DCT

1:22-cv-00162

Acerta Pharma BV v. Cipla Ltd

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I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 1:22-cv-00162, D. Del., 02/04/2022
  • Venue Allegations: Venue is alleged to be proper as to Cipla USA, Inc. because it is a Delaware corporation and thus "resides" in the district. Venue is alleged as proper for Cipla Limited, a foreign corporation, because it is subject to the court's personal jurisdiction.
  • Core Dispute: Plaintiffs allege that Defendant's Abbreviated New Drug Application (ANDA) seeking approval to market a generic version of the cancer drug CALQUENCE® (acalabrutinib) infringes five U.S. patents covering the active compound, its specific crystalline forms, pharmaceutical compositions, and methods of treatment.
  • Technical Context: The technology relates to acalabrutinib, a Bruton's tyrosine kinase (BTK) inhibitor used for treating certain B-cell malignancies, such as mantle cell lymphoma and chronic lymphocytic leukemia.
  • Key Procedural History: The lawsuit was filed under the Hatch-Waxman Act, triggered by a notice letter from Cipla dated December 29, 2021. This letter informed Plaintiffs of Cipla's ANDA filing (No. 216507), which included a Paragraph IV Certification asserting that three of the patents-in-suit are invalid, unenforceable, and/or will not be infringed by Cipla's proposed generic product.

Case Timeline

Date Event
2011-07-19 U.S. Patent Nos. 9,758,524 & 10,239,883 Priority Date
2014-01-21 U.S. Patent No. 10,272,083 Priority Date
2015-12-28 U.S. Patent Nos. 9,796,721 & 10,167,291 Priority Date
2017-09-12 U.S. Patent No. 9,758,524 Issues
2017-10-24 U.S. Patent No. 9,796,721 Issues
2019-01-01 U.S. Patent No. 10,167,291 Issues
2019-03-26 U.S. Patent No. 10,239,883 Issues
2019-04-30 U.S. Patent No. 10,272,083 Issues
2021-12-29 Cipla sends Notice Letter to Plaintiffs
2022-02-04 Complaint Filing Date

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 addresses the need for therapies targeting B-cell immunity for autoimmune diseases and B-cell malignancies, noting that some existing Bruton's Tyrosine Kinase (Btk) inhibitors are not selective over other kinase families, which could lead to adverse effects (’524 Patent, col. 2:1-62).
  • The Patented Solution: The invention provides a class of 4-imidazopyridazin-1-yl-benzamide compounds that act as Btk inhibitors (’524 Patent, col. 2:63-67). Specifically, the patent claims a method of using the compound acalabrutinib to treat Mantle Cell Lymphoma (MCL) (’524 Patent, col. 150:4-10).
  • Technical Importance: The invention provided a new chemical entity for use as a Btk inhibitor, a key target in the treatment of various B-cell cancers.

Key Claims at a Glance

  • The complaint asserts infringement of at least Claim 1 (Compl. ¶38).
  • The essential elements of independent Claim 1 are:
    • A method of treating Mantle Cell Lymphoma (MCL) in a human subject,
    • the method comprising administering to the human subject a compound 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,
    • in an amount effective to treat MCL in the human subject.
  • The complaint reserves the right to assert other claims, including dependent claims (Compl. ¶38).

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

The Invention Explained

  • Problem Addressed: Similar to the ’524 Patent from the same family, this patent addresses the need for B-cell therapies for diseases including B-cell malignancies, highlighting Btk as a key therapeutic target (’883 Patent, col. 1:29-65).
  • The Patented Solution: The invention provides the same class of 4-imidazopyridazin-1-yl-benzamide compounds that act as Btk inhibitors (’883 Patent, col. 2:63-67). This patent specifically claims a method of using the compound acalabrutinib to treat chronic lymphocytic leukemia (CLL) (’883 Patent, col. 149:35-42).
  • Technical Importance: The invention claims a method of using the acalabrutinib compound for a different indication, CLL, expanding its patented therapeutic application.

Key Claims at a Glance

  • The complaint asserts infringement of at least Claim 1 (Compl. ¶55).
  • The essential elements of independent Claim 1 are:
    • A method of treating chronic lymphocytic leukemia in a human subject,
    • the method comprising administering to the human subject a compound 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.
  • The complaint reserves the right to assert other claims, including dependent claims (Compl. ¶55).

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 does not claim the acalabrutinib compound itself, but rather a specific crystalline solid form of it (’721 Patent, col. 1:17-23). The invention is defined by a characteristic pattern of peaks observed during X-ray powder diffraction (XRPD), a technique used to identify the physical structure of a solid material (’721 Patent, col. 12:20-30).

Asserted Claims

At least Claim 1 (Compl. ¶72).

Accused Features

The complaint alleges that the manufacture and composition of Cipla's ANDA Product will infringe the claims to this specific crystal form (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 claims a solid pharmaceutical composition that includes the specific crystalline form of acalabrutinib identified in the ’721 Patent (’291 Patent, col. 1:15-28). The claims require a specific dosage range (95-105 mg) of this crystal form combined with at least one pharmaceutically acceptable excipient (’291 Patent, col. 128:51-64).

Asserted Claims

At least Claim 1 (Compl. ¶89).

Accused Features

The complaint alleges that Cipla’s 100 mg oral capsule formulation will infringe the claims to this specific pharmaceutical 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 claims a method of treating mantle cell lymphoma (MCL) by administering a specific dosage regimen of acalabrutinib (’083 Patent, col. 99:1-8). The key claimed feature is the specific dosing instruction: "a dose of 100 mg twice daily" of the BTK inhibitor (’083 Patent, Claim 8).

Asserted Claims

At least Claim 8 (Compl. ¶107).

Accused Features

The complaint alleges that Cipla's proposed generic product and its associated labeling will instruct for the infringing method of use, specifically the administration of 100 mg of acalabrutinib twice daily (Compl. ¶29, ¶109).

III. The Accused Instrumentality

Product Identification

The accused instrumentality is Cipla's proposed generic version of CALQUENCE® (acalabrutinib) 100 mg oral capsules, for which Cipla submitted Abbreviated New Drug Application (ANDA) No. 216507 to the FDA for approval (Compl. ¶1, ¶29).

Functionality and Market Context

The complaint alleges that Cipla's ANDA Product is a generic version of CALQUENCE®, a kinase inhibitor containing the active ingredient acalabrutinib (Compl. ¶24-25). As an ANDA product, its intended function is to be bioequivalent to CALQUENCE®, which is indicated for the treatment of mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL), and small lymphocytic lymphoma (SLL) (Compl. ¶24). The lawsuit arises from Cipla's submission of the ANDA seeking approval to commercially manufacture and sell this generic version prior to the expiration of the patents-in-suit (Compl. ¶1).

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 complaint alleges Cipla's ANDA seeks approval for a generic version of CALQUENCE®, which is indicated for treating MCL, and that Cipla's proposed labeling will direct use for this indication. ¶24, ¶40 col. 2:32-35
the method comprising administering to the human subject a compound 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, Cipla's ANDA Product is alleged to contain acalabrutinib, which is the compound recited in the claim. The complaint provides a structural diagram of this compound. ¶25, ¶35 col. 150:4-10
in an amount effective to treat MCL in the human subject. The proposed labeling for Cipla's ANDA Product will allegedly direct administration in a dose effective to treat MCL, mirroring the approved use of CALQUENCE®. ¶24, ¶40 col. 150:9-10

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 complaint alleges Cipla's ANDA seeks approval for a generic version of CALQUENCE®, which is indicated for treating chronic lymphocytic leukemia, and that its proposed labeling will instruct for this use. ¶24, ¶57 col. 149:35-36
the method comprising administering to the human subject a compound 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. Cipla's ANDA Product is alleged to contain acalabrutinib, the compound recited in the claim. The complaint provides a structural diagram of this compound. ¶25, ¶52 col. 149:37-42

Identified Points of Contention

  • Scope Questions: For the method-of-use patents (’524, ’883, and ’083), a central question for induced infringement will be whether the final, FDA-approved label for Cipla's ANDA Product will instruct or encourage physicians to prescribe the drug for the specific indications (MCL, CLL) and at the specific dosage ("100 mg twice daily") recited in the claims.
  • Technical Questions: For the patents claiming a specific crystal form (’721) and a composition containing it (’291), a key factual question will be whether Cipla's ANDA Product actually contains the (S)-4-(8-amino-3-(1-but-2-ynoylpyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(pyridin-2-yl)benzamide compound in the specific crystal form defined by the claimed X-ray powder diffraction peaks. The complaint alleges that the chemical structure shown in a diagram is the active ingredient in the accused product (Compl. ¶35, ¶52, ¶103).

V. Key Claim Terms for Construction

The Term

"a crystal form of... characterized by an X-ray powder diffraction pattern comprising peaks at 6.4° ±0.2° 20, 8.6° ±0.2° 20, 10.5° ±0.2° 20, 11.6° ±0.2° 20 and 15.7° ±0.2° 20" (from Claim 1 of the ’721 and ’291 patents)

Context and Importance

This term is the core limitation defining the inventions of the ’721 and ’291 patents. The infringement analysis for these patents will depend entirely on whether Cipla's generic product exhibits an XRPD pattern with peaks at these specific angular positions, within the specified margin of error (±0.2°). Practitioners may focus on this term because minor variations in manufacturing can produce different crystal forms (polymorphs), and the scope of the "±0.2°" term will be critical in determining literal infringement.

Intrinsic Evidence for Interpretation

  • Evidence for a Broader Interpretation: The patent explicitly includes a margin of error ("±0.2° 20"), suggesting the claims are not limited to the exact peak values but are intended to cover minor, instrument-related variations (’721 Patent, col. 12:20-30). The specification notes that peak positions "may vary" depending on measurement conditions and sample preparation, which may support construing the claimed values as representative rather than rigidly absolute (’721 Patent, col. 12:51-13:7).
  • Evidence for a Narrower Interpretation: The patent distinguishes the claimed crystal form (Form I) from other forms, such as Form II and Form III, which have different, distinct XRPD patterns (’721 Patent, FIG. 1, FIG. 12, FIG. 21). This detailed differentiation between polymorphs could support an argument that the claimed peak ranges must be strictly met to distinguish the patented invention from other, non-infringing crystal forms.

VI. Other Allegations

Indirect Infringement

The complaint alleges both induced and contributory infringement for all asserted patents. Inducement is based on the allegation that Cipla's proposed labeling will instruct physicians and patients to administer the generic drug in a manner that infringes the method-of-use claims (e.g., Compl. ¶41, ¶58, ¶75, ¶92, ¶110). Contributory infringement is based on the allegation that Cipla's product and its labeling are especially made for an infringing use and are not suitable for substantial non-infringing use (e.g., Compl. ¶42, ¶59, ¶76, ¶93, ¶111).

Willful Infringement

The complaint alleges that Cipla 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 forms the basis for a willfulness claim (e.g., Compl. ¶44, ¶61, ¶78, ¶95, ¶113). The alleged pre-suit knowledge stems from at least the date of Cipla's notice letter, December 29, 2021 (Compl. ¶10).

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

  • A core issue will be one of technical identity: Does the crystalline form of acalabrutinib in Cipla’s ANDA product exhibit an X-ray powder diffraction pattern that falls within the specific peak ranges, including the defined margin of error, claimed in the ’721 and ’291 patents? This will be a central evidentiary battleground likely resolved through competing expert analysis of the physical product.
  • A second key question will be one of induced infringement: Will Cipla’s final, FDA-approved product label contain instructions that inevitably lead physicians and patients to practice the patented methods of treating specific cancers (’524 and ’883 patents) with the specific dosage regimen claimed in the ’083 patent (100 mg twice daily)?
  • A third dispositive issue will be patent validity: In its Paragraph IV certification, Cipla asserts that the patents are invalid and/or unenforceable. Consequently, a central focus of the litigation will be on Cipla's ability to prove, by clear and convincing evidence, that the asserted claims are invalid, likely on grounds of anticipation or obviousness in light of prior art in the field of BTK inhibitors.