DCT

1:18-cv-00237

Pharmacyclics LLC v. Shilpa Medicare Ltd

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I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 1:18-cv-00237, D. Del., 02/09/2018
  • Venue Allegations: Venue is alleged to be proper for the foreign defendants under the theory that they may be sued in any judicial district. The complaint also alleges that the defendants intend to market and sell their generic products in Delaware and have previously engaged in patent litigation in the district.
  • Core Dispute: Plaintiff alleges that Defendants' Abbreviated New Drug Applications (ANDAs) seeking approval to market generic versions of the cancer drug IMBRUVICA® (ibrutinib) constitute an act of infringement of five U.S. patents covering crystalline forms of ibrutinib and methods of its use.
  • Technical Context: The technology relates to specific crystalline forms (polymorphs) and methods of use for ibrutinib, a small molecule inhibitor of Bruton's tyrosine kinase (BTK) used in the treatment of various B-cell malignancies.
  • Key Procedural History: This action was initiated under the Hatch-Waxman Act following Plaintiffs’ receipt of Paragraph IV Notice Letters from Defendants, which asserted that their proposed generic products do not infringe the asserted patents or that the patents are invalid. The complaint alleges inconsistencies between the data provided in Shilpa's notice letter and the contents of its ANDA submission.

Case Timeline

Date Event
2011-06-03 Priority Date for ’999, ’881, and ’883 Patents
2012-06-04 Priority Date for ’753 and ’455 Patents
2015-04-07 U.S. Patent No. 8,999,999 Issues
2016-03-29 U.S. Patent No. 9,296,753 Issues
2017-08-08 U.S. Patent No. 9,725,455 Issues
2017-10-31 U.S. Patent No. 9,801,881 Issues
2017-10-31 U.S. Patent No. 9,801,883 Issues
2017-12-28 Shilpa sends Paragraph IV Notice Letter to Plaintiffs
2018-01-02 Sun sends Paragraph IV Notice Letter to Plaintiffs
2018-02-09 Complaint Filed

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

U.S. Patent No. 9,296,753 - "Crystalline Forms of a Bruton's Tyrosine Kinase Inhibitor," Issued March 29, 2016

The Invention Explained

  • Problem Addressed: The patent background describes the role of Bruton's tyrosine kinase (Btk) in B-cell signaling pathways and its importance as a therapeutic target for diseases benefiting from Btk inhibition ('753 Patent, col. 1:28-43). The development of a drug product requires a stable, well-characterized physical form of the active pharmaceutical ingredient.
  • The Patented Solution: The invention provides specific crystalline forms of the Btk inhibitor ibrutinib ('753 Patent, Abstract). These forms, including solvates and anhydrous polymorphs, are characterized by analytical data such as X-Ray powder diffraction (XRPD) patterns, which helps ensure reproducibility and stability in a pharmaceutical composition ('753 Patent, col. 2:45-51, Fig. 1).
  • Technical Importance: Identifying and characterizing distinct crystalline forms of a drug is critical for pharmaceutical development, as different forms can possess different solubility, stability, and bioavailability profiles, directly impacting a drug's safety and efficacy.

Key Claims at a Glance

  • The complaint alleges infringement of one or more of claims 1-18 (Compl. ¶69). Independent claim 1 is representative.
  • Independent Claim 1:
    • A crystalline Form A of 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one
    • that has an X-Ray powder diffraction (XRPD) pattern as shown in FIG. 1.
  • The complaint does not explicitly reserve the right to assert dependent claims for this patent.

U.S. Patent No. 9,725,455 - "Crystalline Forms of a Bruton's Tyrosine Kinase Inhibitor," Issued August 8, 2017

The Invention Explained

  • Problem Addressed: Similar to the ’753 Patent, this patent addresses the need for stable and well-defined physical forms of the Btk inhibitor ibrutinib for use in pharmaceutical products ('455 Patent, col. 1:28-43).
  • The Patented Solution: This patent, a continuation of the application leading to the ’753 Patent, claims specific crystalline forms of ibrutinib, defined by a set of characteristic peaks in an X-ray powder diffraction (XRPD) pattern ('455 Patent, Claim 1). This method of claiming provides a different scope of protection than claiming by reference to a figure, defining the novel form by its most prominent analytical features ('455 Patent, col. 2:45-51).
  • Technical Importance: Patenting crystalline forms defined by specific analytical data is a common and important strategy in the pharmaceutical industry to protect novel, commercially valuable forms of an active ingredient.

Key Claims at a Glance

  • The complaint alleges infringement of one or more of claims 1-13 (Compl. ¶81). Independent claim 1 is representative.
  • Independent Claim 1:
    • A crystalline Form A of 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one
    • that has an X-ray powder diffraction (XRPD) pattern comprising 2-Theta peaks at 5.7±0.1°, 18.9±0.1°, and 21.3±0.1°.
  • The complaint does not explicitly reserve the right to assert dependent claims for this patent.

U.S. Patent No. 8,999,999 - "Use of Inhibitors of Bruton's Tyrosine Kinase (BTK)," Issued April 7, 2015

  • Technology Synopsis: The patent claims a method of treating a hematological malignancy. The method involves administering an irreversible Btk inhibitor to induce "lymphocytosis," which is a temporary increase in the number of lymphocytes in the peripheral blood, followed by a subsequent decrease ('999 Patent, Abstract). This transient lymphocytosis is described as a pharmacodynamic marker of the drug's mechanism of action, where malignant cells are mobilized from lymphoid tissues into the blood before being cleared.
  • Asserted Claims: The complaint alleges infringement of "one or more claims" of the ’999 Patent without specifying any particular claims (Compl. ¶110).
  • Accused Features: The complaint alleges that Sun's ANDA product, if approved and marketed, would be used according to its label to treat hematological malignancies in a manner that practices the claimed method (Compl. ¶¶110-112).

U.S. Patent No. 9,801,881 - "Use of Inhibitors of Bruton's Tyrosine Kinase (BTK)," Issued October 31, 2017

  • Technology Synopsis: This patent claims methods for treating relapsed or refractory chronic lymphocytic leukemia (CLL) in patients who have a specific nucleic acid deletion in chromosome 17 (del 17p). The claimed method requires administering a specific daily oral dose of ibrutinib ('881 Patent, Abstract, Claim 1). This invention targets a specific, high-risk patient sub-population for whom certain standard therapies may be less effective.
  • Asserted Claims: The complaint alleges infringement of "one or more claims" of the ’881 Patent without further specification (Compl. ¶119).
  • Accused Features: The complaint alleges that the labeled indications for Sun's proposed generic product will lead to its use in treating the specific patient population defined in the claims, thereby inducing infringement (Compl. ¶¶119, 121).

U.S. Patent No. 9,801,883 - "Use of Inhibitors of Bruton's Tyrosine Kinase (BTK)," Issued October 31, 2017

  • Technology Synopsis: This patent claims a method of treating chronic lymphocytic leukemia (CLL) in an individual who is "treatment-naive" and at least 65 years of age. The method involves administering a specific daily oral dose of 420 mg of ibrutinib ('883 Patent, Abstract, Claim 1). The invention is directed to a first-line therapy setting for a specific elderly patient population.
  • Asserted Claims: The complaint alleges infringement of "one or more claims" of the ’883 Patent without identifying specific claims (Compl. ¶128).
  • Accused Features: The complaint alleges that Sun's proposed generic ibrutinib product will be prescribed according to its label for the first-line treatment of elderly CLL patients, which would practice the patented method (Compl. ¶¶128, 130).

III. The Accused Instrumentality

  • Product Identification: The accused instrumentalities are the proposed generic ibrutinib capsule products described in Shilpa's ANDA No. 211261 and Sun's ANDA No. 211319 (Compl. ¶1).
  • Functionality and Market Context: The accused products are generic versions of IMBRUVICA®, a "highly successful" and "ground-breaking" drug that functions as an irreversible inhibitor of Bruton's tyrosine kinase (BTK) (Compl. ¶¶1-2). IMBRUVICA® is approved for treating various cancers of the blood and bone marrow, including mantle cell lymphoma and chronic lymphocytic leukemia (Compl. ¶¶3, 5-6). By filing their ANDAs, Defendants seek FDA approval to market therapeutically equivalent generic versions of IMBRUVICA® prior to the expiration of Plaintiffs' patents (Compl. ¶1). The act of filing an ANDA with a Paragraph IV certification is itself an act of infringement under 35 U.S.C. § 271(e)(2)(A), which forms the basis for this lawsuit (Compl. ¶71).

IV. Analysis of Infringement Allegations

The complaint does not provide a claim chart or a detailed narrative of its infringement theory. It makes general allegations that the Defendants' ANDA products will infringe "one or more claims" of each asserted patent (e.g., Compl. ¶¶68, 80, 92, 101, 110, 119, 128). The infringement allegations are based on the statutory act of filing an ANDA seeking approval for a generic drug prior to the expiration of the patents listed in the FDA's Orange Book for that drug.

  • Identified Points of Contention:
    • Factual Questions (Polymorph Patents '753 and '455): The primary point of contention will likely be a factual dispute over the physical form of the ibrutinib active pharmaceutical ingredient in the Defendants' ANDA products. The central question is whether the generic products contain the specific "crystalline Form A" as defined by the XRPD data in the patent claims. The complaint suggests a potential conflict on this issue, noting that the data Shilpa provided in its notice letter to support non-infringement was allegedly not contained in its ANDA or Drug Master File (Compl. ¶¶57, 70, 75).
    • Legal Questions (Method-of-Use Patents '999, '881, and '883): The dispute over these patents will center on the legal doctrine of induced infringement. The key question is whether the proposed product labels for the generic drugs will instruct or encourage medical professionals to prescribe the drug in a manner that directly infringes the claimed methods—for example, by treating the specific patient populations (e.g., treatment-naive, del 17p) with the specified dosage regimens.

No probative visual evidence provided in complaint.

V. Key Claim Terms for Construction

  • The Term: "crystalline Form A"
  • Context and Importance: This term appears in the independent claims of both the ’753 and ’455 Patents. The entire infringement analysis for these patents depends on whether the accused generic products contain this specific crystalline form of ibrutinib. Practitioners may focus on whether this term is defined solely by the recited XRPD data or if it incorporates other physical properties disclosed in the specification.
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: The patents define Form A by referencing specific XRPD data ('753 Patent, col. 2:45-47; '455 Patent, col. 2:48-51). A party could argue that the term's scope is limited to materials meeting these specific diffraction patterns, regardless of other physical properties, and that "comprising" in the '455 claims means the presence of additional XRPD peaks does not avoid infringement.
    • Evidence for a Narrower Interpretation: The specifications also disclose other analytical data for Form A, such as Infrared (IR) spectra, Differential Scanning Calorimetry (DSC) thermograms, and Thermo-gravimetric analysis (TGA) thermograms ('753 Patent, Figs. 2-4). A party could argue that these properties are inherent and necessary characteristics of "crystalline Form A," potentially narrowing the claim scope to polymorphs that exhibit all or most of these disclosed features.

VI. Other Allegations

  • Indirect Infringement: The complaint alleges that upon approval, Defendants will actively induce and/or contribute to the infringement of all asserted patents (e.g., Compl. ¶¶56, 63, 72). For the method-of-use patents (’999, ’881, ’883), this allegation is based on the premise that the product labeling for the generic drugs will instruct physicians and patients to use the drugs in an infringing manner.
  • Willful Infringement: The complaint alleges that Defendants had "actual and constructive notice" of the asserted patents prior to filing their ANDAs and proceeded without "adequate justification" for their non-infringement assertions (e.g., Compl. ¶¶73-74, 95-96). This conduct is alleged to make the case "exceptional" under 35 U.S.C. § 285, which could entitle Plaintiffs to an award of attorneys' fees.

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

  • A core issue will be one of polymorphic identity: What is the actual crystalline form of the ibrutinib in the proposed generic products? The resolution of the infringement claims for the '753 and '455 patents will depend entirely on factual evidence from analytical testing (e.g., XRPD) of the defendants' drug substances.
  • A key legal question will be induced infringement: Will the final, FDA-approved product labels for the generic drugs contain indications and instructions that encourage physicians to prescribe the drug in a manner that falls within the scope of the method-of-use claims of the '999, '881, and '883 patents?
  • A significant procedural question may be whether the defendants’ pre-suit conduct, particularly the basis for their Paragraph IV certifications and the alleged inconsistencies noted in the complaint, was objectively baseless, which could support Plaintiffs' request for a finding that the case is "exceptional."