DCT

1:24-cv-00315

Pfizer Inc v. MSN Laboratories Private Ltd

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Key Events
Complaint

I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 1:24-cv-00315, D. Del., 03/08/2024
  • Venue Allegations: Venue is alleged to be proper for MSN Laboratories as a non-U.S. resident and for MSN Pharmaceuticals based on its incorporation in Delaware.
  • Core Dispute: Plaintiffs allege that Defendants' proposed generic version of the drug OXBRYTA® (voxelotor), as described in an Abbreviated New Drug Application (ANDA) filed with the FDA, will infringe five U.S. patents covering crystalline forms, tablet formulations, and dosing regimens for the active ingredient voxelotor.
  • Technical Context: The technology relates to pharmaceutical treatments for sickle cell disease, a hematological disorder affecting red blood cells, by stabilizing hemoglobin with the active pharmaceutical ingredient voxelotor.
  • Key Procedural History: The lawsuit is a Hatch-Waxman action triggered by Defendants' submission of ANDA No. 219094 to the FDA and a subsequent Paragraph IV Notice Letter, dated January 24, 2024, certifying that the patents-in-suit are invalid, unenforceable, or will not be infringed by the proposed generic product.

Case Timeline

Date Event
2014-02-07 Earliest Priority Date (’071, ’502, ’720 Patents)
2016-09-20 Issue Date (U.S. Patent No. 9,447,071)
2016-10-12 Earliest Priority Date (’035 Patent)
2016-12-02 Earliest Priority Date (’382 Patent)
2019-12-03 Issue Date (U.S. Patent No. 10,493,035)
2020-07-28 Issue Date (U.S. Patent No. 10,722,502)
2021-06-01 Issue Date (U.S. Patent No. 11,020,382)
2022-09-27 Issue Date (U.S. Patent No. 11,452,720)
2024-01-24 Date of Defendants' Paragraph IV Notice Letter to Plaintiffs
2024-03-08 Complaint Filing Date

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

U.S. Patent No. 9,447,071 - "Crystalline Polymorphs of the Free Base of 2-Hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)-pyridin-3-yl)methoxy)benzaldehyde"

The Invention Explained

  • Problem Addressed: The patent addresses the need to identify and characterize stable physical forms of an active pharmaceutical ingredient, which is critical for consistent manufacturing, chemical stability, and therapeutic efficacy (’502 Patent, col. 1:60 - col. 2:12, a related patent describing the same technology).
  • The Patented Solution: The invention is a specific crystalline form, or polymorph, of the active ingredient known as voxelotor (referred to as "Compound 1"). This specific form is an "ansolvate," meaning its crystal lattice is substantially free of solvent molecules, and is defined by a unique pattern of peaks when analyzed with X-ray powder diffraction (XRPD) (’071 Patent, Abstract; col. 3:35-43). The complaint includes a chemical structure diagram illustrating Compound 1 (Compl. ¶43).
  • Technical Importance: Identifying a stable, reproducible crystalline form of a drug is essential for developing a safe and effective pharmaceutical product with predictable properties like solubility and bioavailability (’502 Patent, col. 2:1-12).

Key Claims at a Glance

  • The complaint asserts independent claim 1 (Compl. ¶43).
  • The essential elements of claim 1 are:
    • A crystalline ansolvate of Compound 1.
    • Wherein the crystalline ansolvate is characterized by at least one X-ray powder diffraction peak (using Cu Kα radiation) selected from the group consisting of 13.37°, 14.37°, 19.95°, and 23.92° 2θ (each with a tolerance of ±0.2°).

U.S. Patent No. 10,493,035 - "Tablets Comprising 2-Hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)-pyridin-3-yl)methoxy)benzaldehyde"

The Invention Explained

  • Problem Addressed: The patent addresses the challenge of creating a high-dose oral tablet for Compound 1. High clinical doses can lead to a large "pill burden" for patients, which reduces adherence, and formulating a high-drug-load tablet that is physically stable and can be manufactured at scale presents significant technical hurdles (’035 Patent, col. 1:36 - col. 2:2).
  • The Patented Solution: The invention is a specific tablet formulation comprising high concentrations of Compound 1 (50-70% by weight) combined with specific amounts of particular excipients, such as microcrystalline cellulose, croscarmellose sodium, and magnesium stearate. This combination is designed to produce a robust, high-drug-load tablet suitable for commercial manufacturing (’035 Patent, col. 2:5-20; Abstract). The complaint provides a visual of the chemical structure of Compound 1, which is the active ingredient in the claimed tablet (Compl. ¶68).
  • Technical Importance: This formulation enables the administration of a high therapeutic dose in a smaller number of pills, which can improve patient compliance and treatment outcomes (’035 Patent, col. 1:40-44).

Key Claims at a Glance

  • The complaint asserts independent claim 1 (Compl. ¶68).
  • The essential elements of claim 1 are:
    • A tablet comprising:
    • (i) about 50% to about 70% by weight of Compound 1;
    • (ii) about 30% to about 40% by weight of microcrystalline cellulose;
    • (iii) about 0.25% to about 3% by weight of croscarmellose sodium;
    • (iv) about 1% to about 5% by weight of magnesium stearate;
    • (v) about 0.5% to about 2.5% of sodium lauryl sulfate; and
    • (vi) about 0.25% to about 5% by weight of colloidal silicon dioxide.
    • Wherein the percentages are relative to the total weight of the tablet.

U.S. Patent No. 10,722,502 - "Crystalline Polymorphs of the Free Base of 2-Hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)-pyridin-3-yl)methoxy)benzaldehyde"

  • Technology Synopsis: This patent claims a composition comprising the same crystalline ansolvate form of Compound 1 as the ’071 patent, but adds the limitation that the composition must be "substantially free of other ansolvate polymorphs" of the compound. This is intended to protect a purer, more stable version of the drug substance (’502 Patent, Abstract).
  • Asserted Claims: The complaint asserts independent claim 1 (Compl. ¶93).
  • Accused Features: The complaint alleges that MSN's ANDA Product will contain a composition comprising the claimed crystalline ansolvate of Compound 1 that is substantially free of other polymorphs (Compl. ¶94).

U.S. Patent No. 11,020,382 - "Dosing Regimens for 2-Hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)-pyridin-3-yl)methoxy)benzaldehyde"

  • Technology Synopsis: This patent claims a method for treating sickle cell disease. The inventive step is the specific dosing regimen: administering about 1500 mg of Compound 1 once daily, where the compound is in the specific crystalline ansolvate form characterized by the same XRPD peaks as in the ’071 patent (’382 Patent, Abstract; col. 1:10-18).
  • Asserted Claims: The complaint asserts independent claim 1 (Compl. ¶118).
  • Accused Features: The complaint alleges that the proposed labeling for MSN's ANDA Product will instruct physicians and patients to use the drug in a manner that directly infringes the claimed method, specifically by administering it orally at a dose of about 1500 mg once daily (Compl. ¶119).

U.S. Patent No. 11,452,720 - "Crystalline Polymorphs of the Free Base of 2-Hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)-pyridin-3-yl)methoxy)benzaldehyde"

  • Technology Synopsis: This patent claims a method for treating sickle cell disease by administering a composition that contains two active ingredients: the specific crystalline ansolvate of Compound 1 (as in the ’071 patent) and "another active agent." This protects combination therapies (’720 Patent, Abstract).
  • Asserted Claims: The complaint asserts independent claim 1 (Compl. ¶143).
  • Accused Features: The complaint alleges, upon information and belief, that MSN's ANDA Product will be used in a method for treating sickle cell disease that involves administering a composition containing the claimed crystalline form of Compound 1 along with another active agent (Compl. ¶144).

III. The Accused Instrumentality

Product Identification

The accused instrumentality is "MSN's ANDA Product," identified as voxelotor tablets for which Defendants seek FDA approval under ANDA No. 219094 (Compl. ¶¶1, 16).

Functionality and Market Context

The complaint alleges that MSN's ANDA Product is a generic copy of Plaintiffs' OXBRYTA® tablets, a treatment for sickle cell disease in adults and pediatric patients (Compl. ¶¶14, 18). It further alleges that the ANDA relies on the bioequivalence of MSN's product to OXBRYTA® (Compl. ¶19). By filing the ANDA, Defendants are seeking regulatory approval to manufacture and sell their generic voxelotor tablets in the U.S. before the expiration of the patents-in-suit (Compl. ¶16).

IV. Analysis of Infringement Allegations

U.S. Patent No. 9,447,071 Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
A crystalline ansolvate of Compound 1: [structure depicted] The complaint alleges, upon information and belief, that "MSN's ANDA Product will contain a crystalline ansolvate of Compound 1." The chemical structure of Compound 1 is depicted in the complaint. ¶44; ¶43 col. 3:35-43
wherein the crystalline ansolvate is characterized by at least one X-ray powder diffraction peak (Cu Kα radiation) selected from 13.37°, 14.37°, 19.95° and 23.92° 2θ (each ±0.2° 2θ). The complaint alleges that the crystalline ansolvate of Compound 1 in MSN's ANDA Product will be "characterized by at least one X-ray powder diffraction peak (Cu Kα radiation) selected from 13.37°, 14.37°, 19.95°, and 23.92° 2θ (each ±0.2° 2θ)." ¶44 col. 3:39-43; ’502 Patent, col. 4:1-12

U.S. Patent No. 10,493,035 Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
A tablet comprising: The complaint alleges, upon information and belief, that "MSN's ANDA Product will be a tablet." ¶69 col. 2:15-16
(i) about 50% to about 70% by weight of Compound 1... The complaint alleges the accused tablet will comprise "about 50% to about 70% by weight of Compound 1." ¶69 col. 2:16-17
(ii) about 30% to about 40% by weight of microcrystalline cellulose; The complaint alleges the accused tablet will comprise "about 30 % to about 40 % by weight of microcrystalline cellulose." ¶69 col. 13:50-51
(iii) about 0.25% to about 3% by weight of croscarmellose sodium; The complaint alleges the accused tablet will comprise "about 0.25% to about 3% by weight of croscarmellose sodium." ¶69 col. 13:52-53
(iv) about 1% to about 5% by weight of magnesium stearate; The complaint alleges the accused tablet will comprise "about 1% to about 5% by weight of magnesium stearate." ¶69 col. 13:54-55
(v) about 0.5% to about 2.5% of sodium lauryl sulfate; and The complaint alleges the accused tablet will comprise "about 0.5% to about 2.5% of sodium lauryl sulfate." ¶69 col. 13:56-57
(vi) about 0.25% to about 5% by weight of colloidal silicon dioxide... The complaint alleges the accused tablet will comprise "about 0.25% to about 5% by weight of colloidal silicon dioxide." ¶69 col. 13:58-59

Identified Points of Contention

  • Technical Questions: The complaint alleges infringement "upon information and belief" because Plaintiffs have had "very limited information" about the actual nature and formulation of MSN's product (Compl. ¶21). A primary technical question will be whether discovery confirms that MSN's manufacturing process consistently produces the specific crystalline ansolvate defined by the claimed XRPD peaks. Similarly, discovery will be needed to determine if the final composition of MSN's tablet falls within the specific weight percentage ranges claimed in the ’035 patent.
  • Scope Questions: For the ’035 patent, the construction of the term "about" will be a central issue. The dispute may focus on whether "about" allows for a standard range of deviation (e.g., ±10%) or if the specific context of a pharmaceutical formulation requires a narrower interpretation limited to minor manufacturing variances. For the ’071 and ’502 patents, a question may arise as to whether MSN's product, even if crystalline, meets the claim limitation of being an "ansolvate," particularly if trace solvents are present.

V. Key Claim Terms for Construction

Term: "crystalline ansolvate"

(asserted in Claim 1 of the ’071, ’502, ’382, and ’720 patents)

  • Context and Importance: This term is fundamental to the patents covering the physical form of the drug substance. Its construction will be critical because if the accused product is found to be amorphous, a different polymorph, or a solvate (a crystal form containing trapped solvent molecules), infringement may be avoided. Practitioners may focus on this term because Defendants in ANDA cases frequently challenge infringement by arguing their generic product has a different physical form than the one claimed.
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: The patents define a "crystalline ansolvate" as "a crystalline solid form of the free base" of Compound 1 (’502 Patent, col. 13:1-3). Plaintiffs may argue this definition is broad and that the term is primarily meant to distinguish the claimed form from solvates or amorphous forms.
    • Evidence for a Narrower Interpretation: Defendants may argue that the term must be read narrowly in light of the specific XRPD peaks used to characterize it in the claims. They could contend that any crystalline form not matching those specific peaks is not the claimed "crystalline ansolvate," or that the term implies an absolute absence of any solvent, which may be difficult to achieve in a commercial product.

Term: "about"

(asserted in Claim 1 of the ’035 patent)

  • Context and Importance: This term modifies every percentage range in the formulation claim. Its interpretation will determine the scope of the claim and whether a formulation with ingredient percentages slightly outside the recited numbers still infringes. This is a common point of contention in pharmaceutical formulation cases where generic manufacturers may design their products to be close to, but not exactly matching, the patented formulation.
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: The patent provides an explicit definition, stating that "about" can mean "within ±30%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range" (’035 Patent, col. 12:8-15). Plaintiffs may argue that this language demonstrates the patentee's intent for the term to have significant breadth.
    • Evidence for a Narrower Interpretation: Defendants may argue that despite the broad general definition, the specific context of the examples, which provide precise formulations, suggests a narrower reading is appropriate for the claims. They may also point to the doctrine of claim differentiation if dependent claims recite narrower ranges, suggesting the independent claim's "about" must be broader than those.

VI. Other Allegations

Indirect Infringement

The complaint alleges that Defendants will induce and contribute to the infringement of the method-of-use patents (’382 and ’720 patents) (Compl. ¶¶117, 142). The basis for this allegation is that the proposed product labeling for MSN's generic drug will instruct medical professionals and patients to administer the drug in accordance with the patented methods (e.g., at the claimed 1500 mg once-daily dose for treating sickle cell disease) (Compl. ¶¶119, 144).

Willful Infringement

The complaint alleges that Defendants have acted with "full knowledge" of the patents-in-suit and "without a reasonable basis for believing that they would not be liable for infringement" (Compl. ¶¶45, 70, 95, 120, 145). This allegation is based on Defendants' Paragraph IV certification, which required them to review and make assertions regarding each of the patents-in-suit, thereby establishing pre-suit knowledge.

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

  • A key evidentiary question will be one of physical identity: will discovery and expert analysis confirm that MSN's proposed generic product contains the specific crystalline "ansolvate" polymorph of voxelotor—as defined by the X-ray diffraction peaks—claimed in the ’071 and ’502 patents, or will it prove to be an amorphous form or a different, non-infringing polymorph?
  • A central issue of claim construction will be the scope of the term "about" in the ’035 formulation patent. The case may turn on whether the court adopts a broad, percentage-based definition as provided in the specification, or a narrower interpretation based on the precise formulations described in the patent's examples, thereby determining if MSN's formulation infringes.
  • For the method-of-use patents (’382 and ’720), the dispute will likely focus on induced infringement: does the language of MSN's proposed product label actively encourage or instruct physicians and patients to administer the generic drug in the specific dosage regimens and combinations claimed in the patents, making infringement by end-users a virtual certainty upon the product's launch?