By Kevin E. Noonan –

In recent years, the Federal Circuit has, with varying levels of agreement, considered what behavior by generic drugmakers constitutes inducement of infringement regarding so-called “off-label” prescribing for indications not covered in their approved label (known as a “skinny label; see “GlaxoSmithKline LLC v. Teva Pharmaceuticals USA, Inc. (Fed. Cir. 2020)“).  In the latest instance (see “Amarin Pharma, Inc. v. Hikma Pharmaceuticals USA Inc. (Fed. Cir. 2024)“), the Solicitor General filed its amicus brief (at the Supreme Court’s behest) regarding the issue, once again (as has been done before; see “Solicitor General Files Brief Advocating Certiorari Grant in Teva Pharmaceuticals v. GlaxoSmithKline; Court Declines Invitation“) arguing that the Court should grant certiorari.  Somewhat surprisingly, on January 16, the Court did just that, and will consider one of these two Questions Presented by Hikma in its Petition:

1. When a generic drug label fully carves out a patented use, are allegations that the generic drugmaker calls its product a “generic version” and cites public information about the branded drug (e.g., sales) enough to plead induced infringement of the patented use?

2. Does a complaint state a claim for induced infringement of a patented method if it does not allege any instruction or other statement by the defendant that encourages, or even mentions, the patented use?

Perhaps even more surprisingly, the Court set an accelerated schedule for oral argument on April 27.

To recap, 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 being less than 150 mg/dL) (termed 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 indication; 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” provision of the statute).  The 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.”

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.

The District Court granted Hikma’s motion to dismiss under Federal Rule of Civil Procedure 12(b)(6) for failure to state a claim, and the Federal Circuit reversed, relying on Takeda Pharms. U.S.A., Inc. v. W.-Ward Pharm. Corp., 785 F.3d 625, 632 n.4 (Fed. Cir. 2015), that there is no need to have a generic label contains a “‘clear statement’ discouraging use of the patented indication” to avoid infringement liability.  The Federal Circuit specifically held that:

[I]t [would] at least [be] plausible that a physician could read Hikma’s press releases—touting sales figures attributable largely to an infringing use, and calling Hikma’s product the “generic version” of a drug that is indicated “in part” for the SH indication—as an instruction or encouragement to prescribe that drug for any of the approved uses of icosapent ethyl, particularly where the label suggests that the drug may be effective for an overlapping patient population [and] at least plausible that a physician may recognize that, by marketing its drug in the broad therapeutic category of “Hypertriglyceridemia” on its website, Hikma was encouraging prescribing the drug for an off-label use [emphasis in Hikma’s opening brief].

Amarin’s Respondent’s Opening Brief makes two arguments.  Substantively the brief addresses Hikma’s contentions that Amarin had not provided sufficient support in its complaint to survive its motion to dismiss.  The more cogent argument is procedural, that in response to a motion to dismiss, Amarin was to be given the benefit of all their well-plead facts as being true and having found this to be the case the Federal Circuit did not err in permitting the matter to go to trial (which will be the outcome should the Supreme Court affirm).

Amarin’s substantive infringement arguments focus on inducement of infringement generally, not limited to the more limited context of the Hatch-Waxman Act or pharmaceuticals.  Amarin argues that the reason for the skinny label pathway is that FDA regulates approval for indications and so a generic drug maker can have approval for a non-patented use but there can be off-label use that is infringing.  Their ultimate argument is that Hikma informed the public that the off-label used was safe and effective for the patent-protected indication, in a context of how the second indication was greeted by doctors (a “game changer,” providing the incentive for off-label use and knowledge of the benefits of that use by doctors).  And regarding the consequence of Hikma’s behavior, Amarin emphasizes the investment (“more than 8,000 hypertriglyceridemia patients taking statins” and costing “hundreds of millions of dollars,” specifically more than $300 million”) needed to establish the safety and efficacy of the second indication, and the relative value of the two indications (“By the time petitioners brought their generic product to market, they knew that Vascepa’s patented CV indication accounted for the vast majority of prescriptions and Vascepa’s commercial identity.”)  These arguments cast Hikma as an infringer taking advantage of Amarin’s investment (matched with a certain amount of hagiography about the second indication and response from physicians, not only for patients but also “the overall healthcare system”).  As a counterargument to the accusations from Hikma (and others) regarding drug prices, the brief asserts that “[o]ne economic study found that the costs of Vascepa are ‘offset by cost savings from reducing the occurrence of high-cost major adverse cardiovascular events.’”

At its roots, Amarin contends that Hikma lied and their marketing that their product was useful for treating “hypertriglyceridemia” was sufficiently broad to encompass both the unpatented SH and the patented CV indications.  According to Amarin, “Petitioners’ statements thus increased the likelihood of infringement in this particular context—even though similar references to other generic medicines in other contexts likely would not raise similar concerns,” distinguishing this fact pattern to constitute a special case (and not to have the Court render a decision directed towards a more general rule).  Amarin argues that the Court should consider the “full course of [Hikma’s] conduct,” not just the label, and that such “full course of conduct” amounted to “deliberate efforts to market their product as ‘generic Vascepa’ to steer sales away from Amarin’s product and toward their own for a patented use.”

Amarin also counters Hikma’s contentions in its Opening Brief that its statements asserted by Amarin in support of their arguments before the District Court and Federal Circuit amounted to merely “anodyne statements about skinny-labeled generics” by asserting that Hikma’s website and advertising statements were not so benign; for example, by using “hypertriglyceridemia” Amarin argues that Hikma intentionally (and “unambiguously”) implicated the infringing use.  The brief provides an apt comparison:

There are seven other manufacturers in the same market selling the same generic drug using materially identical “skinny labels” as petitioners.  But respondents have not sued any other manufacturer that confined its marketing to unpatented indications.  Petitioners alone chose to publish statements that healthcare providers would interpret as encouraging prescriptions that infringe respondents’ patents.

The brief turns to statements from the Solicitor General’s amicus brief (which urged the Court to grant certiorari), that it is “important to the federal scheme that generic manufacturers not urge medical professionals to infringe brand-name manufacturers’ method-of-use patents” because “patents play a critical role in incentivizing drug developers to undertake extraordinarily expensive clinical trials, fund additional research, and discover new cures.”  Approval of the skinny label according to Amarin  is tied to an agreement from generic drug makers not to infringe the patented indications, with the benefit that “[f]iling a section viii statement can avoid the possibility of pre-launch litigation and the automatic 30-month stay of approval under paragraph IV.”  As a consequence, the generic drug manufacturer who obtains skinny label approval “enjoys a lucrative opportunity—the right to sell the same product as the branded drug with only a tiny fraction of the pioneer’s upfront investment” according to Amarin.

With regard to the standards required to establish inducing infringement liability, the brief recognizes the intentional aspect of the tort (Commil USA, LLC v. Cisco Sys., Inc., 575 U.S. 632, 642 (2015)), the need for active steps by the inducing party under Metro-Goldwyn-Mayer Studios, Inc. v. Grokster, Ltd., 545 U.S. 913, 935-936 (2005), and that here Hikma’s advertising is enough.  Amarin’s position is that the element at issue was whether Hikma took “active steps . . . taken to encourage direct infringement” under Grokster.  Amarin reminds the Court that the Federal Circuit had found that “[I]t is undisputed that Amarin’s complaint sufficiently alleges (1) that health-care providers directly infringe the asserted patents by prescribing Hikma’s generic icosapent ethyl product for the off-label CV indication, and (2) that Hikma had the requisite intent and knowledge to induce that infringement.”  The brief cites three lines of Supreme Court’s precedent in support of its argument regarding the sufficiency of its complaint: (1) underlying direct infringement by one or more third parties, Limelight Networks, Inc. v. Akamai Techs., Inc., 572 U.S. 915, 920-21 (2014); (2) the inducing party’s specific intent to infringe, Global-Tech Appliances, Inc. v. SEB S.A., 563 U.S. 754, 761 n.2, 766 (2011); and (3) “active steps . . . taken to encourage direct infringement,” Metro-Goldwyn-Mayer Studios, Inc. v. Grokster, Ltd., 545 U.S. 913, 936 (2005).  Amarin cites Grokster as standing for the proposition that advertisement could satisfy this prong, in view of the context of these advertisements (wherein there was established “an inextricable connection in the marketplace between Vascepa and its primary, patented CV indication”).

Amarin also addresses the “inevitable infringement” argument (i.e., that State “automatic substitution” laws would inevitably lead to off-label use to minimize Hikma’s liability for any such infringement) by arguing that absolving infringers from liability on these grounds was not Congress’s intent, and that Hikma had forfeited this argument in the proceedings below.  The brief cites Caraco Pharm. Laboratories, Ltd. v. Novo Nordisk A/S, 566 U.S. 399, 415, 419 (2012), in opposition to Hikma’s argument that “doctors and patients will inevitably infringe.”  The brief also contends that the Solicitor General raised the State law automatic generic substitution issue “at the eleventh hour” and the Court should not consider it (albeit that seems unlikely).  Maybe a more compelling argument is that this should not be a question of the quantum of the harm but rather its existence (the brief noting the various extents of such substitutions state-by-state).

Regarding Amarin’s procedural arguments, the brief asserts that because this was a motion to dismiss, Amarin was given the benefit of all their well-plead facts as being true which included that Hikma “‘actively’ induced healthcare providers’ direct infringement.’”  This lower threshold enabled the Federal Circuit to find that the “affirmative” and “active” steps to induce infringement arose from the “label in combination with [their] public statements and marketing materials” (emphasis in brief), and this raised a factual dispute regarding whether Hikma’s behavior amounted to inducement of infringement.  (This is perhaps Amarin’s best legal argument but of course it is also an argument that the Court should not have granted cert in the first place.)  Amarin contends that its complaint stated a plausible claim for induced infringement that the Federal Circuit properly permitted to move to discovery, because “[m]ost elements of induced infringement [were] unchallenged” and active infringement found support in Hikma’s advertising behavior.  Further, Amarin contends that Hikma (and the Solicitor General) were wrong because for the Court to find for Hikma would amount to “adopt[ing] the defendants‘ version (i.e., the movant’s version) of the alleged facts,” which is contrary to the standard for a court to assess a motion to dismiss, and wherein the court’s assessment of those facts “cannot be resolved at the pleadings stage.”  And “Petitioners’ defenses share a fundamental defect: they assume the defendants’ version of facts and draw inferences against the plaintiffs.”  Amarin contends that the proper standard is “whether petitioners’ ‘communications’ could be ‘reasonably understood’ to encourage infringement” and here cardiovascular physicians are “sophisticated actors” in this regard (i.e., not readily fooled).  The brief also rejects Hikma’s “passive” inducement argument, both because it hasn’t been made previously and because there was nothing passive about what Hikma discloses.  Amarin also contends that, “[s]traying even further from bedrock pleading standards, petitioners demand that this Court credit their post-hoc explanations for their statements.”

On factual questions whether the Court should condemn Hikma’s behavior as infringing, Amarin further contends that the language used by Hikma has consequences; it would have been different if Hikma had advertised as “generic icosapent ethyl” instead of “generic Vascepa” in it advertising, for example.  The brief further contends that “Petitioners’ icosapent product is not a full “generic equivalent” or “generic Vascepa” because FDA evaluated and approved it only for the labeled SH indication; FDA did not evaluate its therapeutic equivalence for the CV use” and yet Hikma’s off-label use encourages unvetted outcomes.

The latter portion of the brief raises (as it must before the Supreme Court) the policy implications of finding in Hikma’s favor.  The brief assets that “[a]dopting petitioners’ and the government’s arguments would distort patent law in at least two ways: they would (1) foreclose induced infringement claims unless the defendant used explicit, smoking-gun language; and (2) demand that inducement be the primary or exclusive cause of direct infringement.”  On the other hand, affirming the Federal Circuit’s decision would support the patent and regulatory scheme for pharmaceuticals and not “disturb Congress’s carefully balanced incentive structure and risk stifling revolutionary and life-saving discoveries.”  “Holding generic manufacturers liable for their induced infringement is essential to a properly functioning section viii pathway,” Amarin argues and is based on incentives and costs for secondary indications.  Contrary to Hikma’s arguments, all the other generic icosapent ethyl drugs are on the market with the same label and accordingly, Amarin contends, this it isn’t a defective label problem it is a behavior problem.  The brief further challenges statistics recited by Hikma and amici regarding the effects of GlaxoSmithKline skinny label decision (which the Court deigned not to grant cert); see GlaxoSmithKline LLC v. Teva Pharms. USA, Inc., 7 F.4th 1320 (Fed. Cir. 2021).  Finally, “[t]he economic policy underlying the federal drug and patent laws, moreover, is ‘for Congress, not the courts,’” the brief citing Georgia v. Public.Resource.Org, Inc., 590 U.S. 255, 272 (2020).

The brief calls for the Court to withdraw the writ for inconsistencies between the Petition and Hikma’s argument in its Opening brief.  In recent similar circumstances, Amain contends, where petitioners before the Court have argued one thing to secure review and something else at the merits stage, this Court has dismissed the writs of certiorari as improvidently granted.  See, e.g., Facebook, Inc. v. Amalgamated Bank, 604 U.S. 4 (2024) (per curiam); NVIDIA Corp. v. E. Ohman J:or Fonder AB, 604 U.S. 20 (2024) (per curiam).  The same result may be warranted here.  On these grounds, Amarin suggests that the Court dismiss certiorari and send back to the District Court with instructions to grant Amarin leave to amend according to what the Court determines are the proper standards and not with prejudice as Hikma contends.