DCT

1:23-cv-00629

Astellas Pharma Inc v. Evitalin LLC

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I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 1:23-cv-00629, D. Del., 10/05/2023
  • Venue Allegations: Venue is alleged to be proper in the District of Delaware because Defendants are organized under the laws of Delaware, conduct business within the state, and have committed the alleged acts of infringement in the district.
  • Core Dispute: Plaintiff alleges that Defendants’ compounded mirabegron pharmaceutical products infringe four patents related to the mirabegron chemical compound, its specific crystalline forms, pharmaceutical compositions containing it, and its use as a method for treating overactive bladder.
  • Technical Context: The technology concerns small-molecule pharmaceuticals, specifically the compound mirabegron, which is a beta-3 adrenergic agonist used to treat overactive bladder.
  • Key Procedural History: The complaint notes that U.S. Patent No. 6,346,532, which claims the mirabegron compound, survived an ex parte reexamination proceeding where its validity was confirmed. It also references prior litigation in the same district, [Astellas Pharma Inc.](https://ai-lab.exparte.com/party/astellas-pharma-us-inc) v. Actavis Elizabeth LLC, which resulted in constructions for the key claim terms "main peaks" and "α-form crystal," central to two of the patents-in-suit. Plaintiff also alleges Defendants had pre-suit knowledge of the patents based on cease-and-desist letters sent in June 2019 and February 2023.

Case Timeline

Date Event
1997-10-17 ’532 Patent Priority Date
2001-10-30 ’117 and ’049 Patents Priority Date
2002-02-12 ’532 Patent Issue Date
2002-11-07 ’474 Patent Priority Date
2008-03-11 ’117 Patent Issue Date
2011-07-19 ’049 Patent Issue Date
2012-06-28 FDA Approval of Myrbetriq® (mirabegron)
2014-09-16 ’474 Patent Issue Date
2015-02-24 ’532 Patent Reexamination Certificate Issue Date
2019-05-31 Alleged Start of Infringing Activity by Defendants
2019-06-14 Plaintiff Sends First Cease-and-Desist Letter
2023-02-15 Plaintiff Sends Second Cease-and-Desist Letter
2023-10-05 First Amended Complaint Filing Date

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

U.S. Patent No. 6,346,532 - “Amide Derivatives or Salts Thereof”

The Invention Explained

  • Problem Addressed: The patent describes a need for new therapeutic agents for diabetes mellitus. At the time, existing treatments were accompanied by a continuous hyperglycemic state, and previously developed β3-receptor agonists, while useful for obesity and hyperglycemia, caused side effects such as increased heart rate and muscular tremor due to their non-selective action on β1- and β2-receptors (’532 Patent, col. 1:10-54).
  • The Patented Solution: The invention discloses a class of novel amide derivatives, defined by a general chemical structure (Formula I), that possess both insulin secretion-promoting and insulin sensitivity-potentiating actions. These compounds are described as achieving their therapeutic effect through a selective stimulating action on β3-receptors in humans, thereby avoiding the side effects associated with less selective compounds (’532 Patent, col. 2:23-41).
  • Technical Importance: The invention provided a chemical scaffold for compounds that could potentially treat diabetes and obesity with a more favorable side-effect profile by targeting the human β3-receptor with greater selectivity (’532 Patent, col. 2:34-41).

Key Claims at a Glance

  • The complaint asserts independent claim 1 and dependent claim 5 (Compl. ¶130, 138).
  • Independent Claim 1: A compound of formula (I), or a salt thereof, which covers a genus of chemical structures defined by several constituent chemical groups (R², A, B, X, Z, etc.).
  • Claim 5: A specific compound falling within the genus of claim 1, which is (R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetic acid anilide (the chemical name for mirabegron), or a salt thereof.

U.S. Patent No. 7,342,117 - “α-Form or β-Form Crystal of Acetanilide Derivative”

The Invention Explained

  • Problem Addressed: The patent explains that the previously known dihydrochloride salt form of mirabegron has "strong hygroscopicity and is unstable," making its use as a medicine problematic for industrial-scale manufacturing, formulation, and storage (’117 Patent, col. 1:30-44).
  • The Patented Solution: The invention discloses two new, stable crystalline forms (polymorphs) of the mirabegron free base, designated "α-form" and "β-form." The α-form is described as being particularly stable, non-hygroscopic, and suitable for use as a medicine, while the β-form is described as a useful intermediate for producing the α-form (’117 Patent, col. 1:47-2:5). The patent defines these crystal forms by their unique physical characteristics, such as their powder X-ray diffraction (XRPD) patterns and heat absorption peaks in differential scanning calorimetry (DSC) analysis (’117 Patent, col. 2:6-30).
  • Technical Importance: The development of stable, non-hygroscopic crystalline forms of an active pharmaceutical ingredient is a critical step in drug development, enabling consistent manufacturing, reliable shelf-life, and predictable bioavailability (’117 Patent, col. 1:35-44).

Key Claims at a Glance

  • The complaint asserts independent claim 1 (Compl. ¶146, 155).
  • Independent Claim 1: A crystal of (R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilide that is defined by a combination of two physical properties:
    • a heat absorption peak at 142 to 146° C. in the DSC analysis; and
    • having main peaks at around specific diffraction angles (5.32, 8.08, 15.28, 17.88, 19.04, 20.20, 23.16 and 24.34 in terms of 2θ(°)) in the powder X-ray diffraction.

U.S. Patent No. 7,982,049 - “α-Form or β-Form Crystal of Acetanilide Derivative”

  • Technology Synopsis: This patent is related to the ’117 Patent and addresses the same technical problem of mirabegron salt instability. It claims pharmaceutical compositions that comprise the stable α-form or β-form crystals of mirabegron, combined with a pharmaceutically acceptable carrier (Compl. ¶70-71; ’049 Patent, Abstract).
  • Asserted Claims: The complaint asserts at least Claim 1 (Compl. ¶164, 173).
  • Accused Features: Defendants’ Mirabegron Products are alleged to be solid pharmaceutical compositions in capsule form that comprise the claimed α-form crystal of mirabegron and a pharmaceutically acceptable carrier (Compl. ¶93, 166, 175).

U.S. Patent No. 8,835,474 - “Remedy for Overactive Bladder Comprising Acetic Acid Anilide Derivative As The Active Ingredient”

  • Technology Synopsis: This patent claims a new use for the mirabegron compound. The invention is a method for treating overactive bladder (OAB) in a subject by administering an effective amount of mirabegron or a salt thereof (’474 Patent, Abstract).
  • Asserted Claims: The complaint asserts at least Claim 1 (Compl. ¶182, 192).
  • Accused Features: Defendants are accused of inducing and contributing to the infringement of this method patent by marketing, offering to sell, and selling their Mirabegron Products with instructions and promotional materials that explicitly direct their use for treating OAB (Compl. ¶185, 187, 196).

III. The Accused Instrumentality

Product Identification

  • The accused products are identified as “Defendants’ Mirabegron Products,” which are compounded immediate release capsules containing 20 mg and 40 mg of mirabegron (Compl. ¶21, 110, 122).

Functionality and Market Context

  • The products are compounded by Defendant PharmaLabs and marketed by Defendant menMD through an online platform directly to patients and healthcare providers (Compl. ¶86, 88). The complaint alleges these products are offered for sale specifically for the treatment of overactive bladder and its symptoms, such as urinary incontinence (Compl. ¶87, 121). A screenshot from menMD's product page shows bottles labeled "Mirabegron Capsules" and lists "Used to treat urinary incontinence" as a key feature (Compl. ¶105, Ex. L). Another screenshot of a prescription order form lists "Mirabegron 20mg IR Capsules" and "Mirabegron 40mg IR Capsules" under the heading "PELVIC HEALTH Overactive Bladder" (Compl. ¶111, Ex. Q). The complaint alleges these products have not been approved by the FDA (Compl. ¶99).

IV. Analysis of Infringement Allegations

’532 Patent Infringement Allegations

Claim Element (from Independent Claim 5) Alleged Infringing Functionality Complaint Citation Patent Citation
A compound of claim 1 which is (R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetic acid anilide Defendants’ Mirabegron Products comprise the specific chemical compound known as mirabegron, which corresponds to the compound defined in the claim. ¶132; ¶140 col. 24:14-20
or a salt thereof. The complaint alleges infringement by the compound itself, without specifying whether it is a salt. ¶132; ¶140 col. 24:20-20

’117 Patent Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
A crystal of (R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilide Defendants’ Mirabegron Products allegedly contain crystalline mirabegron, which is the compound recited in the claim. ¶149; ¶158 col. 12:18-22
having a heat absorption peak at 142 to 146° C. in the DSC analysis The complaint alleges that the accused products fall within the scope of the claim, which requires this DSC peak characteristic of the α-form crystal. ¶149; ¶158 col. 12:22-24
and having main peaks at around 5.32, 8.08, 15.28, 17.88, 19.04, 20.20, 23.16 and 24.34 in the terms of 2θ(°) in the powder X-ray diffraction. The complaint alleges that the crystalline mirabegron in the accused products exhibits these characteristic XRPD peaks. ¶149; ¶158 col. 12:24-28
  • Identified Points of Contention:
    • Scope Questions: The primary dispute identified in the complaint for the ’117 and ’049 Patents concerns the proper construction of the term "main peaks." The complaint alleges Defendants' non-infringement position is based on an interpretation that requires high relative intensity for a peak to be considered "main" (Compl. ¶118). This raises the question of whether the court's prior construction of "main peaks"—which explicitly rejected a relative intensity requirement—will be adopted or distinguished in this case (Compl. ¶63, 118).
    • Technical Questions: A central technical question will be what the analytical data (XRPD and DSC) for Defendants' compounded mirabegron API actually shows. The complaint contends that the XRPD peaks at approximately 16.3° and 18.6° 2θ, which Defendants allegedly argued demonstrated non-infringement, are in fact present in the patent's own depiction of the infringing α-form crystal (Compl. ¶117). This suggests a factual dispute over whether the accused product's full analytical signature matches that of the claimed α-form crystal.

V. Key Claim Terms for Construction

  • The Term: "main peaks"
  • Context and Importance: This term, appearing in Claim 1 of the ’117 Patent, is critical because Defendants' non-infringement argument is allegedly premised on it (Compl. ¶115, 118). The definition of what constitutes a "main peak" in the context of an XRPD pattern will likely determine infringement of the patents claiming specific crystalline forms. Practitioners may focus on this term because its interpretation—specifically whether it includes a relative intensity requirement—directly addresses the non-infringement theory advanced by Defendants' counsel pre-suit.
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: The specification of the parent ’117 Patent states that with respect to XRPD data, "since a relative intensity can vary a little depending upon the direction of crystal growth, particle size and measurement condition, it should not be strictly interpreted" (’117 Patent, col. 2:13-18). The complaint also points to a prior court ruling that construed "main peaks" to mean "peaks that are characteristic of the particular crystal form as distinguished from other crystal forms" and rejected a construction based on relative intensity (Compl. ¶63, 118).
    • Evidence for a Narrower Interpretation: An argument for a narrower interpretation might suggest that the ordinary meaning of "main" implies prominence or significance, which in XRPD analysis is commonly associated with higher relative intensity. The patent figures themselves depict the recited peaks as being among the most intense in the pattern, which could be cited to support an implicit intensity requirement (’117 Patent, Fig. 4).

VI. Other Allegations

  • Indirect Infringement: The complaint alleges inducement and contributory infringement of the ’474 method patent. The inducement allegations are based on Defendants’ marketing materials, website, price lists, and prescription order forms, which allegedly encourage and instruct customers and healthcare providers to use the Mirabegron Products for the patented purpose of treating overactive bladder (Compl. ¶185, 187). Contributory infringement is alleged on the basis that the product is a material part of the invention, is not a staple article of commerce, and has no substantial non-infringing use, as its only indicated use is the infringing one (Compl. ¶194, 196, 200).
  • Willful Infringement: The complaint alleges willful infringement based on Defendants' knowledge of the patents-in-suit no later than June 14, 2019, the date of a cease-and-desist letter from Plaintiffs (Compl. ¶101, 124). Willfulness is further alleged based on continued infringement after a second letter in February 2023 and after the filing of the original complaint in this action on June 9, 2023 (Compl. ¶108, 126).

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

  • A core issue will be one of claim construction and issue preclusion: can Defendants distinguish the facts of this case from the court's prior ruling in Astellas v. Actavis to argue for a narrower construction of "main peaks" that includes a relative intensity requirement, or will the prior construction be deemed controlling?
  • A key evidentiary question will be one of analytical characterization: what will forensic laboratory analysis of the accused compounded products reveal about their precise chemical and polymorphic identity, and will that evidence demonstrate the presence of the claimed α-form crystal as defined by the patent's analytical parameters?
  • A central question for the method-of-use patent will be intent to induce infringement: does the extensive documentation of Defendants' marketing, pricing, and ordering systems, which explicitly and exclusively target the "overactive bladder" indication, satisfy the legal standard for specific intent to encourage infringing acts by physicians and patients?