The provisions of U.S. regulatory law regarding FDA approval for less than all the indications for which an innovator drug was approved under 21 U.S.C. § 355(j)(2)(A)(viii) (the so-called "skinny label) has in the recent past raised something of a kerfuffle before the Federal Circuit (see "GlaxoSmithKline LLC v. Teva Pharmaceuticals USA (Fed. Cir. 2022)"). In contrast, the patency of skinny label approvals under the patent statute was affirmed by the Federal Circuit in a December 7th decision in H. Lundbeck A/S v. Lupin Ltd.
The case arose in ANDA litigation in which Lundbeck and assorted plaintiffs asserted U.S. Patent No. 9,278,096, directed to use of the antidepressant vortioxetine (Trintellix®) for treating patients who discontinued or reduced treatment with other antidepressants due to "sexually related adverse effects," and U.S. Patent No. 9,125,910 for treating patients with vortioxetine for cognitive impairment against all defendants, and U.S. Patent No. 9,101,626, directed to methods for making vortioxetine against defendant Lupin. Takeda is the NDA holder for Trintellix® and the opinion notes that two patents not in suit, U.S. Patent No. 7,144,884 and 8,476,297 (on the drug compound) expire on June 17, 2026 and expired on October 2, 2022, respectively. In contrast, the patents in suit expire on March 21, 2032 (the '096 patent) and June 15, 2027 (the '910 patent). Defendants filed "Paragraph III" ANDAs on the '884 and '297 patents, which ANDAs are limited to treatment of major depressive disorder; this indication is not claimed in the '096 or '910 patents-in-suit.
Claims 1 and 7 of the '096 patent are representative of claims for treating depression without or with reduced adverse sexual side effects with vortioxetine:
1. A method for the treatment of a disease selected from the group consisting of depression, anxiety, abuse and chronic pain, comprising the administration of a therapeutically effective amount of [vortioxetine] or a pharmaceutically acceptable salt thereof to a patient in need thereof, wherein said patient has previously received medication or is still receiving medication for the treatment of said disease, the medication is ceased or reduced or has to be ceased or reduced due to sexually related adverse events, and the medication is selected from the group consisting of selective serotonin reuptake inhibitors, selective noradrenaline reuptake inhibitors, noradrenaline/serotonin reuptake inhibitors, and tri-cyclics.
6. The method according to claim 1, wherein Compound I or a pharmaceutically acceptable salt thereof is administered to the patient in unit doses of about 1–50 mg.
7. The method according to claim 6, wherein the patient is administered between about 1 and 20 mg per day of the hydrobromic acid salt of Compound I orally.
Claims 1, 3, and 6 of the '096 patent are representative of claims for treating cognitive impairment with vortioxetine:
1. A method of treating cognitive impairment involving decline in speed of processing, executive function, attention, or verbal learning and memory in a patient diagnosed with depression, the method comprising administering a therapeutically effective amount of [vortioxetine] or a pharmaceutically acceptable salt thereof to the patient, wherein . . . the method alleviates a symptom or complication of the cognitive impairment or delays the progression of the cognitive impairment.
3. The method of claim 1, wherein the depression is major depressive disorder.
6. The method of claim 3, wherein the method comprises administering a hydrobromide salt of [vortioxetine] to the patient.
Plaintiffs asserted induced or contributory infringement against defendants, asking the District Court for an injunction until the '096 and '910 patents expired. The District Court held that defendants' ANDAs "neither induced infringement of nor contributorily infringed" the '096 nor '910 patents, and denied the injunction. Plaintiffs appealed this judgment.
In addition, plaintiffs asserted the '626 patent against defendant Lupin, the opinion stating that claims 1 and 11 were representative; claim 1 recites:
1. A process for the preparation of [vortioxetine] or a pharmaceutically salt thereof, the process comprising reacting compound II . . ., with a compound of formula III . . ., and a compound [IV] . . ., in the presence of a solvent, a base and a palladium catalyst consisting of a palladium source and a phosphine ligand at a temperature between 60° C. and 130° C.
The District Court construed the claims consistent with plaintiffs' interpretation of the word "reacting" and held Lupin's method of producing vortioxetine would infringe. Lupin cross-appealed this judgment.
The Federal Circuit affirmed, in an opinion by Judge Dyk joined by Judges Prost and Hughes. Plaintiffs argued that an infringement action under § 271(e)(2)(A) "creates a separate cause of action that does not require a showing of direct, induced, or contributory infringement by the ANDA filer"; in other words filing an ANDA by itself is an act of infringement. In the context of this lawsuit, Plaintiffs also asserted that "it makes no difference that the drug is proposed to be sold for a use not covered by the '096 and '910 patents because the drug could be prescribed for those patented uses." The panel rejected this argument, stating that "'the use . . . claimed in a patent' under section 271(e)(2)(A) must be the use for which an applicant is seeking marketing approval" under their case law.** The opinion cites Warner-Lambert Co. v. Apotex Corp., 316 F.3d 1348, 1365 (Fed. Cir. 2003), in support of this determination, the opinion stating that how a drug was used was a necessary factor in determining infringement. This is because otherwise the NDA holder for a particular drug could extend its exclusivity "by regularly filing a new patent application claiming a narrow method of use not covered by its NDA, [which] would confer substantial additional rights on pioneer drug patent owners that Congress quite clearly did not intend to confer," citing Warner Lambert. Despite the possibility of off-label use, that possibility does not override the basis in § 271(e)(2)(A) to be limited to preventing an ANDA filer from approval for uses subject to patent protection; here, defendants do not seek approval for the uses claimed in the '096 and '910 patents. Such uses do not raise infringement liability under §§ 271(a), 271(b), or 271(c) and § 271(e)(2)(A) does not create infringement liability independently of these statutory bases for finding infringement, according to the Federal Circuit.
Turning to the District Court's findings that defendants' ANDAs did not constitute infringement of claim 7 under § 271(b), the opinion cites that "instructions may not merely describe an infringing mode; they must 'evidence intent to encourage infringement,'" citing Takeda Pharms. U.S.A., Inc. v. West-Ward Pharm. Corp., 785 F.3d 625, 630–31 (Fed. Cir. 2015). Plaintiffs' sole evidence for inducing infringement liability was the FDA-approved label, which does not induce infringement of the asserted claims of the '096 patent because it is limited to the indication for treating major depressive disorder (which indication the opinion notes predates the '096 patent). The opinion expressly distinguishes this situation with that in GlaxoSmithKline LLC v. Teva Pharmaceuticals USA, Inc., 7 F.4th 1320, 1333 (Fed. Cir. 2021), where there was evidence of the existence of advertising or promotional activities and materials that encouraged infringement inter alia by off-label use stratagems. The panel reiterates their interpretation of § 271(e)(2)(A) that "a patentee can[not] bar the sale of a drug for a use covered only by patents that will have expired simply by securing a new patent for an additional, narrower use," citing Warner-Lambert. Further, the Court opined:
[W]e do not see how, in the normal course, a label required to market the drug for a use covered by expired patents could demonstrate the required specific intent to encourage infringement of new patents covering different uses.
The panel notes that there may be circumstances (related to safety, for example) where FDA requires a new patented method of use to be included on the label due to such safety concerns, citing for example AstraZeneca LP v. Apotex, Inc., 633 F.3d 1042, 1060– 61 (Fed. Cir. 2010) (instructions to lower a dose for safety reasons); Vanda Pharms. Inc. v. West-Ward Pharms. Int'l Ltd., 887 F.3d 1117, 1131 (Fed. Cir. 2018) (requiring a test and adjustment of drug dose accordingly); and Eli Lilly & Co. v. Teva Parenteral Medicines, Inc., 845 F.3d 1357, 1365, 1368–69 (Fed. Cir. 2017) (taking a supplement to reduce "potentially life-threatening toxicities"). That is not the case here according to the opinion. Rather, these defendants had properly under the statute "carved out" the indications encompassed by the '096 patent claims, and accordingly the Court held that "[t]he district court correctly determined that, under these circumstances and consistent with our cases," the proposed ANDA labels "will not encourage, recommend, or promote an infringing use."
The opinion concludes its considerations of the induced infringement issue by rejecting plaintiffs' argument that physicians could prescribe the approved drug based on their own "background knowledge together with information in the carved-out label," stating that "mere knowledge of possible infringement by others does not amount to inducement; specific intent and action to induce infringement must be proven," again based on the Warner=Lambert opinion. Also rejected was plaintiffs' assertion of error by the District Court in "ignoring the lower doses recited in the '096 patent claims, while at the same time arguing with regard to claim validity that the skilled worker would have recognized the lower incidence of adverse sexual events that resulted at any of the approved dosages, the panel stating that "Plaintiffs cannot now fault the district court for crediting their own argument."
With regard to contributory infringement, the panel likewise rejected plaintiffs' arguments, here because there is no liability for contributory infringement for selling an article that is "suitable for substantial noninfringing use" under the statute, 35 U.S.C. § 271(c). The opinion states that the District Court properly found that vortioxetine had such substantial noninfringing uses over the claims of the '096 patent, for example, by prescribing the drug to "patients with no prior treatment, patients with prior treatment other than with the drugs referenced in the '096 patent, and in cases where the prior antidepressant was ceased or reduced for reasons other than sexually related adverse events (for example, due to poor efficacy)." Similarly for the '910 patent, substantial noninfringing uses found sufficient to avoid contributory infringement include "prescription for treating MDD, prescription to patients without cognitive impairment, and prescription for purposes unrelated to cognition." And plaintiffs' assertion that these uses may infringe other Lundbeck patents is not relevant, according to the Court, because the determination under § 271(c) relates and is limited to substantial noninfringing uses of the asserted patents.
In Lupin's cross-appeal regarding the District Court's infringement determination of the '626 patent, the Court found no basis to adopt Lupin's narrow interpretation of the term "reacting" based on the term's plain meaning and rejected Lupin's assertion of the prosecution history for its contrary construction. The Court found no error by the District Court either for its claim construction nor its infringement determination.
The Court apportioned costs to the defendants in plaintiffs' appeal of the judgment of non-infringement of the '096 and '910 patents and to plaintiffs in defendant Lupin's appeal of the District Court's judgment of infringement of the '626 patent.
Lundbeck A/S v. Lupin Ltd. (Fed. Cir. 2023)
Panel: Circuit Judges Dyk, Prost, and Hughes
Opinion by Circuit Judge Dyk
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