Vanda Pharmaceuticals Inc. v. West-Ward Pharmaceuticals

United States Court of Appeals
for the Federal Circuit
______________________
VANDA PHARMACEUTICALS INC.,
Plaintiff-Appellee
AVENTISUB LLC,
Plaintiff
v.
WEST-WARD PHARMACEUTICALS
INTERNATIONAL LIMITED, WEST-WARD
PHARMACEUTICALS CORP.,
Defendants-Appellants
______________________
2016-2707, 2016-2708
______________________
Appeals from the United States District Court for the
District of Delaware in Nos. 1:13-cv-01973-GMS, 1:14-cv-
00757-GMS, Judge Gregory M. Sleet.
______________________
Decided: April 13, 2018
______________________
NICHOLAS P. GROOMBRIDGE, Paul, Weiss, Rifkind,
Wharton & Garrison LLP, New York, NY, argued for
plaintiff-appellee. Also represented by KIRA A. DAVIS,
DANIEL KLEIN, ERIC ALAN STONE, JOSEPHINE YOUNG.
KENNETH G. SCHULER, Latham & Watkins LLP,
Chicago, IL, argued for defendants-appellants. Also
2 VANDA PHARM. INC. v. WEST-WARD PHARM. INT’L LTD.
represented by DANIEL BROWN, New York, NY; ROBERT J.
GAJARSA, Washington, DC.
______________________
Before PROST, Chief Judge, LOURIE and HUGHES, Circuit
Judges.
Opinion for the court filed by Circuit Judge LOURIE.
Dissenting opinion filed by Chief Judge PROST.
LOURIE, Circuit Judge.
West-Ward Pharmaceuticals International Limited
and West-Ward Pharmaceuticals Corp. (collectively,
“West-Ward”) appeal from the decision of the United
States District Court for the District of Delaware holding,
after a bench trial, claims 1–9, 11–13, and 16 (“the assert-
ed claims”) of U.S. Patent 8,586,610 (“the ’610 patent”)
infringed and not invalid. See Vanda Pharm. Inc. v.
Roxane Labs., Inc., 203 F. Supp. 3d 412 (D. Del. 2016)
(“Opinion”). For the following reasons, we affirm.
BACKGROUND
I.
Aventisub LLC (“Aventisub”) owns and Vanda Phar-
maceuticals Inc. (“Vanda” and collectively, with Avent-
isub, “Plaintiffs”) holds an exclusive worldwide license to
U.S. Reissue Patent 39,198 (“the ’198 patent”). The ’198
patent expired on November 15, 2016. 1 Vanda also owns
the ’610 patent, which will expire on November 2, 2027.
1 The parties have not appealed any determinations
with respect to the ’198 patent. The parties stipulated to
the infringement of claim 3 of the ’198 patent and the
court concluded that claim 3 would not have been obvious.
VANDA PHARM. INC. v. WEST-WARD PHARM. INT’L LTD. 3
The ’610 patent relates to a method of treating schiz-
ophrenia patients with iloperidone wherein the dosage
range is based on the patient’s genotype. The cytochrome
P450 2D6 gene (“CYP2D6”) encodes an enzyme known to
metabolize a large number of drugs, including iloperidone.
’610 patent col. 1 ll. 29–36. The ’610 patent teaches “that
treatment of a patient, who has lower CYP2D6 activity
than a normal person, with a drug[, such as iloperidone,]
that is pre-disposed to cause QT 2 prolongation and is
metabolized by the CYP2D6 enzyme, can be accom-
plish[ed] more safely by administering a lower dose of the
drug than would be administered to a person who has
normal CYP2D6 enzyme activity.” Id. col. 2 ll. 15–21. QT
prolongation can lead to serious cardiac problems. The
’610 patent refers to patients who have lower than normal
CYP2D6 activity as CYP2D6 poor metabolizers. It pro-
vides examples of dose reductions for poor metabolizers
compared to the dose given to someone with a wildtype
genotype. Id. col. 9 ll. 34–47, col. 11 ll. 22–28.
Claim 1 of the ’610 patent is representative and reads
as follows:
A method for treating a patient with iloperidone,
wherein the patient is suffering from schizophre-
nia, the method comprising the steps of:
determining whether the patient is a CYP2D6
poor metabolizer by:
obtaining or having obtained a biological
sample from the patient;
and
2 The QT interval is the time between the Q and T
waves of the heart rhythm. When corrected for the pa-
tient’s heart rate it is abbreviated QTc.
4 VANDA PHARM. INC. v. WEST-WARD PHARM. INT’L LTD.
performing or having performed a geno-
typing assay on the biological sample to
determine if the patient has a CYP2D6
poor metabolizer genotype; and
if the patient has a CYP2D6 poor metabolizer
genotype, then internally administering iloperi-
done to the patient in an amount of 12 mg/day or
less, and
if the patient does not have a CYP2D6 poor me-
tabolizer genotype, then internally administering
iloperidone to the patient in an amount that is
greater than 12 mg/day, up to 24 mg/day,
wherein a risk of QTc prolongation for a patient
having a CYP2D6 poor metabolizer genotype is
lower following the internal administration of 12
mg/day or less than it would be if the iloperidone
were administered in an amount of greater than
12 mg/day, up to 24 mg/day.
Id. col. 17 ll. 2–25.
Vanda owns New Drug Application (“NDA”) 22-192
for Fanapt® (iloperidone), an atypical antipsychotic
approved by the U.S. Food and Drug Administration
(“FDA”) in 2009 under 21 U.S.C. § 355(b) for the treat-
ment of patients with schizophrenia. Vanda was able to
obtain FDA approval for iloperidone based, at least in
part, on the invention disclosed in the ’610 patent, which
reduces the side effects associated with QTc prolongation,
enabling safer treatment of patients with schizophrenia.
The ’198 patent and the ’610 patent are listed in connec-
tion with Fanapt® in the FDA’s Approved Drug Products
with Therapeutic Equivalence Evaluations, commonly
known as the “Orange Book.”
VANDA PHARM. INC. v. WEST-WARD PHARM. INT’L LTD. 5
II.
In 2013, West-Ward 3 filed Abbreviated New Drug Ap-
plication (“ANDA”) 20-5480 seeking approval to commer-
cially manufacture, use, offer to sell, and sell a generic
version of Fanapt® in 1 mg, 2 mg, 4 mg, 6 mg, 8 mg, 10
mg, and 12 mg strengths for the treatment of schizophre-
nia pursuant to 21 U.S.C. § 355(j). At that time, the ’610
patent had not yet issued and only the ’198 patent was
listed in the Orange Book. The ANDA contained a certifi-
cation per 21 U.S.C. § 355(j)(2)(A)(vii)(IV) (“Paragraph IV
certification”) that the ’198 patent was invalid and/or
would not be infringed by West-Ward. West-Ward then
sent the notice required by 21 U.S.C. § 355(j)(2)(B) (“Par-
agraph IV notice”) of its Paragraph IV certification. On
November 25, 2013, Plaintiffs filed Civil Action No. 13-
1973 (“2013 suit”) in the U.S. District Court for the Dis-
trict of Delaware (“district court”) alleging infringement of
the ’198 patent.
The proposed ANDA label is substantially identical in
all material respects to the Fanapt® label. The proposed
label states that: iloperidone is “indicated for the treat-
ment of adults with schizophrenia,” J.A. 15104 § 1; “[t]he
recommended target dosage of iloperidone tablets is 12 to
24 mg/day,” J.A. 15103; “[t]he recommended starting dose
for iloperidone tablets is 1 mg twice daily,” J.A. 15105
§ 2.1; and “[i]loperidone must be titrated slowly from a
low starting dose,” J.A. 15105 § 2.1. The proposed label
provides that the “[i]loperidone dose should be reduced by
one-half for poor metabolizers of CYP2D6 [see Pharmaco-
kinetics (12.3)].” J.A. 15105 § 2.2. Section 5.2, entitled
3 During the pendency of this appeal, ownership of
ANDA 20-5480 transferred from Roxane Laboratories Inc.
to West-Ward. For simplicity, we refer to the ANDA
applicant throughout as West-Ward.
6 VANDA PHARM. INC. v. WEST-WARD PHARM. INT’L LTD.
“QT Prolongation,” explains: “iloperidone was associated
with QTc prolongation of 9 msec at an iloperidone dose of
12 mg twice daily” and that “[c]aution is warranted when
prescribing iloperidone . . . in patients with reduced
activity of CYP2D6 [see Clinical Pharmacology (12.3)].”
J.A. 5106–07 § 5.2.
III.
Meanwhile, the ’610 patent issued on November 19,
2013, and on June 16, 2014, Vanda filed Civil Action No.
14-757 (“2014 suit”) in the district court alleging in-
fringement of the ’610 patent. On January 15, 2015,
Vanda listed the ’610 patent in the Orange Book for
Fanapt®. On May 6, 2015, West-Ward sent Vanda a
Paragraph IV notice with respect to the ’610 patent
notifying Vanda that it amended ANDA 20-5480 to con-
tain a Paragraph IV certification that the ’610 patent is
invalid and/or not infringed. J.A. 19696; see 21 U.S.C.
§ 355(j)(2)(B)(ii)(II). The district court consolidated the
2013 and 2014 suits.
Following a bench trial, the district court found that
West-Ward’s proposed products induce infringement of
the asserted claims of the ’610 patent, but do not contrib-
utorily infringe them. Opinion, 203 F. Supp. 3d at 435.
The court held that West-Ward’s “submission of a para-
graph IV certification for the ’610 [p]atent is an act of
infringement” and that Vanda’s expert Dr. Alva “practiced
the steps of the ’610 [p]atent claims” with Fanapt®. Id. at
433. The court found that the proposed ANDA label
“recommends”: (1) “practitioners use iloperidone to treat
patients suffering from schizophrenia”; (2) “oral admin-
istration of iloperidone tablets at 12 to 24 mg/day to non-
genotypic CYP2D6 poor metabolizers and 12 mg/day or
less to genotypic CYP2D6 poor metabolizers”; and
(3) “practitioners perform or have performed a genotyping
assay to determine whether patients are CYP2D6 poor
VANDA PHARM. INC. v. WEST-WARD PHARM. INT’L LTD. 7
metabolizers.” Id. at 432 (first citing J.A. 15104–05 §§ 1,
2.1, 2.2; then citing J.A. 15120–21 § 12.3).
The district court also held that the asserted claims
were not invalid under § 101, § 103, or § 112 for lack of
written description. The court did conclude that “the
asserted claims depend upon laws of nature,” specifically,
“the relationship between iloperidone, CYP2D6 metabo-
lism, and QTc prolongation.” Id. at 428–29. But the court
explained that the ’610 patent “addresses natural rela-
tionships to which the claims add conducting CYP2D6
genotyping tests to determine the appropriate dose of
iloperidone to reduce QTc-related risks.” Id. at 429. “The
court f[ound] that while it may have been conventional to
investigate for side-effects, [West-Ward] has not proven
by clear and convincing evidence that the precise test and
the discovered results were routine or conventional.” Id.
The court found that the data disclosed in the patent were
“sufficient to support possession of the claimed dosage
range, even if not statistically significant.” Id. at 431.
The court determined that 35 U.S.C. § 271(e)(4)(A) re-
lief was unavailable for the ’610 patent because it did not
issue until after the ANDA was filed. 4 Id. at 435. The
court determined that injunctive relief was appropriate,
4 The court specifically stated that Vanda was “not
entitled to relief pursuant to 35 U.S.C. § 271(e)(4)(A) for
the ’610 [p]atent because the ’610 [p]atent did not issue
until after the effective date of any FDA approval of
[West-Ward’s] ANDA . . . .” Opinion, 203 F. Supp. 3d at
435. But the parties have treated the district court’s
reference to “the effective date of any FDA approval” as a
typographical error, and the district court’s rationale as
being based on the ’610 patent not having issued until
after the filing date of the ANDA. See Appellant Br. 28;
Appellee Br. 60 & n.6. We do the same.
8 VANDA PHARM. INC. v. WEST-WARD PHARM. INT’L LTD.
however, pursuant to its “general equitable power.” Id.
The court enjoined West-Ward from engaging in the
commercial manufacture, use, offer to sell, sale in or
importation into the United States of West-Ward’s ANDA
product prior the expiration of the ’610 patent. The court
further ordered that “[t]he effective date of any [FDA]
approval of [West-Ward’s] ANDA No. 20-5480 shall be a
date not earlier than the latest of the expiration of the
’610 [p]atent or any applicable exclusivities and exten-
sions.” J.A. 33
West-Ward timely appealed from the district court’s
final judgment. We have jurisdiction under 28 U.S.C.
§ 1295(a)(1).
DISCUSSION
On appeal from a bench trial, we review a district
court’s conclusions of law de novo and its findings of fact
for clear error. Golden Blount, Inc. v. Robert H. Peterson
Co., 365 F.3d 1054, 1058 (Fed. Cir. 2004). A factual
finding is only clearly erroneous if, despite some support-
ing evidence, we are left with the definite and firm convic-
tion that a mistake has been made. United States v. U.S.
Gypsum Co., 333 U.S. 364, 395 (1948); see also Polaroid
Corp. v. Eastman Kodak Co., 789 F.2d 1556, 1559 (Fed.
Cir. 1986) (“The burden of overcoming the district court’s
factual findings is, as it should be, a heavy one.”).
I. Jurisdiction
We must first address whether the district court
properly exercised jurisdiction over the 2014 suit. On
November 16, 2017, we directed supplemental briefing on
jurisdiction. Both parties responded with supplemental
briefing, which, inter alia, addressed whether there is
district court jurisdiction under the Drug Price Competi-
tion and Patent Term Restoration Act of 1984 (“the
Hatch-Waxman Act”), Pub. L. No. 98-417, 98 Stat. 1585
(1984) over an action in which the asserted patent issued
VANDA PHARM. INC. v. WEST-WARD PHARM. INT’L LTD. 9
after the ANDA was filed and the complaint was filed
before the ANDA applicant submitted a Paragraph IV
certification for the asserted patent.
Vanda argues that its allegations of infringement un-
der 35 U.S.C. § 271(e)(2) created subject matter jurisdic-
tion in the district court under 28 U.S.C. § 1331 and
§ 1338(a), and presented a justiciable controversy. Vanda
further argues that the Declaratory Judgment Act, 28
U.S.C. § 2201, provides an alternative basis for jurisdic-
tion because it alleged that West-Ward would infringe the
’610 patent under 35 U.S.C. § 271(a), (b), or (c) by selling
iloperidone.
West-Ward argues that 35 U.S.C. § 271(e)(2) does not
create a basis for subject matter jurisdiction over Vanda’s
infringement claims. West-Ward contends that a claim
for § 271(e)(2) infringement can only be based on patents
that have issued before an ANDA is filed. Moreover,
West-Ward argues, even if the amended Paragraph IV
certification could qualify as an act of infringement under
§ 271(e)(2), jurisdiction would still be lacking because the
certification was not made before the 2014 suit was filed.
West-Ward further argues that there is declaratory
judgment jurisdiction over its claims for relief, but not
over Vanda’s claims for infringement.
We agree with Vanda that the district court had ju-
risdiction over this case. We have previously explained
that:
By enacting § 271(e)(2), Congress thus established
a specialized new cause of action for patent in-
fringement. When patentees pursue this route,
their claims necessarily arise under an Act of
Congress relating to patents. In short, “[o]nce
Congress creates an act of infringement, jurisdic-
tion in the district courts is proper under 28
U.S.C. § 1338(a).”
10 VANDA PHARM. INC. v. WEST-WARD PHARM. INT’L LTD.
AstraZeneca Pharm. LP v. Apotex Corp. (AstraZeneca II),
669 F.3d 1370, 1377 (Fed. Cir. 2012) (alteration in origi-
nal) (quoting Allergan, Inc. v. Alcon Labs., Inc., 324 F.3d
1322, 1330 (Fed. Cir. 2003)). The Supreme Court has
similarly explained that “the federal courts have jurisdic-
tion over [a suit alleging infringement under § 271(e)(2)]
for a single, simple reason: It ‘ar[ose] under a[n] Act of
Congress relating to patents.’” Caraco Pharm. Labs., Ltd.
v. Novo Nordisk A/S (Caraco II), 566 U.S. 399, 412 n.5
(2012) (second and third alterations in original) (quoting
28 U.S.C. § 1338(a)).
Here, Vanda’s complaint alleged that West-Ward in-
fringed the ’610 patent under 35 U.S.C. § 271(e)(2)(A) by
filing the ANDA. J.A. 10002. Nothing more was required
to establish the district court’s subject matter jurisdiction
pursuant to 28 U.S.C. § 1338(a). See AstraZeneca II, 669
F.3d at 1377 (explaining that “the requirements for
jurisdiction in the district courts are met once a patent
owner alleges that another’s filing of an ANDA infringes
its patent under § 271(e)(2), and this threshold jurisdic-
tional determination does not depend on the ultimate
merits of the claims”).
West-Ward’s arguments relating to whether there was
a qualifying act of infringement raise potential merits
problems, not jurisdictional issues. We have previously
rejected the argument that a court’s jurisdiction “hinged
on whether [plaintiff] asserted a ‘valid’ claim under
§ 271(e)(2).” Id. The Supreme Court has similarly ex-
plained that “[t]he want of an infringing act [under
§ 271(e)(2)] is a merits problem, not a jurisdictional one.”
Caraco II, 566 U.S. at 412 n.5. Thus, whether Vanda
alleged, and subsequently proved, an infringing act is a
merits question, not a jurisdictional one.
Moreover, an actual controversy has existed between
the parties from the time when the suit was commenced.
See Teva Pharm. USA, Inc. v. Novartis Pharm. Corp., 482
VANDA PHARM. INC. v. WEST-WARD PHARM. INT’L LTD. 11
F.3d 1330, 1339–45 (Fed. Cir. 2007) (reversing district
court’s conclusion that it lacked jurisdiction because there
was no justiciable controversy between the ANDA appli-
cant and NDA holder where there was a prior suit be-
tween the parties involving a different patent to which
the ANDA applicant had submitted a Paragraph IV
certification). “To qualify as a case fit for federal-court
adjudication, ‘an actual controversy must be extant at all
stages of review,’” including “‘at the time the complaint is
filed.’” Arizonans for Official English v. Arizona, 520 U.S.
43, 67 (1997) (quoting Preiser v. Newkirk, 422 U.S. 395,
401 (1975)). Here, West-Ward had filed an ANDA and
Vanda had sued it. The mere fact that West-Ward had
not submitted a Paragraph IV certification for the ’610
patent until after Vanda filed suit does not establish that
there was not a justiciable controversy over which the
court could exercise jurisdiction. See Glaxo, Inc. v. Novo-
pharm, Ltd., 110 F.3d 1562, 1569 (Fed. Cir. 1997) (“[Sec-
tion] 271(e)(2) provide[s] patentees with a defined act of
infringement sufficient to create case or controversy
jurisdiction to enable a court to promptly resolve any
dispute concerning infringement and validity.”); DuPont
Merck Pharm. Co. v. Bristol-Myers Squibb Co., 62 F.3d
1397, 1401 (Fed. Cir. 1995) (reversing a district court’s
determination in declaratory judgment action “that an
actual controversy would only occur upon [ANDA appli-
cants’] filing of paragraph IV certifications”). 5
Thus, the district court properly had jurisdiction over
the ‘610 patent under the Hatch-Waxman Act.
5 Because we determine that 28 U.S.C. § 1338(a)
provides a proper basis for jurisdiction, we do not reach
the parties’ declaratory judgment jurisdiction arguments.
12 VANDA PHARM. INC. v. WEST-WARD PHARM. INT’L LTD.
II. Infringement
In a bench trial, infringement is a question of fact
that we review for clear error. Alza Corp. v. Mylan Labs.,
Inc., 464 F.3d 1286, 1289 (Fed. Cir. 2006). An infringe-
ment inquiry pursuant to 35 U.S.C. § 271(e)(2)(A) “is
focused on a comparison of the asserted patent [claims]
against ‘the product that is likely to be sold following
ANDA approval.’” Alcon Research Ltd. v. Barr Labs., Inc.,
745 F.3d 1180, 1186 (Fed. Cir. 2014) (quoting Abbott
Labs. v. TorPharm, Inc., 300 F.3d 1367, 1373 (Fed. Cir.
2002)). The patentee 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).
A. The Applicability of 35 U.S.C. § 271(e)(2)(A)
We first address whether, beyond the jurisdictional
question, a claim for infringement of the ’610 patent
under 35 U.S.C. § 271(e)(2)(A) can lie where the ’610
patent issued after the original ANDA was submitted and
Vanda sued West-Ward for infringement of the asserted
claims prior to West-Ward submitting a Paragraph IV
certification. The district court held that West-Ward’s
submission of the Paragraph IV certification for the ’610
patent was an act of infringement. See Opinion, 203 F.
Supp. 3d at 433. We review the district court’s statutory
interpretation without deference. Warner–Lambert, 316
F.3d at 1355.
Vanda argues that it proved an act of infringement
under 35 U.S.C. § 271(e)(2). According to Vanda, “[w]here
a patent issues after an ANDA is filed but before FDA
approval, and where—as here—the applicant submits a
Paragraph IV certification directed at the new patent,
that amendment of the ANDA is an act of infringement
under Section 271(e)(2).” Appellee Br. 60.
VANDA PHARM. INC. v. WEST-WARD PHARM. INT’L LTD. 13
West-Ward responds that there can be no infringe-
ment under § 271(e)(2) because the ANDA was filed
before the ’610 patent issued. West-Ward contends that
the statutorily defined act of infringement excludes
amendments to an ANDA and “only reaches ANDAs
submitted ‘for a drug claimed in a patent or the use of
which is claimed in a patent’—not a drug that might or
might not later be claimed in a patent or one that has
been claimed in a provisional patent application or a
patent-pending.” Reply Br. 33 (emphases in original)
(quoting 35 U.S.C. § 271(e)(2)(A)) (other internal quota-
tion marks omitted).
The Hatch-Waxman Act amended the Federal Food,
Drug, and Cosmetic Act and the patent laws to enable
generic drugs to be more easily approved and to respond
to loss of effective patent life resulting from the require-
ment that drug products require premarket testing and
then must undergo FDA review, actions that consume
significant portions of a patent term. See Eli Lilly & Co.
v. Medtronic, Inc., 496 U.S. 661, 669–70 (1990). The
Hatch-Waxman Act “str[ikes] a balance between two
competing policy interests: (1) inducing pioneering re-
search and development of new drugs and (2) enabling
competitors to bring low-cost, generic copies of those
drugs to market.” Andrx Pharm., Inc. v. Biovail Corp.,
276 F.3d 1368, 1371 (Fed. Cir. 2002).
Section 202 of the Act, codified at 35 U.S.C.
§ 271(e)(2)(A), created an “artificial” act of infringement.
Eli Lilly, 496 U.S. at 678. That provision provides in
relevant part:
It shall be an act of infringement to submit . . . an
application under section 505(j) of the Federal
Food, Drug, and Cosmetic Act[, codified at 21
U.S.C. § 355(j),] . . . for a drug claimed in a patent
or the use of which is claimed in a patent, . . . if
the purpose of such submission is to obtain ap-
14 VANDA PHARM. INC. v. WEST-WARD PHARM. INT’L LTD.
proval under such Act to engage in the commer-
cial manufacture, use, or sale of a drug . . .
claimed in a patent or the use of which is claimed
in a patent before the expiration of such patent.
35 U.S.C. § 271(e)(2) (emphases added). It “facilitates the
early resolution of patent disputes between generic and
pioneering drug companies by providing that the mere act
of filing a Paragraph IV ANDA constitutes an act of
patent infringement.” Caraco Pharm. Labs., Ltd. v.
Forest Labs., Inc. (Caraco I), 527 F.3d 1278, 1283 (Fed.
Cir. 2008). Litigation does not have to be delayed until
actual sale of an accused product.
Although we agree with West-Ward that only an is-
sued patent can give rise to a valid infringement claim
under § 271(e)(2)(A), we disagree that that conclusion
precludes Vanda’s infringement claim in this case. The
’610 patent is a patent “for a drug . . . the use of which is
claimed in a patent,” 35 U.S.C. § 271(e)(2)(A), as contem-
plated in the Act even though it issued after West-Ward
filed its ANDA. West-Ward subsequently amended its
ANDA to include a Paragraph IV certification for the ’610
patent after it issued. The infringement analysis under
§ 271(e)(2)(A) “require[s] consideration of the amended
ANDA.” Ferring B.V. v. Watson Labs., Inc.-Fla., 764 F.3d
1382, 1390 (Fed. Cir. 2014). “There is no support for the
proposition that the question of infringement must be
addressed solely based on the initial ANDA filing, given
that the statute contemplates that the ANDA will be
amended as a matter of course.” Id. Thus, amendments
to an ANDA, including a Paragraph IV certification for a
later-issued patent, can constitute an act of infringement
under § 271(e)(2)(A). See Bristol-Myers Squibb Co. v.
Royce Labs., Inc., 69 F.3d 1130, 1135 (Fed. Cir. 1995)
(holding that by amending an ANDA to include a Para-
graph IV certification, the applicant “committed an act of
infringement under the Hatch-Waxman Act because it
sought ‘to obtain approval . . . to engage in the commercial
VANDA PHARM. INC. v. WEST-WARD PHARM. INT’L LTD. 15
manufacture, use, or sale of a drug . . . claimed in a patent
. . . before the expiration of such patent’” (alternations in
original) (quoting 35 U.S.C. § 271(e)(2)(A))).
Here, it is undisputed that West-Ward amended the
ANDA by submitting a Paragraph IV certification regard-
ing the ’610 patent after that patent issued. J.A. 19696;
J.A. 6414–15; Appellant Br. 10; Appellee Br. 59. Such an
act is a qualifying act of infringement under
§ 271(e)(2)(A). 6 A filer of an ANDA is therefore subject to
a § 271(e)(2)(A) infringement claim on a patent that
issues after the filing of the ANDA, but before FDA ap-
proval. The resolution of infringement claims under
§ 271(e)(2)(A) for patents that issue after an ANDA is
submitted, but before it is approved, “facilitates the early
resolution of patent disputes between generic and pio-
neering drug companies” in accordance with the purpose
of § 271(e)(2)(A). Caraco I, 527 F.3d at 1283.
The FDA regulatory framework and the legislative
history further demonstrate that West-Ward is incorrect
in asserting that “application” in § 271(e)(2)(A) excludes
amendments to the ANDA. Sections 101 and 102 of the
Hatch-Waxman Act amended the Federal Food, Drug, and
Cosmetics Act to create an abbreviated regulatory path-
way for approval of generic drugs, codified at 21 U.S.C.
6 We note that West-Ward did not argue to the dis-
trict court at the pleadings stage that the complaint
should be dismissed for failure to state a claim upon
which relief could be granted on this basis. Cf. Astra-
Zeneca II, 669 F.3d at 1381 (concluding that “the district
court erred in part by concluding that [patentee’s] failure
to state a cognizable § 271(e)(2) claim defeated its juris-
diction” and affirming the dismissal for “fail[ure] to state
a § 271(e)(2) claim” where applicant moved to dismiss
both for lack of jurisdiction and failure to state a claim).
16 VANDA PHARM. INC. v. WEST-WARD PHARM. INT’L LTD.
§ 355(j), and to require NDA applicants to file certain
patent information with the FDA, codified at 21 U.S.C.
§ 355(b)(1), (c)(2). NDA holders have a continuing obliga-
tion to amend the NDA to include the same patent infor-
mation for patents that issue after the NDA is approved.
See 21 U.S.C. § 355(c)(2). The FDA lists this patent
information in the Orange Book.
ANDA applications must contain one of four certifica-
tions for patents “for which information is required to be
filed under [21 U.S.C. § 355(b) or (c)]”: (1) “that such
patent information has not been filed;” (2) “that such
patent has expired;” (3) “the date on which such patent
will expire;” and (4) “that such patent is invalid or will not
be infringed by the manufacture, use, or sale of the new
drug for which the application is submitted.” 21 U.S.C.
§ 355(j)(2)(A)(vii). If the ANDA applicant makes a Para-
graph IV certification, it must provide notice to the NDA
holder of the certification. Id. § 355(j)(2)(B). Prior to FDA
approval, ANDA applicants generally must amend or
supplement ANDAs to submit an appropriate patent
certification for patents that issue after submission of the
ANDA. See id. § 355(j)(2)(B)(ii)(II); 21 C.F.R.
§ 314.94(a)(12)(viii)(C)(ii). Thus, the regulatory frame-
work expressly contemplates certifications for patents
that issue after the ANDA is filed.
The type of certification under 21 U.S.C.
§ 355(j)(2)(A)(vii) impacts when FDA approval may be
made effective. 21 U.S.C. § 355(j)(5). If an ANDA appli-
cant submits a Paragraph IV certification, the statute
provides for a thirty-month stay of effective FDA approval
that may be shortened or lengthened in certain circum-
stances. Id. § 355(j)(5)(B)(iii). Congressional amendment
of the thirty-month stay provision since the enactment of
the Hatch-Waxman Act further supports the conclusion
that “application” in 35 U.S.C. § 271(e)(2) includes
amendments to the ANDA.
VANDA PHARM. INC. v. WEST-WARD PHARM. INT’L LTD. 17
As originally enacted, the Hatch-Waxman Act provid-
ed for a thirty-month stay as long as the suit was brought
within 45 days of receipt of the Paragraph IV notice. See
Hatch-Waxman Act, Pub. L. 98–417, § 101, 98 Stat. at
1589. Multiple thirty-month stays could therefore be
triggered for the same ANDA as a consequence of the
ANDA applicant submitting Paragraph IV certifications
and notices for patents listed in the Orange Book that
issued both before and after the submission of the origi-
nal ANDA application. See Andrx, 276 F.3d at 1378
(noting that FDA “treated the listing in the Orange Book
of [a patent that issued after the ANDA was submitted] as
requiring a new thirty-month stay of its approval of
Andrx’s ANDA”).
In 2003, Congress amended 21 U.S.C. § 355(j) to elim-
inate the possibility of multiple thirty-month stays for the
same ANDA. See Medicare Prescription Drug, Improve-
ment, and Modernization Act of 2003 (“the MMA”), Pub.
L. 108-173, § 1101, 117 Stat. 2066, 2449 (2003); H.R.
Conf. Rep. No. 108-391, at 835–36 (2003), reprinted in
2003 U.S.C.C.A.N. 1808, 2187. The MMA changed the
requirements to obtain a thirty-month stay to add that
the patent information for the patent to which the Para-
graph IV certification is directed must have been submit-
ted to the FDA “before the date on which the [ANDA]
application (excluding an amendment or supplement to the
application) . . . was submitted.” MMA, Pub. L. 108-173,
§1101(a)(2), 117 Stat. at 2449 (emphasis added) (codified
at 21 U.S.C. § 355(j)(5)(B)(iii)). The MMA did not contain
a corresponding amendment to 35 U.S.C. § 271(e)(2) to
exclude amendments and supplements to the ANDA as
cognizable acts of infringement even though it amended
§ 271(e) in other ways. Id. § 1101(d), 117 Stat. at 2457.
This history thus further supports the conclusion that
“application” in § 271(e)(2) includes amendments to the
ANDA. See Gross v. FBL Fin. Servs., Inc., 557 U.S. 167,
174 (2009) (“When Congress amends one statutory provi-
18 VANDA PHARM. INC. v. WEST-WARD PHARM. INT’L LTD.
sion but not another, it is presumed to have acted inten-
tionally.”). Thus, the district court properly conducted its
infringement analysis for the ’610 patent pursuant to 35
U.S.C. § 271(e)(2)(A).
B. Inducement 7
We now turn to the merits of the infringement find-
ing. West-Ward argues that the district court clearly
erred in finding that it would induce infringement be-
cause Vanda failed to prove the requisite direct infringe-
ment and specific intent to induce infringement. Vanda
responds that the district court correctly found that West-
Ward will induce infringement of the asserted claims.
The statute provides that “[w]hoever actively induces
infringement of a patent shall be liable as an infringer.”
35 U.S.C. § 271(b). However, direct infringement is a
necessary predicate for a finding of induced infringement
in the usual patent infringement case. Limelight Net-
works, Inc. v. Akamai Techs., Inc., 134 S. Ct. 2111, 2117
(2014). It also “must be established that the defendant
possessed specific intent to encourage another’s infringe-
ment and not merely that the defendant had knowledge of
the acts alleged to constitute inducement.” DSU Med.
Corp. v. JMS Co., 471 F.3d 1293, 1306 (Fed. Cir. 2006) (en
banc in relevant part) (internal quotation omitted).
Circumstantial evidence can support a finding of specific
intent to induce infringement. AstraZeneca LP v. Apotex,
Inc. (AstraZeneca I), 633 F.3d 1042, 1060 (Fed. Cir. 2010)
(citing Water Techs. Corp. v. Calco, Ltd., 850 F.2d 660,
668 (Fed. Cir. 1988)).
7 Because we conclude that the district court did
not clearly err in finding induced infringement, we need
not and do not reach Vanda’s arguments in the alterna-
tive on contributory infringement.
VANDA PHARM. INC. v. WEST-WARD PHARM. INT’L LTD. 19
We have held that “[i]nducement can be found where
there is ‘[e]vidence of active steps taken to encourage
direct infringement,’ which can in turn be found in ‘adver-
tising an infringing use or instructing how to engage in an
infringing use.’” Takeda Pharm. U.S.A., Inc. v. W.-Ward
Pharm. Corp., 785 F.3d 625, 630–31 (Fed. Cir. 2015)
(second alteration in original) (quoting Metro–Goldwyn–
Mayer Studios Inc. v. Grokster, Ltd., 545 U.S. 913, 936
(2005)). Where “the proposed label instructs users to
perform the patented method . . . the proposed label may
provide evidence of [the ANDA applicant’s] affirmative
intent to induce infringement.” AstraZeneca I, 633 F.3d
at 1060. When proof of specific intent depends on the
label accompanying the marketing of a drug inducing
infringement by physicians, “[t]he label must encourage,
recommend, or promote infringement.” Takeda, 785 F.3d
at 631. The contents of the label itself may permit the
inference of specific intent to encourage, recommend, or
promote infringement. See Sanofi v. Watson Labs. Inc.,
875 F.3d 636, 646 (Fed. Cir. 2017).
West-Ward argues that the district court clearly erred
in finding that its proposed label “satisfies” the asserted
claims because the language of the label itself cannot
constitute direct infringement of the asserted method
claims. See Opinion, 203 F. Supp. 3d at 432. West-Ward
also contends that the court clearly erred in finding that
Dr. Alva practiced the asserted claims because he never
administered an allegedly infringing dose to a poor me-
tabolizer.
Vanda responds that it did not need to prove instanc-
es of direct infringement by physicians because this is a
Hatch-Waxman case where infringement is statutorily-
defined to be the filing of an ANDA or an amendment
thereto, not by selling a product. Even though not re-
quired, Vanda contends, it identified a doctor, Dr. Alva,
who practiced the steps of the asserted claims with Fan-
apt®. Vanda argues that the asserted claims do not
20 VANDA PHARM. INC. v. WEST-WARD PHARM. INT’L LTD.
require that a single physician administer iloperidone to
both poor and non-poor CYP2D6 metabolizers, and that
West-Ward’s argument to the contrary is waived because
it was raised for the first time on appeal.
We agree with Vanda that a patentee does not need to
prove an actual past instance of direct infringement by a
physician to establish infringement under 35 U.S.C.
§ 271(e)(2)(A). As we have explained, “section 271(e)(2)(A)
makes it possible for a patent owner to have the court
determine whether, if a particular drug were put on the
market, it would infringe the relevant patent.” Bristol-
Myers Squibb, 69 F.3d at 1135 (emphases in original). A
§ 271(e)(2)(A) infringement suit differs from typical in-
fringement suits in that the infringement inquiries “are
hypothetical because the allegedly infringing product has
not yet been marketed.” Warner-Lambert, 316 F.3d at
1365 (emphasis added); see also Glaxo, 110 F.3d at 1570
(“The relevant inquiry is whether patentee has proven by
a preponderance of the evidence that the alleged infringer
will likely market an infringing product.”).
Similarly, patentees in Hatch-Waxman litigations as-
serting method patents do not have to prove that prior
use of the NDA-approved drug satisfies the limitations of
the asserted claims. See, e.g., Sanofi, 875 F.3d at 643
(affirming inducement finding where the district court
found “the inducing act will be the marketing by [ANDA
applicants] of their generic dronedarone drugs with the
label described” and “the induced act will be the admin-
istration of dronedarone by medical providers to patients
meeting the criteria set forth in the [claims at issue]”); Eli
Lilly & Co. v. Teva Parenteral Meds., Inc., 845 F.3d 1357,
1368 (Fed. Cir. 2017) (explaining “we have not required
evidence regarding the general prevalence of the induced
activity”); AstraZeneca I, 633 F.3d at 1057 (affirming
district court’s grant of a preliminary injunction based on
claims of induced infringement where the district court
found that “the proposed label would cause some users to
VANDA PHARM. INC. v. WEST-WARD PHARM. INT’L LTD. 21
infringe the asserted method claims”); see also Warner-
Lambert, 316 F.3d at 1364 (“The infringement case is
therefore limited to an analysis of whether what the
generic drug maker is requesting authorization for in the
ANDA would be an act of infringement if performed.”).
Accordingly, Vanda can satisfy its burden to prove the
predicate direct infringement by showing that if the
proposed ANDA product were marketed, it would infringe
the ’610 patent. The district court made factual findings
that the proposed label “recommends” that physicians
perform the claimed steps, see Opinion, 203 F. Supp. 3d at
432–33, and its analysis of the proposed label to assess
potential direct infringement by physicians was proper
under our precedent. See, e.g., Ferring B.V. v. Watson
Labs., Inc.-Fla., 764 F.3d 1401, 1408 (Fed. Cir. 2014)
(“The infringement determination is thus based on con-
sideration of all the relevant evidence, and because drug
manufacturers are bound by strict statutory provisions to
sell only those products that comport with the ANDA’s
description of the drug, the ANDA itself dominates the
analysis.” (internal quotation marks and alterations
omitted)); AstraZeneca I, 633 F.3d at 1060 (explaining
that the district court “correctly determined” that lan-
guage in the ANDA label “would inevitably lead some
consumers to practice the claimed method”).
Turning to specific intent, West-Ward argues that
Vanda failed to prove that its proposed label would “‘en-
courage’ or ‘recommend’ a direct infringer (a psychiatrist
or other physician) to perform each step of the claimed
methods.” Appellant Br. 36 (quoting Takeda, 785 F.3d at
631). West-Ward contends that the substantial number of
noninfringing uses precludes a finding of specific intent as
a matter of law. See Warner-Lambert, 316 F.3d at 1365.
Vanda responds that the district court did not clearly
err in finding that the proposed label recommends per-
formance of all the claimed steps. Vanda argues that
22 VANDA PHARM. INC. v. WEST-WARD PHARM. INT’L LTD.
potential noninfringing uses do not preclude a finding of
specific intent to induce infringement in this case.
We agree with Vanda that the district court did not
clearly err in finding induced infringement of independent
claims 1, 9, and 13. 8 Section 2 of the proposed label is
entitled “Dosage and Administration.” J.A. 15105 § 2.
Section 2.1 entitled, “Usual Dose,” states:
Iloperidone must be titrated slowly from a low
starting dose . . . . The recommended starting
dose for iloperidone tablets is 1 mg twice daily.
Dose increases to reach the target range of 6 to 12
mg twice daily (12 to 24 mg/day) may be made
with daily dosage adjustments not to exceed 2 mg
twice daily (4 mg/day). The maximum recom-
mended dose is 12 mg twice daily (24 mg/day). . . .
Prescribers should be mindful of the fact that pa-
tients need to be titrated to an effective dose of
iloperidone.
Id. § 2.1 (emphases added). Section 2.2, entitled “Dosage
in Special Populations,” states: “Dosage adjustment for
8 Because we affirm the district court’s infringe-
ment findings with respect to these independent claims,
we need not reach this issue regarding the dependent
claims because any error in the district court’s analysis of
the dependent claims is harmless. See TiVo, Inc. v.
EchoStar Commc’ns Corp., 516 F.3d 1290, 1312 (Fed. Cir.
2008) (affirming infringement finding as to some but not
all claims and explaining that “[b]ecause the damages
calculation at trial was not predicated on the infringe-
ment of particular claims, and because we have upheld
the jury’s verdict that all of the accused devices infringe
the software claims, we affirm the damages award en-
tered by the district court”).
VANDA PHARM. INC. v. WEST-WARD PHARM. INT’L LTD. 23
patients taking iloperidone who are poor metabolizers of
CYP2D6: Iloperidone dose should be reduced by one-half
for poor metabolizers of CYP2D6 [see Pharmacokinetics
(12.3)].” Id. § 2.2 (second emphasis added).
Section 12.3 of the proposed label, entitled “Pharma-
cokinetics,” states:
Approximately 7 to 10% of Caucasians and 3 to
8% of Black/African Americans lack the capacity
to metabolize CYP2D6 substrates and are classi-
fied as poor metabolizers (PM), whereas the rest
are intermediate, extensive or ultrarapid metabo-
lizers. Co-administration of iloperidone with
known strong inhibitors of CYP2D6 like fluoxetine
results in a 2.3 fold increase in iloperidone plasma
exposure, and therefore one-half of the iloperidone
dose should be administered.
Similarly, PMs of CYP2D6 have higher exposure
to iloperidone compared with [extensive metabo-
lizers] and PMs should have their dose reduced by
one-half. Laboratory tests are available to identify
CYP2D6 PMs.
J.A. 15121 § 12.3 (emphasis added).
Thus, the district court did not clearly err in finding
that § 12.3 “recommends that practitioners perform or
have performed a genotyping assay to determine whether
patients are CYP2D6 poor metabolizers.” Opinion, 203 F.
Supp. 3d at 432. Experts for both parties testified that
the referred-to “laboratory tests” are “genotyping tests.”
J.A. 6939 (234:8–235:13) (Vanda’s expert); J.A. 7103–04
(566:10–568:2) (West-Ward’s expert). The district court
thus found that “when the label states that ‘laboratory
tests’ are available to identify poor metabolizers, the label
is referring to ‘genotyping tests.’” Opinion, 203 F. Supp.
3d at 433 (citing testimony of both parties’ experts). We
discern no clear error in this finding.
24 VANDA PHARM. INC. v. WEST-WARD PHARM. INT’L LTD.
The label instructs practitioners that “PMs should
have their dose reduced by one-half. [Genotyping tests]
are available to identify CYP2D6 PMs.” J.A. 15121
§ 12.3. The court did not clearly err in finding that this
constitutes a recommendation to perform genotyping tests
on iloperidone patients. That West-Ward introduced
other evidence that could have supported a contrary
finding does not compel the conclusion that the district
court clearly erred. See Anderson v. City of Bessemer City,
470 U.S. 564, 574 (1985) (“Where there are two permissi-
ble views of the evidence, the factfinder’s choice between
them cannot be clearly erroneous.”). Moreover, the court’s
decision to credit the plausible testimony of certain wit-
nesses and reject the testimony of West-Ward’s witness as
not credible, Opinion, 203 F. Supp. 3d at 433, “can virtu-
ally never be clear error,” Anderson, 470 U.S. at 575.
We reject West-Ward’s contention that the lack of an
express finding by the district court that the label recom-
mends obtaining a biological sample requires a remand.
The district court found induced infringement of the
independent claims, which necessarily required a finding
of inducement of the limitation requiring “obtaining or
having obtained a biological sample from the patient.”
’610 patent col. 17 ll. 7–8 (claim 1), col. 18 ll. 9–10 (claim
9), col. 18 ll. 34–35 (claim 13). West-Ward has pointed to
no evidence in the record to dispute the testimony of
Vanda’s witnesses at trial that the genotyping assays the
court found were recommended by the label require
obtaining a biological sample. J.A. 6928 (190:14–191:1);
J.A. 6939 (235:18–23). Given this undisputed evidence
and the court’s finding that the label recommends geno-
typing assays, we see no clear error in the court’s implicit
finding that the proposed label recommends obtaining a
biological sample. See, e.g., Para-Ordnance Mfg., Inc. v.
SGS Importers Int’l, Inc., 73 F.3d 1085, 1090 (Fed. Cir.
1995) (explaining that “[f]rom the decision of the district
court, we can, and do, accept the implicit fact-finding”).
VANDA PHARM. INC. v. WEST-WARD PHARM. INT’L LTD. 25
The district court also did not clearly err in finding
that “[t]he label recommends oral administration of
iloperidone tablets at 12 to 24 mg/day to non-genotypic
CYP2D6 poor metabolizers and 12 mg/day or less to
genotypic CYP2D6 poor metabolizers.” Opinion, 203 F.
Supp. 3d at 432 (citing J.A. 15105 §§ 2.1, 2.2). The label
recommends a “[u]sual” target dose range (12 to 24
mg/day) and maximum dose (24 mg/day) and then in-
structs medical providers to “reduce[]” the dose for genetic
CYP2D6 poor metabolizers (a “[s]pecial population”) “by
one-half.” J.A. 15015 §§ 2.1, 2.2; see also J.A. 15103; J.A.
15121 § 12.3. A one-half reduction of the usual dose
amounts yields a target dose range of 6 to 12 mg/day and
a maximum dose of 12 mg/day for poor metabolizers.
That the label also directs a medical provider to titrate
the dosage does not negate its clear recommendations on
ultimate dosage range and maximum amount.
Similarly, the fact that the target dose range for geno-
typic non-poor metabolizers (12 to 24 mg/day) includes 12
mg/day does not compel a finding of noninfringement.
The independent claims require administering “greater
than 12 mg/day, up to 24 mg/day” of iloperidone to non-
poor metabolizers. ’610 patent col. 17 ll. 17–20 (claim 1),
col. 18 ll. 16–18 (claim 9), col. 18 ll. 44–47 (claim 13).
Even if not every practitioner will prescribe an infringing
dose, that the target dose range “instructs users to per-
form the patented method” is sufficient to “provide evi-
dence of [West-Ward’s] affirmative intent to induce
infringement.” AstraZeneca I, 633 F.3d at 1060; see also
Eli Lilly, 845 F.3d at 1369 (explaining that “evidence that
the product labeling that Defendants seek would inevita-
bly lead some physicians to infringe establishes the
requisite intent for inducement”).
Finally, West-Ward’s reliance on Warner-Lambert, an
off-label use case, is misplaced. In Warner-Lambert, we
explained that “it defies common sense to expect that
[ANDA applicant] will actively promote the sale of its
26 VANDA PHARM. INC. v. WEST-WARD PHARM. INT’L LTD.
approved [ANDA product], in contravention of FDA
regulations, for a use that (a) might infringe [NDA hold-
er’s] patent and (b) constitutes such a small fraction of
total sales.” Warner-Lambert, 316 F.3d at 1365. In the
context of that off-label use case where there were “sub-
stantial noninfringing uses,” we declined to “infer” intent
to induce infringement. Id. Here, the district court found
that the proposed label itself recommends infringing acts.
Accordingly, even if the proposed ANDA product has
“substantial noninfringing uses,” West-Ward may still be
held liable for induced infringement. “Section 271(b), on
inducement, does not contain the ‘substantial noninfring-
ing use’ restriction of section 271(c), on contributory
infringement.” Sanofi, 875 F.3d at 646. Thus, “a person
can be liable for inducing an infringing use of a product
even if the product has substantial noninfringing us-
es . . . .” Id. (citing Grokster, 545 U.S. at 934–37).
III. Patent Subject Matter Eligibility
We next address whether the asserted claims are di-
rected to patent-eligible subject matter. West-Ward
argues that the asserted claims are ineligible under § 101
because they are directed to a natural relationship be-
tween iloperidone, CYP2D6 metabolism, and QT prolon-
gation, and add nothing inventive to those natural laws
and phenomena. West-Ward contends that the asserted
claims are indistinguishable from those held invalid in
Association for Molecular Pathology v. Myriad Genetics,
Inc., 569 U.S. 576 (2013) and Mayo Collaborative Services
v. Prometheus Laboratories, Inc., 566 U.S. 66 (2012).
Vanda responds that the asserted claims are patent-
eligible under § 101 at both steps of Mayo/Alice. Vanda
contends that the district court erred in holding that the
asserted claims are directed to a law of nature. According
to Vanda, the court’s “conclusions that the asserted claims
‘depend upon,’ ‘touch[] upon,’ and ‘address’ laws of nature
and natural phenomena do not, as a matter of law, estab-
VANDA PHARM. INC. v. WEST-WARD PHARM. INT’L LTD. 27
lish that the asserted claims are directed to a patent-
ineligible concept under Step 1 of the Alice/Mayo analy-
sis.” Appellee Br. 45 (alteration and emphasis in origi-
nal).
Section 101 of the Patent Act states that “[w]hoever
invents or discovers any new and useful process, machine,
manufacture, or composition of matter, or any new and
useful improvement thereof, may obtain a patent therefor,
subject to the conditions and requirements of this title.”
35 U.S.C. § 101. However, § 101 “contains an important
implicit exception”: “‘laws of nature, natural phenomena,
and abstract ideas’ are not patentable.” Mayo, 566 U.S. at
70 (alteration omitted) (quoting Diamond v. Diehr, 450
U.S. 175, 185 (1981)).
The Supreme Court has established a two-step
framework to determine patent subject matter eligibility
under 35 U.S.C. § 101:
First, we determine whether the claims at issue
are directed to one of those patent-ineligible con-
cepts. If so, we then ask, “[w]hat else is there in
the claims before us?” To answer that question,
we consider the elements of each claim both indi-
vidually and “as an ordered combination” to de-
termine whether the additional elements
“transform the nature of the claim” into a patent-
eligible application. We have described step two
of this analysis as a search for an “‘inventive con-
cept’”—i.e., an element or combination of elements
that is “sufficient to ensure that the patent in
practice amounts to significantly more than a pa-
tent upon the [ineligible concept] itself.”
Alice Corp. Pty. v. CLS Bank Int’l, 134 S. Ct. 2347, 2355
(2014) (citations omitted) (alteration in original) (quoting
Mayo, 566 U.S. at 72–73, 75–79).
28 VANDA PHARM. INC. v. WEST-WARD PHARM. INT’L LTD.
Step one requires determining “whether the claims at
issue are directed to one of those patent-ineligible con-
cepts.” Id. (emphasis added); see also Enfish, LLC v.
Microsoft Corp., 822 F.3d 1327, 1335 (Fed. Cir. 2016).
The Supreme Court has cautioned that “too broad an
interpretation of” ineligible subject matter “could eviscer-
ate patent law” because “all inventions at some level
embody, use, reflect, rest upon, or apply laws of nature,
natural phenomena, or abstract ideas.” Mayo, 566 U.S. at
71. Accordingly, at step one, “it is not enough to merely
identify a patent-ineligible concept underlying the claim;
we must determine whether that patent-ineligible concept
is what the claim is ‘directed to.’” Rapid Litig. Mgmt. Ltd.
v. CellzDirect, Inc., 827 F.3d 1042, 1050 (Fed. Cir. 2016).
If the claims are not directed to a patent ineligible concept
at step one, we need not address step two of the inquiry.
See Enfish, 822 F.3d at 1339. That is the case here.
Consistent with Supreme Court precedent, we agree
with Vanda that the asserted claims are not directed to
patent-ineligible subject matter. 9 Claim 1 recites “[a]
method for treating a patient with iloperidone, wherein
the patient is suffering from schizophrenia.” ’610 patent
col. 17 ll. 2–3. Claim 1 requires specific steps: (1) deter-
mining the patient’s CYP2D6 metabolizer genotype by (a)
obtaining a biological sample and (b) performing a geno-
typing assay; and (2) administering specific dose ranges of
iloperidone depending on the patient’s CYP2D6 genotype.
Id. col. 17 ll. 2–25.
West-Ward contends that the Supreme Court held
that similar claims were patent ineligible in Mayo and
Myriad. The patent in Mayo claimed a method for “opti-
mizing” the dosage of thiopurine drugs by administering
9 For purposes of validity, the parties did not argue
the claims separately, so they rise or fall together.
VANDA PHARM. INC. v. WEST-WARD PHARM. INT’L LTD. 29
thiopurine drugs to a patient and measuring the level of
certain metabolites in the blood, wherein the level of
metabolites indicates whether to adjust the dosage.
Mayo, 566 U.S. at 74–75. The Supreme Court held that
the claims recited a natural law, and did not include any
“additional features that provide practical assurance that
the process is more than a drafting effort designed to
monopolize the law of nature itself.” Id. at 77.
This case, however, is not Mayo. First, the claims in
Mayo were not directed to a novel method of treating a
disease. Instead, the claims were directed to a diagnostic
method based on the “relationships between concentra-
tions of certain metabolites in the blood and the likelihood
that a dosage of a thiopurine drug will prove ineffective or
cause harm.” Id. This “relation is a consequence of the
ways in which thiopurine compounds are metabolized by
the body—entirely natural processes. And so a patent
that simply describes that relation sets forth a natural
law.” Id.
Although the representative claim in Mayo recited
administering a thiopurine drug to a patient, the claim as
a whole was not directed to the application of a drug to
treat a particular disease. See id. at 74, 87. Importantly,
the Supreme Court explained that the administering step
was akin to a limitation that tells engineers to apply a
known natural relationship or to apply an abstract idea
with computers. See id. at 78 (comparing the claim in
Mayo to “Einstein telling linear accelerator operators
about his basic law and then trusting them to use it
where relevant”). To further underscore the distinction
between method of treatment claims and those in Mayo,
the Supreme Court noted that “[u]nlike, say, a typical
patent on a new drug or a new way of using an existing
drug, the patent claims do not confine their reach to
particular applications of those laws.” Id. at 87.
30 VANDA PHARM. INC. v. WEST-WARD PHARM. INT’L LTD.
In this case, the ’610 patent claims are directed to a
method of using iloperidone to treat schizophrenia. The
inventors recognized the relationships between iloperi-
done, CYP2D6 metabolism, and QTc prolongation, but
that is not what they claimed. They claimed an applica-
tion of that relationship. Unlike the claim at issue in
Mayo, the claims here require a treating doctor to admin-
ister iloperidone in the amount of either (1) 12 mg/day or
less or (2) between 12 mg/day to 24 mg/day, depending on
the result of a genotyping assay. The specification further
highlights the significance of the specific dosages by
explaining how certain ranges of administered iloperidone
correlate with the risk of QTc prolongation. See, e.g., ’610
patent at col. 4 ll. 1–15. Thus, the ’610 patent claims are
“a new way of using an existing drug” that is safer for
patients because it reduces the risk of QTc prolongation.
Mayo, 566 U.S. at 87.
Moreover, unlike the claim in Mayo, to the extent that
preemption is a concern, the ’610 patent claims do not “tie
up the doctor’s subsequent treatment decision.” Id. at 86.
The claim in Mayo did not go beyond recognizing (i.e.,
“indicates”) a need to increase or decrease a dose. Id. at
75. In Mayo, “a doctor . . . could violate the patent even if
he did not actually alter his treatment decision in the
light of the test.” Id. The claim was not a treatment
claim. It was “not limited to instances in which the doctor
actually decreases (or increases) the dosage level where
the test results suggest that such an adjustment is advis-
able.” Id. at 76. Thus, the claim in Mayo did not involve
doctors using the natural relationship between the me-
tabolite level and lessening “the likelihood that a dosage
of a thiopurine drug will prove ineffective or cause harm.”
Id. at 77. The claims in Mayo therefore “tie up the doc-
tor’s subsequent treatment decision whether that treat-
ment does, or does not, change in light of the inference he
has drawn using the correlations. And they threaten to
VANDA PHARM. INC. v. WEST-WARD PHARM. INT’L LTD. 31
inhibit the development of more refined treatment rec-
ommendations . . . .” Id. at 86–87.
Here, the ’610 patent claims recite the steps of carry-
ing out a dosage regimen based on the results of genetic
testing. The claims require doctors to “internally admin-
ister[] iloperidone to the patient in an amount of 12
mg/day or less” if the patient has a CYP2D6 poor metabo-
lizer genotype; and “internally administer[] iloperidone to
the patient in an amount that is greater than 12 mg/day,
up to 24 mg/day” if the patient does not have a CYP2D6
poor metabolizer genotype. ’610 patent col. 17 ll. 13–20.
These are treatment steps. In contrast, as shown above,
the claim in Mayo stated that the metabolite level in
blood simply “indicates” a need to increase or decrease
dosage, without prescribing a specific dosage regimen or
other added steps to take as a result of that indication.
Mayo, 566 U.S. at 75. Here, the claims do not broadly “tie
up the doctor’s subsequent treatment decision.” Id. at 86.
Our decision in CellzDirect supports concluding that
these claims are patent eligible. In that case, we held
that “a method of producing a desired preparation of
multi-cryopreserved hepatocytes cells” was patent eligi-
ble. CellzDirect, 827 F.3d at 1047. We explained that
“[t]he end result of the . . . claims is not simply an obser-
vation or detection of the ability of hepatocytes to survive
multiple freeze-thaw cycles. Rather, the claims [were]
directed to a new and useful method of preserving hepato-
cyte cells.” Id. at 1048. We further emphasized that “the
natural ability of the subject matter to undergo the pro-
cess does not make the claim ‘directed to’ that natural
ability.” Id. at 1049 (emphasis in original). Otherwise,
claims directed to actually “treating cancer with chemo-
therapy” or “treating headaches with aspirin” would be
patent ineligible. Id.
Nor does Myriad compel a different outcome. The Su-
preme Court in Myriad held “that a naturally occurring
32 VANDA PHARM. INC. v. WEST-WARD PHARM. INT’L LTD.
DNA segment is a product of nature and not patent
eligible merely because it has been isolated, but that
cDNA is patent eligible because it is not naturally occur-
ring.” Myriad, 569 U.S. at 580. The Court was careful to
note that “method claims” and “patents on new applica-
tions of knowledge about [particular] genes” were “not
implicated by [its] decision.” Id. 595–96 (emphasis in
original). The ’610 patent does not claim naturally occur-
ring DNA segments. Rather, the asserted claims fall
squarely within categories of claims that the Court stated
were not implicated by its decision.
At bottom, the claims here are directed to a specific
method of treatment for specific patients using a specific
compound at specific doses to achieve a specific outcome.
They are different from Mayo. They recite more than the
natural relationship between CYP2D6 metabolizer geno-
type and the risk of QTc prolongation. Instead, they
recite a method of treating patients based on this rela-
tionship that makes iloperidone safer by lowering the risk
of QTc prolongation. Accordingly, the claims are patent
eligible.
IV. Written Description
We next consider West-Ward’s argument that the dis-
trict court erred in finding that the claims are not invalid
for lack of adequate written description. To satisfy the
written description requirement the patent disclosure
must “reasonably convey[] to those skilled in the art that
the inventor had possession of the claimed subject matter
as of the filing date.” Ariad Pharm., Inc. v. Eli Lilly &
Co., 598 F.3d 1336, 1351 (Fed. Cir. 2010) (en banc).
Whether a claim satisfies the written description re-
quirement is a question of fact that we review for clear
error following a bench trial. Alcon Research, 745 F.3d at
1190.
West-Ward argues that the asserted claims are inva-
lid for lack of written description because nothing in the
VANDA PHARM. INC. v. WEST-WARD PHARM. INT’L LTD. 33
’610 patent demonstrates possession of the claimed dos-
age ranges for poor and non-poor CYP2D6 metabolizer
genotypes. West-Ward contends that the description does
not contain experiments with doses of 12 mg/day or less
given to poor metabolizers, and reports data that does not
support the claimed poor-metabolizer dose range.
Vanda responds that the district court did not clearly
err in finding that the ’610 patent adequately describes
the claimed dosages for poor metabolizers. Vanda con-
tends that West-Ward waived any written description
challenge to the dosages for non-poor metabolizers, and
that West-Ward’s argument is, in any event, meritless.
We agree with Vanda that the district court did not
clearly err in finding that the ’610 patent contains ade-
quate written description for the claimed “12 mg/day or
less” dosage range for poor metabolizers. The patent
reports the results of tests comparing the concentrations
of P88 and P95, iloperidone’s two main metabolites, and
changes in QTc interval upon administration of doses of
iloperidone, both with and without the addition of a
CYP2D6 inhibitor, to individuals with wildtype or a poor
metabolizer genotype associated with two common
CYP2D6 polymorphisms. ’610 patent col. 4 l. 62–col. 10
l. 56. The patent reports that “QTc prolongation is corre-
lated to the ratios of P88/P95 and (iloperidone+P88)/P95.”
Id. col. 9 ll. 57–58.
The ’610 patent further explains that the reported re-
sults “show that patients can be more safely treated with
iloperidone if the dose of iloperidone is adjusted based on
the CYP2D6 genotype of each patient,” id. col. 9 ll. 31–34;
accord id. col. 2 ll. 15–24, and provides examples of such
doses, id. col. 9 ll. 34–47, col. 11 ll. 22–28. For a poor
metabolizer, those examples include reducing the dose of
iloperidone administered by “75% or less, 50% or less, or
25% or less of the dose typically administered to a patient
having a CYP2D6 genotype that results in a CYP2D6
34 VANDA PHARM. INC. v. WEST-WARD PHARM. INT’L LTD.
protein” with wildtype activity. Id. col. 9 ll. 34–43. The
patent then provides a specific example of a dose for non-
poor metabolizers, “24 mg per day,” and the appropriate
reduction for a poor metabolizer “reduced dosage of 18, 12,
or 6 mg per day.” Id. col. 9 ll. 43–47. The disclosure of a
dose outside of the claimed range does not compel a
finding that the asserted claims lack adequate written
description. See Scriptpro, LLC v. Innovation Assocs.,
Inc., 762 F.3d 1355, 1359 (Fed. Cir. 2014) (“It is common,
and often permissible, for particular claims to pick out a
subset of the full range of described features, omitting
others.”).
The district court heard testimony that the data re-
ported in the ’610 patent show a trend for higher QTc
prolongation among genotypic CYP2D6 poor metabolizers
given a 24 mg/day dose, and support a reduction in dose
for CYP2D6 poor metabolizers by a factor of 1.5 to 3.5.
West-Ward introduced some testimony challenging the
sufficiency of the data and the lack of statistical analysis,
but that does not render the court’s reliance on testimony
supporting validity impermissible. See Anderson, 470
U.S. at 574–75. On this record, we cannot say that the
district court clearly erred in finding that the ’610 patent
sufficiently discloses the claimed range for poor metabo-
lizers.
Moreover, West-Ward waived its written description
challenge with respect to non-poor metabolizers by failing
to properly present it to the trial court. The Supreme
Court has observed that as a “general rule . . . a federal
appellate court does not consider an issue not passed
upon below.” Singleton v. Wulff, 428 U.S. 106, 120 (1976).
Although appellate courts have discretion to decide when
to deviate from this general waiver rule, see id. at 121,
West-Ward has not articulated a basis for us to reach this
issue for the first time on appeal and we discern none, see
HTC Corp. v. IPCom GmbH & Co., KG, 667 F.3d 1270,
1282–83 (Fed. Cir. 2012).
VANDA PHARM. INC. v. WEST-WARD PHARM. INT’L LTD. 35
West-Ward points only to a single page in each of its
opening and reply post-trial briefs to support its claim
that this issue is not waived. Those pages make passing
reference to the dosage range for non-poor metabolizers in
the context of the written description arguments West-
Ward advanced for poor metabolizers. West-Ward does
not point us to any argument or evidence that it advanced
before the district court specifically with respect to non-
poor metabolizers. Indeed, West-Ward did not identify
lack of written description with respect to non-poor me-
tabolizer dose range in its pretrial submissions identify-
ing the issues to be tried. West-Ward has thus waived
any further argument that the non-poor metabolizer
dosage range was not adequately supported by the writ-
ten description.
V. Injunctive Relief
We finally address the propriety of the injunctive re-
lief awarded by the district court. West-Ward argues that
the injunctions were not supported by the courts “general
equitable power,” and the lack of jurisdiction or an in-
fringing act under 35 U.S.C. § 271(e)(2) precludes uphold-
ing the injunctions under 35 U.S.C. § 271(e)(4). West-
Ward contends that “the FDA has independently deter-
mined that litigation over the ’610 patent should not
delay approval of iloperidone ANDAs filed before the
patent issued and was submitted to the agency.” Appel-
lant Br. 62 (citing https://www.accessdata.fda.gov/drug-
satfda_docs/appletter/2016/207231Orig1s000ltr.pdf).
West-Ward further argues that because Vanda did not
cross-appeal the denial of an injunction under 35 U.S.C.
§ 271(e)(4) that provision cannot be an alternative ground
to uphold the FDA injunction.
Vanda responds that the district court’s injunctions
can be affirmed under 35 U.S.C. § 271(e)(4) and that the
court erred in not granting relief pursuant to that provi-
sion. In any event, Vanda contends that the district court
36 VANDA PHARM. INC. v. WEST-WARD PHARM. INT’L LTD.
did not err in granting injunctive relief pursuant to its
equitable powers against West-Ward.
We agree with Vanda that 35 U.S.C. § 271(e)(4) sup-
ports the injunctive relief granted by the district court.
As discussed above, the district court properly held that
Vanda had established infringement of the ’610 patent
under § 271(e)(2). Section 271(e)(4) provides in relevant
part:
For an act of infringement described in paragraph
(2)—
(A) the court shall order the effective date
of any approval of the drug or veterinary
biological product involved in the in-
fringement to be a date which is not earli-
er than the date of the expiration of the
patent which has been infringed,
(B) injunctive relief may be granted
against an infringer to prevent the com-
mercial manufacture, use, offer to sell, or
sale within the United States or importa-
tion into the United States of an approved
drug, veterinary biological product, or bio-
logical product,
...
The remedies prescribed by subparagraphs (A),
(B), (C), and (D) are the only remedies which may
be granted by a court for an act of infringement
described in paragraph (2), except that a court
may award attorney fees under section 285.
35 U.S.C. § 271(e)(4). Section 271(e)(4) contains no carve-
out for patents that issue after the date of submission of
the original ANDA. Moreover, the statute explicitly
states that “the only remedies” a court may grant follow-
ing an infringement finding under § 271(e)(2) are pursu-
VANDA PHARM. INC. v. WEST-WARD PHARM. INT’L LTD. 37
ant to § 271(e)(4)(A)–(D) and attorney fees pursuant to
§ 285. Accordingly, upon a finding of patent infringement
under § 271(e)(2), the district court must order remedies
in accordance with § 271(e)(4).
West-Ward’s reliance on the FDA’s letter approving a
different company’s ANDA 20-7231 for iloperidone tablets
is misplaced. The letter indicates that because the ’610
patent was “submitted to the [FDA] after submission of
[that] ANDA,” litigation with respect to the ’610 patent
“would not create a statutory stay of approval.”
https://www.accessdata.fda.gov/drugsatfda_docs/appletter
/2016/207231Orig1s000ltr.pdf. The FDA letter merely
recognizes that the issuance of the ’610 patent after
submission of that ANDA renders the thirty-month statu-
tory stay inapplicable. See 21 U.S.C. § 355(j)(5)(B)(iii)
(providing that triggering of thirty-month stay requires,
inter alia, that the NDA holder submit necessary “patent
information before the date on which the application
(excluding an amendment or supplement to the applica-
tion) . . . was submitted” (emphasis added)). It says
nothing about whether the FDA would or would not
change the effective approval date of the ANDA pursuant
to a 35 U.S.C. § 271(e)(4)(A) court order if the ’610 patent
were found valid and infringed. West-Ward’s argument
thus improperly conflates the requirements to obtain a
thirty-month stay under § 355(j)(5)(B)(iii) with the relief
available pursuant to § 271(e)(4) following a finding of
patent infringement under § 271(e)(2).
In fact, where “the FDA has already approved the
ANDA, the district court’s [§ 271(e)(4)(A)] order would
[only] alter the effective date of the application, thereby
converting a final approval into a tentative approval.” In
re Omeprazole Patent Litig., 536 F.3d 1361, 1367–68 (Fed.
Cir. 2008); see also Mylan Labs., Inc. v. Thompson, 389
F.3d 1272, 1281–84 (D.C. Cir. 2004) (affirming revocation
of final FDA approval of an ANDA and resetting of the
effective approval date following a judgment of patent
38 VANDA PHARM. INC. v. WEST-WARD PHARM. INT’L LTD.
infringement pursuant to the district court’s § 271(e)(4)(A)
order where the infringement suit was filed too late to
trigger the 30-month stay). And the FDA is entitled not
to set an approval date prior to the expiration of a patent
that has been found to be infringed under § 271(e)(4)(A)
and not invalid in a Hatch-Waxman case. The district
court’s authority to grant the remedies provided in 35
U.S.C. § 271(e)(4) following a judgment of patent in-
fringement under § 271(e)(2) is not limited to those cir-
cumstances expressly listed in 21 U.S.C. § 355(j)(5)(B)(iii).
See Ortho-McNeil Pharm., Inc. v. Mylan Labs., Inc., 520
F.3d 1358, 1366 (Fed. Cir. 2008) (“The district court was
correct to reset the effective date of an ANDA directly
under 35 U.S.C. § 271 without going through 21 U.S.C.
§ 355.”).
Because we sustain the district court’s infringement
finding under § 271(e)(2), we also affirm the court’s grant
of injunctive relief. Although the district court erred in
concluding that the remedies pursuant to § 271(e)(4) were
unavailable, the court granted Vanda injunctive relief
consistent with those remedies. We may thus affirm the
district court’s grant of injunctive relief pursuant to
§ 271(e)(4).
Additionally, Vanda did not need to file a cross-appeal
to allow us to affirm the district court’s grant of injunctive
relief with respect to the FDA. Without filing a cross-
appeal, “an appellee may ‘urge in support of a decree any
matter appearing in the record, although his argument
may involve an attack upon the reasoning of the lower
court,’ but may not ‘attack the decree with a view either to
enlarging his own rights thereunder or of lessening the
rights of his adversary.’” El Paso Nat. Gas Co. v. Neztso-
sie, 526 U.S. 473, 479 (1999) (quoting United States v. Am.
Ry. Exp. Co., 265 U.S. 425, 435 (1924)); see also Radio
Steel & Mfg. Co. v. MTD Prods., Inc., 731 F.2d 840, 844
(Fed. Cir. 1984) (holding that “a party will not be permit-
ted to argue before us an issue on which it has lost and on
VANDA PHARM. INC. v. WEST-WARD PHARM. INT’L LTD. 39
which it has not appealed, where the result of acceptance
of its argument would be a reversal or modification of the
judgment rather than an affirmance”).
The district court expressly ordered relief that Vanda
argues may be affirmed on the basis of § 271(e)(4). See
J.A. 33. Thus, our affirmance does not enlarge Vanda’s
rights under the judgment or require its amendment.
Indeed, Vanda could not have filed a cross-appeal in this
case because “[a] party that is not adversely affected by a
judgment lacks standing to [cross-appeal].” TypeRight
Keyboard Corp. v. Microsoft Corp., 374 F.3d 1151, 1156
(Fed. Cir. 2004).
We have considered West-Ward’s remaining argu-
ments but find them to be unpersuasive.
CONCLUSION
For the foregoing reasons, we affirm the district
court’s decision.
AFFIRMED
United States Court of Appeals
for the Federal Circuit
______________________
VANDA PHARMACEUTICALS INC.,
Plaintiff-Appellee
AVENTISUB LLC,
Plaintiff
v.
WEST-WARD PHARMACEUTICALS
INTERNATIONAL LIMITED, WEST-WARD
PHARMACEUTICALS CORP.,
Defendants-Appellants
______________________
2016-2707, 2016-2708
______________________
Appeals from the United States District Court for the
District of Delaware in Nos. 1:13-cv-01973-GMS, 1:14-cv-
00757-GMS, Judge Gregory M. Sleet.
______________________
PROST, Chief Judge, dissenting.
I would find the asserted patent claims to be directed
to a law of nature. The majority finds the claims herein
are not directed to a natural law at step one of the § 101
analysis, but its efforts to distinguish Mayo cannot with-
stand scrutiny. The majority relies on the claims’ recita-
tion of specific applications of the discovery underpinning
the patent to find no natural law is claimed. But it con-
flates the inquiry at step one with the search for an
2 VANDA PHARM. INC. v. WEST-WARD PHARM. INT’L LTD.
inventive concept at step two. Once the natural law
claimed in the ’610 patent is understood in a manner
consistent with Mayo, what remains fails to supply the
requisite inventive concept to transform the natural law
into patent-eligible subject matter. Although I agree with
the majority’s reasoning that the district court had juris-
diction under the Hatch-Waxman Act, I would not reach
the issues of written description, infringement, and in-
junctive relief because I would find the ’610 patent claims
ineligible subject matter. Accordingly, I respectfully
dissent.
In order “to transform an unpatentable law of nature
into a patent-eligible application of such a law, a patent
must do more than simply state the law of nature while
adding the words ‘apply it.’” Mayo Collaborative Servs. v.
Prometheus Labs., Inc., 566 U.S. 66, 72 (2012). While the
claims here do not solely state a law of nature, they do no
more than simply direct the relevant audience to apply it.
The ’610 patent itself identifies its invention as “com-
pris[ing] the discovery that treatment of a patient, who
has lower CYP2D6 activity than a normal person, with a
drug that is pre-disposed to cause QT prolongation and is
metabolized by the CYP2D6 enzyme, can be accom-
plish[ed] more safely by administering a lower dose of the
drug than would be administered to a person who has
normal CYP2D6 enzyme activity.” ’610 patent col. 2 ll.
15–21. Nevertheless, the majority concludes that the
claims here are not directed to ineligible subject matter at
step one of the Mayo/Alice inquiry. Majority Op. at 28. I
disagree.
The representative claim in Mayo, i.e., Claim 1, recit-
ed:
A method of optimizing therapeutic efficacy for
treatment of an immune-mediated gastrointesti-
nal disorder, comprising:
VANDA PHARM. INC. v. WEST-WARD PHARM. INT’L LTD. 3
(a) administering a drug providing
6-thioguanine to a subject having said
immune-mediated gastrointestinal disor-
der; and
(b) determining the level of 6-thioguanine
in said subject having said immune-
mediated gastrointestinal disorder,
wherein the level of 6-thioguanine less than about
230 pmol per 8x108 red blood cells indicates a
need to increase the amount of said drug subse-
quently administered to said subject and
wherein the level of 6-thioguanine greater than
about 400 pmol per 8x108 red blood cells indicates
a need to decrease the amount of said drug subse-
quently administered to said subject.
Mayo, 566 U.S. at 74–75 (quoting U.S. Patent No.
6,355,623 col. 20 ll. 10–20).
The Court stated that the patent in Mayo “set forth
laws of nature—namely, relationships between concentra-
tions of certain metabolites in the blood and the likelihood
that a dosage of a thiopurine drug will prove ineffective or
cause harm.” Id. at 77. As one example of the laws of
nature set forth in the patent, the Court pointed to Claim
1’s statement “that if the levels of 6-TG in the blood (of a
patient who has taken a dose of a thiopurine drug) exceed
about 400 pmol per 8x108 red blood cells, then the admin-
istered dose is likely to produce toxic side effects.” Id.
Thus, the law of nature identified by the Supreme Court
in Mayo encompassed not only the bare fact of the rela-
tionship between thiopurine metabolite concentrations
and efficacy or side effects of a thiopurine drug, but also
the precise levels of concentration in question. See id. at
74 (“But those in the field did not know the precise corre-
lations between metabolite levels and likely harm or
ineffectiveness. The patent claims at issue here set forth
4 VANDA PHARM. INC. v. WEST-WARD PHARM. INT’L LTD.
processes embodying researchers’ findings that identified
these correlations with some precision.”).
In the present case, Claim 1 of the ’610 patent reads
as follows:
A method for treating a patient with iloperidone,
wherein the patient is suffering from schizophre-
nia, the method comprising the steps of:
determining whether the patient is a CYP2D6
poor metabolizer by:
obtaining or having obtained a biological
sample from the patient;
and
performing or having performed a geno-
typing assay on the biological sample to
determine if the patient has a CYP2D6
poor metabolizer genotype; and
if the patient has a CYP2D6 poor metabolizer
genotype, then internally administering iloperi-
done to the patient in an amount of 12 mg/day or
less, and
if the patient does not have a CYP2D6 poor me-
tabolizer genotype, then internally administering
iloperidone to the patient in an amount that is
greater than 12 mg/day, up to 24 mg/day,
wherein a risk of QTc prolongation for a patient
having a CYP2D6 poor metabolizer genotype is
lower following the internal administration of 12
mg/day or less than it would be if the iloperidone
were administered in an amount of greater than
12 mg/day, up to 24 mg/day.
’610 patent col. 17 ll. 2–25.
VANDA PHARM. INC. v. WEST-WARD PHARM. INT’L LTD. 5
This claim, which is representative of the ’610 patent,
also sets forth a natural relationship—namely, the rela-
tionship between the CYP2D6 genotype and the likelihood
that a dosage of iloperidone will cause QTc prolongation.
The majority notes that the claims in Mayo were directed
to the relationships that comprised the natural law, and
not “to a novel method of treating a disease.” Majority
Op. at 29. Here, according to the majority, while the
inventors recognized a natural law, “that is not what they
claimed.” Id. at 30. Rather, the claims of the ’610 patent
require a treating doctor to administer iloperidone in
“specific dosages” based on the results of a genotyping
assay. Id. But reciting specific metes and bounds in the
claims did not prevent the Supreme Court from conclud-
ing those claims set forth a natural law in Mayo. We are
not free to depart from the Supreme Court’s holding.
As the majority notes, the ’610 patent claims a meth-
od of treating schizophrenia with iloperidone “that is safer
for patients because it reduces the risk of QTc prolonga-
tion.” Majority Op. at 30. This is no more than an opti-
mization of an existing treatment of schizophrenia, just as
the claims in Mayo concerned “optimizing therapeutic
efficacy” of thiopurine drugs. Mayo warned against
“drafting effort[s] designed to monopolize the law of
nature itself.” 566 U.S. at 77. The majority does not heed
that warning.
The Court in Mayo found that the claim limitation
concerning “administering” a thiopurine drug to a patient
“simply refer[red] to the relevant audience, namely doc-
tors who treat patients with certain diseases with thiopu-
rine drugs”—an audience that existed long before the
patent disclosure. Id. at 78. So too here. The audience of
physicians treating schizophrenia with iloperidone long
predated the ’610 patent. The patent simply discloses the
natural law that a known side effect of the existing
treatment could be reduced by administering a lower dose
to CYP2D6 poor-metabolizers. It claims no more than
6 VANDA PHARM. INC. v. WEST-WARD PHARM. INT’L LTD.
instructions directing that audience to apply the natural
law in a routine and conventional manner.
The majority fails to reconcile this substantive simi-
larity between our case and Mayo. Instead, it points to
the specific dosages as a distinction between the adminis-
tering step here and that in Mayo. But Mayo examined
the significance of the “administering” step in its search
for an inventive concept, not as part of the determination
whether the claims were directed to a natural law at the
threshold. And the specific dosage adds nothing inventive
to the claims beyond the natural law.
Nor does the other element of specificity identified by
the majority rescue the claims. The claims here specify a
means of identifying a patient’s genotype (a “genetic
assay”), while the claims in Mayo left open the means of
measuring the relevant metabolite. But the genetic assay
is purely conventional pre-solution activity that cannot be
used to circumvent eligibility under § 101. See Mayo, 566
U.S. at 79.
The majority notes the claims here require treatment
with iloperidone within the dosage range indicated, while
the claims in Mayo could be infringed by treatment with
thiopurine “whether that treatment does, or does not,
change in light of the inference” indicated by the natural
law. Mayo, 566 U.S. at 86 (emphasis added); see Majority
Op. at 30–31. But that inquiry in Mayo also came as part
of the search for an inventive concept, and requiring a
dosage instead of indicating a dosage is not sufficient at
step two. The difference is of no moment.
The majority points to the Supreme Court’s statement
in Mayo that “[u]nlike, say, a typical patent on a new drug
or a new way of using an existing drug, the patent claims
do not confine their reach to particular applications of
those laws.” Majority Op. at 29–30 (quoting Mayo, 566
U.S. at 87). It similarly points to our decision in Rapid
Litigation Management Ltd. v. CellzDirect, Inc., wherein
VANDA PHARM. INC. v. WEST-WARD PHARM. INT’L LTD. 7
we indicated that “the natural ability of the subject mat-
ter to undergo the process does not make the claim ‘di-
rected to’ that natural ability,” lest we find ineligible
methods of “treating cancer with chemotherapy (as di-
rected to cancer cells’ inability to survive chemotherapy),
or treating headaches with aspirin (as directed to the
human body’s natural response to aspirin).” 827 F.3d
1042, 1049 (Fed. Cir. 2016). But that is not this case.
Whatever weight can be ascribed to the foregoing
statements about methods of treatment, we remain
beholden to the holding of Mayo, which, in my view,
requires us to find the claims directed to a natural law at
step one. (And I find no inventive concept in the claims
once the natural law at issue is properly understood in
view of Mayo.) 1
My conclusion is not at odds with CellzDirect. There,
the alleged law of nature was the capability of hepatocyte
cells to survive multiple freeze-thaw cycles. Because the
“end result” of the claims therein was “not simply an
observation or detection of the ability of hepatocytes to
survive multiple freeze-thaw cycles” but rather “a new
1 Indeed, the unpredictable results of clinical test-
ing regarding the relationship among CYP2D6, iloperi-
done, and QTc prolongation formed the basis of the
district court’s finding of non-obviousness. See J.A. 13–
15. In particular, the district court pointed to West-
Ward’s evidence that “it was unpredictable whether any
dosage adjustment would be needed for CYP2D6 poor
metabolizers, much less the amount of adjustment needed
to achieve the pharmacokinetic profile seen in normal
metabolizers.” J.A. 14. That is, the district court found
non-obviousness based on the revelation of the natural
law underpinning the claims, not in any other aspect of
the claims.
8 VANDA PHARM. INC. v. WEST-WARD PHARM. INT’L LTD.
and useful method of preserving hepatocyte cells,” we held
the claims were not directed to a law of nature. Id. at
1049.
Here, the end result of the claimed process is no more
than the conclusion of a natural law. The fact that a
reduction of iloperidone dosage in poor metabolizers to the
may reduce QTc prolongation is both the means and the
ends of this claim. The recitation of the specific dosages
adds no more than a conventional application of that
natural law. I see no distinction from Mayo, so I would
hold the asserted claims directed to ineligible subject
matter and lacking an inventive concept sufficient to
transform it into patent-eligible subject matter. I respect-
fully dissent.