Merck Sharp & Dohme Corp v. Mylan Laboratories Ltd

I. Executive Summary and Procedural Information

• Parties & Counsel:
  • Plaintiff: Merck Sharp & Dohme Corp. (New Jersey)
  • Defendant: Fresenius Kabi USA, LLC (Delaware)
  • Plaintiff’s Counsel: McCarter & English, LLP
• Case Identification: 1:18-cv-00196, D. Del., 02/02/2018
• Venue Allegations: Venue is alleged to be proper in the District of Delaware because Defendant is a Delaware limited liability company and conducts business in the state.
• Core Dispute: Plaintiff alleges that Defendant’s submission of an Abbreviated New Drug Application (ANDA) for a generic intravenous posaconazole solution infringes patents covering the formulation of Plaintiff’s branded drug, NOXAFIL®.
• Technical Context: The technology concerns pharmaceutical formulations designed to overcome the poor water solubility of posaconazole, a broad-spectrum antifungal agent, to enable its administration as a stable intravenous solution.
• Key Procedural History: This action was initiated under the Hatch-Waxman Act following Defendant’s submission of ANDA No. 209983 with a Paragraph IV certification. Plaintiff received a notice letter from Defendant dated December 21, 2017, asserting that the patents-in-suit are invalid, unenforceable, and/or would not be infringed by the proposed generic product.

Case Timeline

Date	Event
2010-06-29	Priority Date for ’790 and ’297 Patents
2015-05-05	U.S. Patent No. 9,023,790 Issued
2016-06-07	U.S. Patent No. 9,358,297 Issued
2017-12-21	Date of Defendant's Paragraph IV Notice Letter to Plaintiff
2018-02-02	Complaint Filed

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

U.S. Patent No. 9,023,790 - “Posaconazole Intravenous Solution Formulations Stabilized by Substituted B-Cyclodextrin”

• Patent Identification: U.S. Patent No. 9,023,790, “Posaconazole Intravenous Solution Formulations Stabilized by Substituted B-Cyclodextrin,” issued May 5, 2015.

The Invention Explained

• Problem Addressed: The patent addresses the challenge that posaconazole, a potent antifungal drug, is "poorly-aqueous soluble," which severely limits its bioavailability and makes creating a stable, sufficiently concentrated intravenous (IV) formulation difficult (’790 Patent, col. 1:56-61). An effective IV formulation is needed for patients who cannot take oral medicine, such as those who are unconscious or have difficulty swallowing (’790 Patent, col. 2:1-6).
• The Patented Solution: The invention uses a specific solubilizing agent, sulfobutylether-β-cyclodextrin (SBECD), in an acidified aqueous solution to form a complex with posaconazole, thereby dramatically increasing its solubility. The resulting composition allows for a stable, injectable solution suitable for intravenous administration, and may also include a chelating agent like EDTA to improve long-term stability and prevent discoloration (’790 Patent, Abstract; col. 2:10-23; col. 7:46-54).
• Technical Importance: This formulation technology enabled the development of a commercially viable intravenous version of a critical antifungal drug, filling a therapeutic gap for high-risk, immunocompromised patients who require parenteral administration (’790 Patent, col. 1:46-55).

Key Claims at a Glance

• The complaint asserts infringement of one or more unspecified claims; Claim 1 is the first independent claim.
• Independent Claim 1 requires:
  • A pharmaceutical composition for intravenous administration.
  • Comprising posaconazole or a salt thereof.
  • Comprising a modified β-cyclodextrin, specifically sulfobutylether-β-cyclodextrin "having a degree of substitution of 6.5 and a molecular weight of 2163 g/mole."
  • In an aqueous solution with a pH between about 2.0 and about 3.5.
  • Wherein the posaconazole concentration is between about 14 and 22 mg/mL and the modified β-cyclodextrin concentration is between about 350 and 450 mg/mL.
• The complaint does not foreclose the assertion of dependent claims.

U.S. Patent No. 9,358,297 - “Posaconazole Intravenous Solution Formulations Stabilized by Substituted ß-Cyclodextrin”

• Patent Identification: U.S. Patent No. 9,358,297, “Posaconazole Intravenous Solution Formulations Stabilized by Substituted ß-Cyclodextrin,” issued June 7, 2016.

The Invention Explained

• Problem Addressed: As a continuation of the application leading to the ’790 Patent, the ’297 Patent addresses the same technical problem: the poor aqueous solubility of posaconazole and the need for a stable intravenous formulation for patients who cannot take oral dosage forms (’297 Patent, col. 2:1-9).
• The Patented Solution: The patented solution is functionally identical to that of the ’790 Patent, using an acidified solution of sulfobutylether-β-cyclodextrin to solubilize posaconazole for intravenous delivery. The specification similarly describes the use of a chelating agent to ensure stability (’297 Patent, Abstract; col. 2:25-31).
• Technical Importance: The technical contribution is the same as the parent ’790 Patent.

Key Claims at a Glance

• The complaint asserts infringement of one or more unspecified claims; Claim 1 is the first independent claim.
• Independent Claim 1 requires:
  • A pharmaceutical composition for intravenous administration.
  • Comprising "100 mg to 400 mg of posaconazole" or a salt thereof.
  • Comprising a modified β-cyclodextrin, specifically sulfobutylether-β-cyclodextrin "having a degree of substitution of 6.5 and a molecular weight of 2163 g/mole."
  • In an aqueous solution with a pH between about 2.0 and about 3.5.
  • Wherein the posaconazole concentration is between about 14 and 22 mg/mL and the modified β-cyclodextrin concentration is between about 350 and 450 mg/mL.
• The complaint does not foreclose the assertion of dependent claims.

III. The Accused Instrumentality

• Product Identification: The accused instrumentality is the generic posaconazole product described in Fresenius’s Abbreviated New Drug Application (ANDA) No. 209983, referred to as the "ANDA Posaconazole Product" (Compl. ¶1).
• Functionality and Market Context: The complaint alleges that the ANDA Posaconazole Product is a generic version of Merck’s NOXAFIL® intravenous (infusion) solution, formulated at a strength of 300 mg/16.7 mL (18 mg/mL) (Compl. ¶1). By filing its ANDA, Fresenius represented to the FDA that its proposed product has the same active ingredient, method of administration, dosage form, and strength as NOXAFIL®, and that it is bioequivalent to NOXAFIL® (Compl. ¶15). The act of filing the ANDA to seek approval for this generic product before the expiration of the patents-in-suit constitutes the act of infringement alleged in the complaint (Compl. ¶17, ¶24).

IV. Analysis of Infringement Allegations

No probative visual evidence provided in complaint.

The complaint, as is common in initial ANDA pleadings, does not provide a detailed claim chart mapping specific elements of the accused product to the patent claims. The infringement allegation is statutory, arising under 35 U.S.C. § 271(e)(2), which defines the submission of an ANDA for a drug claimed in a patent as an act of infringement.

The central theory of infringement is that since Fresenius seeks approval for a generic version of Merck's NOXAFIL® for Injection and has certified its product is bioequivalent, the Fresenius product will necessarily contain the same components and properties as NOXAFIL® (Compl. ¶¶ 1, 15). The complaint further alleges that NOXAFIL® for Injection is an embodiment of the patents-in-suit (Compl. ¶9). Therefore, the complaint alleges, the ANDA Posaconazole Product, if approved and marketed, would infringe the asserted patents. The litigation will focus on discovering the precise formulation disclosed in the Fresenius ANDA and comparing it to the limitations of the asserted claims.

• Identified Points of Contention:
  • Technical Questions: A primary question for the court will be factual: Does the formulation described in Fresenius's confidential ANDA submission fall within the specific numerical ranges recited in the asserted claims? This includes the posaconazole concentration, the SBECD concentration, the solution's pH, and the physical properties of the SBECD used (degree of substitution and molecular weight).
  • Scope Questions: The dispute may center on whether Fresenius has successfully "designed around" the claims. For example, if the Fresenius product utilizes a pH or concentration that is close to but outside the claimed ranges, the construction of the term "about" will become critical to the infringement analysis. Fresenius's notice letter states a position of non-infringement, suggesting it may argue that its formulation avoids at least one claim limitation (Compl. ¶14).

V. Key Claim Terms for Construction

For both the ’790 and ’297 Patents

• The Term: "about"

• Context and Importance: This term qualifies every critical numerical range in the independent claims, including pH, posaconazole concentration, and cyclodextrin concentration. Its construction is central to defining the scope of the claims and will likely be dispositive if the Fresenius formulation's parameters are near the boundaries of the claimed ranges.

• Intrinsic Evidence for Interpretation:

  • Evidence for a Broader Interpretation: The specification frequently uses "about" when discussing formulation parameters, which may suggest the inventors intended the term to cover normal manufacturing variances and values functionally equivalent to the stated numbers (’790 Patent, col. 2:40-52).
  • Evidence for a Narrower Interpretation: The patents provide data showing that solubility is highly dependent on pH (e.g., Figure 1), and the specification identifies a specific target pH of 2.6 for the clinical formulation (’790 Patent, col. 10:7-9). A party could argue that these functional considerations require the term "about" to be construed narrowly to preserve the claimed invention's stability and solubility characteristics.

• The Term: "sulfobutylether-β-cyclodextrin having a degree of substitution of 6.5 and a molecular weight of 2163 g/mole"

• Context and Importance: This limitation recites very specific physical properties for the key excipient. The infringement analysis will depend on whether this language is interpreted as requiring these exact average values or as describing a particular, commercially available grade of SBECD (i.e., Captisol®).

• Intrinsic Evidence for Interpretation:

  • Evidence for a Broader Interpretation: The specification discloses that Captisol® is the trade name for the SBECD being used and that it has an average degree of substitution of ~6.5 (’790 Patent, col. 5:3-10; Table 1). A party may argue the claim language describes the properties of this specific, preferred excipient and should not be read so narrowly as to exclude other batches of Captisol® or functionally identical SBECDs with minor variations in these average properties.
  • Evidence for a Narrower Interpretation: The patentees chose to include these specific numerical values in the claim itself, rather than just claiming "sulfobutylether-β-cyclodextrin" more generally. A party will argue that these values are definitive limitations, not merely illustrative, and that any SBECD used in an accused product must meet these parameters for literal infringement. The patent also evaluates and distinguishes between different cyclodextrins, suggesting the specific chemical structure and properties are critical to the invention (’790 Patent, col. 6:61-65; Fig. 2).

VI. Other Allegations

• Indirect Infringement: The complaint alleges that upon approval of its ANDA, Fresenius would induce infringement by providing prescribing instructions to healthcare professionals, pharmacies, and end users, encouraging them to use the product in an infringing manner (Compl. ¶20, ¶27).
• Willful Infringement: Willfulness is not explicitly alleged as a separate count, but the complaint asserts that Fresenius had "actual and constructive knowledge" of the patents prior to filing its ANDA, and the prayer for relief requests a declaration that the case is exceptional under 35 U.S.C. § 285, which can be a predicate for enhanced damages or attorney's fees (Compl. ¶21, ¶28, ¶K).

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

• A central evidentiary question will be one of precise formulation: Does the posaconazole formulation detailed in Fresenius’s confidential ANDA filing meet every quantitative limitation recited in the asserted claims, including the specific concentration ranges, pH range, and detailed physical properties of the cyclodextrin excipient?
• A core issue will be one of claim construction and scope: If the Fresenius formulation is close to, but not exactly matching, the claimed numerical values, the case will turn on the interpretation of the term "about". Can this term be construed to encompass the Fresenius product, or did Fresenius successfully "design around" the literal claim scope?
• A key defense will likely be the invalidity challenge: As raised in its notice letter, Fresenius will likely argue that the claimed formulations are obvious over the prior art. The question for the court will be whether it was obvious to a person of ordinary skill to combine a specific type of cyclodextrin (SBECD) with posaconazole within the claimed pH and concentration ranges to achieve a stable IV solution with the desired properties.