DCT

1:16-cv-00942

Astellas Pharma Inc v. Aurobindo Pharma Ltd

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I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 1:16-cv-00942, D. Del., 10/13/2016
  • Venue Allegations: Venue is alleged to be proper in the District of Delaware based on the Delaware incorporation of two of the Defendant entities and one of the Plaintiff entities. The complaint also alleges Defendants conduct business in Delaware and that Delaware is a likely destination for the accused generic drug products.
  • Core Dispute: Plaintiffs allege that Defendants' filing of an Abbreviated New Drug Application (ANDA) to market a generic version of Plaintiffs' Myrbetriq® product constitutes an act of infringement of four patents covering crystal forms of the active ingredient mirabegron, pharmaceutical compositions thereof, and methods of its use.
  • Technical Context: The technology concerns specific crystalline forms (polymorphs) of the compound mirabegron and its use in pharmaceutical compositions to treat overactive bladder, a condition affecting urinary control.
  • Key Procedural History: The lawsuit was initiated under the Hatch-Waxman Act following Defendants' submission of ANDA No. 209413 and a subsequent "Notice Letter" to Plaintiffs, which included a Paragraph IV certification asserting that the patents-in-suit are invalid, unenforceable, and/or not infringed. One of the asserted patents, U.S. Patent No. RE44,872, is a reissue patent.

Case Timeline

Date Event
2001-10-30 Earliest Priority Date for '117 and '049 Patents
2002-11-07 Earliest Priority Date for '474 and '872 Patents
2008-03-11 U.S. Patent No. 7,342,117 Issues
2011-07-19 U.S. Patent No. 7,982,049 Issues
2012-06-28 FDA Approves Myrbetriq® NDA No. 202611
2014-04-29 U.S. Patent No. RE44,872 Re-issues
2014-09-16 U.S. Patent No. 8,835,474 Issues
2016-09-08 Aurobindo sends Notice Letter regarding ANDA No. 209413
2016-10-13 Complaint Filed

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

U.S. Patent No. 7,342,117 - “α-Form or β-Form Crystal of Acetanilide Derivative,” issued March 11, 2008

The Invention Explained

  • Problem Addressed: The patent's background section states that a previously known dihydrochloride salt form of the active compound was "strongly hygroscopic and is unstable," making its use as a medicine "problematic" (’117 Patent, col. 1:31-33). Such properties can complicate industrial-scale manufacturing, storage, and formulation ('117 Patent, col. 1:36-44).
  • The Patented Solution: The invention provides novel, more stable crystalline forms of the active compound's free base, designated "α-form" and "β-form" crystals ('117 Patent, col. 1:49-56). The patent teaches that the α-form, in particular, is stable, "does not exhibit hygroscopicity," and is therefore "suitable for use as a medicine" ('117 Patent, col. 1:62-65). The β-form is identified as a useful intermediate for producing the more stable α-form ('117 Patent, col. 2:3-5). These forms are distinguished by their unique powder X-ray diffraction (PXRD) patterns and Differential Scanning Calorimetry (DSC) thermal analysis peaks ('117 Patent, col. 2:6-16).
  • Technical Importance: The discovery of stable, non-hygroscopic polymorphs is a critical step in pharmaceutical development, enabling consistent manufacturing, long-term product stability, and reliable dosing ('117 Patent, col. 1:34-44).

Key Claims at a Glance

  • The complaint asserts at least independent claim 1 (Compl. ¶48).
  • Claim 1 Elements:
    • A crystal of (R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilide
    • having a heat absorption peak at 142 to 146° C. in the DSC analysis
    • 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.

U.S. Patent No. 7,982,049 - “α-Form or β-Form Crystal of Acetanilide Derivative,” issued July 19, 2011

The Invention Explained

  • Problem Addressed: The patent identifies the same problem as its parent '117 Patent: the instability and strong hygroscopicity of the previously known dihydrochloride salt of the compound ('049 Patent, col. 1:40-42).
  • The Patented Solution: As a continuation of the application leading to the '117 Patent, this patent claims not just the crystal forms themselves, but "solid pharmaceutical composition[s]" that comprise either the α-form or β-form crystal combined with a "pharmaceutically acceptable carrier" ('049 Patent, Abstract; col. 3:9-19). This extends patent protection to the finished drug product.
  • Technical Importance: This invention covers the practical application of the novel crystal forms by combining them with excipients to create a drug product suitable for administration to a patient.

Key Claims at a Glance

  • The complaint asserts at least independent claim 1 and dependent claims 5, 9, and 13 (Compl. ¶52).
  • Independent Claim 1 Elements:
    • A solid pharmaceutical composition
    • comprising the α-form crystal of (R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilide
    • and a pharmaceutically acceptable carrier.

U.S. Patent No. 8,835,474 - “Remedy for Overactive Bladder Comprising Acetic Acid Anilide Derivative As The Active Ingredient,” issued September 16, 2014

  • Technology Synopsis: The patent addresses the need for improved treatments for overactive bladder (OAB), noting the side effects and limitations of existing anticholinergic drugs ('474 Patent, col. 1:25-33). The invention is based on the discovery that the compound mirabegron has a potent bladder relaxation effect and is useful as a remedy for OAB, particularly for mitigating urinary urgency and prolonging urination intervals ('474 Patent, Abstract; col. 4:33-43).
  • Asserted Claims: At least claims 1, 3-4, 6-7, 9-10, and 12 are asserted, with claim 1 being independent (Compl. ¶56).
  • Accused Features: The accused feature is the intended use of Aurobindo's generic mirabegron product for the treatment of OAB, the indication for which Aurobindo seeks FDA approval (Compl. ¶56).

U.S. Reissue Patent No. RE44,872 - “Remedy for Overactive Bladder Comprising Acetic Acid Anilide Derivative As The Active Ingredient,” re-issued April 29, 2014

  • Technology Synopsis: This patent is a reissue of a patent from the same family as the '474 Patent and is also directed to methods of treating OAB by administering mirabegron. The claims cover treating specific patient populations, such as adult subjects and non-adult subjects who are not suffering from diabetes (Compl. ¶¶32-33; '872 Patent, col. 15:11-26, claims 1, 13-14).
  • Asserted Claims: At least claims 1, 3-4, 6, 8-9, and 11-14 are asserted, with claims 1, 13, and 14 being independent (Compl. ¶74).
  • Accused Features: The accused feature is the intended use of Aurobindo's generic mirabegron product to treat OAB, as allegedly instructed on its proposed product label (Compl. ¶74).

III. The Accused Instrumentality

Product Identification

The accused instrumentality is "Aurobindo's ANDA Product," a generic version of Myrbetriq® extended-release tablets in a 50 mg strength, for which Aurobindo seeks FDA approval via ANDA No. 209413 (Compl. ¶41).

Functionality and Market Context

The product is an oral pharmaceutical composition containing the active ingredient mirabegron and is intended for the treatment of overactive bladder (Compl. ¶41). The complaint provides the chemical formula for mirabegron, identifying the active pharmaceutical ingredient at the heart of the dispute (Compl. ¶36). The filing of the ANDA is alleged to be an attempt to market a generic equivalent to Plaintiffs' branded Myrbetriq® product prior to the expiration of the patents-in-suit (Compl. ¶41, ¶43). The complaint includes a chemical structure diagram to depict the mirabegron compound (Compl. ¶36).

IV. Analysis of Infringement Allegations

’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 is alleged to contain "a crystal form of mirabegron." ¶48 col. 1:49-56
...having a heat absorption peak at 142 to 146° C. in the DSC analysis 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 does not provide specific analytical data but alleges the crystal form in the ANDA Product meets the claim limitations. ¶48 col. 2:6-16

’049 Patent Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
A solid pharmaceutical composition... The ANDA Product is alleged to be a "pharmaceutical composition in an oral dosage form." ¶41 col. 3:9-12
...comprising the α-form crystal of (R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilide... The ANDA Product is alleged to contain "a crystal form of mirabegron." ¶52 col. 3:9-12
...and a pharmaceutically acceptable carrier. The ANDA Product is alleged to contain "a pharmaceutically acceptable carrier." ¶52 col. 3:12-19
  • Identified Points of Contention:
    • Technical Questions: A primary point of contention for the '117 and '049 patents will be one of polymorphic identity. The complaint makes conclusory allegations that Aurobindo's product contains the claimed crystal form but provides no supporting analytical data. The central technical question is whether Aurobindo's ANDA product, upon testing, will exhibit the specific PXRD peaks and DSC thermal properties required by the claims for the "α-form" crystal.
    • Scope Questions: The term "around" in the '117 patent's description of PXRD peaks raises a question of scope. The court may need to determine the degree of variability permitted by this term, which could be pivotal to the infringement analysis.

V. Key Claim Terms for Construction

  • The Term: "main peaks at around [list of 2θ values]" ('117 Patent, Claim 1)
  • Context and Importance: This phrase defines the crystalline "fingerprint" of the patented α-form. Infringement of the '117 patent, and consequently the '049 patent, hinges on whether Aurobindo's product has a PXRD pattern that falls within the scope of this limitation. Practitioners may focus on this term because disputes over polymorph patents often devolve into arguments over the precision of analytical measurements and the meaning of inexact terms like "around."
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: The patent itself suggests that the PXRD pattern should not be interpreted with rigid strictness, stating that "relative intensity can vary a little depending upon the direction of crystal growth, particle size and measurement condition, [so] it should not be strictly interpreted" ('117 Patent, col. 2:12-16). The use of "around" may be argued to reflect this intended flexibility.
    • Evidence for a Narrower Interpretation: The patent provides a specific list of eight peak locations to define the α-form, as well as a representative PXRD diagram (FIG. 3). A party could argue that this combination creates a specific and limiting definition, and that "around" only accounts for minor, ordinary experimental variance, not the absence of peaks or the presence of significant additional ones.

VI. Other Allegations

  • Indirect Infringement: The complaint alleges both induced and contributory infringement of the '474 and '872 method-of-use patents.
    • The inducement theory is based on allegations that Aurobindo's proposed product label "explicitly instructs" healthcare providers and patients to use the ANDA Product to treat overactive bladder in a manner that directly infringes the method claims (Compl. ¶¶ 61, 79).
    • The contributory infringement theory is based on allegations that the ANDA Product is a material part of the invention, is "especially adapted" for the infringing use, and has "no substantial non-infringing uses" (Compl. ¶¶ 69, 71, 87, 89).
  • Willful Infringement: Willfulness is not pleaded as a separate count, but the prayer for relief requests a finding that the case is "exceptional" and an award of attorney fees (Compl., Prayer for Relief ¶G). The complaint alleges that Aurobindo had pre-suit knowledge of the patents via its Notice Letter (Compl. ¶18, ¶¶ 59, 77).

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

  • A central question will be one of polymorphic identity: Will discovery and analytical testing show that the crystalline form of mirabegron in Aurobindo's ANDA product possesses the specific PXRD and DSC characteristics of the "α-form" crystal as defined in the '117 and '049 patents? The outcome of this technical "battle of the experts" will be dispositive for the composition-of-matter claims.
  • A second key issue will concern infringement and validity of the method claims: For the '474 and '872 patents, if Aurobindo’s proposed label mirrors the indication for Myrbetriq®, inducement may be relatively clear. The focus would then shift to Aurobindo’s defenses of invalidity (e.g., obviousness) and non-infringement, which were asserted in its Paragraph IV letter but are not yet detailed in the pleadings.
  • Finally, the assertion of the '872 reissue patent raises a potential issue of intervening rights: The court may need to consider whether the asserted reissue claims are substantively identical to the original claims and whether Aurobindo engaged in any conduct that would give rise to an intervening rights defense under 35 U.S.C. § 252.