DCT

1:22-cv-00154

Acerta Pharma BV v. Alembic Pharma Ltd

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I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 1:22-cv-00154, D. Del., 02/02/2022
  • Venue Allegations: Venue is alleged to be proper in the District of Delaware because Defendant Alembic Pharmaceuticals, Inc. is a Delaware corporation and thus "resides" in the district. Venue over foreign Defendant Alembic Pharmaceuticals Limited is alleged to be proper in any district where it is subject to personal jurisdiction.
  • Core Dispute: Plaintiffs allege that Defendant’s filing of an Abbreviated New Drug Application (ANDA) to market a generic version of the cancer drug CALQUENCE® (acalabrutinib) constitutes an act of infringement of five patents related to the drug's active compound, crystalline forms, pharmaceutical compositions, and methods of use.
  • Technical Context: The technology relates to inhibitors of Bruton's tyrosine kinase (BTK), a key enzyme in B cell signaling pathways, used for treating B-cell malignancies like mantle cell lymphoma and chronic lymphocytic leukemia.
  • Key Procedural History: The litigation was initiated under the Hatch-Waxman Act, triggered by Defendant’s submission of ANDA No. 216775 to the U.S. Food and Drug Administration (FDA). The complaint states that on December 28, 2021, Defendant sent a "Notice Letter" with a Paragraph IV Certification asserting that its proposed generic product would not infringe U.S. Patent Nos. 9,796,721 and 10,167,291, or that these patents are invalid.

Case Timeline

Date Event
2011-07-19 Priority Date for ’524 and ’883 Patents
2014-01-21 Priority Date for ’083 Patent
2015-12-28 Priority Date for ’721 and ’291 Patents
2017-09-12 U.S. Patent No. 9,758,524 Issued
2017-10-24 U.S. Patent No. 9,796,721 Issued
2019-01-01 U.S. Patent No. 10,167,291 Issued
2019-03-26 U.S. Patent No. 10,239,883 Issued
2019-04-30 U.S. Patent No. 10,272,083 Issued
2021-12-28 Alembic sends Paragraph IV Notice Letter to Plaintiffs
2022-02-02 Complaint Filed

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

U.S. Patent No. 9,758,524 - “4-Imidazopyridazin-1-yl-Benzamides as BTK Inhibitors”

The Invention Explained

  • Problem Addressed: The patent background describes that while Bruton's tyrosine kinase (BTK) is a key target for treating B cell malignancies and autoimmune diseases, existing kinase inhibitors often lack selectivity. Specifically, inhibition of Src-family kinases can lead to significant adverse effects, creating a need for more selective BTK inhibitors. (’883 Patent, col. 2:20-53).
  • The Patented Solution: The invention provides a class of chemical compounds, specifically 6-5 membered fused pyridine rings, that are designed to selectively inhibit BTK. The claims are directed to methods of using one such compound, acalabrutinib, to treat specific cancers. (’883 Patent, col. 2:54-65; col. 3:1-12).
  • Technical Importance: The development of selective BTK inhibitors represents a significant advance in targeted cancer therapy, offering the potential for effective treatment of B cell disorders while minimizing off-target toxicities associated with less selective drugs. (’883 Patent, col. 2:5-9).

Key Claims at a Glance

  • The complaint asserts independent claim 1 (Compl. ¶38).
  • Claim 1 of the ’524 Patent covers:
    • A method of treating Mantle Cell Lymphoma (MCL) in a human subject.
    • The method comprises administering to the subject a specific compound, (S)-4-(8-amino-3-(1-but-2-ynoylpyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(pyridin-2-yl)benzamide (acalabrutinib), or a pharmaceutically acceptable salt thereof.
    • The administration is in an amount effective to treat MCL. (Compl. ¶35).
  • The complaint does not explicitly reserve the right to assert dependent claims for this patent.

U.S. Patent No. 10,239,883 - “4-Imidazopyridazin-1-yl-Benzamides as BTK Inhibitors”

The Invention Explained

  • Problem Addressed: As with its parent, the ’524 patent, the ’883 Patent addresses the need for BTK inhibitors that are selective over other kinases, such as those in the Src-family, to avoid adverse side effects in treating B cell-related disorders. (’883 Patent, col. 2:20-53).
  • The Patented Solution: The patent discloses the same class of 6-5 membered fused pyridine ring compounds, including acalabrutinib, as a solution to the problem of non-selective kinase inhibition. This patent specifically claims a method of using this compound to treat chronic lymphocytic leukemia. (’883 Patent, col. 2:54-65; col. 3:1-12).
  • Technical Importance: This technology provides a targeted therapeutic option for chronic lymphocytic leukemia, a prevalent B cell malignancy, by selectively inhibiting BTK to disrupt the signaling pathways that promote cancer cell survival and proliferation. (’883 Patent, col. 1:27-32, col. 2:5-9).

Key Claims at a Glance

  • The complaint asserts independent claim 1 (Compl. ¶55).
  • Claim 1 of the ’883 Patent covers:
    • A method of treating chronic lymphocytic leukemia in a human subject.
    • The method comprises administering to the subject the compound (S)-4-(8-amino-3-(1-but-2-ynoylpyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(pyridin-2-yl)benzamide (acalabrutinib), or a pharmaceutically acceptable salt thereof. (Compl. ¶52).
  • The complaint does not explicitly reserve the right to assert dependent claims for this patent.

U.S. Patent No. 9,796,721 - “Crystal Forms of (S)-4-(8-amino-3-(1-but-2-ynoylpyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(pyridin-2-yl)benzamide”

  • Technology Synopsis: This patent addresses the technical challenge of developing stable and manufacturable solid forms of the acalabrutinib drug substance (Compl. ¶67). The patented solution is a specific crystalline form (polymorph) of the acalabrutinib compound, which is defined by a characteristic pattern of peaks when analyzed by X-ray powder diffraction (XRPD), ensuring consistent physical properties like solubility and stability. (’291 Patent, col. 1:15-25, col. 2:15-32).
  • Asserted Claims: The complaint asserts independent claim 1 (Compl. ¶72).
  • Accused Features: The crystalline form of the acalabrutinib active pharmaceutical ingredient in Defendant’s proposed generic product is accused of infringement (Compl. ¶72).

U.S. Patent No. 10,167,291 - “Pharmaceutical Compositions Comprising a Crystal Form of (S)-4-(8-amino-3-(1-but-2-ynoylpyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(pyridin-2-yl)benzamide”

  • Technology Synopsis: This patent relates to formulating the specific crystalline form of acalabrutinib into a final drug product (Compl. ¶84). It claims a solid pharmaceutical composition that combines a specific dose range (95-105 mg) of the crystalline acalabrutinib with at least one pharmaceutically acceptable excipient, creating a stable and effective oral dosage form. (’291 Patent, col. 23:55-65).
  • Asserted Claims: The complaint asserts independent claim 1 (Compl. ¶89).
  • Accused Features: Defendant’s proposed 100 mg acalabrutinib oral capsule product is accused of infringing by allegedly containing the claimed composition (Compl. ¶29, ¶89).

U.S. Patent No. 10,272,083 - “Methods of Treating Chronic Lymphocytic Leukemia and Small Lymphocytic Leukemia Using a BTK Inhibitor”

  • Technology Synopsis: This patent addresses the need for specific, effective dosing regimens for treating certain leukemias (Compl. ¶101). The invention claims a method of treating mantle cell lymphoma (MCL) by orally administering a specific dose—100 mg twice daily—of a BTK inhibitor, which is identified as acalabrutinib. (’083 Patent, col. 1:11-14, claim 8).
  • Asserted Claims: The complaint asserts independent claim 8 (Compl. ¶106).
  • Accused Features: The infringement allegation is based on the use of Defendant’s proposed product in accordance with its proposed labeling, which Plaintiffs allege will direct administration of the infringing dosing regimen (Compl. ¶108).

III. The Accused Instrumentality

Product Identification

The accused instrumentality is "Alembic's ANDA Product," which is a proposed generic version of CALQUENCE® (acalabrutinib) 100 mg oral capsules, submitted to the FDA for approval under ANDA No. 216775 (Compl. ¶1, ¶25, ¶29).

Functionality and Market Context

The product is a kinase inhibitor whose active ingredient is acalabrutinib (Compl. ¶24). It is intended for the treatment of adult patients with mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) (Compl. ¶24). The complaint frames the submission of the ANDA as an artificial act of infringement under 35 U.S.C. § 271(e)(2) for the purpose of obtaining FDA approval to market this generic drug prior to the expiration of the Patents-in-Suit (Compl. ¶28).

IV. Analysis of Infringement Allegations

U.S. Patent No. 9,758,524 Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
A method of treating Mantle Cell Lymphoma ("MCL") in a human subject, the method comprising administering to the human subject a compound... The complaint alleges that Alembic's proposed labeling will direct the use of its ANDA product for the treatment of MCL, thereby inducing physicians and patients to perform the claimed method. ¶40 ’883 Patent, col. 1:27-32
...which is (S)-4-(8-amino-3-(1-but-2-ynoylpyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(pyridin-2-yl)benzamide... or a pharmaceutically acceptable salt thereof... Alembic’s ANDA is for an acalabrutinib oral capsule, which contains the claimed compound. The complaint includes a chemical diagram of this structure. ¶29, ¶35 ’883 Patent, col. 7:1-67
...in an amount effective to treat MCL in the human subject... The proposed product is a 100 mg capsule, which corresponds to the dosage of the branded product CALQUENCE®, indicated for treating MCL. ¶29 ’883 Patent, col. 31:45-50

The complaint provides a chemical structure diagram of the acalabrutinib compound, which is central to the asserted claims of the ’524 and ’883 patents (Compl. p. 9).

Identified Points of Contention

  • Scope Questions: A central question in ANDA litigation involving method-of-use claims is whether the defendant’s proposed label will induce infringement. The analysis may turn on whether the label encourages, recommends, or promotes the specific patented use, and whether any non-infringing uses are substantial.
  • Technical Questions: While the identity of the chemical compound itself may not be in dispute, the infringement analysis for the method claim is a legal and factual question of intent and inducement, based on the contents of Alembic's ANDA and proposed labeling, which are not yet public.

U.S. Patent No. 10,239,883 Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
A method of treating chronic lymphocytic leukemia in a human subject, the method comprising administering to the human subject a compound... The complaint alleges that Alembic's proposed labeling will direct the use of its ANDA product for the treatment of chronic lymphocytic leukemia. ¶57 ’883 Patent, col. 1:27-32
...which is (S)-4-(8-amino-3-(1-but-2-ynoylpyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(pyridin-2-yl)benzamide, having the structure: [diagram] or a pharmaceutically acceptable salt thereof... Alembic’s ANDA product contains the claimed compound, acalabrutinib. The complaint provides a visual of the compound's structure. ¶29, ¶52 ’883 Patent, col. 7:1-67

The complaint provides a second, identical chemical structure diagram of acalabrutinib in its allegations regarding the ’883 patent (Compl. p. 12).

Identified Points of Contention

  • Scope Questions: As with the ’524 patent, the dispute will likely focus on whether the contents of Alembic's proposed labeling are sufficient to establish inducement of infringement for the treatment of chronic lymphocytic leukemia.
  • Technical Questions: The complaint does not provide sufficient detail for analysis of the specific language in the proposed label. The key question is evidentiary: what will Alembic’s proposed label instruct physicians to do?

V. Key Claim Terms for Construction

  • The Term: "treating" (in "method of treating Mantle Cell Lymphoma" and "method of treating chronic lymphocytic leukemia")
  • Context and Importance: This term defines the scope of the claimed method. Its construction is critical because infringement hinges on whether the actions encouraged by the defendant's proposed label fall within the patent's definition of "treating." Practitioners may focus on this term to determine if the label must explicitly mention specific clinical outcomes or merely direct administration for the indicated disease.
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: The specification provides a broad definition of "therapeutic effect," which includes "slowing, halting, or reversing the progression of a disease or condition, or any combination thereof." (’883 Patent, col. 9:15-21). This could support a construction where merely administering the drug for the disease constitutes "treating."
    • Evidence for a Narrower Interpretation: The detailed description discusses specific clinical contexts and outcomes related to B cell malignancies. (’883 Patent, col. 2:5-9). A defendant may argue that "treating" should be limited to achieving specific endpoints or be understood in the context of the specific patient populations described, potentially narrowing the scope of induced infringement.

VI. Other Allegations

  • Indirect Infringement: The complaint alleges active inducement of infringement for all five patents. The basis for this allegation is that Alembic knows of the patents and intends for its ANDA product to be used in an infringing manner, as will be directed by its proposed product labeling and other marketing materials. (Compl. ¶41, ¶58, ¶75, ¶92, ¶109). The complaint also alleges contributory infringement, stating the ANDA product is not suitable for substantial non-infringing use. (Compl. ¶42, ¶59, ¶76, ¶93, ¶110).
  • Willful Infringement: The complaint alleges that Alembic has acted with "full knowledge" of the patents-in-suit and "without a reasonable basis for believing that it would not be liable for infringing," which is the basis for a willfulness claim. (Compl. ¶44, ¶61, ¶78, ¶95, ¶112). This allegation is predicated on pre-suit knowledge established by Alembic's Paragraph IV certification and Notice Letter. (Compl. ¶26).

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

  • Inducement via Product Labeling: A primary issue for the method-of-use patents (’524, ’883, ’083) will be one of induced infringement: will the language in Alembic's proposed label be found to actively encourage or instruct physicians to prescribe the generic product for the patented methods of treating MCL and CLL, and at the patented dosage, or does the label allow for substantial non-infringing uses?
  • Polymorphic Identity: A key evidentiary question for the crystal form and composition patents (’721, ’291) will be one of technical identity: does the active pharmaceutical ingredient in Alembic’s proposed product, as manufactured and formulated, meet the specific X-ray powder diffraction peak limitations that define the patented crystalline form?
  • Hatch-Waxman Framework: Underlying the entire dispute is the statutory framework of the Hatch-Waxman Act. The central legal question is whether Alembic's act of filing its ANDA—seeking to market a generic version of CALQUENCE®—justifies a court order preventing the FDA from approving that ANDA until after the patents-in-suit have expired.