DCT

1:22-cv-00155

Acerta Pharma BV v. Natco Pharma Ltd

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I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 1:22-cv-00155, D. Del., 02/02/2022
  • Venue Allegations: Venue is alleged to be proper in the District of Delaware because Defendant Natco Pharma, Inc. is a Delaware corporation that resides in the district, and Defendant Natco Pharma Limited is a foreign corporation subject to suit in any judicial district.
  • Core Dispute: Plaintiffs allege that Defendant’s submission of an Abbreviated New Drug Application (ANDA) to the FDA for a generic version of the cancer drug CALQUENCE® (acalabrutinib) infringes six patents covering the compound, its crystalline forms, pharmaceutical compositions, and methods of use.
  • Technical Context: The technology relates to acalabrutinib, a Bruton's tyrosine kinase (BTK) inhibitor used for treating certain types of lymphoma and leukemia, a significant market in oncology therapeutics.
  • Key Procedural History: This lawsuit was triggered by a Paragraph IV Certification notice letter, dated December 20, 2021, in which Natco informed Plaintiffs of its ANDA filing and asserted that the patents-in-suit would not be infringed or are invalid/unenforceable. The action was filed within the 45-day window provided under the Hatch-Waxman Act, which triggers an automatic 30-month stay of FDA approval for Natco's ANDA.

Case Timeline

Date Event
2011-07-19 Priority Date for '504, '524, and '883 Patents
2014-01-21 Priority Date for '083 Patent
2015-07-02 Priority Date for '721 and '291 Patents
2016-03-22 U.S. Patent No. 9,290,504 Issued
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
2021-12-20 Natco's Notice Letter Sent
2022-02-02 Complaint Filed

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

U.S. Patent No. 9,290,504 - “4-Imidazopyridazin-1-yl-Benzamides and 4-Imidazotriazin-1-yl-Benzamides as BTK Inhibitors” (Issued March 22, 2016)

The Invention Explained

  • Problem Addressed: The patent addresses the need for therapies targeting B-cell mediated autoimmune diseases and B-cell malignancies by modulating B-lymphocyte activation (U.S. Patent No. 10,239,883, col. 1:24-33). Specifically, it seeks to develop inhibitors for Bruton's tyrosine kinase (Btk), a key protein in B-cell signaling pathways, while avoiding inhibition of Src-family kinases, which could cause serious adverse effects ('883 Patent, col. 2:19-53).
  • The Patented Solution: The invention provides a class of 6-5 membered fused pyridine ring compounds that function as Btk inhibitors ('883 Patent, col. 2:56-65). The patent discloses the chemical structure of these compounds, including the specific enantiomer that became the active ingredient acalabrutinib, and their potential use in therapy ('883 Patent, col. 2:60-65).
  • Technical Importance: The invention provided a novel chemical scaffold for inhibiting Btk, a clinically validated target for treating various B-cell cancers ('883 Patent, col. 2:1-4).

Key Claims at a Glance

  • The complaint asserts independent claims 1 and 30 (Compl. ¶38).
  • Claim 30, the more specific of the two, claims the single chemical compound:
    • (S)-4-(8-amino-3-(1-but-2-ynoylpyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(pyridin-2-yl)benzamide.

U.S. Patent No. 9,758,524 - “4-Imidazopyridazin-1-yl-Benzamides as BTK Inhibitors” (Issued September 12, 2017)

The Invention Explained

  • Problem Addressed: This patent addresses the same technical problem as the ’504 Patent: the need for effective Btk inhibitors for treating B-cell related disorders (U.S. Patent No. 9,758,524, col. 1:24-33).
  • The Patented Solution: The patent claims a specific method of using the compound disclosed in the ’504 Patent to treat a particular disease ('524 Patent, col. 2:56-65). It moves beyond the compound itself to claim a specific therapeutic application ('524 Patent, Abstract).
  • Technical Importance: This patent established a specific, claimed therapeutic use for the acalabrutinib compound in treating Mantle Cell Lymphoma (MCL), providing a targeted method for its clinical application ('524 Patent, Abstract).

Key Claims at a Glance

  • The complaint asserts independent claim 1 (Compl. ¶56).
  • Claim 1 contains the following essential elements:
    • A method of treating Mantle Cell Lymphoma (“MCL”) in a human subject.
    • The method comprises 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 administration is in an amount effective to treat MCL in the human subject.

U.S. Patent No. 10,239,883 - “4-Imidazopyridazin-1-yl-Benzamides as BTK Inhibitors” (Issued March 26, 2019)

  • Technology Synopsis: This patent, from the same family as the '504 and '524 patents, claims a method of treating a different cancer, chronic lymphocytic leukemia (CLL), by administering the acalabrutinib compound ('883 Patent, Abstract).
  • Asserted Claims: Independent claim 1 is asserted (Compl. ¶71, ¶74).
  • Accused Features: The use of Natco's ANDA product in accordance with its proposed labeling, which is expected to include an indication for CLL (Compl. ¶76).

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” (Issued October 24, 2017)

  • Technology Synopsis: This patent addresses the problem of identifying stable solid forms of the acalabrutinib compound suitable for pharmaceutical formulation (U.S. Patent No. 10,167,291, col. 2:15-35). The invention is a specific crystalline form of the compound, defined by characteristic peaks in an X-ray powder diffraction (XRPD) pattern ('291 Patent, Abstract).
  • Asserted Claims: Independent claim 1 is asserted (Compl. ¶88, ¶91).
  • Accused Features: The solid form of the acalabrutinib active pharmaceutical ingredient contained within Natco's ANDA product (Compl. ¶91).

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” (Issued January 1, 2019)

  • Technology Synopsis: This patent claims a solid pharmaceutical composition that includes the specific crystal form of acalabrutinib from the '721 patent ('291 Patent, Abstract). The invention specifies a composition comprising the crystal form within a defined dosage range (95-105 mg) along with at least one pharmaceutically acceptable excipient ('291 Patent, col. 128:51-60).
  • Asserted Claims: Independent claim 1 is asserted (Compl. ¶105, ¶108).
  • Accused Features: Natco's 100 mg acalabrutinib oral capsule product, which is alleged to be a solid pharmaceutical composition falling within the claimed dosage range (Compl. ¶28, ¶108).

U.S. Patent No. 10,272,083 - “Methods of Treating Chronic Lymphocytic Leukemia and Small Lymphocytic Leukemia Using a BTK Inhibitor” (Issued April 30, 2019)

  • Technology Synopsis: This patent claims a method of treating mantle cell lymphoma (MCL) by orally administering a specific dosage regimen of the acalabrutinib compound: 100 mg twice daily ('083 Patent, Abstract, claim 8).
  • Asserted Claims: Claim 8 is asserted (Compl. ¶122, ¶126).
  • Accused Features: The use of Natco's 100 mg ANDA product in accordance with its proposed labeling, which Plaintiffs allege will instruct for twice-daily administration for the treatment of MCL (Compl. ¶128).

III. The Accused Instrumentality

Product Identification

  • Natco's ANDA Product No. 216768, which seeks FDA approval for a generic version of CALQUENCE® (acalabrutinib) 100 mg oral capsules (Compl. ¶1, ¶28).

Functionality and Market Context

  • The accused product is a generic drug intended to be a bioequivalent substitute for Plaintiffs' branded CALQUENCE® product (Compl. ¶25). CALQUENCE® is a kinase inhibitor indicated for treating adult patients with mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL), or small lymphocytic lymphoma (SLL) (Compl. ¶24). The complaint alleges that Natco's product contains the acalabrutinib compound and that its proposed labeling will direct medical professionals and patients to use it for the same approved indications, thereby directly competing with the branded product upon FDA approval (Compl. ¶28, ¶41, ¶59). The complaint provides a chemical structure diagram of the acalabrutinib compound that is alleged to be the active ingredient in Natco's product (Compl. ¶35).

IV. Analysis of Infringement Allegations

U.S. Patent No. 9,290,504 Infringement Allegations

Claim Element (from Independent Claim 30) Alleged Infringing Functionality Complaint Citation Patent Citation
The 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. Natco’s ANDA product is a 100 mg oral capsule containing the active ingredient acalabrutinib, which is alleged to be the compound recited in the claim. ¶28, ¶38 U.S. Patent No. 10,239,883, col. 81:43-67
  • Identified Points of Contention:
    • Scope Questions: The complaint states Natco’s notice letter challenged the '504 patent claims on validity grounds rather than non-infringement (Compl. ¶39). This suggests the primary dispute may be over patent validity, not whether the accused product meets the claim limitations. A potential point of contention, however, could be whether Natco's product is an infringing "isolated compound" as required by claim 1 (Compl. ¶34), a term not present in claim 30.
    • Technical Questions: A key technical question for the court will be the chemical analysis of Natco's ANDA product to confirm that it contains the specific (S)- enantiomer of the claimed compound.

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, Natco’s proposed product labeling is alleged to instruct physicians and patients to use the ANDA product for the treatment of MCL, one of the approved indications for CALQUENCE®. ¶24, ¶59 U.S. Patent No. 9,758,524, col. 2:56-65
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, Natco’s ANDA product contains the recited compound as its active ingredient. ¶28, ¶53, ¶56 '524 Patent, col. 11:10-24
in an amount effective to treat MCL in the human subject. Natco’s 100 mg oral capsule, when administered according to the proposed labeling, is alleged to constitute an amount effective to treat MCL. ¶28, ¶53 '524 Patent, col. 31:37-67
  • Identified Points of Contention:
    • Legal Questions: The central issue for this method claim will be induced infringement. The analysis will focus on whether the language in Natco's proposed product label directs, encourages, or recommends that medical professionals prescribe the drug in a manner that practices each step of the claimed method (Compl. ¶59, ¶60).
    • Scope Questions: Does the phrase "an amount effective to treat MCL" require a specific clinical outcome or is it satisfied by providing a bioequivalent dose to the approved branded product? The defendant may argue for a narrower construction requiring a particular level of efficacy that its product or label does not guarantee.

V. Key Claim Terms for Construction

  • The Term: "an amount effective to treat MCL" (from '524 Patent, claim 1)
  • Context and Importance: This term is critical because it defines the required therapeutic outcome of the claimed method. Its construction will determine what Plaintiffs must prove regarding the effect of administering Natco's product according to its label. Practitioners may focus on this term because if it is construed to require a specific, high threshold of clinical efficacy, it could create a higher burden of proof for infringement.
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: The patent specification describes that a "therapeutically effective amount" is an amount sufficient to elicit a "biological or medical response," which can include "alleviating the symptoms of the disease or disorder being treated" (U.S. Patent No. 10,239,883, col. 9:15-20). This language may support a broader interpretation not tied to a specific clinical trial endpoint.
    • Evidence for a Narrower Interpretation: The specification also provides specific dosage ranges, such as "from 0.5 to 100 mg per day" ('883 Patent, col. 31:40-45). A defendant might argue that these specific examples limit the scope of an "effective amount" to only those dosages explicitly studied or disclosed, potentially creating a non-infringement argument if their labeled dose differs.

VI. Other Allegations

  • Indirect Infringement: For all asserted patents, the complaint alleges active inducement and contributory infringement. The basis for inducement is that Natco, with knowledge of the patents, will instruct and encourage physicians and patients to infringe through its product labeling and marketing materials (Compl. ¶42, ¶60, ¶77, ¶94, ¶111, ¶129). Contributory infringement is based on allegations that Natco's product is especially made for an infringing use and is not a staple article suitable for substantial non-infringing use (Compl. ¶43, ¶61, ¶78, ¶95, ¶112, ¶130).
  • Willful Infringement: The complaint alleges that Natco 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 supports a claim for willfulness (Compl. ¶45, ¶63, ¶80, ¶97, ¶114, ¶132). This knowledge is based on Natco's December 20, 2021 notice letter, establishing pre-suit knowledge of the patents.

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

  • A core issue will be one of induced infringement: for the method-of-use patents ('524, '883, '083), the case will likely turn on whether the specific instructions and indications in Natco’s proposed product labeling are sufficient to prove that Natco actively encouraged and intended for physicians to prescribe, and patients to use, the generic drug in a manner that directly practices the patented methods of treatment.
  • A key evidentiary question will be one of physical identity: for the patents covering crystalline forms and compositions ('721, '291), the dispute will center on scientific evidence. Can Plaintiffs prove through techniques like XRPD that the solid form of acalabrutinib manufactured for Natco’s ANDA product possesses the specific, claimed crystalline structure, or will discovery reveal a distinct, non-infringing polymorph?
  • While infringement appears to be the focus of the complaint, the ultimate disposition of the case will likely depend on validity. The complaint notes that Natco's Paragraph IV certification relies on assertions of invalidity and unenforceability (Compl. ¶26, ¶39, ¶57, ¶125), signaling that the primary legal battleground will likely be Natco's attempt to prove that the asserted patent claims are invalid under U.S. patent law.