DCT

2:15-cv-06541

Merck Sharp & Dohme Corp v. Actavis Laboratories FL Inc

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I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 2:15-cv-06541, D.N.J., 08/31/2015
  • Venue Allegations: Plaintiffs allege venue is proper in the District of New Jersey based on Defendants' substantial, continuous, and systematic contacts with the state, including maintaining principal places of business in Parsippany, New Jersey, and conducting activities related to the development, marketing, and sale of generic pharmaceutical products in the district.
  • Core Dispute: Plaintiffs allege that Defendants' filing of an Abbreviated New Drug Application (ANDA) to market a generic version of Plaintiffs' DIFICID® (fidaxomicin) tablets constitutes an act of infringement of five patents related to the fidaxomicin compound, its stereochemically pure forms, and its crystalline polymorphs.
  • Technical Context: The technology concerns fidaxomicin, a macrocyclic antibiotic used for treating Clostridium difficile-associated diarrhea, a significant and potentially life-threatening gastrointestinal infection often acquired in healthcare settings.
  • Key Procedural History: The litigation was initiated under the Hatch-Waxman Act following Plaintiffs' receipt of a notice letter from Actavis dated July 23, 2015, which informed Plaintiffs that Actavis had filed ANDA No. 208443 containing a Paragraph IV certification, asserting that the patents-in-suit are invalid, unenforceable, and/or will not be infringed by the proposed generic product.

Case Timeline

Date Event
2004-05-14 Earliest Priority Date for '489 and '551 Patents
2007-01-22 Earliest Priority Date for '508, '249, and '510 Patents
2008-05-27 '508 Patent Issued
2011-01-04 '249 Patent Issued
2011-03-15 '489 Patent Issued
2013-11-19 '551 Patent Issued
2014-10-14 '510 Patent Issued
2015-07-23 Date of Actavis's ANDA Notice Letter
2015-08-31 Complaint Filing Date

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

U.S. Patent No. 7,906,489 - "18-Membered Macrocycles and Analogs Thereof"

  • Patent Identification: U.S. Patent No. 7,906,489, "18-Membered Macrocycles and Analogs Thereof," issued March 15, 2011 (Compl. ¶37).

The Invention Explained

  • Problem Addressed: The patent's background describes the challenge of treating antibiotic-associated diarrhea (AAD), particularly cases caused by Clostridium difficile, and notes the growing problem of antibiotic resistance, which limits the effectiveness of existing treatments like vancomycin and metronidazole ('489 Patent, col. 5:1-50).
  • The Patented Solution: The invention is directed to methods of treating C. difficile infections using a stereochemically pure form of an antibiotic called Tiacumicin B (fidaxomicin). The inventors discovered that the "R-isomer" of the compound, specifically the stereochemical configuration at the C-19 position, exhibits surprisingly higher biological activity than other isomers ('489 Patent, col. 6:21-34; Abstract). By using a composition that is substantially pure R-Tiacumicin B, the method provides a more potent treatment.
  • Technical Importance: This discovery enabled the development of a more effective, targeted antibiotic therapy using a specific, highly active stereoisomer, addressing a critical need for new treatments against a serious nosocomial pathogen ('489 Patent, col. 6:1-5).

Key Claims at a Glance

The complaint asserts infringement of "one or more claims" without specifying them (Compl. ¶63). Independent claim 1 is representative:

  • A method of treating diarrhea caused by C. difficile gastrointestinal infection in a human patient in need thereof
  • comprising orally administering to said patient a therapeutically effective amount of a compound having the formula (IV) [R-Tiacumicin B] or a pharmaceutically acceptable salt thereof
  • combined with one or more pharmaceutically acceptable carriers
  • wherein the compound having formula (IV) is greater than 90% by weight stereomerically pure ('489 Patent, col. 30:60-67).

U.S. Patent No. 8,586,551 - "18-Membered Macrocycles and Analogs Thereof"

  • Patent Identification: U.S. Patent No. 8,586,551, "18-Membered Macrocycles and Analogs Thereof," issued November 19, 2013 (Compl. ¶40).

The Invention Explained

  • Problem Addressed: As with its parent '489 patent, this patent addresses the need for effective treatments for bacterial infections like C. difficile-associated diarrhea ('551 Patent, col. 5:1-58).
  • The Patented Solution: Rather than claiming a method of use, this patent claims the purified compound itself. The invention is the isolated R-Tiacumicin B compound, which is "free from other stereoisomers" ('551 Patent, col. 30:4-9). This composition of matter claim is based on the same underlying discovery as the '489 patent: the superior and unexpected potency of the stereochemically pure R-isomer ('551 Patent, col. 6:16-32).
  • Technical Importance: By claiming the isolated, purified active molecule, the patent provides a distinct and fundamental layer of intellectual property protection for the drug substance itself, complementing the method-of-use claims of the '489 patent.

Key Claims at a Glance

The complaint asserts infringement of "one or more claims" without specifying them (Compl. ¶77). Independent claim 1 is representative:

  • An isolated compound having the formula [for R-Tiacumicin B]
  • free from other stereoisomers of the compound ('551 Patent, col. 30:4-9).

Multi-Patent Capsule: U.S. Patent No. 7,378,508

  • Patent Identification: U.S. Patent No. 7,378,508, "Polymorphic Crystalline Forms of Tiacumicin B," issued May 27, 2008 (Compl. ¶43).
  • Technology Synopsis: This patent addresses the technical challenge that a given pharmaceutical compound can exist in different solid-state crystal structures, or polymorphs, which can affect its stability, manufacturability, and bioavailability ('508 Patent, col. 2:1-27). The invention discloses and claims specific, novel polymorphic forms of Tiacumicin B that are suitable for use in a pharmaceutical product.
  • Asserted Claims: One or more unspecified claims (Compl. ¶91).
  • Accused Features: The crystalline form of the fidaxomicin active pharmaceutical ingredient in Actavis's ANDA product (Compl. ¶91).

Multi-Patent Capsule: U.S. Patent No. 7,863,249

  • Patent Identification: U.S. Patent No. 7,863,249, "Macrolide Polymorphs, Compositions Comprising Such Polymorphs, and Methods of Use and Manufacture Thereof," issued January 4, 2011 (Compl. ¶46).
  • Technology Synopsis: This patent is part of the same family as the '508 patent and is also directed to novel crystalline and amorphous forms of Tiacumicin B ('249 Patent, col. 2:15-24). It claims pharmaceutical compositions comprising specific polymorphic forms, providing protection for the formulated drug product.
  • Asserted Claims: One or more unspecified claims (Compl. ¶105).
  • Accused Features: The fidaxomicin composition, including its specific polymorphic form, in Actavis's ANDA product (Compl. ¶105).

Multi-Patent Capsule: U.S. Patent No. 8,859,510

  • Patent Identification: U.S. Patent No. 8,859,510, "Macrocyclic Polymorphs, Compositions Comprising Such Polymorphs, and Methods of Use and Manufacture Thereof," issued October 14, 2014 (Compl. ¶49).
  • Technology Synopsis: Continuing the work of the other polymorph patents, this patent discloses and claims methods of treating bacterial infections by administering compositions containing specific polymorphic forms of Tiacumicin B ('510 Patent, col. 2:12-25).
  • Asserted Claims: One or more unspecified claims (Compl. ¶119).
  • Accused Features: The use of Actavis's ANDA product, which contains a specific polymorphic form of fidaxomicin, for the treatment of bacterial infections (Compl. ¶119).

III. The Accused Instrumentality

  • Product Identification: "Actavis's Fidaxomicin Tablets," a proposed generic drug product that is the subject of Abbreviated New Drug Application (ANDA) No. 208443 (Compl. ¶52).
  • Functionality and Market Context: The accused product is an oral tablet intended as a generic copy of Plaintiffs' DIFICID® tablets (Compl. ¶52). The complaint alleges that by filing its ANDA, Actavis represented to the FDA that its product has the same active ingredient (fidaxomicin), method of administration, dosage form, and strength as DIFICID®, and is bioequivalent to it (Compl. ¶55). Upon approval, the product would be marketed for the treatment of Clostridium difficile-associated diarrhea, directly competing with DIFICID® (Compl. ¶57). No probative visual evidence provided in complaint.

IV. Analysis of Infringement Allegations

'489 Patent Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
A method of treating diarrhea caused by C. difficile gastrointestinal infection in a human patient... Actavis's ANDA product is intended for the treatment of Clostridium difficile-associated diarrhea, and its proposed labeling will direct this use by medical professionals and patients. ¶57 col. 30:60-62
...comprising orally administering...a therapeutically effective amount... The accused ANDA product is an oral tablet formulation containing fidaxomicin. ¶52, ¶55 col. 30:62-63
...of a compound having the formula (IV)... The active ingredient in the ANDA product is fidaxomicin, the compound of formula (IV). ¶55 col. 30:63-64
...wherein the compound...is greater than 90% by weight stereomerically pure. The complaint alleges the ANDA product is a generic copy of DIFICID®, which contains the stereomerically pure R-isomer of fidaxomicin, thereby implicitly alleging it meets the purity requirement. ¶55, ¶63 col. 30:65-67

'551 Patent Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
An isolated compound having the formula: [R-Tiacumicin B] The active pharmaceutical ingredient in the accused ANDA product is fidaxomicin, which the complaint alleges is a copy of the branded drug's active ingredient. ¶55, ¶77 col. 30:4-6
...free from other stereoisomers of the compound. The complaint alleges that the ANDA product is a generic copy of DIFICID®, which contains the R-isomer of fidaxomicin free from other stereoisomers, thereby implicitly alleging it meets this limitation. ¶55, ¶77 col. 30:7-9
  • Identified Points of Contention:
    • Scope Questions: The primary dispute for the '551 Patent will likely involve the construction of the term "free from other stereoisomers." Does this term require 100% purity, or does it permit a de minimis or trace level of other stereoisomers? Similarly, for the '489 Patent, the scope of "greater than 90% by weight stereomerically pure" may be disputed, particularly regarding the methods used to measure such purity.
    • Technical Questions: A central evidentiary question will be the actual stereochemical purity of the fidaxomicin API manufactured and used by Actavis. The litigation will likely involve detailed chemical analysis to determine if the composition of the accused ANDA product falls within the scope of the asserted claims.

V. Key Claim Terms for Construction

  • The Term: "free from other stereoisomers" ('551 Patent, claim 1)

  • Context and Importance: This term's construction is dispositive for infringement of the '551 Patent. As an absolute term, its interpretation will determine whether any detectable amount of another stereoisomer is sufficient to place the accused product outside the claim scope. Practitioners may focus on this term because absolute purity is often technically unachievable in pharmaceutical manufacturing.

  • Intrinsic Evidence for Interpretation:

    • Evidence for a Broader Interpretation: A party may argue that in the context of the specification, "free from" should be understood as "substantially pure." The specification repeatedly highlights the invention as being the "substantially pure R-Tiacumicin B" ('551 Patent, col. 6:30-31) and defines "substantially stereomerically pure" as comprising "greater than about 97% by weight of one stereoisomer" ('551 Patent, col. 12:31-34). This suggests the patentee equated being "free from" other isomers with achieving a very high, but not necessarily absolute, level of purity.
    • Evidence for a Narrower Interpretation: A party may argue that the patentee chose the absolute phrase "free from" in the claim, despite using the qualified term "substantially pure" throughout the specification. Under the doctrine of claim differentiation, this choice could be interpreted to mean that the claim requires a higher standard of purity than the embodiments described in the specification, potentially approaching 100%.

  • The Term: "greater than 90% by weight stereomerically pure" ('489 Patent, claim 1)

  • Context and Importance: This term sets the specific purity threshold required for the infringing method. The outcome of the infringement analysis for the '489 patent will depend on whether Actavis's product is proven to meet this numerical limitation.

  • Intrinsic Evidence for Interpretation:

    • Evidence for a Broader Interpretation: A party could argue this is a straightforward numerical limit that should be given its plain and ordinary meaning without further construction. The specification provides context by describing a range of purities, and the claim simply sets a floor at 90% ('489 Patent, col. 13:12-25).
    • Evidence for a Narrower Interpretation: The complaint does not provide sufficient detail for analysis of potential arguments for a narrower interpretation beyond the plain language of the claim.

VI. Other Allegations

  • Indirect Infringement: The complaint alleges induced infringement, stating that Defendants intend to cause medical professionals and patients to infringe the method patents by seeking FDA approval for a product with proposed labeling that directs the claimed therapeutic use (Compl. ¶¶67, 81, 95). It further alleges contributory infringement on the basis that Actavis's ANDA Product is especially made or adapted for infringing uses and is not suitable for substantial noninfringing use (Compl. ¶¶70, 84, 98).
  • Willful Infringement: Willfulness is alleged based on Defendants' knowledge of the patents, which existed at least as of the date the ANDA was submitted with its Paragraph IV certification (Compl. ¶¶71, 85, 99). The complaint further alleges that Defendants "acted without a reasonable basis for believing that they would not be liable for infringing" the patents-in-suit (Compl. ¶¶72, 86, 100).

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

  • A core issue will be one of definitional scope: how will the court construe the purity limitations in the asserted claims? Specifically, can the absolute term "free from other stereoisomers" in the '551 Patent be interpreted to permit trace amounts of impurities, and what are the analytical standards for measuring the "greater than 90% by weight" purity required by the '489 Patent?
  • A key evidentiary question will be one of chemical composition: what is the actual stereochemical purity of the fidaxomicin active ingredient in Actavis's proposed generic product? The case will likely turn on detailed factual evidence developed through discovery and expert testing to determine if the accused product meets the purity thresholds defined by the claims.
  • A third central question will relate to the polymorph patents: can Plaintiffs prove that the specific crystalline form of fidaxomicin used by Actavis is the same as one of the novel forms claimed in the '508, '249, or '510 patents, which are defined by specific X-ray powder diffraction and other physical characteristics?