The Federal Circuit once again had an opportunity to opine on the extent of behavior by a generic drugmaker who opts to accept a "section viii carve-out" in its FDA approval (resulting in a so-called "skinny label) on liability for inducing infringement in Amarin Pharma, Inc. v. Hikma Pharmaceuticals USA Inc.
The case arose over Amarin's Vascepa® (icosapent ethyl) drug product, an omega-3 fatty acid from fish oil, for treatment of severe hypertriglyceridemia (blood triglyceride levels at least 500 mg/dL; normal range is less than 150 mg/dL) (the "SH indication"). Amarin also later received approval for a second indication, reducing cardiovascular disease risk (wherein the second approval removed a Limitation of Use in this regard on the original label) (the "CV indication"). Hikma filed its ANDA against the first approved Vascepa® product; upon Amarin receiving its second FDA approval Hikma filed a section viii statement to carve-out the CV indication under 21 U.S.C. § 355(j)(2)(A)(viii) (the so-called "skinny label"). FDA approved Hikma's skinny label ANDA in 2020 not containing the CV Limitation of Use on the label.
Thereafter, in a series of press releases, Hikma asserted its product as a "generic version of Amarin's Vascepa®." In a particular press release, Hikma claimed its two-month U.S. sales to be $1.1 billion, a figure for all uses of its product, with up to 75% of these sales being for the putatively carved-out CV (off-label) indication (albeit there being other press releases emphasizing the limitation of FDA approval to the SH indication). And on Hikma's website, while asserting an AB rating for its product (generic approval for all indications on the label), the website also said "Hikma's generic version is indicated for fewer than all approved indications of the Reference Listed Drug."
In the ensuing litigation (this case), Amarin sued Hikma for inducement of infringement under 35 U.S.C. § 271(b) of Orange Book listed U.S. Patent Nos. 9,700,537 and 10,568,861 (for claim 1 of the '527 patent and claim 1 and 2 of the '861 patent):
'537 patent:
1. A method of reducing occurrence of a cardiovascular event in a hypercholesterolemia patient consisting of:
identifying a patient having triglycerides (TG) of at least 150 mg/DL and HDL-C of less than 40 mg/dL in a blood sample taken from the patient as a risk factor of a cardiovascular event, wherein the patient has not previously had a cardiovascular event, and administering ethyl icosapentate in combination with a 3-hydroxy3-methylglutaryl coenzyme A reductase inhibitor,
wherein said 3-hydroxyl-3-methylglutaryl coenzyme A reductase inhibitor is administered to the patient at least one of before, during and after administering the ethyl icosapentate; and wherein the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor is selected from the group consisting of pravastatin, lovastatin, simvastatin, fluvastatin, atorvastatin, pitavastatin, rosuvastatin, and salts thereof, and
wherein daily dose of the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor are 5 to 60 mg for pravastatin, 2.5 to 60 mg for simvastatin, 10 to 180 mg for fluvastatin sodium, 5 to 120 mg for atorvastatin calcium hydrate, 0.5 to 12 mg for pitavastatin calcium, 1.25 to 60 mg for rosuvastatin calcium, 5 to 160 mg for lovastatin, and 0.075 to 0.9 mg for cerivastatin sodium.
'861 patent:
1. A method of reducing risk of cardiovascular death in a subject with established cardiovascular disease, the method comprising administering to said subject about 4 g of ethyl icosapentate per day for a period effective to reduce risk of cardiovascular death in the subject.
2. The method of claim 1, wherein the subject has a fasting baseline triglyceride level of about 135 mg/dL to about 500 mg/dL and a fasting baseline LDL-C level of about 40 mg/dL to about 100 mg/dL.
In its complaint, Amarin asserted Hikma's press releases, website content, and product label as evidence of "specific intent to actively encourage physicians to directly infringe the asserted patents by prescribing its generic icosapent ethyl product for the off-label CV indication, an indication for which Hikma did not get FDA approval."
The District Court granted Hikma's motion to dismiss under Fed. R. Civ. Pro. 12(b)(6) for failure to state a claim in Amarin's complaint alleging inducement of infringement, based on its determination that the complaint failed to allege facts that Hikma had taken "affirmative steps" to induce infringement (a decision contrary to the recommendation of the magistrate judge to whom the district court judge referred the motion). The District Court judge cited the cautionary language in Hikma's label regarding side effects as "hardly instruction or encouragement" for the alleged off-label use and that removal of the CV Limitation of Use from Hikma's label would not have been persuasive that its product had been "shown to reduce cardiovascular risk" and thus to have "encourage[d] its use for that purpose." The distinction relied upon by the District Court was that "'merely describing an infringing [treatment] mode is not the same as recommending, encouraging, or promoting an infringing use,'" quoting, with alterations, Takeda Pharms. U.S.A., Inc. v. W.-Ward Pharm. Corp., 785 F.3d 625, 631 (Fed Cir. 2015). With regard to Hikma's press releases and other public statements, the District Court considered that while they "may be relevant to Hikma's intent to induce infringement" (emphasis in opinion), they were not evidence of "an inducing act" constituting a separate element for inducement under § 271(b). The website evidence was deemed insufficient because it did not "rise to the level of encouraging, recommending, or promoting taking Hikma's generic for the reduction of CV risk," comparing GlaxoSmithKline LLC v. Teva Pharms. USA, Inc., 7 F.4th 1320, 1336 (Fed. Cir. 2021) (per curiam) ("GSK"), with Grunenthal GmbH v. Alkem Lab'ys Ltd., 919 F.3d 1333, 1339 (Fed. Cir. 2019).
The Federal Circuit reversed in an opinion by Judge Lourie, joined by Chief Judge Moore and District Court Judge Albright (W.D. Tx), sitting by designation. The opinion begins by emphasizing that the matter below was not an ANDA case under 35 U.S.C. § 271(e)(2)(A), wherein the alleged infringement does not involve an infringing act other than filing the ANDA (what the opinion denotes as a "hypothetical" act of infringement, based on what would arise if the ANDA applicant received FDA approval and marketed the allegedly infringing generic drug). The panel also asserted that this is not a typical "skinny label" case under section viii wherein the plaintiff asserts the generic label isn't "skinny enough" and wherein "the label alone induces infringement," relying on H. Lundbeck A/S v. Lupin Ltd., 87 F.4th 1361, 1370 (Fed. Cir. 2023), and HZNP Meds. LLC v. Actavis Lab'ys UT, Inc., 940 F.3d 680, 699 (Fed. Cir. 2019). The basis for Amarin's assertions, in the Federal Circuit's view, is the combination of the skinny label and Hikma's "public statements and marketing" of its approved generic product (which the opinion states makes this "nothing more than a run-of-the-mill induced infringement case," a characterization perhaps motivated by the contretemps arising in its decisions in GSK, see "GlaxoSmithKline LLC v. Teva Pharmaceuticals USA (Fed Cir. 2020)" and "GlaxoSmithKline LLC v. Teva Pharmaceuticals USA (Fed. Cir. 2022)", and Hikma's assertions of the consequences that would arise if the Federal Circuit reversed, see below). In such a case, the standard the Court applied was "whether the totality of the allegations, taken as true, plausibly plead that Hikma induced infringement" (emphasis in opinion) that would provide "substantial evidence to support a jury verdict of induced infringement."
The panel noted that the case has come before them in a "nascent" stage, without the benefit of discovery or as an appeal of denial of a preliminary injunction motion or an appeal of a summary judgment motion or post-trial motion (citing several of the Court's earlier precedent on skinny label cases having those attributes). As a consequence, the Court stated it is responsible here for "reviewing allegations, not findings, for plausibility, not probability" under Bell Atl. Corp. v. Twombly, 550 U.S. 544, 556 (2007)(emphasis in opinion).
Turning to the evidence relied upon by the District Court in granting Hikma's motion, the opinion states as being "undisputed" that there has been direct infringement by doctors and other healthcare providers in prescribing Hikma's alleged infringing product for off-label use (the CV indication) and that Hikma had "the requisite intent and knowledge to induce that infringement" as found by the District Court. This leads the Court to determining whether Hikma "actively" induced healthcare providers' direct infringement. At least due to the analytical basis for reviewing motions to dismiss ("[a]ccepting all well-pleaded facts as true and drawing all reasonable inferences in Amarin's favor"), the opinion finds that it did. However, the panel discarded any implication that Hikma's label (the "Indications & Usage" section) provides "implied or express instruction to prescribe the drug for the CV indication."
The panel instead turned to the parties' contentions. First, Amarin's complaint alleged that other portions of Hikma's label (specifically, "the clinical studies section, which describes statin-treated patients with the same cardiovascular event history and lipid levels covered by the asserted patents") would teach physicians that the product could be prescribed for treating cardiovascular risk (because, inter alia, the patient populations for the SH and CV indications overlap). Moreover Amarin contended that while FDA approved removal of the CV Limitation of Use regarding CV indications from their label it did not do so for Hikma's label. Hikma's removal of the CV Limitation of Use regarding CV indications as well as including warnings of potential cardiovascular side effects from its drug, Amarin contended, communicated to physicians that its generic drug could be used off-label for the CV indication.
Hikma for its part argued that Amarin was asserting a requirement (and infringement liability for the absence thereof) for language discouraging infringement contrary to law, relying on Takeda Pharms. U.S.A., Inc. v. W.-Ward Pharm. Corp., 785 F.3d 625, 631 (Fed Cir. 2015). Hikma attempted to take refuge (as has arisen in other skinny label disputes) on FDA's requirement that the label for generic copies of branded approved drugs be "the same as the labeling approved for the listed drug" under 21 U.S.C. § 355(j)(2)(A)(v). Also, Hikma argued that its silence regarding its product's effects on risk of cardiovascular complications "cannot plausibly instruct infringement." Finally, Hikma argued that it is "implausible" and "borderline frivolous" to contend (as Amarin does) that information related to clinical studies and attendant warnings about side effects would encourage a physician to prescribe their drug.
The Federal Circuit conceded that Hikma's label does not "recommend[], encourag[e], or promot[e] an infringing use" as a matter of law as found by the District Court. But (agreeing with the magistrate judge) the Court (and Amarin) did not rely on the label alone. Rather, it is the combination (emphasis in opinion) of the label and Hikma's "public statements and marketing materials" that render the District Court's grant of Hikma's motion to dismiss to be in error. Specifically, the Court considered that while the "AB rating" description on Hikma's website may be broad enough to encompass both infringing and non-infringing uses (and thus not support a finding of inducement liability) their press releases consistently characterized their drug as being a "generic equivalent to Vascepa®" and cite the SH indication limitation as being only a part of their approved indication. These implications were supported by reports on sales figures resulting in large (75%) part from off-label use for CV indications. "Those allegations, taken together with those relating to Hikma's label, at least plausibly state a claim for induced infringement," the Court held.
Importantly, these allegations by Amarin regarding Hikma's inducement liability are, according to the opinion, "question[s] of fact—not law" and therefore are "not proper for resolution on a motion to dismiss." The panel asserted they "[we]re unpersuaded" by Hikma's arguments that, because these facts are not in dispute the District Court was correct in deciding to grant Hikma's motion to dismiss on legal grounds. And the opinion distinguishes earlier cases where inducement was decided as a matter of law on the procedural posture of one such case, wherein HZNP was decided ("critically") on summary judgment and was solely based on the contents of the label; the parties access to discovery placing this case (motion to dismiss) on a different footing, insofar as Amarin was entitled to having all factual considerations and inferences in its favor (finding Amarin's contentions on how Hikma's statements and representations could "plausibly" suggest to a physician that its drug was effective the CV indications). The panel also refused to interpret Hikma's representations regarding its AB rating for the drug as being sufficient to insulate it from inducing infringement liability.
The opinion also rejects Hikma's assertions that reversing the district court would be contrary to the Court's decision in GSK, distinguishing that decision on the basis of procedural differences (a motion to dismiss here with a post-trial judgment as a matter of law there) as well as substantive distinctions (there, the label itself taught an infringing use and hence "it was reasonable for the jury to find that the generic manufacturer's marketing of its product as an "AB rated generic equivalent" encouraged physicians to prescribe the drug for the infringing use instructed by the label"), which is not the case here. Here, Amarin was entitled to have all its allegations accepted as true in the context of a motion to dismiss, including their allegations that "Hikma did much more than call its product a 'generic version' of Vascepa" in the face of evidence of Hikma's other activities.
The opinion disdainfully rejects Hikma's "inflated characterizations" regarding the dire consequences for section viii carve-outs should the Court rule (as it does) against them. The opinion states its decision is "limited to the allegations before us" and "guided by the standard of review appropriate for this stage of proceedings," while pledging fealty to the "careful balance struck by the Hatch-Waxman Act regarding section viii carve-outs." The Court cautioned generic drugmakers that "clarity and consistency in a generic manufacturer's communications regarding a drug marketed under a skinny label may be essential in avoiding liability for induced infringement," which was not found here.
This case is remanded to the District Court where, absent settlement (unlikely in view of Hikma's $1 billion + annual sales) the Federal Circuit will likely have the opportunity to rule on the substantive questions regarding skinny label inducement raised by these circumstances.
Amarin Pharma, Inc. v. Hikma Pharmaceuticals USA Inc. (Fed. Cir. 2024)
Panel: Chief Judge Moore, Circuit Judge Lourie, and District Judge Albright (sitting by designation)
Opinion by Circuit Judge Lourie
[View source.]
