ward Pharm. Corp., 785 F.3d 625, 631 (Fed. Cir.
2015). To show inducement, Eli Lilly carries the burden
of further proving “specific intent and action to induce
infringement.”      Takeda, 785 F.3d at 631.           Mere
“knowledge of the acts alleged to constitute infringement”
is not sufficient. DSU Med., 471 F.3d at 1305.
    As noted before, the district court found that the ad-
ministration of folic acid before pemetrexed administra-
tion was “not merely a suggestion or recommendation, but
a critical step.” Eli Lilly III, 126 F. Supp. 3d at 1042. It
further held that Defendants induce physicians’ infringe-
16     ELI LILLY AND COMPANY   v. TEVA PARENTERAL MEDICINES

ment because physicians act “in accordance with Defend-
ants’ proposed labeling.” Id. Accordingly, the district
court concluded that Defendants would induce infringe-
ment of the ’209 patent.
     Defendants submit that, even if there is direct in-
fringement, their product labeling does not induce such
infringement. They argue that Eli Lilly has not offered
any evidence of what physicians do “in general,” offering
instead only “speculation about how physicians may act.”
Appellants’ Opening Br. 24 (second emphasis added).
Furthermore, they submit that physicians “who merely
follow the product label” are not induced to infringe
because physicians must go beyond the labeling instruc-
tions—such as by prescribing specific doses of folic acid or
requiring patients to keep “pill counts” or “pill diaries”—
to infringe. Id. at 23, 26. We agree with Eli Lilly that
Defendants’ arguments are unavailing.
     We make two observations at the outset. First, to be
clear, the intent for inducement must be with respect to
the actions of the underlying direct infringer, here physi-
cians. Second, we have not required evidence regarding
the general prevalence of the induced activity. When the
alleged inducement relies on a drug label’s instructions,
“[t]he question is not just whether [those] instructions
describ[e] the infringing mode, . . . but whether the in-
structions teach an infringing use such that we are willing
to infer from those instructions an affirmative intent to
infringe the patent.” Takeda, 785 F.3d at 631 (internal
quotation marks omitted). “The label must encourage,
recommend, or promote infringement.” Id. For purposes
of inducement, “it is irrelevant that some users may
ignore the warnings in the proposed label.” AstraZeneca
LP v. Apotex, Inc., 633 F.3d 1042, 1060 (Fed. Cir. 2010).
    Depending on the clarity of the instructions, the deci-
sion to continue seeking FDA approval of those instruc-
tions may be sufficient evidence of specific intent to
ELI LILLY AND COMPANY   v. TEVA PARENTERAL MEDICINES     17

induce infringement. Id. at 1059. With respect to those
instructions, we held in AstraZeneca that a label that
instructed users to follow the instructions in an infringing
manner was sufficient even though some users would not
follow the instructions. Id. at 1059–60. This was true
even though the product in question had substantial
noninfringing uses. Id.
     Conversely, “vague” instructions that require one to
“look outside the label to understand the alleged implicit
encouragement” do not, without more, induce infringe-
ment. Takeda, 785 F.3d at 632, 634. Defendants try to
analogize the product labeling here to the labeling in
Takeda that we held did not provide clear enough instruc-
tions for the infringing use to show inducement. Takeda,
however, is distinguishable. The generic manufacturer in
that case sought FDA approval for a generic drug to be
used as a prophylaxis for gout flares—a use not covered
by the patents that had been asserted. Id. at 628. The
only link between the proposed use described on the
labeling and the patented use was an instruction stating,
“[i]f you have a gout flare while taking [the drug], tell
your healthcare provider.” Id. at 632 (first alteration in
original) (internal quotation marks omitted). The patent
owner argued that physicians who are accordingly con-
sulted might prescribe the drug for the infringing, off-
label use and that the accused infringer was willfully
blind to this possibility. Id. We rejected the patent
owner’s reliance on such “vague label language” and
“speculation about how physicians may act.” Id. The
product labeling here is not so tenuously related to the
use covered by the asserted claims, and Eli Lilly does not
need to rely on speculation about physician behavior.
    Again, the product labeling includes repeated instruc-
tions and warnings regarding the importance of and
reasons for folic acid treatment, and there is testimony
that the Physician Prescribing Information, as the name
indicates, is directed at physicians. See J.A. 2181, 11253,
18       ELI LILLY AND COMPANY   v. TEVA PARENTERAL MEDICINES

11255, 11256, 11258, 11278. The instructions are unam-
biguous on their face and encourage or recommend in-
fringement.
     Defendants rely heavily on evidence that physicians
as a matter of practice take steps beyond the instructions
in the product labeling, such as asking patients to keep
pill diaries or pill counts, or confirming compliance with
folic acid administration. For example, they point to Dr.
Chabner’s testimony that he gives patients instructions
“beyond what the instruction is in th[e] patient infor-
mation.” J.A. 2235–36. But the asserted claims do not
recite additional steps such as pill diaries, pill counts, and
compliance measures. Where the product labeling al-
ready encourages infringement of the asserted claims, as
it does here, a physician’s decision to give patients even
more specific guidance is irrelevant to the question of
inducement. 7
    In sum, evidence that the product labeling that De-
fendants seek would inevitably lead some physicians to
infringe establishes the requisite intent for inducement.
The district court did not clearly err in concluding that
Defendants would induce infringement of the asserted
claims of the ’209 patent.
                              II
    We turn next to the district court’s holding that the
limitation “vitamin B12” was not indefinite. Pursuant to
35 U.S.C. § 112, ¶ 2, a patent specification must “conclude
with one or more claims particularly pointing out and
distinctly claiming the subject matter which the applicant

     7  As Dr. Chabner testified, such additional instruc-
tions are rightfully “left to the medical judgment of [the]
doctor,” depending on the circumstances. J.A. 2231.
ELI LILLY AND COMPANY   v. TEVA PARENTERAL MEDICINES      19

regards as his invention.” 8 The district court considered
the indefiniteness of the asserted claims before the Su-
preme Court changed the relevant standard in Nautilus,
Inc. v. Biosig Instruments, Inc., 134 S. Ct. 2120 (2014),
and held that “vitamin B12” was not indefinite. 9 Eli Lilly
& Co. v. Teva Parenteral Meds., Inc. (Eli Lilly I), No. 1:10-
cv-1376-TWP-DKL, 2012 WL 2358102, at *11–12 (S.D.
Ind. June 20, 2012). The district court further construed
“vitamin B12” to mean “cyanocobalamin,” a particular
vitamin supplement. Id. at *12.
    In Nautilus, the Supreme Court rejected our “not
amenable to construction or insolubly ambiguous” stand-
ard for indefiniteness and articulated, instead, that “a
patent is invalid for indefiniteness if its claims, read in
light of the specification delineating the patent, and the
prosecution history, fail to inform, with reasonable cer-
tainty, those skilled in the art about the scope of the
invention.” 134 S. Ct. at 2124. Indefiniteness is a ques-
tion of law that we review de novo. Teva Pharm. USA,
Inc. v. Sandoz, Inc., 789 F.3d 1335, 1341 (Fed. Cir. 2015).
We have reiterated post-Nautilus that “general principles
of claim construction apply” to the question of indefinite-

    8   Paragraph 2 of 35 U.S.C. § 112 was replaced with
§ 112(b) by § 4(c) of the AIA, and § 4(e) makes that change
applicable “to any patent application that is filed on or
after” September 16, 2012. Pub. L. No. 112–29, § 4, 125
Stat. at 296–97. Because the application resulting in the
’209 patent was filed before that date, we refer to the pre-
AIA version of § 112.
    9   Under the prevailing standard at the time, a term
was indefinite only if it was “not amenable to construc-
tion” or was “insolubly ambiguous.” Datamize, LLC v.
Plumtree Software, Inc., 417 F.3d 1342, 1347 (Fed. Cir.
2005) (internal quotation marks omitted), overruled by
Nautilus, 134 S. Ct. at 2124.
20        ELI LILLY AND COMPANY   v. TEVA PARENTERAL MEDICINES

ness. Biosig Instruments, Inc. v. Nautilus, Inc., 783 F.3d
1374, 1377 (Fed. Cir. 2015) (internal quotation marks
omitted).    Accordingly, we review subsidiary factual
determinations made by the district court based on ex-
trinsic evidence for clear error. Id.; see also Teva, 789
F.3d at 1341–42 (reviewing subsidiary factual findings in
the indefiniteness context for clear error).
    The parties do not dispute that, depending on the con-
text, “vitamin B12” can be used in the art to refer either
to cyanocobalamin specifically or, more broadly, to a class
of compounds including pharmaceutical derivatives of
cyanocobalamin. The parties do not dispute that the
written description of the ’209 patent uses the term both
ways. 10 Defendants argue that, because “vitamin B12” is
used in two different ways in the intrinsic record, “it is
impossible to determine” which meaning applies to the
claims “with any reasonable certainty,” as required by
Nautilus. Appellants’ Opening Br. 31. Eli Lilly counters
that the claims of the ’209 patent “involve administering a
vitamin B12 supplement to a patient,” and in that context,
“the one and only meaning” of vitamin B12 to a person of
ordinary skill is cyanocobalamin. Appellee’s Br. 35.
    The district court expressly “accept[ed]” the testimony
of Eli Lilly’s expert, Dr. O’Dwyer, who concluded that a
person of ordinary skill would understand “vitamin B12”
to mean cyanocobalamin in the context of the patent
claims. Eli Lilly I, 2012 WL 2358102, at *11. We do not

     10 The specification provides that “[t]he term ‘vita-
min B12’ refers to vitamin B12 and its pharmaceutical
derivatives,” and that “[p]referably the term refers to
vitamin B12, cobalamin, and chlorocobalamin.” ’209
patent col. 5 ll. 5–10. The district court held, and Defend-
ants do not dispute on appeal, that this language did not
signify that the patentee was redefining the term “vita-
min B12.” Eli Lilly I, 2012 WL 2358102, at *10–11.
ELI LILLY AND COMPANY   v. TEVA PARENTERAL MEDICINES      21

defer to Dr. O’Dwyer’s “ultimate conclusion about claim
meaning in the context of th[e] patent,” as that is a legal
question. Teva, 789 F.3d at 1342. But the district court’s
underlying determination, based on extrinsic evidence, of
what a person of ordinary skill would understand “vita-
min B12” to mean in different contexts is a question of
fact. See id. (“Understandings that lie outside the patent
documents about the meaning of terms to one of skill in
the art or the science or state of the knowledge of one of
skill in the art are factual issues.”). Dr. O’Dwyer testified
that, although “vitamin B12” can refer to a class of com-
pounds in other contexts, it refers specifically to cyanoco-
balamin when “vitamin B12” is prescribed in the medical
field. See, e.g., J.A. 3571 (“‘Vitamin B12’ is used by medi-
cal oncologists to mean a particular vitamin supplement,
and medical oncologists refer to ‘vitamin B12,’ and pre-
scribe ‘vitamin B12,’ without further explanation or
definition.”). We see no clear error in the district court’s
acceptance of the understanding that “vitamin B12,”
when used to refer to vitamin B12 supplementation in a
medical context, refers to cyanocobalamin. 11 In view of
this understanding, and because the specification uses
“vitamin B12” primarily in two ways, we do not face the
problem that we did in Teva, in which the disputed term
did “not have a plain meaning to one of skill in the art”
that could be determined from context. 789 F.3d at 1345.
    The claim language here would inform a person of or-
dinary skill that the term “vitamin B12,” as used in the
’209 patent claims, refers to “cyanocobalamin.” First, the
claims, on their face, are directed to administering vita-

    11  Indeed, Defendants’ expert, Dr. Green, agreed
that “in the strict biochemical nomenclature, the term
‘vitamin B12’ is restricted to cyanocobalamin,” J.A. 3767,
and that it can refer specifically to cyanocobalamin in the
context of vitamin B12 injections, J.A. 3748–49.
22    ELI LILLY AND COMPANY   v. TEVA PARENTERAL MEDICINES

min supplements, including vitamin B12, followed by
chemotherapy treatment. This context informs persons of
ordinary skill that “vitamin B12” is being used to refer to
the supplementation form of vitamin B12, cyanocobala-
min. Second, the structure of the claims also supports
such an understanding. Claim 1 requires administering a
“methylmalonic acid lowering agent . . . selected from the
group consisting of,” inter alia, vitamin B12 and cyanoco-
balamin. ’209 patent col. 10 ll. 61–65. Claim 2, which
depends from claim 1, further requires that “the
methylmalonic acid lowering agent is vitamin B12.” Id. at
col. 10 ll. 66–67. Eli Lilly asserts, and Defendants do not
dispute, that if “vitamin B12” were to refer to a class of
compounds, then claim 2 would be the same scope as
claim 1, as claim 2 “would encompass the same
methylmalonic acid lowering agents set forth in claim 1.”
Appellee’s Br. 36. The doctrine of claim differentiation,
however, presumes that dependent claims are “of narrow-
er scope than the independent claims from which they
depend.” AK Steel Corp. v. Sollac & Ugine, 344 F.3d
1234, 1242 (Fed. Cir. 2003). Reading the claims to re-
quire “vitamin B12” to be a specific compound in the class
of “methylmalonic acid lowering agents” would avoid this
problem, as it would render claim 2, and all of the claims
that depend from it, narrower than claim 1.
    Defendants submit that, if “vitamin B12” means “cya-
nocobalamin,” then claim 1 recites a Markush group of
“methylmalonic acid lowering agents” that lists the same
compound twice. Although we have in some instances
interpreted claim terms to avoid redundancy, “the rule is
not inflexible.” Power Mosfet Techs., LLC v. Siemens AG,
378 F.3d 1396, 1409–10 (Fed. Cir. 2004); see also Multi-
layer Stretch Cling Film Holdings, Inc. v. Berry Plastics
Corp., 831 F.3d 1350, 1363–64 (Fed. Cir. 2016); Manual of
Patent Examining Procedure § 2173.05(h)(I) (“The mere
fact that a compound may be embraced by more than one
member of a Markush group recited in the claim does not
ELI LILLY AND COMPANY   v. TEVA PARENTERAL MEDICINES     23

necessarily render the scope of the claim unclear.”). Here,
the redundancy is supported by the prosecution history,
during which the examiner stated that vitamin B12 and
cyanocobalamin “are the same” agents. J.A. 4239. There-
fore, faced with an interpretation that would read redun-
dancy into claim 1 and another that would violate the
doctrine of claim differentiation, we hold that the claims
here support the former result over the latter.
     We are not persuaded by Defendants’ contention that
the prosecution history fails to “provide reasonable confi-
dence in any particular meaning of the term ‘vitamin
B12.’” Appellants’ Opening Br. 30. In response to the
examiner’s statement that “vitamin B12” and “cyanoco-
balamin” are synonymous, the patentee initially removed
the term “cyanocobalamin” from the proposed claims. See
J.A. 4825–27, 4832–33. Later during prosecution, the
patentee added “cyanocobalamin” back into the claim that
eventually issued as claim 1. J.A. 4836. Defendants do
not point to any reason, though, that a person of ordinary
skill would understand the patentee’s decision to ulti-
mately include “cyanocobalamin” in the claim language to
be a departure from the understanding expressed by the
examiner that “vitamin B12” and “cyanocobalamin” refer
to the same compound. The prosecution history here does
not detract from, and is consistent with, the other intrin-
sic evidence that would inform a skilled artisan regarding
the scope of the claim term “vitamin B12.”
    We therefore hold that a person of ordinary skill in
the art would understand the scope of the claim term
“vitamin B12” with reasonable certainty. Applying Nauti-
lus in this case does not lead us to a different result from
the district court’s conclusion on the question of indefi-
niteness.
                             III
    Next, we address Defendants’ arguments that the as-
serted claims were obvious over several references that
24     ELI LILLY AND COMPANY   v. TEVA PARENTERAL MEDICINES

are not disputed to be prior art as of the critical date in
June 1999. To prevail on obviousness, an alleged infring-
er must prove by clear and convincing evidence “that a
skilled artisan would have been motivated to combine the
teachings of the prior art references to achieve the
claimed invention, and that the skilled artisan would
have had a reasonable expectation of success in doing so.”
Procter & Gamble Co. v. Teva Pharm. USA, Inc., 566 F.3d
989, 994 (Fed. Cir. 2009) (internal quotation marks omit-
ted). Obviousness is a question of law based on underly-
ing facts, and “[o]n appeal from a bench trial, this court
reviews the district court’s conclusions of law de novo and
findings of fact for clear error.” Prometheus Labs., Inc. v.
Roxane Labs., Inc., 805 F.3d 1092, 1097 (Fed. Cir. 2015)
(internal quotation marks omitted).

    In a thorough opinion, the district court found, inter
alia, that a skilled artisan would not have been motivated
to: (1) use folic acid pretreatment with pemetrexed; (2)
use vitamin B12 pretreatment with pemetrexed; or (3) use
the claimed doses and schedules of folic acid and vitamin
B12 pretreatments with pemetrexed. The court also
found that Eli Lilly had established several secondary
considerations in favor of nonobviousness. On appeal,
Defendants contend that all of those findings were erro-
neous. Eli Lilly submits that Defendants’ arguments
“amount to nothing more than an effort to reargue the
facts.” Appellee’s Br. 46.

     We agree with Eli Lilly that Defendants’ arguments
fail to raise reversible error with respect to at least the
findings that a skilled artisan would not have been moti-
vated to use vitamin B12 pretreatment with pemetrexed,
let alone the appropriate doses and schedules of such
vitamin B12 pretreatment.
ELI LILLY AND COMPANY   v. TEVA PARENTERAL MEDICINES       25

                              A
    The district court found, based upon two abstracts
published in 1998 by Dr. Niyikiza (“the Niyikiza ab-
stracts”), 12 that a skilled artisan “would have concluded
that vitamin B12 deficiency was not the problem in
pemetrexed toxicity.” Eli Lilly & Co. v. Teva Parenteral
Meds., Inc. (Eli Lilly II), No. 1:10-cv-01376-TWP-DWL,
2014 WL 1350129, at *10 (S.D. Ind. Mar. 31, 2014). It
further found that a skilled artisan would not have used
vitamin B12 supplementation to address antifolate toxici-
ties because of “concern[] about . . . a reduction of efficacy
of the antifolate” treatment. Id. at *11.
      Dr. Niyikiza was an Eli Lilly scientist at the time and
is the named inventor on the ’209 patent. In 1997, he
performed statistical analyses to try to determine which
clinical trial patients were likely to develop toxicities from
pemetrexed treatment. J.A. 1045, 1071–72. He published
the results in the Niyikiza abstracts and reported a
correlation between increased pemetrexed toxicities and
elevated homocysteine levels. J.A. 7948, 7950–51. Ele-
vated homocysteine levels serve as an indicator of either a
folic acid or vitamin B12 deficiency, but they do not indi-
cate which of those two vitamins is specifically lacking.
J.A. 622, 719, 7910. Levels of another marker, methylma-
lonic acid (“MMA”), serve more specifically as an indicator
of vitamin B12 deficiency. J.A. 720. But the Niyikiza
abstracts reported that “no correlation between toxicity
. . . and [MMA levels] was seen.” J.A. 7948.

    12  C. Niyikiza et al., LY231514 (MTA): Relationship
of Vitamin Metabolite Profile to Toxicity, 17 PROC. OF AM.
SOCIETY OF CLINICAL ONCOLOGY 558a, Abstract 2139
(1998); C. Niyikiza et al., MTA (LY231514): Relationship
of Vitamin Metabolite Profile, Drug Exposure, and Other
Patient Characteristics to Toxicity, 9 ANNALS OF
ONCOLOGY 126, Abstract 609P (4th Supp. 1998).
26     ELI LILLY AND COMPANY   v. TEVA PARENTERAL MEDICINES

    Given the toxicity correlations that Dr. Niyikiza ob-
served with homocysteine levels but not with MMA levels,
Eli Lilly’s experts testified that the Niyikiza abstracts
“present[ed] no evidence for a relationship of vitamin B12
and pemetrexed toxicity” and would not have motivated a
skilled artisan to administer vitamin B12 to patients to
address pemetrexed toxicity. J.A. 1466–67; see also J.A.
1475, 1942. Defendants’ expert, Dr. Ratain, confirmed
that if a patient exhibits elevated homocysteine but
normal MMA levels, a skilled artisan “would conclude
that that patient was folate deficient” but “not [vitamin]
B12 deficient.” J.A. 622–23.
     To try to overcome this missing link between vitamin
B12 deficiency and pemetrexed toxicity, Defendants turn
to other prior art references. They argue that, based on
those references and perhaps preexisting knowledge, a
person of ordinary skill would have known that folate
deficiency is correlated with pemetrexed toxicity and that
vitamin B12 “directly affect[s] the amount of folate avail-
able to healthy cells.” Appellants’ Opening Br. 45 (citing
J.A. 2482, 7894, 7910–11, 8086). As a result, they argue,
skilled artisans would have been motivated to use vitamin
B12, along with folic acid, to address pemetrexed toxici-
ties. Id. Put another way, if we assume that the prior art
would have motivated skilled artisans to use folic acid
pretreatment to counter pemetrexed toxicity (an issue we
do not reach), Defendants submit that those skilled arti-
sans would have also used vitamin B12 as part of the
pretreatment because the biochemical pathways for
vitamin B12 and folic acid are related. Defendants fur-
ther submit that other prior art “expressly teaches that
folic acid supplementation improves the therapeutic index
of pemetrexed,” so a skilled artisan would not have been
concerned about using vitamin B12 supplementation to
reduce pemetrexed toxicities. Id. at 46.
    But the parties’ experts agreed that nothing in the lit-
erature as of the critical date described “cancer patients
ELI LILLY AND COMPANY   v. TEVA PARENTERAL MEDICINES      27

being provided with vitamin B12 supplementation prior to
receiving any antifolate,” with or without folic acid. J.A.
597–98; see also J.A. 1957. Defendants fail to point to
evidence that, even if folic acid supplementation were
known to improve effects of pemetrexed treatment, a
skilled artisan would have thought the same of vitamin
B12. Indeed, Eli Lilly offered expert testimony that a
skilled artisan would have viewed the use of vitamin B12
with antifolates as “a problem” based on “having to in-
crease the [antifolate] dose to get the same activity” of
cancer treatment. J.A. 1453–54.
     We are therefore not convinced that the district court
committed clear error in concluding that Defendants
failed to carry their burden of proving that it would have
been obvious to a person of ordinary skill to use vitamin
B12 pretreatment to reduce pemetrexed toxicities.
                             B
    Regarding the dose and schedule of vitamin B12, the
district court reiterated that “there are no prior art refer-
ences where any amount of vitamin B12 pretreatment had
been used with an antifolate in the treatment of cancer.”
Eli Lilly II, 2014 WL 1350129, at *13 (emphasis added).
The court also discounted Defendants’ citations to litera-
ture outside the field of oncology. Id. at *13–14.
    Defendants argue that, “[o]nce a [skilled artisan] is
motivated to use vitamin B12 pretreatment,” selecting a
dose and schedule for vitamin B12 “would have been
routine.” Appellants’ Opening Br. 47. Setting aside
motivation to use vitamin B12 pretreatment in the first
instance, Defendants only cite evidence of vitamin B12
doses and schedules that are “routine” in other medical
contexts. See, e.g., J.A. 8150, 8169, 756–57. There is no
evidence that, considering the context of pemetrexed
treatment and associated toxicity problems, a person of
ordinary skill would have applied such doses and sched-
ules wholesale.
28     ELI LILLY AND COMPANY   v. TEVA PARENTERAL MEDICINES

    We therefore also see no clear error in the court’s find-
ing that Defendants failed to carry their burden of prov-
ing that the prior art disclosed the claimed doses and
schedules of vitamin B12 for purposes of pemetrexed
pretreatment.
                             C
   Defendants make two additional, overarching argu-
ments that we also find unavailing.

    First, Defendants cite PharmaStem Therapeutics, Inc.
v. ViaCell, Inc., 491 F.3d 1342 (Fed. Cir. 2007), to argue
that the district court erred by accepting expert testimony
that was inconsistent with the express disclosures of the
prior art. But PharmaStem is distinguishable. In that
case, we discounted testimony regarding prior art refer-
ences that “[could not] be reconciled with statements
made by the inventors in the joint specification [of the
asserted patents] and with the prior art references them-
selves.” Id. at 1361. Here, despite Defendants’ aver-
ments, we do not perceive any irreconcilable differences
between the prior art disclosures on their face and the
testimony regarding whether a person of ordinary skill
would have been motivated to use vitamin B12 pretreat-
ment in the claimed doses and schedules with pemetrexed
treatment.

    Second, Defendants argue that the district court
committed legal error by requiring an express prior art
disclosure of the claimed combination because KSR Inter-
national Co. v. Teleflex Inc., 550 U.S. 398 (2007), rejected
such a “rigid” formula in favor of a more flexible inquiry.
Id. at 402–03. While KSR did make the obviousness
inquiry more flexible, it does not advance Defendants’
position here. Defendants cite to two prior art references
that would purportedly “motivate a [skilled artisan] to
ELI LILLY AND COMPANY   v. TEVA PARENTERAL MEDICINES      29

review literature regarding known doses and schedules
for vitamin B12 supplementation.” Appellants’ Opening
Br. 51. But those references merely note in passing that
vitamin B12 can be related to homocysteine levels and
folate biochemical pathways. See J.A. 7894, 7910. De-
fendants do not cite to any testimony to support their
contention that those references would motivate a skilled
artisan to arrive at the claimed use of vitamin B12 as a
pretreatment for pemetrexed, especially in view of the
evidence of gaps and concerns regarding the prior art
discussed above.

    The district court did not commit reversible error in
finding that the prior art fails to render obvious use of
vitamin B12 pretreatment with pemetrexed, or use of the
doses and schedules of vitamin B12 that are recited in the
asserted claims. We therefore affirm the determination of
nonobviousness. We need not reach the other grounds put
forth for obviousness.
                             IV
    Finally, we address Defendants’ argument that the
district court erred in holding that the asserted claims are
not invalid for obviousness-type double patenting over
U.S. Patent No. 5,217,974 (“’974 patent”), an earlier
patent also owned by Eli Lilly.
    The judicially-created “doctrine of obviousness-type
double patenting is intended to ‘prevent the extension of
the term of a patent . . . by prohibiting the issuance of the
claims in a second patent not patentably distinct from the
claims of the first patent.’” Eli Lilly & Co. v. Teva Paren-
teral Meds., Inc., 689 F.3d 1368, 1376 (Fed. Cir. 2012)
(alteration in original) (quoting In re Longi, 759 F.2d 887,
892 (Fed. Cir. 1985)). After determining the differences in
the claims of the earlier and later patents, the court must
determine if the alleged infringer has proven by clear and
convincing evidence that the claims are not patentably
30     ELI LILLY AND COMPANY   v. TEVA PARENTERAL MEDICINES

distinct. Eli Lilly & Co. v. Barr Labs., Inc., 251 F.3d 955,
962, 968 (Fed. Cir. 2001). “A later patent claim is not
patentably distinct from an earlier claim if the later claim
is obvious over, or anticipated by, the earlier claim.” Id.
Even where a patent is found invalid for obviousness-type
double patenting, though, a patentee may file a terminal
disclaimer. Boehringer Ingelheim Int’l GmbH v. Barr
Labs., Inc., 592 F.3d 1340, 1347 (Fed. Cir. 2010); see also
Perricone v. Medicis Pharm. Corp., 432 F.3d 1368, 1375
(Fed. Cir. 2005) (noting that there is no “prohibition on
post-issuance terminal disclaimers” and that “[a] terminal
disclaimer can indeed supplant a finding of invalidity for
double patenting”). Obviousness-type double patenting is
a question of law based on underlying facts, so “[o]n
appeal from a bench trial, this court reviews the district
court’s conclusions of law de novo and findings of fact for
clear error.” Prometheus, 805 F.3d at 1097 (internal
quotation marks omitted).
     Defendants argued to the district court that the as-
serted claims of the ’209 patent are obvious variants of
claim 20 of the ’974 patent. The court found that the
asserted claims differ from claim 20 of the ’974 patent “in
that the Asserted Claims limit the drug to pemetrexed
and the administration to a patient, use a dose range for
folic acid of 350–1000 μg or 350–600 μg and add[] vitamin
B12, whereas claim 20 of the ’974 Patent discloses the use
of a much greater amount of folic acid—500–30,000 μg—
with an antifolate . . . administered to a mammal.” Eli
Lilly II, 2014 WL 1350129, at *17. In particular, the ’974
patent lacks any recitation of vitamin B12 pretreatment,
let alone dosage ranges or schedules of such pretreatment.

    For many of the same reasons it articulated in its ob-
viousness analysis and with additional explanation, the
district court found that the use of pemetrexed, use of
vitamin B12, and doses and schedules of the asserted
claims were patentably distinct from claim 20 of the ’974
patent. Id. at *17–18. In relevant part, the district court
ELI LILLY AND COMPANY   v. TEVA PARENTERAL MEDICINES    31

held that, “as previously discussed, there would have been
no reason for a [skilled artisan] to add vitamin B12 to the
folic acid pretreatment.” Id. at *17. For the same reasons
that we discussed with respect to nonobviousness, the
court did not err in finding that those limitations regard-
ing vitamin B12 would not have been obvious to a person
of ordinary skill.
    Therefore, we affirm the district court’s conclusion
that the asserted claims are not invalid for obviousness-
type double patenting.
                        CONCLUSION
    For the foregoing reasons, we affirm the district
court’s judgment.
                        AFFIRMED