DCT

1:22-cv-00854

Chemo Research SL v. Encube Ethicals Private Ltd

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I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 1:22-cv-00854, D. Del., 06/24/2022
  • Venue Allegations: Venue is alleged to be proper because Defendant is a foreign entity suable in any judicial district and has allegedly committed acts of infringement in Delaware.
  • Core Dispute: Plaintiffs allege that Defendant’s Abbreviated New Drug Application to market a generic version of NUVESSA® vaginal gel infringes seven patents related to metronidazole formulations.
  • Technical Context: The technology concerns aqueous-based gel formulations containing the antimicrobial drug metronidazole, used for treating bacterial vaginosis, a common vaginal infection.
  • Key Procedural History: This is a Hatch-Waxman action triggered by Defendant’s filing of Abbreviated New Drug Application (ANDA) No. 216795. The complaint states that Defendant provided Plaintiffs with a notice letter containing a Paragraph IV certification, alleging that the claims of the patents-in-suit are invalid.

Case Timeline

Date Event
2008-02-02 Earliest Priority Date for ’097, ’678, ’792 Patents
2011-02-22 U.S. Patent No. 7,893,097 Issues
2011-06-28 Earliest Priority Date for ’276, ’858, ’634, ’155 Patents
2014-02-25 U.S. Patent No. 8,658,678 Issues
2014-11-04 U.S. Patent No. 8,877,792 Issues
2015-02-03 U.S. Patent No. 8,946,276 Issues
2015-12-01 U.S. Patent No. 9,198,858 Issues
2019-03-26 U.S. Patent No. 10,238,634 Issues
2020-03-24 U.S. Patent No. 10,596,155 Issues
2022-05-13 Defendant’s Notice Letter Dated
2022-05-16 Plaintiffs Receive Notice Letter
2022-06-24 Complaint Filed

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

U.S. Patent No. 7,893,097 - “Methods and Compositions for Increasing Solubility of Azole Drug Compounds that are Poorly Soluble in Water,” Issued Feb. 22, 2011

The Invention Explained

  • Problem Addressed: The patent’s background section describes the technical challenge that many azole drugs, such as metronidazole, are poorly soluble in water, which limits the ability to create stable, high-concentration topical formulations for medical treatment (’097 Patent, col. 1:12-30).
  • The Patented Solution: The invention claims to solve this problem through a synergistic solvent system. The detailed description explains that combining an azole drug in an aqueous fluid with at least two components from the group of a polyol (e.g., propylene glycol), a polyol ether (e.g., ethoxydiglycol), and a low carbon organic alcohol (e.g., benzyl alcohol) produces a greater increase in solubility than would be expected from the additive effects of the individual components (’097 Patent, col. 2:1-5, col. 3:6-14).
  • Technical Importance: This approach enables the creation of physically stable aqueous solutions of azole drugs at higher concentrations (e.g., 1.0% or greater), which is desirable for many topical applications to achieve therapeutic efficacy (’097 Patent, col. 1:47-50).

Key Claims at a Glance

  • The complaint asserts at least independent claim 1 (Compl. ¶31).
  • Claim 1: A method of treating a dermatologic or mucosal disorder that is responsive to therapy with an azole compound, which comprises topically applying to the skin or mucosal surfaces of an individual in need of such therapy a stable aqueous solution comprising:
    • an azole compound; and
    • at least two of a polyol, a polyol ether, and a low carbon organic alcohol.

U.S. Patent No. 8,658,678 - “Methods and Compositions for Increasing Solubility of Azole Drug Compounds that are Poorly Soluble in Water,” Issued Feb. 25, 2014

The Invention Explained

  • Problem Addressed: The patent addresses the same technical problem as the ’097 Patent: the low aqueous solubility of azole compounds like metronidazole, which complicates the formulation of high-concentration topical products (’678 Patent, col. 1:12-30).
  • The Patented Solution: The invention is a composition, rather than a method, that embodies the same synergistic solvent system described in the ’097 Patent. The solution combines an azole drug with at least two solvents from the categories of polyols, polyol ethers, and low carbon organic alcohols to achieve enhanced solubility in an aqueous fluid (’678 Patent, col. 2:1-5, col. 3:6-14).
  • Technical Importance: The invention provides a stable, high-concentration aqueous composition of an azole drug suitable for topical administration, overcoming the drug's inherent poor solubility (’678 Patent, col. 1:47-50).

Key Claims at a Glance

  • The complaint asserts at least independent claim 1 (Compl. ¶41).
  • Claim 1: A pharmaceutical composition for treating a dermatologic or mucosal disorder, comprising a stable aqueous solution of:
    • an azole compound;
    • water; and
    • at least two of a polyol, a polyol ether, and a low carbon organic alcohol.

U.S. Patent No. 8,877,792 - “Compositions for Increasing Solubility of Azole Drug Compounds that are Poorly Soluble in Water,” Issued Nov. 4, 2014

  • Patent Identification: U.S. Patent No. 8,877,792, “Compositions for Increasing Solubility of Azole Drug Compounds that are Poorly Soluble in Water,” Issued Nov. 4, 2014 (Compl. ¶18).
  • Technology Synopsis: This patent, part of the same family as the ’097 and ’678 Patents, discloses compositions that use a synergistic combination of solvents (polyols, polyol ethers, low carbon organic alcohols) to increase the solubility of poorly water-soluble azole drugs in an aqueous solution (’792 Patent, Abstract).
  • Asserted Claims: At least independent claim 1 (Compl. ¶52).
  • Accused Features: The accused Generic Gel Product allegedly contains metronidazole, an azole compound, in a formulation that infringes the claimed composition (Compl. ¶53).

U.S. Patent No. 8,946,276 - “High Dosage Mucoadhesive Metronidazole Aqueous-Based Gel Formulations and Their Use to Treat Bacterial Vaginosis,” Issued Feb. 3, 2015

  • Patent Identification: U.S. Patent No. 8,946,276, “High Dosage Mucoadhesive Metronidazole Aqueous-Based Gel Formulations and Their Use to Treat Bacterial Vaginosis,” Issued Feb. 3, 2015 (Compl. ¶19).
  • Technology Synopsis: This patent addresses the shortcomings of existing 0.75% metronidazole gels, which require multi-day treatment and exhibit high recurrence rates for bacterial vaginosis (’276 Patent, col. 2:5-34). The invention is a "high dosage" (e.g., 1-2% by weight) mucoadhesive aqueous gel formulation of metronidazole, intended to provide a more effective cure, potentially with a single application, and reduce recurrence rates (’276 Patent, col. 2:40-54).
  • Asserted Claims: At least independent claim 1 (Compl. ¶62).
  • Accused Features: The accused Generic Gel Product is alleged to be a high dosage (1.3%) aqueous gel containing metronidazole for treating bacterial vaginosis (Compl. ¶¶63-64).

U.S. Patent No. 9,198,858 - “Methods of Treating Bacterial Vaginosis with Aqueous-based Metronidazole Gel Formulations,” Issued Dec. 1, 2015

  • Patent Identification: U.S. Patent No. 9,198,858, “Methods of Treating Bacterial Vaginosis with Aqueous-based Metronidazole Gel Formulations,” Issued Dec. 1, 2015 (Compl. ¶20).
  • Technology Synopsis: This patent is directed to methods of treating bacterial vaginosis by applying a high-dosage, aqueous-based gel formulation of metronidazole. The described technology aims to improve upon existing treatments by enabling more effective cures and reducing recurrence rates, potentially with fewer applications (’858 Patent, col. 2:5-34, col. 2:40-54).
  • Asserted Claims: At least independent claim 1 (Compl. ¶73).
  • Accused Features: The accused Generic Gel Product contains 1.3% metronidazole and is intended for the treatment of bacterial vaginosis, allegedly infringing the claimed method (Compl. ¶¶74-75).

U.S. Patent No. 10,238,634 - “Aqueous-based Metronidazole Gel Formulations,” Issued Mar. 26, 2019

  • Patent Identification: U.S. Patent No. 10,238,634, “Aqueous-based Metronidazole Gel Formulations,” Issued Mar. 26, 2019 (Compl. ¶21).
  • Technology Synopsis: This patent describes mucoadhesive aqueous-based gel formulations containing 1-2% metronidazole. The formulation is designed to deliver higher local concentrations of the drug compared to conventional 0.75% gels, thereby providing a more effective treatment for bacterial vaginosis, potentially in a single dose (’634 Patent, col. 2:40-54).
  • Asserted Claims: At least independent claim 1 (Compl. ¶84).
  • Accused Features: Encube’s Generic Gel Product is alleged to be a 1.3% metronidazole gel composition that infringes the patent’s claims (Compl. ¶85).

U.S. Patent No. 10,596,155 - “Aqueous-based Metronidazole Gel Formulations,” Issued Mar. 24, 2020

  • Patent Identification: U.S. Patent No. 10,596,155, “Aqueous-based Metronidazole Gel Formulations,” Issued Mar. 24, 2020 (Compl. ¶22).
  • Technology Synopsis: This patent, related to the ’634 Patent, also discloses high-dosage (1-2%) aqueous-based metronidazole gel formulations. It is directed to compositions intended to overcome the shortcomings of lower-concentration gels for treating bacterial vaginosis by providing superior efficacy and potentially reducing recurrence (’155 Patent, col. 2:5-34, col. 2:40-54).
  • Asserted Claims: At least independent claim 1 (Compl. ¶94).
  • Accused Features: The complaint alleges that the composition of Encube’s 1.3% metronidazole Generic Gel Product infringes the claims of the patent (Compl. ¶95).

III. The Accused Instrumentality

No probative visual evidence provided in complaint.

Product Identification

The accused instrumentality is Defendant Encube’s "Generic Gel Product," which is the subject of ANDA No. 216795 (Compl. ¶1). It is identified as a generic version of NUVESSA® (metronidazole), 1.3% vaginal gel (Compl. ¶¶1, 63).

Functionality and Market Context

The Generic Gel Product is an aqueous-based vaginal gel for the treatment of bacterial vaginosis (Compl. ¶14). The complaint alleges that the product has the same active ingredient, method of administration, dosage form, and strength (1.3% metronidazole) as NUVESSA® and is bioequivalent to it (Compl. ¶¶28, 63). It is intended for commercial manufacture, use, and sale in the United States upon FDA approval (Compl. ¶1). The complaint alleges that the product will be marketed with prescribing instructions substantially similar to those for NUVESSA® (Compl. ¶43, ¶64).

IV. Analysis of Infringement Allegations

’097 Patent Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
A method of treating a dermatologic or mucosal disorder that is responsive to therapy with an azole compound... The Generic Gel Product is a generic version of NUVESSA®, which is approved for the treatment of bacterial vaginosis, a mucosal disorder. ¶14, ¶43 col. 1:31-36
...which comprises topically applying to the skin or mucosal surfaces of an individual in need of such therapy a stable aqueous solution... The Generic Gel Product is a vaginal gel for topical application to mucosal surfaces. It is alleged to be an embodiment of the claimed stable aqueous solution. ¶1, ¶28 col. 2:47-53
...comprising: an azole compound; and... The Generic Gel Product includes metronidazole, which is alleged to be a poorly soluble imidazole or triazole (azole) chemical compound. ¶32 col. 1:20-22
...at least two of a polyol, a polyol ether, and a low carbon organic alcohol. The complaint does not specify the excipients in the Generic Gel Product but alleges that its formulation infringes. The basis for infringement under the Hatch-Waxman Act is the filing of an ANDA for a product that, if marketed, would infringe. ¶30, ¶31 col. 2:1-5

’678 Patent Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
A pharmaceutical composition for treating a dermatologic or mucosal disorder, comprising a stable aqueous solution of: The Generic Gel Product will be marketed with prescribing instructions for treating bacterial vaginosis, a mucosal disorder. ¶43 col. 1:31-36
an azole compound; The Generic Gel Product contains metronidazole, which is identified as an azole compound. ¶42 col. 1:20-22
water; and... The product is an aqueous-based gel formulation. ¶22, Background col. 2:1-2
at least two of a polyol, a polyol ether, and a low carbon organic alcohol. The complaint alleges that the composition of the Generic Gel Product infringes, implying it contains the claimed combination of excipients. ¶41 col. 2:2-5
  • Identified Points of Contention:
    • Scope Questions: The primary dispute for the ’097, ’678, and ’792 Patents will likely center on claim construction. A central question may be whether the specific combination of excipients in Encube's ANDA formulation falls within the scope of the claimed solvent system (e.g., "at least two of a polyol, a polyol ether, and a low carbon organic alcohol"). For the later family of patents (’276, ’858, ’634, ’155), a question of scope will be whether the term "high dosage," defined in the specification as "about 1-2% by weight," reads on the accused 1.3% formulation.
    • Technical Questions: A key technical question for the court will be whether the excipients in the Generic Gel Product function in the same way as described in the patents. For the early family of patents, does Encube’s formulation rely on the claimed synergistic effect to achieve its 1.3% concentration, or does it use a different, non-infringing technology? For the later patents, what evidence does the complaint provide that the accused product is a "mucoadhesive" gel as required by the claims? The complaint's allegations are based on the ANDA filing and bioequivalence, leaving the specific technical mechanism of the generic formulation as a central point for discovery and contention.

V. Key Claim Terms for Construction

The complaint does not provide sufficient detail for a definitive analysis, but practitioners may focus on the following terms from the asserted independent claims of the '097 and '678 Patents.

  • The Term: "a stable aqueous solution"

  • Context and Importance: The stability of the formulation is a cornerstone of the invention, which aims to overcome the tendency of high-concentration metronidazole to precipitate out of solution, especially at cold temperatures (’097 Patent, col. 1:41-47). The definition of "stable" will be critical. Encube may argue its product achieves stability through means not claimed in the patents, or that the Plaintiffs' definition of "stable" is indefinite.

  • Intrinsic Evidence for Interpretation:

    • Evidence for a Broader Interpretation: The claims do not explicitly define "stable," which could support giving the term its plain and ordinary meaning as understood by a person of ordinary skill in the art.
    • Evidence for a Narrower Interpretation: The specification provides context, stating that physically stable solutions "can withstand exposure to cold temperatures encountered during shipping" and are limited to about 0.7% w/w without the invention (’097 Patent, col. 1:41-47). Plaintiffs may argue this context limits the term to formulations that remain physically stable under such conditions.

  • The Term: "a polyol"

  • Context and Importance: This term, along with "polyol ether" and "low carbon organic alcohol," defines the components of the synergistic solvent system. Whether an excipient in Encube's formulation qualifies as a "polyol" for purposes of the claimed invention will be a key infringement question. Encube might argue that an ingredient that is chemically a polyol is used in its formulation for a different purpose (e.g., as a gelling agent or humectant) and not as part of the claimed solubilizing system.

  • Intrinsic Evidence for Interpretation:

    • Evidence for a Broader Interpretation: The specification provides a broad definition: "The term 'polyol' is synonymous with 'polyhydric alcohol' and refers to an alcohol that contains more than one hydroxyl group. Examples of polyols include polyether glycols, propylene glycol, and sugar alcohols." (’097 Patent, col. 2:20-24).
    • Evidence for a Narrower Interpretation: Plaintiffs may argue that the term must be construed in the context of the invention's purpose—to act as one component of a synergistic solubilizing system. An excipient that does not contribute to this synergistic effect, even if it is a polyol, might be argued to fall outside the claim scope.

VI. Other Allegations

  • Indirect Infringement: The complaint alleges that upon FDA approval and commercial marketing, Encube will actively induce infringement by encouraging healthcare professionals, pharmacies, and end-users to use the Generic Gel Product in an infringing manner, pointing to the product's proposed prescribing instructions (Compl. ¶¶ 36, 47, 68).
  • Willful Infringement: The complaint does not contain an explicit count for willful infringement. However, it alleges that Encube had "actual and constructive knowledge" of the patents-in-suit prior to filing its ANDA and was aware that the filing would constitute an act of infringement (Compl. ¶¶ 37, 48, 58, 69, 80, 90, 101). These allegations may form the basis for a later claim for enhanced damages.

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

  • A core issue will be one of claim construction and scope: can the general terms "polyol," "polyol ether," and "low carbon organic alcohol," which define the patented synergistic solvent system, be construed to read on the specific combination of excipients and their concentrations used in Encube’s ANDA formulation? The outcome will depend on whether the court adopts broad chemical definitions or narrower functional definitions tied to the patent's purpose of enhancing solubility.
  • A key evidentiary question will be one of technical mechanism: assuming Encube's formulation falls within the literal scope of the claims, does it actually function by the patented synergistic mechanism, or does it achieve its 1.3% metronidazole concentration and stability through a different, non-infringing technical pathway? This question will be central to the infringement analysis, particularly as the complaint provides no details on the specific composition of the accused generic product beyond its active ingredient and strength.