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).  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 claims 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 “it [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).

Hikma’s opening brief characterizes the issues before the Supreme Court as involving “the affirmative conduct a complaint must allege to state a plausible claim of ‘actively induce[d] infringement of a patent’” under 35 U.S.C. § 271(b) and emphasizes Congressional intent to “facilitate the approval of generic drugs as soon as patents allow” under the Hatch-Waxman Act, citing Caraco Pharm. Labs., Ltd. v. Novo Nordisk A/S, 566 U.S. 399, 405 (2012).  Also, Hikma argues that Congress enacted the Section viii carveout in the Hatch-Waxman Act fully aware of the existence of state laws regarding “automatic substitution” of generic for branded drugs (Inwood Labs., Inc. v. Ives Labs., Inc., 456 U.S. 844, 847 & n.4 (1982)), as introducing a certain inevitability for “off-label” use under the Section viii carve-out regime, and relying on the need for affirmative conduct to raise inducement to infringe liability for generic drugmakers.

The brief cites earlier Federal Circuit precedent that seemed to accommodate these circumstances, citing AstraZeneca Pharms. LP v. Apotex Corp., 669 F.3d 1370, 1380 (Fed. Cir. 2012), but argues that if these situations were no longer accommodated (“If merely alleging that a generic drug with a skinny label will inevitably be substituted for patented uses were enough to plead active inducement”) then the skinny label regime would be at risk and Congressional intent thwarted (“At the time of section viii’s adoption, it was thus widely understood that doctors and patients necessarily would infringe method-of-treatment patents despite the use of skinny labels”).  With regard to that intent, Hikma tells the Court that Congress enacted the statute to provide the advantages to generic drugmakers that it does not provoke litigation like a Paragraph IV notice does and does not involve the 30-month stay for approval (with resulting delay in getting generic drugs to patients directed to indications no longer having regulatory or patent exclusivity).

Regarding the evidence that proved persuasive before the Federal Circuit, the brief adopts the Solicitor General’s language that it constitute “the most routine and anodyne statements about skinny-labeled generics” as well as not being limited to statements addressed to doctors and patients.  Hikma argues that:

Where, as here, a skinny label fully carves out all patented uses under section viii, allegations that the generic drugmaker simply calls its product a “generic version” of the branded drug and cites public information about the drug (for example, sales figures) are insufficient to state a claim under § 271(b).

The quanta of evidence accepted by the Federal Circuit in coming to its conclusions were three according to the brief:  Hikma communications contained in its FDA-approved skinny label; pre-launch press releases to investors announcing litigation victories; and information appearing on its website.  Hikma argues that the evidence attributed to the label included the absence of a “CV Limitation of Use” on Hikma’s “skinny” label (because that limitation was not on the Amarin label and those labels were required under FDA regulations to be identical); warnings on patient information leaflets stating possible side effects including cardiovascular disease; statements on patient information leaflets regarding alternative prescriptions (“other purposes”); and “other elements” of the label, such as administration accompanying statin use.  This evidence, Amarin had successfully argued before the Federal Circuit, supported its inducement of infringement assertions considered in combinations of the skinny label in view of Hikma’s public statements, including prelaunch press releases related to Hikma’s litigation victories, baldly stating “Hikma’s generic version of Amarin Corporation’s Vascepa®” does not infringe six US patents.  Hikma accuses Amarin of asserting inducement because the materials do not include affirmative prohibitions against using Hikma’s Vascepa® generic for “the CV indication” and included its sales information that included all uses not just the approved (and non-infringing) SH uses.

Hikma argued that there was no evidence of active inducement and thus the Federal Circuit was not justified in requiring discovery, and that “mere inferences or assumptions about how third parties might react to vague communications that lack any instruction or encouragement to infringe cannot trigger liability.”  Further, according to Hikma’s brief “[the Court] did not identify any alleged statement by Hikma that mentions, much less encourages, administering icosapent ethyl for ‘reducing risk of cardiovascular death’ or ‘reducing occurrence of a cardiovascular event’ when taken with a statin, as Amarin’s patents require.”  Also, “[n]or did the Federal Circuit point to any alleged statement by Hikma instructing doctors and patients that they should use its generic product as they use Vascepa for its CV indication (no such statement exists).”  Hikma contends that establishing inducement required “active inducement” (unambiguously) and liability would only properly arise by the accused infringer taking affirmative steps, citing Metro-Goldwyn-Mayer Studios Inc. v. Grokster, Ltd., 545 U.S. 913, 936–937 (2005) (“The inducement rule, instead, premises liability on purposeful, culpable expression and conduct, and thus does nothing to compromise legitimate commerce or discourage innovation having a lawful promise”) and Global-Tech Appliances, Inc. v. SEB S.A., 563 U.S. 754, 760 (2011) (“the inducer must persuade another to engage in conduct that the inducer knows is infringement”), analogized to aiding-and-abetting liability under Smith & Wesson Brands v. Estados Unidos Mexicanos, 605 U.S. 280, 291 (2025).  Further, Hikma argues that the induced acts must be infringing, citing Commil USA, LLC v. Cisco Sys., Inc., 575 U.S. 632, 637 (2015), and the behavior Amarin asserts was not infringement because it was limited to the unpatented invention (the SH embodiments).  Under these circumstances, Hikma argues Amarin’s complaint failed to make a claim, relying on the difference between enabling the court to draw a reasonable inference of liability from the facts asserted in the claim and facts merely consistent with liability (“it stops short of the line between possibility and plausibility of entitlement to relief”).

The brief makes a variety of procedural arguments based on the status of the case (on a motion to dismiss under Fed. R. Civ. Pro. 12(b)(6)) and sufficiency of pleadings standards citing Ashcroft v. Iqbal and Bell Atl. Corp. v. Twombly (“there is no plausible allegation that Hikma’s statements actively induce specific conduct that satisfies all claim steps for any asserted claim”).  These include that “Amarin and the Federal Circuit purport to ‘read’ instructions that Hikma never made into anodyne statements of generic equivalence—effectively misattributing a physician’s intervening reliance on their own knowledge and independent judgment to Hikma.”  The consequence of the Court not remedying this situation will be, as Hikma argues, that “[a]llowing cases like this one to survive the pleadings stage would eviscerate section viii, which was designed to expedite generic-drug competition without litigation” (emphasis in brief).

Applying these pleading standards to Amarin’s complaint, Hikma argues that Hikma’s label encourages non-infringing use (i.e., only the non-infringing SH indication) and that Hikma did not actively induce infringement for other uses (and even when cardiovascular uses are mentioned there is a warning against doing so).

On the merits Hikma argues that the accused statements were insufficient to encourage infringement, in part because they were accurate, i.e., that Hikma’s product was a generic version of Amarin’s drug.  Further, Hikma contends that the information regarding Vascepa’s sales not relevant to how the drug is prescribed or taken, and the website was not directed to doctors or patients but rather to investors (although that information was available to both doctors and patients,

Finally, the brief contains policy arguments regarding the consequences should the Court permit the Federal Circuit’s decision to stand.  These include that it would act to nullify Section viii by creating disincentives for using the skinny label approach; these consequences are based on the fact that, unlike ANDA litigation, cases brought under §271(b) would be brought after the generic version of a branded drug was sold on the market and thus subject to monetary damages (which, as here, would be exposed to willful infringement enhancement).  Nor would the § 271(b) regime provide the 30-month stay in generic drug approval which has provided an incentive for generic drug development.  Hikma urges the Court that “[a]bsurdly, the decision below makes skinny labels riskier than paragraph IV certifications” on these grounds.

Amarin’s brief will be the subject of a future post.