DCT

1:25-cv-01016

Array Biopharma Inc v. Alembic Pharma Ltd

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I. Executive Summary and Procedural Information

Case Timeline

Date Event
2014-11-16 Priority Date for ’414, ’861, ’993, ’505, and ’936 Patents
2017-10-10 U.S. Patent No. 9,782,414 Issued
2019-01-08 U.S. Patent No. 10,172,861 Issued
2019-05-14 U.S. Patent No. 10,285,993 Issued
2020-10-13 U.S. Patent No. 10,799,505 Issued
2020-10-27 U.S. Patent No. 10,813,936 Issued
2025-06-30 Alembic’s Notice Letter to Plaintiffs
2025-08-13 Complaint Filed

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

U.S. Patent No. 9,782,414 - “Crystalline form of (S)-N-(5-((R)-2-(2,5-difluorophenyl)-pyrrolidin-1-yl)-pyrazolo[1,5-A]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide hydrogen sulfate”

  • Patent Identification: U.S. Patent No. 9,782,414, issued October 10, 2017.

The Invention Explained

  • Problem Addressed: The patent family addresses the general need for effective inhibitors of the Trk/neurotrophin pathway for use in treating conditions like cancer and pain, which implies a need for a stable and effective form of the active pharmaceutical ingredient for administration (U.S. Patent 10,172,861, col. 2:5-14).
  • The Patented Solution: The invention is a method of treating cancer in pediatric patients by administering a specific crystalline polymorph of larotrectinib hydrogen sulfate, identified as "Form (I-HS)" (Compl. ¶36). This specific solid-state form is defined by its characteristic X-ray powder diffraction (XRPD) pattern, which provides a consistent and reproducible structure for formulation into a dosage form (’414 Patent, col. 5:1-14).
  • Technical Importance: Developing a specific, stable crystalline form of a drug substance is critical for ensuring consistent purity, stability, and bioavailability in a commercial pharmaceutical product (U.S. Patent 10,172,861, col. 15:35-col. 16:15).

Key Claims at a Glance

  • The complaint asserts independent claims 1 and 21 (Compl. ¶¶36, 37, 41).
  • Essential elements of independent Claim 1 include:
    • A method of treating cancer in a pediatric patient in need thereof;
    • Detecting a cancer in the patient that exhibits a dysregulation of a NTRK gene, a Trk protein, or expression or level of the same;
    • Administering a therapeutically effective amount of a dosage form comprising a crystalline form (I-HS) having a specified chemical formula; and
    • Wherein the crystalline form has an X-ray powder diffraction pattern comprising peaks at °2θ values of 18.4±0.2, 20.7±0.2, 23.1±0.2, and 24.0±0.2.
  • Essential elements of independent Claim 21 are substantially similar, claiming a method of treating a cancer exhibiting the same dysregulation in a pediatric patient by administering the specified crystalline form (I-HS) (Compl. ¶37).
  • The complaint notes that Defendant did not contest infringement of dependent claims 2-10 and 22-25 in its notice letter (Compl. ¶42).

U.S. Patent No. 10,172,861 - “Crystalline form of (S)-N-(5-((R)-2-(2,5-difluorophenyl)-pyrrolidin-1-yl)-pyrazolo[1,5-A]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide hydrogen sulfate”

  • Patent Identification: U.S. Patent No. 10,172,861, issued January 8, 2019.

The Invention Explained

  • Problem Addressed: As with the ’414 Patent, the technical context is the need for a stable and effective form of the larotrectinib sulfate compound for therapeutic use (’861 Patent, col. 1:19-2:65).
  • The Patented Solution: The ’861 Patent claims the composition of matter itself: the specific crystalline form (I-HS) of larotrectinib hydrogen sulfate, identified by its chemical formula and its characteristic XRPD pattern (’861 Patent, col. 5:1-14; Abstract). The patent specification provides detailed analytical data, such as the XRPD diffractogram in Figure 1, to define this specific polymorph (’861 Patent, Fig. 1).
  • Technical Importance: This patent claims the physical substance itself, providing a basis to exclude others from making, using, or selling this specific crystalline form, which is asserted to be a stable and manufacturable version of the drug (U.S. Patent 10,172,861, col. 15:35-col. 16:15).

Key Claims at a Glance

  • The complaint asserts independent claim 1 (Compl. ¶¶58, 62).
  • Essential elements of independent Claim 1 include:
    • A crystalline form (I-HS) having a specified chemical formula;
    • Wherein the crystalline form is characterized by having an X-ray powder diffraction (XRPD) pattern comprising peaks at °2θ values of 18.4±0.2, 20.7±0.2, 23.1±0.2, and 24.0±0.2.
  • The complaint states that Defendant did not contest infringement of dependent claims 2-9 in its notice letter (Compl. ¶63).

U.S. Patent No. 10,285,993 - “Crystalline form of (S)-N-(5-((R)-2-(2,5-difluorophenyl)-pyrrolidin-1-yl)-pyrazolo[1,5-A]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide hydrogen sulfate”

  • Patent Identification: U.S. Patent No. 10,285,993, issued May 14, 2019 (Compl. ¶77).
  • Technology Synopsis: This patent claims a method of treating cancer that is specifically "mediated by a Trk kinase" (Compl. ¶79). The claimed method involves administering the same crystalline form (I-HS) of larotrectinib hydrogen sulfate, defined by its characteristic XRPD peaks.
  • Asserted Claims: Independent claim 1 (Compl. ¶79).
  • Accused Features: The accused features are Alembic's ANDA product (a capsule containing larotrectinib sulfate) and its proposed labeling, which allegedly directs its use for treating cancer in a manner covered by the patent (Compl. ¶¶82-83).

U.S. Patent No. 10,799,505 - “Crystalline form of (S)-N-(5-((R)-2-(2,5-difluorophenyl)-pyrrolidin-1-yl)-pyrazolo[1,5-A]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide hydrogen sulfate”

  • Patent Identification: U.S. Patent No. 10,799,505, issued October 13, 2020 (Compl. ¶98).
  • Technology Synopsis: This patent claims the crystalline form (I-HS) of larotrectinib hydrogen sulfate as a composition of matter, adding a negative limitation that distinguishes it from other forms. The claim requires the crystalline form to be "substantially free of the amorphous form," focusing on the purity of the polymorph (Compl. ¶100).
  • Asserted Claims: Independent claim 1 (Compl. ¶100).
  • Accused Features: Alembic's ANDA product, a capsule containing larotrectinib sulfate, is alleged to be the claimed crystalline form that is substantially free of the amorphous form (Compl. ¶¶103-104).

U.S. Patent No. 10,813,936 - “Crystalline form of (S)-N-(5-((R)-2-(2,5-difluorophenyl)-pyrrolidin-1-yl)-pyrazolo[1,5-A]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide hydrogen sulfate”

  • Patent Identification: U.S. Patent No. 10,813,936, issued October 27, 2020 (Compl. ¶119).
  • Technology Synopsis: This patent claims a method of treating a specific subset of cancers—lung cancer, undifferentiated sarcoma, acute myeloid leukemia, and colorectal cancer—where the cancer exhibits one or more NTRK gene fusions (Compl. ¶121). The method comprises administering the same crystalline form (I-HS) defined by its chemical formula and XRPD peaks.
  • Asserted Claims: Independent claim 1 (Compl. ¶121).
  • Accused Features: Alembic's ANDA product and its proposed labeling are alleged to direct the treatment of one or more of the claimed cancers in patients with the specified genetic markers (Compl. ¶¶124-125).

III. The Accused Instrumentality

Product Identification

"Alembic’s ANDA Products," identified as Larotrectinib Capsules in 25 mg and 100 mg dosages, for which Alembic seeks FDA approval under ANDA No. 220639 (Compl. ¶¶1-2).

Functionality and Market Context

The accused products contain the active ingredient larotrectinib sulfate, a tropomyosin receptor kinase (TRK) inhibitor (Compl. ¶¶29, 40). They are generic versions of Plaintiffs' branded product, VITRAKVI®, which is used to treat adults and children with solid tumors that have a neurotrophic receptor tyrosine kinase (NTRK) gene fusion (Compl. ¶¶7, 29). The act of infringement alleged under 35 U.S.C. § 271(e)(2)(A) is the submission of the ANDA itself for the purpose of obtaining approval to commercially manufacture and sell the product prior to the expiration of the patents-in-suit (Compl. ¶43). The complaint provides a chemical structure diagram of the crystalline form (I-HS) of larotrectinib sulfate, which is the subject of the patents and the alleged form of the accused product (Compl. ¶36, p. 10).

IV. Analysis of Infringement Allegations

'414 Patent Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
A method of treating cancer in a pediatric patient... comprising: a) detecting a cancer... that exhibits a dysregulation of a NTRK gene...; and b) administering to the pediatric patient a therapeutically effective amount of a dosage form... The proposed labeling for Alembic's ANDA Product will allegedly direct physicians and patients to perform the claimed method of treating cancer in pediatric patients with the specified genetic markers. ¶41 col. 9:25-34
...a dosage form comprising a crystalline form (I-HS) having the formula... Alembic’s ANDA Product is a capsule containing larotrectinib sulfate, which has the chemical structure of form (I-HS). ¶40 col. 9:65-10:15
...wherein the crystalline form has an X-ray powder diffraction pattern comprising peaks at °2θ values of 18.4±0.2, 20.7±0.2, 23.1±0.2, and 24.0±0.2. The complaint alleges that Alembic, in its Notice Letter, did not contest infringement of claims 1-10 and 21-25, which require this XRPD pattern. ¶42 col. 5:1-14

'861 Patent Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
A crystalline form (I-HS) having the formula... Alembic’s ANDA Product is a capsule containing larotrectinib sulfate, which is alleged to be the claimed crystalline form (I-HS). ¶61 col. 5:1-14
...wherein the crystalline form is characterized by having an X-ray powder diffraction (XRPD) pattern comprising peaks at °2θ values of 18.4±0.2, 20.7±0.2, 23.1±0.2, and 24.0±0.2. The complaint alleges that Alembic, in its Notice Letter, did not contest infringement of claims 1-9, which require this specific XRPD pattern. ¶63 col. 14:29-37

Identified Points of Contention

  • Evidentiary Question: The central technical issue will be whether the larotrectinib sulfate in Alembic's ANDA product is, in fact, the specific "crystalline form (I-HS)" claimed in the patents. This determination will depend on expert analysis of scientific data (e.g., XRPD, differential scanning calorimetry) from Alembic's product.
  • Legal Question: A significant issue may arise from the complaint's allegation that Alembic "did not contest the infringement" of the asserted claims in its Notice Letter (Compl. ¶¶42, 63, 84, 105, 126), while simultaneously filing a Paragraph IV certification that asserts non-infringement (Compl. ¶¶39, 60). This raises the question of what legal effect, if any, the alleged failure to contest has on Alembic's ability to pursue its non-infringement defense.

V. Key Claim Terms for Construction

  • The Term: "crystalline form... characterized by having an X-ray powder diffraction (XRPD) pattern comprising peaks at °2θ values of 18.4±0.2, 20.7±0.2, 23.1±0.2, and 24.0±0.2"

    • Context and Importance: This term is the primary structural definition of the patented invention in the composition claims (e.g., ’861 Patent) and a critical limitation in the method claims (e.g., ’414 Patent). The infringement analysis will likely depend entirely on whether the accused product meets this structural definition. Practitioners may focus on whether "comprising" requires only the presence of these peaks or if the overall pattern must be substantially identical to that disclosed for Form (I-HS).
    • Intrinsic Evidence for Interpretation:
      • Evidence for a Broader Interpretation: The use of the open-ended transitional phrase "comprising" may support an interpretation that the claim is met if the accused product's XRPD pattern includes, at a minimum, the four recited peaks, even if other peaks are also present.
      • Evidence for a Narrower Interpretation: The detailed description of the patents provides extensive characterization data for a single polymorph, designated "crystalline form (I-HS)" (’861 Patent, col. 15:35-16:51; Figs. 1-6). This may support an argument that the claims are limited to this specific polymorph, and that an accused product with a substantially different overall XRPD pattern, even if it shares some peaks, would not be the same "crystalline form."

  • The Term: "substantially free of the amorphous form" (from the ’505 Patent)

    • Context and Importance: This term, appearing in claim 1 of the ’505 Patent, introduces a purity limitation (Compl. ¶100). Its construction will be critical to determining infringement of this patent. The dispute may center on the quantitative threshold for "substantially free."
    • Intrinsic Evidence for Interpretation:
      • Evidence for a Broader Interpretation: The patent does not provide an explicit numerical definition for "substantially free." This may support an argument that the term should be given its plain and ordinary meaning, which could allow for more than trace amounts of amorphous material.
      • Evidence for a Narrower Interpretation: The patent specification emphasizes the stability and superior properties of the crystalline form (I-HS) compared to the amorphous form (’861 Patent, col. 15:35-16:15). This context may support a narrow construction requiring a very high degree of crystallinity, potentially approaching the limits of detection for amorphous content.

VI. Other Allegations

  • Indirect Infringement: The complaint alleges active inducement of infringement for the method of use patents (e.g., ’414, ’993, ’936 Patents). The basis for this allegation is that Alembic, with knowledge of the patents, will sell its ANDA product with proposed labeling that instructs and encourages physicians and patients to use the product in an infringing manner (Compl. ¶¶46, 88, 130).
  • Willful Infringement: The complaint does not use the word "willful." However, it alleges that "Notwithstanding Alembic's knowledge of the claims of the ['414] patent, Alembic has continued to assert its intent to manufacture, offer for sale, sell, distribute, and/or import Alembic's ANDA Product... prior to the expiration of the '414 patent" (Compl. ¶48). This allegation of continued intent to infringe after gaining knowledge of the patents could form the basis for a future willfulness claim based on post-notice conduct.

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

  • A central issue will be one of structural identity: does the active pharmaceutical ingredient in Alembic’s ANDA product exhibit the specific, claimed X-ray powder diffraction pattern of the patented "crystalline form (I-HS)," or does it exist as a different, non-infringing polymorph or in an amorphous state?
  • A key procedural question will be one of estoppel or admission: what is the legal weight of the complaint's allegation that Alembic "did not contest" infringement in its pre-suit notice letter, and does this preclude Alembic from fully litigating its non-infringement defense asserted in its Paragraph IV certification?
  • The ultimate disposition of the case will also turn on validity: can Alembic prove by clear and convincing evidence that the asserted claims to this specific crystalline form and its methods of use are invalid as anticipated or obvious over prior art forms of larotrectinib sulfate?