DCT

1:16-cv-00905

Astellas Pharma Inc v. Actavis Elizabeth LLC

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I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 1:16-cv-00905, D. Del., 10/06/2016
  • Venue Allegations: Venue is based on allegations that Defendants conduct systematic and continuous business in Delaware, a likely destination for the accused generic drug products, and that one of the Plaintiffs, Astellas Pharma Global Development, Inc., is a Delaware corporation that received the Defendants' notice letter.
  • Core Dispute: Plaintiffs allege that Defendants' submission of an Abbreviated New Drug Application (ANDA) to the FDA seeking to market a generic version of the overactive bladder drug Myrbetriq® constitutes an act of infringement of five patents covering the active ingredient mirabegron, its specific crystalline forms, and methods of its use.
  • Technical Context: The technology concerns small-molecule pharmaceutical compounds, specifically β3-adrenergic receptor agonists, developed to treat overactive bladder by relaxing the detrusor smooth muscle.
  • Key Procedural History: This action was initiated under the Hatch-Waxman Act following Defendants' notification to Plaintiffs of their ANDA filing, which included a "Paragraph IV certification" asserting that the patents-in-suit are invalid, unenforceable, or not infringed. The complaint notes that U.S. Patent No. 6,346,532, which covers the mirabegron compound, successfully underwent an ex parte reexamination proceeding where the PTO confirmed its validity and patentability.

Case Timeline

Date Event
1997-10-17 Priority Date for U.S. Patent No. 6346532
2001-10-30 Priority Date for U.S. Patent Nos. 7,342,117 and 7,982,049
2002-02-12 U.S. Patent No. 6,346,532 Issues
2002-11-07 Priority Date for U.S. Patent No. 8,835,474 and U.S. Reissue Patent No. RE44,872
2008-03-11 U.S. Patent No. 7342117 Issues
2011-07-19 U.S. Patent No. 7982049 Issues
2012-06-28 FDA Approves New Drug Application (NDA) for Myrbetriq®
2014-04-29 U.S. Reissue Patent No. RE44,872 Issues
2014-09-16 U.S. Patent No. 8,835,474 Issues
2015-02-24 Reexamination Certificate for U.S. Patent No. 6,346,532 Issues
2016-08-24 Actavis Transmits Notice Letter Regarding ANDA Filing
2016-10-06 Complaint for Patent Infringement Filed

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 that can both promote insulin secretion and potentiate insulin sensitivity (’532 Patent, col. 2:22-30). It further notes that while β3-adrenoceptor agonists were known to have anti-obesity and anti-hyperglycemia effects, existing compounds suffered from side effects due to a lack of selectivity against β1 and β2-receptors in humans (’532 Patent, col. 2:50-61).
  • The Patented Solution: The patent discloses a novel class of amide derivatives that selectively stimulate β3-receptors, thereby providing therapeutic benefits for diabetes, obesity, and hyperlipemia while avoiding the side effects associated with β1 and β2-receptor stimulation (’532 Patent, Abstract; col. 2:22-41). The core of the invention is a general chemical structure, Formula (I), encompassing compounds like mirabegron.
  • Technical Importance: The invention's focus on selectivity for the human β3-receptor addressed a key challenge in the field, aiming to separate desired metabolic effects from undesired cardiovascular (β1) and respiratory (β2) side effects (’532 Patent, col. 2:5-15).

Key Claims at a Glance

  • The complaint asserts independent claim 1 and dependent claims 4, 5, 11, and 15 (Compl. ¶51).
  • Claim 1 claims a compound of a specified general chemical structure, Formula (I), or a salt thereof. The claim defines the scope through a Markush group structure specifying the possible chemical moieties at various positions on the core molecule, including:
    • "ring B" as an optionally substituted heteroaryl group
    • "X" as a linker group such as a bond or lower alkylene
    • "A" as a lower alkylene group
    • Substituents R¹ᵃ, R¹ᵇ, and R² as hydrogen or other small chemical groups
    • "Z" as a nitrogen atom or a =CH- group

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 developed dihydrochloride salt of the active compound, mirabegron, was highly hygroscopic (moisture-absorbing) and unstable, making its use in a pharmaceutical product problematic (’117 Patent, col. 1:30-34). Unstable and hygroscopic compounds are difficult to manufacture, handle, and formulate into a stable drug product with a reliable shelf life.
  • The Patented Solution: The invention discloses novel crystalline forms (polymorphs) of the free base of mirabegron, termed "α-form" and "β-form." The α-form is described as stable and non-hygroscopic, making it suitable for use as a medicine, while the β-form is described as a useful intermediate for producing the α-form (’117 Patent, Abstract; col. 1:45-2:5).
  • Technical Importance: The discovery of stable, non-hygroscopic crystalline forms of a drug substance is a critical step in pharmaceutical development, enabling the creation of a consistent and reliable solid oral dosage form (’117 Patent, col. 1:35-44).

Key Claims at a Glance

  • The complaint asserts at least independent claim 1 (Compl. ¶56). The patent does not appear to contain any dependent claims.
  • Claim 1 claims a specific crystal form of the mirabegron compound, defined by two distinct physical properties:
    • A heat absorption peak between 142° C. and 146° C. as measured by Differential Scanning Calorimetry (DSC).
    • A set of characteristic "main peaks" at specific angles in its powder X-ray diffraction (PXRD) spectrum.

U.S. Patent No. 7,982,049 - "α-Form Or β-Form Crystal Of Acetanilide Derivative"

  • Technology Synopsis: This patent is a continuation of the '117 patent and is directed to the same core technology of stable crystalline forms of mirabegron. It claims pharmaceutical compositions that contain either the α-form or β-form crystal along with a pharmaceutically acceptable carrier (Compl. ¶30).
  • Asserted Claims: Claims 1, 5, 9, and 13 (Compl. ¶60). Claim 1 is independent.
  • Accused Features: The ANDA Product is accused of being a pharmaceutical composition comprising a crystal form of mirabegron and a carrier (Compl. ¶60).

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 previously disclosed compound. It specifically covers methods of treating overactive bladder in a patient by administering an effective amount of mirabegron or a salt thereof (Compl. ¶33).
  • Asserted Claims: Claims 1, 3-4, 6-7, 9-10, and 12 (Compl. ¶64). Claim 1 is independent.
  • Accused Features: The intended use of the ANDA Product, as will allegedly be described in its label, is the treatment of overactive bladder by administering mirabegron (Compl. ¶64, 69).

U.S. Reissue Patent No. RE44,872 - "Remedy for Overactive Bladder Comprising Acetic Acid Anilide Derivative As The Active Ingredient"

  • Technology Synopsis: This patent is a reissue of a parent to the '474 patent and also claims methods of using mirabegron. The claims cover methods of treating overactive bladder in specific patient populations, such as adult subjects or non-diabetic subjects (Compl. ¶¶36-37).
  • Asserted Claims: Claims 1, 3-4, 6, 8-9, and 11-14 (Compl. ¶82). Claim 1 is independent.
  • Accused Features: The intended use of the ANDA Product is for treating overactive bladder in patients, which allegedly corresponds to the claimed methods (Compl. ¶82, 87).

III. The Accused Instrumentality

Product Identification

The accused instrumentality is Defendants' generic version of Myrbetriq® extended-release tablets in 25 mg and 50 mg strengths, referred to as the "ANDA Product" (Compl. ¶45). The action is based on the submission of ANDA No. 209368 seeking FDA approval to market this product (Compl. ¶9, 18).

Functionality and Market Context

The ANDA Product contains the compound mirabegron as its active pharmaceutical ingredient (Compl. ¶18). The complaint provides a diagram depicting the chemical structure of mirabegron, the active ingredient in Myrbetriq® (Compl. ¶40). The product is formulated as an oral extended-release tablet and is intended for the treatment of overactive bladder (OAB) with symptoms of urge urinary incontinence, urgency, and urinary frequency (Compl. ¶41, 45). The filing of the ANDA itself signifies a commercial intent to enter the market for OAB treatments upon receiving FDA approval (Compl. ¶46).

IV. Analysis of Infringement Allegations

6,346,532 Patent Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
A compound of formula (I) . . . or a salt thereof. The ANDA Product contains the compound mirabegron, which the complaint alleges is a compound covered by at least claim 1. ¶51 col. 19:4-13

7,342,117 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 . . . The ANDA Product contains a crystal form of mirabegron. ¶56 col. 1:9-15
. . . having a heat absorption peak at 142 to 146° C. in the DSC analysis . . . The complaint alleges the crystal form of mirabegron in the ANDA Product has the claimed thermal properties. ¶56 col. 2:40-42
. . . 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 the crystal form of mirabegron in the ANDA Product has the claimed powder X-ray diffraction pattern. ¶56 col. 2:7-14

Identified Points of Contention

  • Scope Questions: For the method-of-use patents ('474 and '872), a central question may be whether the claimed methods are valid in light of the '532 patent's disclosure of the compound and its utility as a β3-agonist. The dispute may turn on whether treating overactive bladder was an obvious application of such a compound at the time of the invention.
  • Technical Questions: A primary technical question for the '117 and '049 patents is one of polymorphic identity. The complaint alleges that the ANDA Product contains a "crystal form of mirabegron" that infringes, but provides no technical data (e.g., PXRD or DSC analysis) from the ANDA to support this (Compl. ¶56, 60). The case will require factual development to determine whether the specific crystal form used by Actavis has the precise physical characteristics claimed in the patents, or if Actavis has developed a different, non-infringing polymorph or an amorphous form of the drug.

V. Key Claim Terms for Construction

  • The Term: "around" (from claim 1 of the '117 Patent)
  • Context and Importance: This term appears in the limitation "having main peaks at around 5.32, 8.08..." defining the powder X-ray diffraction pattern. The construction of "around" is critical because it determines the permissible degree of variance from the enumerated peak locations. A narrow construction would make it easier for Actavis to argue non-infringement if its crystal form's peaks deviate even slightly, while a broader construction would give Astellas more leeway to capture crystals with minor experimental variations.
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: The patent uses the term without providing an explicit numerical range, which may support an interpretation that encompasses the ordinary and customary meaning of the term, allowing for known instrumental and experimental variability in PXRD measurements (’117 Patent, col. 2:7-14).
    • Evidence for a Narrower Interpretation: The specification states that "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. 2:12-16). A party could argue this disclaimer applies only to peak intensity, not peak position, suggesting that the positions listed after "around" are meant to be precise, with "around" only accounting for minimal measurement error inherent in the described analytical technique.

VI. Other Allegations

Indirect Infringement

The complaint alleges both induced and contributory infringement of the method-of-use patents ('474 and '872). The inducement allegations are based on Defendants' alleged knowledge of the patents and the assertion that their proposed product label will explicitly instruct healthcare providers and patients to administer the ANDA Product to treat overactive bladder, thereby directly infringing the method claims (Compl. ¶¶69-71, 87-89). The contributory infringement allegations are based on the assertion that the ANDA Product has no substantial non-infringing uses and is especially adapted for the infringing use of treating OAB (Compl. ¶¶77-79, 95-97).

Willful Infringement

The complaint does not contain an explicit count for willful infringement. However, it alleges that Defendants had knowledge of the asserted patents prior to the lawsuit, based on the patents being listed in the FDA's Orange Book and on the "Notice Letter" sent by Actavis to Astellas (Compl. ¶19, 39, 67, 85). The prayer for relief requests a determination that the case is "exceptional" under 35 U.S.C. § 285, a finding often associated with instances of willful infringement (Compl. p. 17, ¶G).

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

  • A central factual question will be one of polymorphic identity: does the crystalline form of mirabegron in Actavis's ANDA product meet the specific powder X-ray diffraction and thermal analysis criteria required by the asserted claims of the '117 and '049 patents, or does it utilize a different, non-infringing crystal form or an amorphous solid?
  • A core legal issue will be one of patent validity: particularly for the method-of-use patents ('474 and '872), can the claims for treating overactive bladder with mirabegron withstand an obviousness challenge in light of the prior art, including the foundational '532 patent that discloses the compound and its general utility as a β3-agonist?
  • A key secondary question will be one of infringement scope: assuming validity of the method claims, does Actavis’s proposed product labeling contain sufficient instructions and indications to establish the specific intent required to prove that Actavis will induce infringement by physicians and patients?