Vanda Pharm. Inc. v. W.-Ward Pharm. Int'l Ltd.

887 F.3d 1117

VANDA PHARMACEUTICALS INC., Plaintiff-Appellee

Aventisub LLC, Plaintiff

v.WEST-WARD PHARMACEUTICALS INTERNATIONAL LIMITED, West-Ward Pharmaceuticals Corp., Defendants-Appellants

2016-2707, 2016-2708

United States Court of Appeals, Federal Circuit.

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 represented by Daniel Brown, New York, NY; Robert J. Gajarsa, Washington, DC.

Before Prost, Chief Judge, Lourie and Hughes, Circuit Judges.

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 asserted 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 Pharmaceuticals Inc. ("Vanda" and collectively, with Aventisub, "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.

The '610 patent relates to a method of treating schizophrenia 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 QT² prolongation and is metabolized by the CYP2D6 enzyme, can be accomplish[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 provides 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 schizophrenia, 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 genotyping 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 iloperidone to the patient in an amount of 12 mg/day or less, and

if the patient does not have a CYP2D6 poor metabolizer 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 treatment 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 connection with Fanapt® in the FDA's Approved Drug Products with Therapeutic Equivalence Evaluations , commonly known as the "Orange Book."

II.

In 2013, West-Ward³ filed Abbreviated New Drug Application ("ANDA") 20-5480 seeking approval to commercially 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 schizophrenia 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 certification 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) ("Paragraph 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 District 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 treatment 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 Pharmacokinetics (12.3) ]." J.A. 15105 § 2.2. Section 5.2, entitled "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 infringement 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 contain 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 contributorily infringe them. Opinion , 203 F.Supp.3d at 435. The court held that West-Ward's "submission of a paragraph 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 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"; and (3) "practitioners perform or have performed a genotyping assay to determine whether patients are CYP2D6 poor 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 metabolism, and QTc prolongation." Id. at 428–29. But the court explained that the '610 patent"addresses natural relationships 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) relief 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, 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 extensions." 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...