DCT

1:24-cv-01084

Astellas Pharma Inc v. Ascent Pharma Inc

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I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 1:24-cv-01084, D. Del., 09/27/2024
  • Venue Allegations: Plaintiff alleges venue is proper in Delaware based on Defendants' systematic and continuous business contacts within the state, including the sale of pharmaceutical products. For Defendant MSN Pharmaceuticals Inc., venue is also based on its incorporation in Delaware.
  • Core Dispute: Plaintiff alleges that Defendants' generic versions of the overactive bladder drug Myrbetriq®, for which they have filed Abbreviated New Drug Applications (ANDAs) with the FDA, will infringe three patents covering specific modified-release formulations and methods of use designed to reduce pharmacokinetic variability when the drug is taken with food.
  • Technical Context: The technology relates to pharmaceutical formulations for extended-release oral tablets, specifically using hydrogel-forming polymers to control drug delivery and mitigate the "food effect," a common challenge where drug absorption rates differ depending on meal consumption.
  • Key Procedural History: The complaint notes that the parties are engaged in separate, ongoing litigation in the same district concerning a different patent (U.S. Patent No. 10,842,780) related to Myrbetriq®. That prior suit was filed before the issuance of the three patents asserted in the current action. The complaint references alleged admissions made by Defendant MSN in the prior litigation regarding the composition and bioequivalence of its ANDA product.

Case Timeline

Date Event
2008-09-30 Earliest Priority Date Asserted (’409 Patent)
2010-03-29 Earliest Priority Date Asserted (’451 Patent, ’189 Patent)
2012-06-28 FDA approves New Drug Application for Myrbetriq® Tablets
2013-05-09 FDA dissolution requirements for mirabegron ANDAs updated
2023-03-22 Date of Ascent’s Notice Letter to Astellas regarding its ANDA filing
2023-05-03 Astellas initiates prior litigation against Ascent over the ’780 Patent
2023-05-18 Date of MSN’s Notice Letter to Astellas regarding its ANDA filing
2023-06-23 Astellas initiates prior litigation against MSN over the ’780 Patent
2023-07-25 U.S. Patent No. 11,707,451 Issues
2024-08-13 U.S. Patent No. 12,059,409 Issues
2024-09-24 U.S. Patent No. 12,097,189 Issues
2024-09-27 Complaint Filed

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

U.S. Patent No. 12,059,409: "Pharmaceutical Composition for Modified Release" (Issued Aug. 13, 2024)

The Invention Explained

  • Problem Addressed: The patent’s background section describes that conventional, immediate-release formulations of the active ingredient, mirabegron, exhibit significant and undesirable pharmacokinetic variability depending on whether the patient has eaten. Specifically, the maximum blood drug concentration (Cmax) in a fasted state was found to be three times higher than in a fed state, creating potential safety and efficacy concerns (’409 Patent, col. 1:50-59).
  • The Patented Solution: The invention is a modified-release tablet that mitigates this "food effect" by controlling the drug's release rate. It employs a "sustained release hydrogel-forming formulation" that combines a specific hydrogel-forming polymer with an additive (a "hydrophilic base") that ensures water can penetrate the tablet to activate the gelling process (’409 Patent, col. 14:14-23). This design makes the formulation's release of the drug, rather than gastrointestinal conditions, the rate-limiting step for absorption, leading to more consistent drug levels (’409 Patent, col. 2:47-54).
  • Technical Importance: This formulation technology aims to provide predictable therapeutic performance for an oral drug regardless of a patient's meal schedule, enhancing patient safety and simplifying dosing instructions (’409 Patent, col. 2:54-58).

Key Claims at a Glance

  • The complaint asserts infringement of one or more claims of the ’409 Patent (Compl. ¶92). Independent Claim 1 is central to the allegations.
  • Essential Elements of Independent Claim 1:
    • A tablet comprising 10 mg to 200 mg of mirabegron or a salt thereof.
    • The tablet is in a sustained release hydrogel-forming formulation.
    • The formulation comprises a hydrogel-forming polymer with an average molecular weight of 200,000 to 7,000,000.
    • The formulation also comprises an additive with a water solubility of at least 0.1 g/mL at 20±5 °C.

U.S. Patent No. 11,707,451: "Pharmaceutical Composition for Modified Release" (Issued Jul. 25, 2023)

The Invention Explained

  • Problem Addressed: Like its counterpart, this patent addresses the "food effect" observed in conventional mirabegron tablets, where pharmacokinetic results varied significantly based on food intake (’451 Patent, col. 1:50-59).
  • The Patented Solution: Rather than claiming the composition itself, this patent claims a method of treating overactive bladder with a "reduced food effect." The method comprises administering a mirabegron tablet formulated to provide "a continuous drug release for at least 4 hours after oral administration" (’451 Patent, Claim 1). By extending the release beyond four hours, the formulation’s properties, not the patient’s digestive state, dictate the rate of drug absorption, thereby minimizing variability (’451 Patent, col. 2:47-54).
  • Technical Importance: This patent protects the therapeutic application of a formulation with specific performance characteristics, linking the technical feature of a minimum release duration directly to the clinical benefit of a reduced food effect (’451 Patent, col. 45:1-12).

Key Claims at a Glance

  • The complaint asserts infringement of one or more claims of the ’451 Patent (Compl. ¶101). Independent Claim 1 is the lead asserted claim.
  • Essential Elements of Independent Claim 1:
    • A method for treating overactive bladder with a reduced food effect.
    • The method comprises administering orally a tablet with 10 mg to 200 mg of mirabegron in a sustained release formulation.
    • The formulation comprises a carrier and provides a continuous drug release for at least 4 hours after administration.
    • The reduced food effect is defined in comparison to an immediate release formulation of mirabegron.

Multi-Patent Capsule: U.S. Patent No. 12,097,189, "Pharmaceutical Composition for Modified Release" (Issued Sep. 24, 2024)

Technology Synopsis

The ’189 Patent claims methods for treating overactive bladder with a reduced food effect, similar to the ’451 Patent. It further refines the definition of "reduced food effect" by adding a specific pharmacokinetic outcome: the claimed method results in a difference in the rate of decrease of maximum drug concentration (Cmax) of 10% or more when compared to an immediate-release capsule formulation of mirabegron (Compl. ¶34).

Asserted Claims

The complaint asserts infringement of one or more claims (Compl. ¶112). Claim 1 is the lead independent claim.

Accused Features

The complaint alleges that Defendants’ ANDA products are required to be bioequivalent to Myrbetriq®, and that Myrbetriq® exhibits the claimed reduction in food effect and Cmax variability. Therefore, Defendants' products will necessarily meet these method claim limitations, and their product labels will induce physicians and patients to perform the infringing method (Compl. ¶¶116-117, 149-151).

III. The Accused Instrumentality

Product Identification

The accused instrumentalities are the generic mirabegron extended-release oral tablets, in 25 mg and 50 mg strengths, for which Defendants Ascent Pharmaceuticals, Inc. (ANDA No. 218172) and MSN (ANDA No. 218543) are seeking FDA approval (Compl. ¶¶6, 11).

Functionality and Market Context

The complaint alleges that to secure FDA approval, Defendants must demonstrate that their generic products are bioequivalent to the reference listed drug, Astellas's Myrbetriq® tablets (Compl. ¶¶64, 70, 81). This requires the ANDA products to have the same active ingredient, dosage form, and administration method, and to exhibit comparable dissolution properties and pharmacokinetic profiles (Compl. ¶¶71, 82). The complaint includes a table from the FDA's "Mirabegron Guidance" that specifies the dissolution testing requirements for establishing this bioequivalence (Compl. p. 13). Plaintiff's infringement theory is premised on the allegation that by meeting these mandatory bioequivalence standards, Defendants' products will necessarily adopt the patented formulation characteristics and performance profiles of Myrbetriq® (Compl. ¶¶96, 105, 116).

IV. Analysis of Infringement Allegations

12,059,409 Patent Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
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, or a pharmaceutically acceptable salt thereof... Defendants’ ANDA Products are extended-release tablets containing either 25 mg or 50 mg of mirabegron. ¶93, ¶124 col. 14:14-18
...in a sustained release hydrogel-forming formulation comprising a hydrogel-forming polymer having an average molecular weight of 200,000 to 7,000,000... The complaint alleges on information and belief that to match the Myrbetriq® dissolution profile, Defendants copied the formulation and used polyethylene oxide (or an equivalent) with a molecular weight in the claimed range. ¶94, ¶125 col. 14:18-21
...and an additive having a water solubility of at least 0.1 g/mL at 20±5 °C. The complaint alleges on information and belief that to match the Myrbetriq® dissolution profile, Defendants copied the formulation and used polyethylene glycol (or an equivalent) with the claimed water solubility. ¶95, ¶126 col. 14:21-23
  • Identified Points of Contention:
    • Scope Questions: The infringement theory relies heavily on the premise that achieving bioequivalence requires copying the patented formulation. A primary question will be whether Defendants’ ANDA products are in fact "sustained release hydrogel-forming formulation[s]" as claimed, or if they achieve bioequivalence through an alternative, non-infringing design.
    • Technical Questions: The case will likely depend on evidence obtained from Defendants' confidential ANDA filings. The central technical question is what specific excipients (polymers and additives) Defendants actually used and whether those components meet the molecular weight and solubility limitations recited in Claim 1 of the ’409 Patent.

11,707,451 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, comprising administering orally to a subject in need thereof a tablet comprising 10 mg to 200 mg of...mirabegron... Defendants’ proposed product labels will instruct for oral administration of their 25 mg or 50 mg mirabegron tablets for the treatment of overactive bladder. ¶76, ¶87, ¶103, ¶135 col. 45:1-7
...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 complaint alleges that because Defendants' products must be bioequivalent to Myrbetriq® tablets, which provide such a release, the accused products will likewise provide a continuous drug release for at least 4 hours. ¶105, ¶138 col. 45:7-11
...wherein the reduced food effect is compared to that after oral administration of an immediate release formulation comprising mirabegron. The complaint alleges that Defendants' proposed product labels will instruct that the tablets can be taken with or without food, which encourages the practice of the claimed method and demonstrates the product has a reduced food effect relative to an immediate-release version. ¶78, ¶89, ¶106, ¶139 col. 45:11-14
  • Identified Points of Contention:
    • Scope Questions: Does meeting the FDA's regulatory standard for "bioequivalence" necessarily mean an ANDA product meets the technical limitation of providing "a continuous drug release for at least 4 hours"? Defendants may argue that different release profiles could still result in a finding of bioequivalence.
    • Technical Questions: For the method claims, infringement hinges on inducement. A key question is whether the instructions in Defendants' proposed product labels will be found to actively encourage or instruct physicians and patients to perform the claimed method of treatment with a reduced food effect.

V. Key Claim Terms for Construction

  • Term: "sustained release hydrogel-forming formulation" (’409 Patent, Claim 1)

    • Context and Importance: This term defines the core structure of the claimed composition. The infringement case against the ’409 Patent depends on whether Defendants’ ANDA products fall within this definition. Practitioners may focus on this term because Defendants could argue they achieved an extended-release profile using a different technology (e.g., an insoluble matrix or an osmotic pump system) that is not "hydrogel-forming."
    • Intrinsic Evidence for Interpretation:
      • Evidence for a Broader Interpretation: The specification lists a wide variety of "hydrogel-forming polymer[s]," including polyethylene oxide, hypromellose, hydroxypropyl cellulose, and others, suggesting the term is intended to cover a class of materials rather than a single specific structure (’409 Patent, col. 10:11-21).
      • Evidence for a Narrower Interpretation: The patent describes the formulation as one that is "almost completely gelled during the retention in the stomach and the small intestine" (’409 Patent, col. 9:25-29). A defendant could argue this functional requirement narrows the term to exclude formulations that do not form a comprehensive gel in this manner.

  • Term: "reduced food effect" (’451 Patent, Claim 1)

    • Context and Importance: This term defines the central therapeutic benefit of the claimed method. Its construction is critical because the parties may dispute what constitutes a "reduced" effect and how it should be measured against the baseline "immediate release formulation."
    • Intrinsic Evidence for Interpretation:
      • Evidence for a Broader Interpretation: Claim 1 of the ’451 patent does not quantify the necessary reduction. Plaintiff may argue that any statistically meaningful decrease in pharmacokinetic variability compared to the immediate release formulation satisfies this limitation. The stated object is to "reduce the effects by food" generally (’451 Patent, col. 2:54-55).
      • Evidence for a Narrower Interpretation: The ’189 Patent, which shares a specification, quantifies a reduced food effect as a "difference in a rate of decrease of Cmax of 10% or more" (’189 Patent, Claim 1). Defendants may argue that this provides context suggesting "reduced" in the ’451 patent implies a similarly meaningful, quantitative threshold rather than any de minimis reduction.

VI. Other Allegations

  • Indirect Infringement: The complaint alleges that Defendants will induce and contribute to the infringement of the method claims of the ’451 and ’189 Patents. The basis for these allegations is the proposed prescribing information (product labels) for the ANDA products, which are expected to be substantially identical to the Myrbetriq® label. The complaint alleges these labels will instruct and encourage healthcare professionals and patients to administer the tablets for treating overactive bladder, including with or without food, which constitutes performance of the patented methods (Compl. ¶¶106-107, 117-118, 139-140, 151-152).
  • Willful Infringement: The complaint does not include a separate count for willful infringement or allege pre-suit knowledge of the patents-in-suit. It alleges that Defendants will have actual knowledge of each patent "at least by the filing date of this Complaint" (Compl. ¶¶108, 119, 141, 153), which may form a basis for seeking enhanced damages for any post-filing infringement.

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

  • A central question will be one of compositional fact: What are the actual ingredients and structural properties of the Defendants’ generic tablets? The litigation will likely turn on evidence from the confidential ANDA submissions that either confirms or refutes the complaint’s core allegation that Defendants copied the patented hydrogel formulation to achieve regulatory bioequivalence.
  • A key legal issue will be one of infringement by equivalence: Can the FDA regulatory standard of "bioequivalence" serve as a proxy for meeting specific patent claim limitations? The court will have to determine whether demonstrating that an ANDA product has a similar pharmacokinetic profile to the brand-name drug is sufficient to prove it also meets the distinct technical requirements of the asserted claims, such as providing "continuous drug release for at least 4 hours."