DCT

2:23-cv-02364

Merck Sharp & Dohme LLC v. Hetero USA Inc

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I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 2:23-cv-02364, D.N.J., 04/28/2023
  • Venue Allegations: Plaintiff alleges venue is proper in the District of New Jersey because Defendant Hetero USA maintains a regular and established place of business in the district, the other Hetero entities are foreign corporations subject to jurisdiction in the district, and the defendants have previously been sued in the district without contesting venue.
  • Core Dispute: Plaintiff alleges that Defendants' filing of an Abbreviated New Drug Application (ANDA) to market a generic version of Plaintiff's ISENTRESS® (raltegravir) product constitutes an act of infringement of a patent covering a specific crystalline salt form of the active ingredient.
  • Technical Context: The technology concerns pharmaceutical salt forms of raltegravir, an HIV integrase inhibitor, which are designed to improve properties like solubility and bioavailability for effective oral drug delivery.
  • Key Procedural History: The litigation was triggered by Defendants' submission of ANDA No. 203540 to the U.S. Food and Drug Administration (FDA) and a subsequent "Notice Letter" to Plaintiff containing a "Paragraph IV certification," which asserted that the patent-in-suit is invalid, unenforceable, and/or will not be infringed by the proposed generic product.

Case Timeline

Date Event
2004-12-03 ’731 Patent Priority Date
2010-07-13 U.S. Patent No. 7,754,731 Issues
2012-01-05 Defendants Send Paragraph IV Notice Letter to Plaintiff
2023-04-28 Complaint Filed

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

U.S. Patent No. 7,754,731 - "Potassium Salt of an HIV Integrase Inhibitor"

The Invention Explained

  • Problem Addressed: The patent's background section describes the HIV retrovirus and identifies the viral integrase enzyme as essential for its life cycle, making it a key target for therapeutic inhibitors (’731 Patent, col. 1:16-48). While a specific HIV integrase inhibitor known as "Compound A" (raltegravir) was known, the patent notes the challenge of formulating it effectively. The specification explains that potassium salts of Compound A are significantly more water-soluble than the free base and that attempts to create a crystalline sodium salt had been unsuccessful, resulting only in amorphous material (’731 Patent, col. 2:1-7).
  • The Patented Solution: The invention provides specific crystalline potassium salts of Compound A. These salts are designed to have improved physicochemical properties, such as higher solubility and better pharmacokinetics, compared to the free base form of the drug (’731 Patent, col. 2:1-5). The patent characterizes distinct crystalline forms (polymorphs), such as the anhydrous "Form 1," by their unique X-ray powder diffraction (XRPD) patterns and differential scanning calorimetry (DSC) curves, which serve as structural fingerprints (’731 Patent, col. 3:4-34; FIG. 1).
  • Technical Importance: For an orally administered drug, creating a stable, soluble, and highly bioavailable solid form is a critical step in transforming a potent chemical compound into a commercially viable and effective medicine (’731 Patent, col. 2:1-5).

Key Claims at a Glance

  • The complaint asserts infringement of "at least one claim of the '731 patent" but does not specify which claims will be asserted (Compl. ¶47). Claim 1 is the broadest independent claim.
  • Independent Claim 1:
    • An anhydrous crystalline potassium salt of Compound A
    • wherein Compound A is of a specified chemical formula (raltegravir)
    • which is characterized by an X-ray powder diffraction pattern obtained using copper Kα radiation which comprises 2θ values in degrees of 5.9, 20.0 and 20.6

III. The Accused Instrumentality

Product Identification

The accused instrumentality is the generic raltegravir drug product described in Defendants' Abbreviated New Drug Application No. 203540 ("Raltegravir ANDA") (Compl. ¶1).

Functionality and Market Context

The complaint alleges that the Raltegravir ANDA seeks FDA approval to market a generic product that is "the same, or substantially the same, as Merck's ISENTRESS®" (Compl. ¶39). ISENTRESS® is a prescription medicine approved for the treatment of HIV infection and contains raltegravir as its active ingredient (Compl. ¶37). The filing of the ANDA itself is the statutorily defined act of infringement alleged in the complaint, preceding any commercial launch (Compl. ¶45).

IV. Analysis of Infringement Allegations

The complaint does not contain a detailed claim chart exhibit. The infringement theory is based on the statutory act of infringement under 35 U.S.C. § 271(e)(2)(A), which arises from the submission of an ANDA seeking approval to market a generic drug prior to the expiration of a patent listed in the FDA's Orange Book (Compl. ¶¶1, 45). The following summary is constructed based on the allegations in the complaint and the necessary characteristics of a generic drug intended to be equivalent to the branded ISENTRESS® product.

No probative visual evidence provided in complaint.

’731 Patent Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
An anhydrous crystalline potassium salt of Compound A... Defendants' Raltegravir ANDA allegedly seeks approval for a generic version of ISENTRESS®, which contains the potassium salt of raltegravir (Compound A) as its active pharmaceutical ingredient. ¶¶1, 39, 47 col. 2:1-5
...wherein Compound A is of formula: [structure shown] The active ingredient in the accused product is raltegravir, which corresponds to the chemical structure of Compound A. ¶¶1, 37 col. 1:49-65
...which is characterized by an X-ray powder diffraction pattern obtained using copper Kα radiation which comprises 2θ values in degrees of 5.9, 20.0 and 20.6 The complaint alleges that upon approval, the commercial manufacture and sale of Defendants' generic raltegravir product will infringe the claims of the ’731 Patent. This implies the product described in the ANDA possesses the claimed crystalline form. ¶¶39, 47, 48 col. 3:7-15

Identified Points of Contention

  • Scope Questions: Defendants' Paragraph IV certification letter asserts non-infringement (Compl. ¶41). This suggests a central dispute will be whether the specific crystalline form (polymorph) of the raltegravir potassium salt used in Defendants' generic product falls within the scope of the asserted claims. The question for the court may be: Does the term "characterized by" require the presence of the recited XRPD peaks and nothing more, or does it imply a broader pattern matching the patent's "Form 1" polymorph?
  • Technical Questions: The primary technical question will be one of physical evidence. What do the XRPD and other characterization data for the active pharmaceutical ingredient in Defendants' ANDA product actually show? The complaint does not provide this technical detail, raising the evidentiary question of whether Defendants' product utilizes the specific "Form 1" crystalline structure defined by the patent or an alternative, non-infringing form (e.g., a different polymorph, a hydrated form, or an amorphous version).

V. Key Claim Terms for Construction

Term: "anhydrous crystalline potassium salt"

  • Context and Importance: This term is fundamental to the claim's scope. Infringement requires that the accused product contains a potassium salt of Compound A that is both "crystalline" (i.e., having an ordered atomic structure, not amorphous) and "anhydrous" (i.e., containing no water of hydration). A product utilizing an amorphous form, a different salt, or a hydrated crystalline form would likely fall outside the literal scope of this claim. Practitioners may focus on this term because developing and claiming a specific, stable polymorph is a common and critical strategy in pharmaceutical patenting.
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: The patent describes multiple crystalline forms, suggesting the general concept of a crystalline potassium salt was part of the invention (’731 Patent, col. 3:4-65).
    • Evidence for a Narrower Interpretation: The patent explicitly distinguishes an "anhydrous crystalline potassium salt" ("Form 1") from a "hydrated crystalline K salt" ("Form 2") (’731 Patent, col. 3:7-8, 3:47-49). This explicit differentiation provides strong evidence that "anhydrous" is a meaningful and strict limitation.

Term: "characterized by an X-ray powder diffraction pattern ... which comprises 2θ values in degrees of 5.9, 20.0 and 20.6"

  • Context and Importance: This phrase defines the specific crystalline "fingerprint" of the claimed invention. Whether the Defendants' product exhibits these characteristic peaks will be a dispositive issue for literal infringement. Disputes over polymorph patents frequently turn on expert analysis and comparison of XRPD data from the patent and the accused product.
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: The use of "comprises" could support an argument that the pattern must include these peaks but is not limited to only these peaks, potentially allowing for some variation or the presence of additional peaks.
    • Evidence for a Narrower Interpretation: The specification directly links these specific 2θ values to the "Form 1" crystalline salt, and Figure 1 provides a graphical representation of this specific form (’731 Patent, col. 3:7-15; FIG. 1). A defendant may argue this language requires the presence of all listed peaks and that the absence of even one peak would avoid infringement.

VI. Other Allegations

Indirect Infringement

The complaint alleges that upon FDA approval, Defendants will induce and contribute to infringement by "marketing, and selling its generic raltegravir product(s) in the United States" with the knowledge and intent that it be used for the patented purpose of treating HIV (Compl. ¶48).

Willful Infringement

The complaint does not contain a formal count for willful infringement. However, it lays the foundation for such a claim by alleging that Defendants have had "actual knowledge of the '731 patent since... at least since January 5, 2012, when the Notice Letter was sent to Merck" (Compl. ¶46). This alleges pre-suit knowledge of the patent and the alleged infringement.

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

  • A central question will be one of polymorphic identity: does the active pharmaceutical ingredient in Hetero's ANDA product possess the specific anhydrous crystalline structure as defined by the X-ray diffraction peaks recited in Claim 1, or does it utilize a different, non-infringing polymorph? This will likely be a battle of competing expert characterization data.
  • A second core issue, raised by Defendants' Paragraph IV certification, will be one of validity: was the specific crystalline Form 1 of raltegravir potassium salt claimed in the ’731 Patent anticipated by any single prior art reference or rendered obvious by the combination of prior art teachings related to raltegravir and the general science of pharmaceutical salt screening and crystallization?