DCT

2:18-cv-11518

Celgene Corp v. Lotus Pharmaceutical Co Ltd

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I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 2:18-cv-11518, D.N.J., 07/10/2018
  • Venue Allegations: Venue is alleged to be proper in the District of New Jersey based on Defendant Alvogen's principal place of business being located within the district and because Defendants have allegedly conducted business in the district and consented to jurisdiction by naming a local agent for service of process.
  • Core Dispute: Plaintiff alleges that Defendants’ filing of an Abbreviated New Drug Application (ANDA) to market generic versions of Plaintiff's REVLIMID® drug product constitutes an act of infringement of three patents directed to specific polymorphic forms of the active ingredient lenalidomide.
  • Technical Context: The patents relate to polymorphism, the ability of a solid chemical compound to exist in multiple crystalline forms, each of which can possess distinct physical properties critical to drug formulation, stability, and bioavailability.
  • Key Procedural History: This action arises under the Hatch-Waxman Act, triggered by Defendants' filing of ANDA No. 210480 with the FDA. In connection with the ANDA, Defendants submitted a Paragraph IV Certification alleging that Plaintiff's patents covering REVLIMID® are invalid, unenforceable, and/or will not be infringed by the proposed generic products.

Case Timeline

Date Event
2003-09-04 Earliest Priority Date for ’357, ’219, and ’598 Patents
2011-07-12 U.S. Patent No. 7,977,357 Issues
2012-06-05 U.S. Patent No. 8,193,219 Issues
2013-04-30 U.S. Patent No. 8,431,598 Issues
2017-07-24 Date Defendants Sent Paragraph IV Notice Letter to Plaintiff
2018-07-10 Complaint Filed

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

U.S. Patent No. 7,977,357 - Polymorphic Forms of 3-(4- amino-1-oxo-1,3 dihydro-isoindol-2-yl)-piperidine-2,6-dione

The Invention Explained

  • Problem Addressed: The patent's background section explains that a single chemical compound can often exist in different solid crystalline forms, known as polymorphs, which may exhibit different physical and chemical properties such as solubility, stability, and compressibility. (’357 Patent, col. 2:23-34). The discovery and characterization of new polymorphic forms is critical for developing safe, effective, and manufacturable drug products that meet regulatory standards. (’357 Patent, col. 2:34-47).
  • The Patented Solution: The invention discloses the discovery and characterization of several distinct polymorphic forms (designated A, B, C, D, E, F, G, and H) of the active pharmaceutical ingredient 3-(4-amino-1-oxo-1,3 dihydro-isoindol-2-yl)-piperidine-2,6-dione, also known as lenalidomide. (’357 Patent, col. 2:58-65). The patent provides methods for making these specific forms and identifies their unique physical properties using analytical techniques such as X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC), as illustrated in Figures 1 and 4 for Form A. (’357 Patent, col. 5:52-col. 6:53).
  • Technical Importance: Identifying and claiming distinct, stable polymorphs of a drug substance allows for consistent manufacturing, ensures predictable bioavailability, and is a key step in creating a commercially viable pharmaceutical product. (’357 Patent, col. 2:40-57).

Key Claims at a Glance

  • The complaint alleges infringement of one or more claims without specifying which ones (Compl. ¶33). Independent claim 1 is representative of claims directed to a specific polymorph.
  • Essential elements of independent claim 1:
    • The unsolvated crystalline Form A of 3-(4-amino-1-oxo-1,3 dihydro-isoindol-2-yl)-piperidine-2,6-dione
    • which has a differential scanning calorimetry thermogram having an endotherm at approximately 270° C.

U.S. Patent No. 8,193,219 - Polymorphic Forms of 3-(4-amino-1-oxo-1,3 dihydro-isoindol-2-yl)-piperidine-2,6-dione

The Invention Explained

  • Problem Addressed: As with the related ’357 Patent, this patent addresses the technical challenge that a single drug compound can exist in various crystalline forms (polymorphs) with differing physical properties, and the resulting need to identify and control which form is used in a final drug product. (’219 Patent, col. 2:27-38).
  • The Patented Solution: The invention claims pharmaceutical compositions comprising specific, characterized polymorphic forms of lenalidomide. (’219 Patent, Abstract). The claims are directed not just to the polymorph itself, but to a solid oral dosage form (e.g., a capsule or tablet) containing a specific amount of the characterized crystalline form combined with a pharmaceutically acceptable carrier. (’219 Patent, col. 21:23-34).
  • Technical Importance: Claiming a specific polymorph within a final drug formulation is a way to protect the commercial product, ensuring that generic competitors cannot simply use the same active ingredient but must also avoid the specific, patented crystalline form in their own formulations. (’219 Patent, col. 2:42-50).

Key Claims at a Glance

  • The complaint alleges infringement of one or more claims without specifying which ones (Compl. ¶44). Independent claim 1 is representative of claims directed to a pharmaceutical composition.
  • Essential elements of independent claim 1:
    • A pharmaceutical composition for oral administration
    • comprising between 5 mg and 25 mg of an unsolvated crystalline 3-(4-amino-1-oxo-1,3 dihydro-isoindol-2-yl)-piperidine-2,6-dione
    • having an X-ray powder diffraction pattern comprising peaks at approximately 8, 14.5, 16, 17.5, 20.5, 24, and 26 degrees 20
    • and a pharmaceutically acceptable excipient, diluent, or carrier
    • wherein the composition is a solid dosage form.

U.S. Patent No. 8,431,598 - Polymorphic Forms of 3-(4-amino-1-oxo-1,3 dihydro-isoindol-2-yl)-piperidine-2,6-dione

Technology Synopsis

  • This patent, part of the same family as the ’357 and ’219 patents, also addresses the technical challenge of polymorphism in the drug substance lenalidomide. The invention is directed to solid forms of the compound that are substantially pure, comprising a high percentage of a single crystalline form, which is critical for ensuring batch-to-batch consistency and predictable performance in a pharmaceutical product.

Asserted Claims

  • The complaint alleges infringement of one or more claims generally (Compl. ¶55). The patent includes independent claims 1, 5, 10, and 14, among others, directed to solid forms of lenalidomide with certain physical characteristics and a high degree of polymorphic purity.

Accused Features

  • The complaint alleges that Defendants' proposed generic drug products, as described in their ANDA, will contain a solid form of lenalidomide that infringes one or more claims of the ’598 patent (Compl. ¶¶51, 53, 55).

III. The Accused Instrumentality

Product Identification

  • The accused instrumentalities are Defendants’ proposed generic lenalidomide capsules in 2.5 mg, 5 mg, 10 mg, 15 mg, 20 mg, and 25 mg dosage strengths ("Defendants' Proposed Products") (Compl. ¶24). This litigation was initiated based on Defendants' filing of Abbreviated New Drug Application No. 210480 seeking FDA approval to market these products. (Compl. ¶1).

Functionality and Market Context

  • The accused products are proposed generic versions of Celgene's branded drug REVLIMID®, which contains the active ingredient lenalidomide and is used in the treatment of diseases including cancer (Compl. ¶¶1, 2, 11). The complaint alleges that Defendants seek to commercially manufacture, use, sell, or import these generic products into the United States prior to the expiration of the patents-in-suit. (Compl. ¶24).

IV. Analysis of Infringement Allegations

The complaint does not provide a claim chart or a detailed narrative theory of infringement for any asserted patent. The infringement allegations are conclusory, stating that Defendants' submission of their ANDA constitutes infringement under 35 U.S.C. § 271(e)(2)(A) because the proposed generic products will infringe one or more claims of the patents-in-suit (Compl. ¶¶31, 42, 53). As there is insufficient detail for a tabular analysis, none is provided. No probative visual evidence provided in complaint.

  • Identified Points of Contention (’357 Patent):

    • Factual Question: The central dispute for a claim like claim 1 will be whether the lenalidomide in Defendants' ANDA product is, in fact, "unsolvated crystalline Form A" as defined by the patent. This will likely involve a battle of experts analyzing the physical characterization data (e.g., DSC, TGA, XRPD) submitted in the ANDA.
    • Scope Question: The analysis will raise the question of how to interpret "approximately 270° C." as required by claim 1. The scope of "approximately" will be critical in determining whether the thermal profile of Defendants' product falls within the claimed range.

  • Identified Points of Contention (’219 Patent):

    • Factual Question: For a composition claim like claim 1, a primary question will be whether the active ingredient in Defendants' proposed capsules exhibits an XRPD pattern with the specific peaks recited in the claim. The presence, absence, and relative intensity of these peaks in the accused product will be a key factual issue.
    • Scope Question: As with the ’357 Patent, the term "approximately" as it applies to the location of XRPD peaks will be a focal point. The litigation may turn on whether the peaks observed in Defendants' product are close enough to the claimed values to be considered "approximately" the same.

V. Key Claim Terms for Construction

  • The Term: "approximately" (e.g., ’357 Patent, col. 22:34; ’219 Patent, col. 21:29)

    • Context and Importance: This term modifies numerical values for physical properties (DSC temperatures, XRPD peak positions) that define the patented crystalline forms. The breadth of this term is central to the infringement analysis, as it determines the permissible range of experimental variation for the accused product's characteristics to fall within the claim scope. Practitioners may focus on this term because the entire infringement question could hinge on whether the data for the accused product is "approximately" the same as the data for the patented polymorph.
    • Intrinsic Evidence for Interpretation:
      • Evidence for a Broader Interpretation: The specification repeatedly uses terms like "about" and "approximately" when describing the physical data, suggesting the patentee understood that these measurements are subject to some experimental variability and did not intend to be limited to the exact values disclosed. (’357 Patent, col. 6:23, 6:30, 10:14).
      • Evidence for a Narrower Interpretation: The patent provides precise numerical data in its figures and examples (e.g., the DSC endotherm for Form A is shown at 270.28°C in FIG. 4). A party could argue that "approximately" should be construed narrowly to cover only the inherent, minor variations associated with the specific analytical equipment used to generate the patent's data.

  • The Term: "unsolvated" (’357 Patent, col. 22:30)

    • Context and Importance: This term distinguishes the claimed "Form A" polymorph from other potential forms that may incorporate solvent molecules into their crystal lattice (solvates or hydrates). The definition is critical because if the accused product contains even trace amounts of solvent or water, Defendants may argue it is not "unsolvated" and therefore does not infringe.
    • Intrinsic Evidence for Interpretation:
      • Evidence for a Broader Interpretation: The term could be interpreted to mean a crystalline form that does not form a stable solvate and is not intentionally prepared in a way to incorporate solvent, rather than requiring absolute 100% purity from any residual solvent molecules that may be present from the manufacturing process.
      • Evidence for a Narrower Interpretation: The specification points to TGA data showing "a small weight increase up to about 150° C., indicating an unsolvated material" for Form A. (’357 Patent, col. 6:26-28). This could be cited to support a narrow definition where any detectable weight loss attributable to solvent would disqualify a sample from being considered "unsolvated."

VI. Other Allegations

  • Indirect Infringement: The complaint alleges that upon FDA approval, Defendants will induce infringement by "intentionally encourag[ing] acts of direct infringement" and will contributorily infringe by selling a product "especially adapted for a use that infringes" for which there is "no substantial non-infringing use." (Compl. ¶¶34-35, 45-46, 56-57). The specific facts alleged are tied to the act of seeking approval to market a generic equivalent for the same indications as the branded drug.
  • Willful Infringement: The complaint does not use the term "willful," but it does allege that the case is "exceptional" and requests an award of attorneys' fees under 35 U.S.C. § 285. (Compl. ¶¶38, 49, 60). The basis for this allegation appears to be Defendants' act of filing the ANDA with a Paragraph IV certification, which demonstrates knowledge of the patents-in-suit.

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

  • A core issue will be one of evidentiary proof: does the analytical data characterizing the lenalidomide in Defendants' ANDA product (e.g., XRPD, DSC, TGA data) demonstrate the specific physical properties required by the asserted claims, or does it show a different, non-infringing polymorphic form?
  • A key legal question will be one of definitional scope: how broadly will the court construe the term "approximately" when applied to the numerical values defining the patented polymorphs? The case's outcome may depend on whether minor variations in analytical measurements between the accused product and the patent's description are sufficient to avoid infringement.
  • An underlying validity question, raised by Defendants' Paragraph IV certification but not detailed in the complaint, will be whether the claimed polymorphic forms are novel and non-obvious over prior art methods of crystallizing the lenalidomide compound.