DCT

2:23-cv-22954

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-22954, D.N.J., 12/07/2023
  • Venue Allegations: Venue is alleged to be proper in the District of New Jersey because Defendant Hetero USA Inc. maintains an established place of business in the district, and because the foreign defendants are subject to personal jurisdiction in the district and have not contested venue in prior New Jersey litigation.
  • Core Dispute: Plaintiff alleges that Defendants' filing of an Abbreviated New Drug Application (ANDA) to market a generic version of Plaintiff's ISENTRESS HD® (raltegravir) constitutes an act of infringement of four patents covering the drug's active ingredient and specific formulations.
  • Technical Context: The technology concerns the potassium salt of raltegravir, an HIV integrase inhibitor, and specific pharmaceutical compositions designed to improve its stability, solubility, and bioavailability for the treatment of HIV infection.
  • Key Procedural History: The litigation was initiated under the Hatch-Waxman Act following Defendants' submission of ANDA No. 218374 to the U.S. Food and Drug Administration. Defendants provided Plaintiff with a "Paragraph IV certification" notice, asserting that the patents-in-suit are invalid, unenforceable, and/or will not be infringed by the commercialization of their proposed generic product.

Case Timeline

Date Event
2004-12-03 Priority Date for ’731 and ’733 Patents
2009-10-26 Priority Date for ’311 and ’888 Patents
2010-07-13 ’731 Patent Issued
2014-07-08 ’733 Patent Issued
2017-05-16 ’311 Patent Issued
2020-09-15 ’888 Patent Issued
2023-10-24 Date of Defendants' Notice Letter to Plaintiff
2023-12-07 Complaint Filing Date

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

U.S. Patent No. 7,754,731 - "Potassium Salt of an HIV Integrase Inhibitor" (issued July 13, 2010)

The Invention Explained

  • Problem Addressed: The patent's background section notes that the free base form of the HIV integrase inhibitor raltegravir has limited water solubility, which can hinder development as an oral drug, and that attempts to create a sodium salt resulted only in an undesirable amorphous material (’731 Patent, col. 2:1-7).
  • The Patented Solution: The invention is a specific, stable, anhydrous crystalline form of the potassium salt of raltegravir, designated "Form 1." This crystalline salt is described as being significantly more soluble in water than the free base, exhibiting improved pharmacokinetics that make it suitable for pharmaceutical compositions (’731 Patent, col. 2:1-7, Abstract). The patent characterizes this specific crystalline structure through its unique X-ray powder diffraction (XRPD) pattern, illustrated in Figure 1 (’731 Patent, col. 3:4-21).
  • Technical Importance: The creation of a stable, soluble crystalline salt form was a critical step in enabling the successful formulation of raltegravir as a commercially viable oral therapeutic for HIV treatment (’731 Patent, col. 2:1-7).

Key Claims at a Glance

  • The complaint does not identify specific asserted claims. Independent Claim 1 is representative:
    • An anhydrous crystalline potassium salt of a specific chemical compound (raltegravir).
    • Which is a "Form 1" crystalline potassium salt.
    • 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.

U.S. Patent No. 8,771,733 - "Pharmaceutical Composition Containing an Anti-Nucleating Agent" (issued July 8, 2014)

The Invention Explained

  • Problem Addressed: The patent describes a problem common to certain drug salts: high solubility at one pH can be lost upon exposure to a different pH, such as the transition from the acidic stomach to the less acidic intestine. This can cause the drug to precipitate out of solution as a less soluble form, thereby reducing its absorption and bioavailability (’733 Patent, col. 1:21-45).
  • The Patented Solution: The invention is a pharmaceutical composition that combines a drug salt (such as raltegravir potassium) with an "anti-nucleating agent." This agent, typically a water-soluble polymer like hydroxypropylmethylcellulose (HPMC), is intended to inhibit or delay the drug's precipitation from a supersaturated solution created in the gastrointestinal tract, thereby allowing more of the drug to be absorbed into the bloodstream (’733 Patent, Abstract; col. 2:53-61).
  • Technical Importance: This formulation technology provides a method to enhance the oral absorption of drug salts that would otherwise exhibit poor bioavailability due to pH-dependent solubility issues in the digestive system (’733 Patent, col. 2:46-52).

Key Claims at a Glance

  • The complaint does not identify specific asserted claims. Independent Claim 1 is representative:
    • A pharmaceutical composition for oral administration as a solid dose.
    • Comprising an effective amount of a base salt of a specific compound (raltegravir).
    • Wherein the salt is characterized by conversion to a less soluble form at a GI-relevant pH below its native pH.
    • Comprising an anti-nucleating agent that is a hydroxyalkylcellulose.

U.S. Patent No. 9,649,311 - "Solid Pharmaceutical Compositions Containing an Integrase Inhibitor" (issued May 16, 2017)

  • Technology Synopsis: This patent addresses the need for a raltegravir-containing tablet that is smaller and has a higher drug load while also providing an improved pharmacokinetic profile, including increased drug absorption and reduced variability, compared to earlier formulations (’311 Patent, col. 3:4-17). The solution is a compressed tablet formulated with specific intragranular and extragranular components, including a binder and superdisintegrants distributed in both phases to control the tablet's disintegration and dissolution properties (’311 Patent, Abstract).
  • Asserted Claims: The complaint does not specify claims; Claim 1 is independent.
  • Accused Features: The complaint alleges infringement by Defendants' generic raltegravir product proposed in ANDA No. 218374, which is alleged to be the same or substantially the same as Merck's ISENTRESS HD® product (Compl. ¶¶1, 42, 62).

U.S. Patent No. 10,772,888 - "Solid Pharmaceutical Compositions Containing an Integrase Inhibitor" (issued September 15, 2020)

  • Technology Synopsis: As a divisional of the application leading to the ’311 patent, this patent covers similar technology. It describes compressed tablets of raltegravir salt comprising distinct intragranular and extragranular components. This specific formulation structure is designed to permit a higher drug load in a smaller tablet while improving the drug's absorption characteristics (’888 Patent, Abstract; col. 3:4-17).
  • Asserted Claims: The complaint does not specify claims; Claim 1 is independent.
  • Accused Features: The complaint alleges infringement by Defendants' generic raltegravir product proposed in ANDA No. 218374 (Compl. ¶¶1, 42, 68).

III. The Accused Instrumentality

Product Identification

  • The accused products are the generic raltegravir tablets for which Defendants seek FDA approval under ANDA No. 218374 (Compl. ¶1).

Functionality and Market Context

  • The accused product is a generic version of Merck's ISENTRESS HD®, which is a 600 mg oral tablet formulation of raltegravir potassium used for the treatment of HIV infection (Compl. ¶¶1, 40, 42). The complaint alleges that the proposed generic product is "the same, or substantially the same, as Merck's ISENTRESS HD®" (Compl. ¶42). The complaint does not provide specific details regarding the composition or formulation of Defendants' proposed generic product. No probative visual evidence provided in complaint.

IV. Analysis of Infringement Allegations

The complaint pleads infringement in a conclusory manner, stating on information and belief that Defendants' generic product "will, if approved and marketed, infringe at least one claim" of each of the patents-in-suit (Compl. ¶¶50, 56, 62, 68). This is a common pleading practice in ANDA litigation where the specifics of the accused product's formulation are not yet known to the plaintiff. The complaint does not contain or reference a claim chart, and therefore a detailed claim chart summary cannot be constructed from the pleading. The narrative infringement theory is that by filing an ANDA for a generic equivalent of ISENTRESS HD®, Defendants' product will necessarily practice the inventions claimed in the patents listed in the FDA's Orange Book for that drug product (Compl. ¶1).

  • Identified Points of Contention:
    • ’731 Patent (API Form): A primary point of contention will likely be whether the raltegravir potassium active pharmaceutical ingredient (API) in Defendants' product is the specific "Form 1" crystalline polymorph required by the claims. The dispute may center on evidence from techniques like XRPD to compare the crystalline structure of Defendants' API against the claimed structure. Defendants' Paragraph IV certification may assert that they use a different, non-infringing polymorphic form of the API.
    • ’733, ’311, and ’888 Patents (Formulation): For the formulation patents, disputes will likely arise over whether the excipients and overall structure of Defendants' tablet meet the specific limitations of the asserted claims. For the ’733 Patent, a key question may be whether any excipient in the accused product functions as an "anti-nucleating agent." For the ’311 and ’888 Patents, the analysis will question whether the accused formulation contains the claimed intragranular and extragranular components in the specified amounts and arrangements.

V. Key Claim Terms for Construction

  • For the ’731 Patent:

    • The Term: "An anhydrous crystalline potassium salt of [raltegravir]... characterized by an X-ray powder diffraction pattern... which comprises 2θ values in degrees of 5.9, 20.0 and 20.6" (from Claim 1).
    • Context and Importance: This term defines the invention's specific crystalline form, or polymorph. Infringement of the ’731 Patent hinges entirely on whether Defendants' API meets this structural definition. Any deviation could support a non-infringement argument.
    • Intrinsic Evidence for Interpretation:
      • Evidence for a Broader Interpretation: The use of "comprises" could suggest the list of XRPD peaks is not exhaustive, allowing for the presence of other, unlisted peaks.
      • Evidence for a Narrower Interpretation: The patent specification provides a specific example, a representative XRPD pattern (Fig. 1), and a detailed list of characteristic peaks that precisely define "Form 1" (’731 Patent, col. 3:4-21; Fig. 1). Courts typically construe claims defining a specific polymorph narrowly to the form disclosed in the patent.

  • For the ’733 Patent:

    • The Term: "anti-nucleating agent" (from Claim 1).
    • Context and Importance: This is a functional claim term. The infringement analysis will depend on whether an excipient in Defendants' formulation performs the claimed function of inhibiting or delaying drug precipitation in the GI tract. Practitioners may focus on this term because Defendants could argue that their excipients serve other standard pharmaceutical purposes (e.g., as binders or fillers) and do not perform the claimed anti-nucleation function.
    • Intrinsic Evidence for Interpretation:
      • Evidence for a Broader Interpretation: The specification provides a functional definition, stating the agent's purpose is to "provide prolonged supersaturation" to permit absorption (’733 Patent, col. 2:53-61). It also defines the agent structurally in broad terms as a "water-soluble polymer" (’733 Patent, col. 4:45-53).
      • Evidence for a Narrower Interpretation: The specification’s examples and detailed description focus heavily on hydroxyalkylcelluloses, particularly HPMC (’733 Patent, col. 5:11-37). Defendants may argue that the term should be construed as limited to this class of polymers or those with very similar properties and mechanisms of action.

VI. Other Allegations

  • Indirect Infringement: The complaint alleges that upon FDA approval, Defendants will infringe by inducement and contribution (Compl. ¶¶51, 57, 63, 69). The alleged basis for inducement is that Defendants' marketing, sale, and product labeling for the generic drug will encourage and instruct physicians and patients to use it in an infringing manner.
  • Willful Infringement: The complaint does not contain a formal count for willful infringement. However, it alleges that Defendants have had "actual knowledge" of each patent-in-suit at least since October 24, 2023, the date of their notice letter (Compl. ¶¶49, 55, 61, 67). This allegation of post-filing knowledge could form the basis for a later claim of willful infringement for any infringing acts that occur after this date.

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

The resolution of this case will likely depend on the court's determination of the following central questions:

  • A core issue will be one of polymorphic identity: Does the active pharmaceutical ingredient in Defendants' proposed generic product possess the specific "Form 1" crystalline structure defined by the X-ray diffraction peaks in the ’731 Patent, or have Defendants developed an alternative, non-infringing form?
  • A second key question will be one of functional equivalence of excipients: Do the inactive ingredients in Defendants' formulation perform the specific functions required by the formulation patents? Specifically, does any component act as an "anti-nucleating agent" as claimed in the ’733 Patent, and does the overall formulation meet the structural "intragranular" and "extragranular" requirements of the ’311 and ’888 Patents?