DCT

1:23-cv-01286

Harmony Biosciences LLC v. Lupin Ltd

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I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 1:23-cv-01286, D. Del., 11/09/2023
  • Venue Allegations: Venue is alleged to be proper in the District of Delaware as Defendants Lupin Pharmaceuticals, Novugen Pharma (USA), and Makro Technologies are Delaware corporations. Venue over foreign defendants Lupin Limited and Novugen Pharma Sdn. Bhd. is asserted based on their being subject to personal jurisdiction in the district.
  • Core Dispute: Plaintiffs allege that Defendants' submission of Abbreviated New Drug Applications (ANDAs) to market generic versions of Plaintiffs' WAKIX® (pitolisant hydrochloride) tablets constitutes an act of infringement of two U.S. patents.
  • Technical Context: The case concerns pitolisant, a histamine H3-receptor antagonist/inverse agonist, which is the first FDA-approved drug in its class for treating excessive daytime sleepiness (EDS) or cataplexy in adults with narcolepsy.
  • Key Procedural History: This action was initiated under the Hatch-Waxman Act following Plaintiffs' receipt of Paragraph IV Notice Letters from Lupin and Novugen on September 27, 2023. These letters certified that the defendants' generic products would not infringe, or that the patents-in-suit are invalid or unenforceable. The filing of this suit within 45 days of receiving the notice letters triggers an automatic 30-month stay of FDA approval for the Defendants' ANDAs.

Case Timeline

Date Event
2005-02-10 ’197 Patent Priority Date
2005-04-01 ’947 Patent Priority Date
2012-06-26 U.S. Patent No. 8,207,197 Issues
2013-07-16 U.S. Patent No. 8,486,947 Issues
2019-08-14 WAKIX® (pitolisant hydrochloride) receives FDA approval
2023-09-27 Plaintiffs receive Paragraph IV Notice Letters from Lupin and Novugen
2023-11-09 Complaint Filed

II. Technology and Patent(s)-in-Suit Analysis

U.S. Patent No. 8,207,197 - "Monohydrochloride Salt of 1-[3-[3-(4-Chlorophenyl) Propoxy]Propyl]-Piperidine," issued June 26, 2012

The Invention Explained

  • Problem Addressed: The patent describes prior forms of the active compound 1-[3-[3-(4-chlorophenyl)propoxy]propyl]-piperidine, noting that the free base is limited by its "oily nature" and the oxalate salt is limited by its "low aqueous solubility," both of which restrict its use as a pharmaceutical ingredient (’197 Patent, col. 1:12-24).
  • The Patented Solution: The invention is a novel crystalline monohydrochloride salt of the compound. This specific salt form is described as having unexpectedly high aqueous solubility (4 g/ml) compared to the prior oxalate salt (0.025 g/ml) and a better stability profile, making it "a more suitable salt for its use as a pharmaceutical ingredient" (’197 Patent, col. 2:58-65; col. 1:20-24). The patent defines this crystalline form by its characteristic X-ray powder diffraction pattern peaks (’197 Patent, col. 2:52-57).
  • Technical Importance: For a drug to be effective and manufacturable as an oral tablet, having a stable, solid crystalline form with high aqueous solubility is a significant technical advantage, improving bioavailability and formulation consistency.

Key Claims at a Glance

  • The complaint asserts that Lupin has infringed "all claims" and Novugen has infringed "at least Claim 1" (Compl. ¶¶100, 126).
  • Independent Claim 1:
    • Crystalline 1-[3-[3-(4-chlorophenyl)propoxy]propyl]-piperidine monohydrochloride of formula (I)
    • optionally comprising water up to 6%, and
    • having an X-ray diffractogram that comprises characteristic peaks (2θ) at 11.2°, 19.9°, 20.7° and 34.1° ±0.2°.

U.S. Patent No. 8,486,947 - "Treatment of Parkinson's Disease, Obstructive Sleep Apnea, Dementia with Lewy Bodies, Vascular Dementia with Non-Imidazole Alkylamines Histamine H₃-Receptor Ligands," issued July 16, 2013

The Invention Explained

  • Problem Addressed: The patent addresses a need for effective treatments for various neurological and sleep-related disorders, including excessive daytime sleepiness, which can be a symptom of conditions like Parkinson's disease, obstructive sleep apnea (OSA), and narcolepsy (’947 Patent, col. 2:35-55). Existing treatments were noted to have limitations.
  • The Patented Solution: The invention is a method of treating these conditions by administering non-imidazole histamine H3-receptor antagonists, such as the pitolisant compound. The patent explains that these compounds "induce an extended wakefulness, an improvement in cognitive processes, a reduction in food intake and a normalization of vestibular reflexes" by increasing the synthesis and release of cerebral histamine (’947 Patent, col. 1:13-18; col. 2:5-8).
  • Technical Importance: The patent proposes a new therapeutic use for a class of compounds, targeting the histamine system to treat symptoms like excessive daytime sleepiness, which were previously managed with drugs acting through different mechanisms.

Key Claims at a Glance

  • The complaint asserts infringement of claims 1-5 and 10-14 against both Lupin and Novugen (Compl. ¶¶85, 113).
  • Independent Claim 1:
    • A method for treating excessive daytime sleepiness
    • comprising administering to a patient in need thereof a compound of formula (IIa):
    • wherein the compound comprises a specific chemical structure (pitolisant) where R¹ and R² form a piperidine ring, chain A is a propyl group, X is oxygen, chain B is a propyl group, and Y is a 4-chlorophenyl group.
    • and wherein said patient is suffering from Parkinson's disease, narcolepsy, or sleep apnea.

III. The Accused Instrumentality

Product Identification

  • The accused instrumentalities are the generic pitolisant hydrochloride tablets described in Lupin’s ANDA No. 218846 and Novugen’s ANDA No. 218834 (Compl. ¶¶57, 69).

Functionality and Market Context

  • The defendants’ ANDA products are intended to be generic versions of Plaintiffs’ WAKIX® tablets (Compl. ¶1). They contain pitolisant hydrochloride as the active ingredient and, according to the complaint, the proposed package inserts will state an indication for the "treatment of excessive daytime sleepiness ('EDS') in adult patients with narcolepsy" (Compl. ¶87). WAKIX® is described as a "first-in-class drug" and the only FDA-approved H3 receptor antagonist for this indication (Compl. ¶2, ¶5). The defendants intend to market and sell their generic products in the U.S. upon FDA approval, prior to the expiration of the patents-in-suit (Compl. ¶¶58, 70).

IV. Analysis of Infringement Allegations

The complaint alleges that the defendants' Paragraph IV notice letters either did not dispute infringement of the asserted claims or, in one instance, did not assert invalidity of a patent, which is an unusual posture for an ANDA litigation complaint. The infringement theory is based on the statutory act of filing an ANDA for a drug claimed in a patent or for a use claimed in a patent. No probative visual evidence provided in complaint.

'197 Patent Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
Crystalline 1-[3-[3-(4-chlorophenyl)propoxy]propyl]-piperidine monohydrochloride of formula (I) The ANDA Products contain pitolisant hydrochloride, which is the monohydrochloride salt of the claimed compound. The complaint alleges that Lupin does not dispute infringement of any claim of the ’197 patent and that Novugen does not assert that any claim of the ’197 patent is invalid. ¶¶63, 75, 86, 114 col. 1:31-45
optionally comprising water up to 6% The complaint does not provide sufficient detail for analysis of this element. col. 2:50-51
having an X-ray diffractogram that comprises characteristic peaks (2θ) at 11.2°, 19.9°, 20.7° and 34.1° ±0.2°. The complaint's allegation that infringement is not disputed implies that the defendants' generic products are or will be formulated with the specific crystalline form defined by these peaks. ¶¶63, 75, 99 col. 2:52-57

'947 Patent Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
A method for treating excessive daytime sleepiness... The proposed package insert for the Lupin ANDA Products states that it will be indicated for the treatment of excessive daytime sleepiness ("EDS") in adult patients with narcolepsy. ¶87 col. 45:15-16
comprising administering... a compound of formula (IIa) [pitolisant]... The defendants' ANDA products contain pitolisant hydrochloride, which is a salt of the compound of formula (IIa). ¶¶86, 114 col. 46:16-41
wherein said patient is suffering from... narcolepsy... The proposed indication for the ANDA products is for treatment of EDS in adult patients with narcolepsy. The complaint alleges that infringement of these claims is not disputed by the defendants. ¶¶62, 87, 112 col. 45:15-16
  • Identified Points of Contention:
    • Factual Questions: A central factual question, particularly for the ’197 patent, will be whether the defendants' generic products actually utilize the specific crystalline form of pitolisant monohydrochloride claimed, as defined by the X-ray diffraction peaks. While the complaint alleges infringement is not disputed, this could still become a point of contention if the defendants' products use a different polymorph.
    • Scope Questions: For the ’947 patent, a key question will be whether the label for the defendants' ANDA products will instruct users in a manner that falls within the scope of the patented method. The complaint alleges the proposed label is for "treatment of excessive daytime sleepiness ('EDS') in adult patients with narcolepsy," which appears to map directly onto the language of claim 1.
    • Validity Challenges: The primary point of contention in this Hatch-Waxman case will likely be the defendants' challenges to the validity and/or enforceability of the patents, which were raised in their Paragraph IV letters but are not detailed in the complaint (Compl. ¶¶59, 71).

V. Key Claim Terms for Construction

  • For the '197 Patent:

    • The Term: "Crystalline... having an X-ray diffractogram that comprises characteristic peaks (2θ) at 11.2°, 19.9°, 20.7° and 34.1° ±0.2°" (Claim 1)
    • Context and Importance: This term defines the specific polymorph of the pitolisant monohydrochloride salt. Practitioners may focus on this term because infringement will depend entirely on whether the defendants' generic products are made with this exact crystalline form. Any other form, even of the same salt, would not literally infringe.
    • Intrinsic Evidence for Interpretation:
      • Evidence for a Broader Interpretation: The specification notes that the crystalline form "may show a variable content of water" but that all samples "correspond to the same crystal structure," which may suggest some tolerance for minor variations as long as the core structure is maintained (’197 Patent, col. 2:1-6).
      • Evidence for a Narrower Interpretation: The claim recites specific 2-theta peaks "±0.2°," which provides a precise, numerically bounded definition. The patent further provides a list of "additional characteristic peaks," reinforcing that a specific, identifiable pattern is being claimed, rather than any crystalline form of the salt (’197 Patent, col. 7:12-15).

  • For the '947 Patent:

    • The Term: "treating excessive daytime sleepiness" (Claim 1)
    • Context and Importance: This term defines the therapeutic purpose of the patented method. Practitioners may focus on this term because induced infringement will depend on whether the defendants' product label instructs or encourages physicians and patients to use the generic drug for this specific purpose.
    • Intrinsic Evidence for Interpretation:
      • Evidence for a Broader Interpretation: The patent specification broadly discusses a range of "sleep and vigilance disorders," including "excessive daytime sleepiness (including narcolepsy or 'sleep attacks')", which could support an interpretation covering a range of symptomatic treatments (’947 Patent, col. 2:40-46).
      • Evidence for a Narrower Interpretation: Claim 1 narrows the method to treating EDS in patients who are also "suffering from Parkinson's disease, narcolepsy, or sleep apnea." This dependent clause may be used to argue that the "treating" step is not a general instruction but is limited to administration within these specific patient populations, a limitation the accused product's label appears to meet.

VI. Other Allegations

  • Indirect Infringement: The complaint alleges that upon FDA approval, the defendants will induce infringement by knowingly and intentionally including a product label and package insert with their ANDA products that contain instructions for physicians and patients to administer the drug in a manner that directly infringes the claims of the patents-in-suit (Compl. ¶¶91, 104, 118, 130).
  • Willful Infringement: The complaint alleges that the defendants had actual, pre-suit knowledge of the patents-in-suit, at the latest by virtue of preparing and sending their Paragraph IV Notice Letters. It is alleged that the defendants' submission of their ANDAs with knowledge of the patents and awareness that their proposed products would infringe constitutes willful infringement and renders the case "exceptional" under 35 U.S.C. § 285 (Compl. ¶¶93-94, 106-107, 120-121, 132-133).

VII. Analyst’s Conclusion: Key Questions for the Case

  • A core issue will be one of validity: As infringement of several key claims is allegedly not disputed, the case will likely focus on the defendants' unstated affirmative defenses and counterclaims that the patents are invalid or unenforceable, the basis for which was outlined in their Paragraph IV letters but is not yet part of the public record.
  • A key evidentiary question will be one of polymorphic identity: For the ’197 patent, discovery will be required to determine if the defendants' generic products are, in fact, formulated with the specific crystalline structure defined by the patent's claims, or if they use a non-infringing alternative polymorph.
  • A central legal question will be one of induced infringement: For the ’947 patent, the analysis will turn on whether the final, FDA-approved label for the defendants' products instructs or encourages administration for the treatment of "excessive daytime sleepiness in... narcolepsy," thereby inducing infringement of the patented method.