DCT

1:23-cv-00819

Astellas Pharma Inc v. Lupin Ltd

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I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 1:23-cv-00819, D. Del., 07/23/2024
  • Venue Allegations: Plaintiff alleges venue is proper in the District of Delaware based on Defendants' incorporation in the state, systematic and continuous business contacts within Delaware, and frequent availment of the state's legal protections.
  • Core Dispute: Plaintiff alleges that Defendants’ generic mirabegron extended-release tablets, approved for treating overactive bladder, infringe a patent covering a modified-release pharmaceutical composition designed to reduce the effect of food on the drug's absorption.
  • Technical Context: The technology involves pharmaceutical formulations for the drug mirabegron that provide sustained release, aiming to ensure consistent therapeutic blood levels regardless of a patient's food intake.
  • Key Procedural History: The lawsuit was initiated under the Hatch-Waxman Act following Defendants' submission of Abbreviated New Drug Applications (ANDAs) to market generic versions of Plaintiff's Myrbetriq® product. The complaint alleges willfulness based on Defendants' knowledge of the patent-in-suit as of the original complaint's filing date.

Case Timeline

Date Event
2010-03-29 ’451 Patent Priority Date
2012-06-28 FDA approves Myrbetriq® New Drug Application
2013-06-20 FDA issues bioequivalence guidance for mirabegron ANDAs
2016-08-25 Lupin submits its ANDA for generic mirabegron (no later than)
2016-09-06 Zydus submits its ANDA for generic mirabegron (no later than)
2019-04-01 Zydus receives tentative FDA approval for its ANDA Products
2022-09-28 Lupin receives final FDA approval for its ANDA Products
2022-09-29 Zydus receives final FDA approval for its ANDA Products
2023-07-25 U.S. Patent No. 11,707,451 is issued
2023-07-28 Original complaint is filed
2023-08-21 ’451 Patent is listed in the FDA's Orange Book
2024-04-20 Lupin and Zydus launch their accused ANDA Products (on or about)
2024-07-23 First Amended Complaint is filed

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

U.S. Patent No. 11,707,451 - "Pharmaceutical Composition for Modified Release"

  • Patent Identification: U.S. Patent No. 11707451 ("the ’451 Patent"), "Pharmaceutical Composition for Modified Release," issued July 25, 2023.

The Invention Explained

  • Problem Addressed: The patent's background section explains that conventional, immediate-release formulations of the active ingredient, mirabegron, exhibit "unexpectedly varied" pharmacokinetics depending on whether the patient has eaten. Specifically, taking the drug with food was found to significantly decrease the maximum blood drug concentration (Cmax) and total drug exposure (AUC), creating a risk of inconsistent dosing and reduced efficacy (’451 Patent, col. 1:49-62).
  • The Patented Solution: The invention is a modified-release pharmaceutical composition designed to control the release rate of mirabegron over an extended period. By making the formulation's drug release the "rate-limiting step for absorption," the invention mitigates the pharmacokinetic variability caused by food intake (’451 Patent, col. 2:48-58). The specification describes various technologies to achieve this, such as hydrogel-forming tablets, which provide a continuous drug release and result in more consistent blood concentration profiles regardless of food consumption (’451 Patent, col. 2:58-65; col. 9:1-12).
  • Technical Importance: This technology allows for a more predictable and reliable therapeutic effect for patients with overactive bladder, improving convenience and clinical outcomes by uncoupling the drug's administration from the patient's meal schedule (’451 Patent, col. 1:43-49, col. 2:23-29).

Key Claims at a Glance

  • The complaint alleges infringement of one or more claims of the ’451 Patent, with independent claim 1 being representative of the asserted method claims (Compl. ¶43, 66).
  • Essential elements of independent claim 1 include:
    • A method for treating overactive bladder with a reduced food effect.
    • The method involves orally administering a tablet with 10 mg to 200 mg of mirabegron in a sustained release formulation.
    • The formulation must comprise a carrier and provide continuous drug release for at least 4 hours.
    • The sustained release formulation must be one of several specified types (e.g., a "sustained release hydrogel-forming formulation").
    • The "reduced food effect" is defined in comparison to an immediate release formulation of mirabegron.

III. The Accused Instrumentality

Product Identification

  • The accused instrumentalities are Lupin's and Zydus's 25 mg and 50 mg generic mirabegron extended-release tablets ("ANDA Products") (Compl. ¶42, 65).

Functionality and Market Context

  • The complaint alleges the ANDA Products are generic versions of Plaintiff's Myrbetriq® tablets and are approved for the treatment of overactive bladder (Compl. ¶42, 50, 65, 73).
  • The complaint provides the chemical structure of the active compound, mirabegron (Compl. ¶22).
  • The ANDA Products are described as "sustained release hydrogel formulations" containing mirabegron in a carrier that provide "a continuous drug release... for at least 4 hours after oral administration" (Compl. ¶45, 68).
  • The complaint asserts that because the ANDA Products are required by the FDA to be bioequivalent to Myrbetriq®—which itself has a reduced food effect—the accused products will "likewise reduce the food effect" when compared to an immediate-release formulation (Compl. ¶39, 46, 69). The defendants launched their products in the U.S. on or about April 20, 2024 (Compl. ¶53, 77).

IV. Analysis of Infringement Allegations

'451 Patent Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
A method for treating overactive bladder such that the treating is with a reduced food effect... Defendants' product labels instruct and encourage physicians and patients to use the ANDA Products for treating overactive bladder. ¶50, 52, 73, 75 col. 1:43-49
...administering orally to a subject in need thereof a tablet comprising 10 mg to 200 mg of (R)-2-(2-aminothiazol-4-yl)-4′-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetic acid anilide... The ANDA Products are oral tablets containing 25 mg or 50 mg of mirabegron, which is within the claimed dosage range. ¶42, 45, 65, 68 col. 9:8-10
...in a sustained release formulation, wherein the sustained release formulation further comprises a carrier and provides a continuous drug release for at least 4 hours after oral administration... The ANDA Products are alleged to be "sustained release hydrogel formulations" comprising a carrier and providing continuous drug release for at least 4 hours. ¶45, 68 col. 2:50-53
...wherein the sustained release formulation is any one selected from the group consisting of a sustained release hydrogel-forming formulation... The complaint alleges that the ANDA Products are "sustained release hydrogel formulations of mirabegron," satisfying the first option of the claim's Markush group. ¶45, 68 col. 45:9-19
...wherein the reduced food effect is compared to that after oral administration of an immediate release formulation... The complaint alleges that because the ANDA Products are bioequivalent to Myrbetriq®, they will provide a reduced food effect compared to an immediate release formulation. ¶39, 46, 69 col. 2:1-6

Identified Points of Contention

  • Scope Questions: A central dispute may concern the "reduced food effect" limitation. The claim defines this effect relative to an immediate release formulation. The complaint's infringement theory rests on the ANDA Products' bioequivalence to Myrbetriq®, which is a sustained release product. A question for the court will be whether this indirect comparison is sufficient to prove infringement, or if direct evidence comparing the accused products to an immediate release formulation is necessary.
  • Technical Questions: Does the "sustained release hydrogel formulation" in the accused products operate in a manner consistent with the teachings of the ’451 Patent? While the complaint makes this allegation, the precise composition and functional properties of the accused formulations will be subject to discovery and may become a point of technical dispute.

V. Key Claim Terms for Construction

The Term: "reduced food effect"

  • Context and Importance: This term is central to the patent's novelty and the core infringement dispute. The definition will determine whether infringement can be established by inference from bioequivalence data or requires direct comparative testing. Practitioners may focus on this term because its construction dictates the type of evidence needed to prove infringement.
  • Intrinsic Evidence for a Broader Interpretation: The specification describes the invention's purpose as designing a formulation where "the drug release from the formulation would become the rate-limiting step for absorption," thereby reducing food effects generally (’451 Patent, col. 2:51-54). This language may support a functional interpretation where any formulation achieving this outcome infringes.
  • Evidence for a Narrower Interpretation: The Background section quantifies the food effect observed in conventional formulations, noting a "rate of decrease of Cmax" of 67% and AUC of 47% (’451 Patent, col. 1:53-58). A defendant may argue that "reduced" should be construed to require a specific, significant degree of reduction, as contextualized by these figures.

The Term: "sustained release hydrogel-forming formulation"

  • Context and Importance: The complaint specifically accuses the ANDA Products of being this type of formulation, making its definition critical for infringement (Compl. ¶45, 68). The dispute will likely center on whether the defendants' specific combination of excipients and their resulting physical properties fall within the claim's scope.
  • Intrinsic Evidence for a Broader Interpretation: The specification provides a broad functional definition and lists numerous exemplary polymers, including polyethylene oxide and hypromellose, that can form a hydrogel to control drug release (’451 Patent, col. 9:1-12, 9:21-49). This may support a construction covering a wide range of common hydrogel-based systems.
  • Evidence for a Narrower Interpretation: The patent provides detailed examples with specific polymers and weight percentages (e.g., Example 1A, ’451 Patent, col. 33:40-34:11). A defendant could argue the term should be limited by these embodiments, potentially requiring a specific composition or gelling characteristic not present in its product.

VI. Other Allegations

  • Indirect Infringement: The complaint alleges inducement based on Defendants' product labels and prescribing information, which are alleged to instruct and encourage medical professionals and patients to administer the products in an infringing manner (i.e., for treating overactive bladder) (Compl. ¶52, 54, 75, 78). Contributory infringement is also alleged on the basis that the ANDA Products are a material part of the invention and are not staple articles of commerce suitable for substantial non-infringing use (Compl. ¶55, 79).
  • Willful Infringement: Willfulness is alleged based on Defendants' knowledge of the ’451 Patent as of the filing of the original complaint on July 28, 2023, followed by the continued manufacture, marketing, and sale of the accused products (Compl. ¶59-60, 81-82).

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

  • A central issue will be one of evidentiary sufficiency: Can Astellas prove that the accused products meet the "reduced food effect" limitation, which the patent defines against an immediate-release formulation, by relying on FDA-mandated bioequivalence data that compares the generic products to Myrbetriq®, a sustained-release formulation?
  • A key question will be one of claim scope: Will the term "reduced food effect" be construed broadly to mean any measurable reduction in food-related pharmacokinetic variability, or will it be limited to the specific quantitative reductions disclosed in the patent's examples? The answer will determine the breadth of the patent's protection and the corresponding difficulty of proving infringement.