DCT

1:24-cv-00726

Veloxis Pharma Inc v. Sun Pharmaceutical Industries Ltd

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I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 1:24-cv-00726, D. Del., 06/19/2024
  • Venue Allegations: Venue is alleged as proper in the District of Delaware because Defendant Sun Pharmaceutical Industries, Inc. is a Delaware corporation and therefore resides in the district.
  • Core Dispute: Plaintiff alleges that Defendants' submission of an Abbreviated New Drug Application (ANDA) to the FDA, seeking to market generic extended-release tacrolimus tablets, constitutes an act of infringement of seven U.S. patents covering formulations and methods of use for Plaintiff's branded drug, ENVARSUS XR®.
  • Technical Context: The technology concerns oral pharmaceutical formulations of tacrolimus, an immunosuppressant drug critical for preventing organ rejection in transplant patients, focusing on improving its stability and creating a more predictable extended-release profile for once-daily administration.
  • Key Procedural History: The action was precipitated by a notice letter dated May 8, 2024, in which Defendants notified Plaintiff of their ANDA filing containing a Paragraph IV certification, asserting that the claims of the listed patents are not infringed and, for one patent, are invalid. Such a certification is considered a statutory act of infringement under the Hatch-Waxman Act, enabling the patent holder to sue before the generic product is marketed.

Case Timeline

Date Event
2008-07-08 Earliest Patent Priority Date for all Patents-in-Suit
2014-04-01 U.S. Patent No. 8,685,998 Issued
2017-01-24 U.S. Patent No. 9,549,918 Issued
2019-01-01 U.S. Patent No. 10,166,190 Issued
2020-12-15 U.S. Patent No. 10,864,199 Issued
2021-09-07 U.S. Patent No. 11,110,081 Issued
2021-09-21 U.S. Patent No. 11,123,331 Issued
2022-08-23 U.S. Patent No. 11,419,823 Issued
2024-05-08 Defendants' ANDA Paragraph IV Notice Letter Sent
2024-06-19 Complaint Filed

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

U.S. Patent No. 8,685,998 - “Tacrolimus for Improved Treatment of Transplant Patients”

  • Issued: April 1, 2014

The Invention Explained

  • Problem Addressed: The patent describes that conventional tacrolimus formulations exhibit large and unpredictable variations in absorption and metabolism among patients, making it difficult to maintain consistent and effective blood concentrations. This variability complicates dosing and can lead to either toxicity or organ rejection. (’199 Patent, col. 2:51-54, col. 3:52-56).
  • The Patented Solution: The invention is a method of treatment using an extended-release oral dosage form of tacrolimus that releases the drug over a prolonged period. This formulation is designed to provide a more predictable pharmacokinetic profile, characterized by a lower peak blood concentration (Cmax) and a higher minimum concentration (Cmin) over a 24-hour period, which allows for safe and effective once-daily dosing. (’199 Patent, Abstract; col. 3:57-62).
  • Technical Importance: By creating a more consistent pharmacokinetic profile and enabling once-daily dosing, the invention aimed to improve patient safety, reduce side effects associated with high peak drug levels, and increase patient compliance. (’199 Patent, col. 4:1-15).

Key Claims at a Glance

  • The complaint asserts at least claim 1. (Compl. ¶36).
  • Claim 1 of the related and asserted ’199 Patent, which is representative, includes the following essential elements for a method of suppressing kidney rejection:
    • Orally administering once daily an extended release pharmaceutical composition comprising tacrolimus.
    • The administration provides a specific pharmacokinetic profile defined by a ratio of AUC values and Cmax values relative to the standard immediate-release product (Prograf®).
    • The composition has a specific in vitro dissolution profile where no more than 63.5% of the tacrolimus is released at the 12-hour time point.
  • The complaint reserves the right to assert additional claims.

U.S. Patent No. 10,166,190 - “Stabilized Tacrolimus Composition”

  • Issued: January 1, 2019

The Invention Explained

  • Problem Addressed: The patent notes that tacrolimus is a poorly soluble substance that can degrade when formulated, particularly in solid dispersions designed to improve bioavailability. A major degradation product is 8-epitacrolimus, and the presence of such impurities is highly undesirable from a regulatory and safety perspective. (’190 Patent, col. 3:9-19, 53-64).
  • The Patented Solution: The patent discloses a pharmaceutical composition that stabilizes tacrolimus by incorporating a "stabilizing agent" into the formulation. This agent is described as a metal-chelating organic acid, such as tartaric acid, which provides a pH below 7 upon re-dispersion in water and prevents or reduces the formation of the 8-epitacrolimus degradation product during storage. (’190 Patent, Abstract; col. 4:16-39, col. 8:5-13).
  • Technical Importance: This stabilization technology enables the creation of solid dispersion formulations of tacrolimus with improved shelf-life and purity, which is critical for the commercial viability of formulations designed to have enhanced bioavailability. (’190 Patent, col. 3:15-24).

Key Claims at a Glance

  • The complaint asserts at least claim 1. (Compl. ¶58).
  • Independent claim 1 includes the following essential elements for a sustained release tablet:
    • A dispersion of tacrolimus.
    • 8-epitacrolimus (as a controlled impurity).
    • A metal chelating agent that is an organic acid.
    • Tacrolimus is the sole active ingredient.
    • The tablet comprises less than 0.5% by weight of 8-epitacrolimus after 12 weeks of storage at 25° C. and 60% relative humidity.
  • The complaint reserves the right to assert additional claims.

U.S. Patent No. 9,549,918 - “Stabilized Tacrolimus Composition”

  • Patent Identification: U.S. Patent No. 9549918, “Stabilized Tacrolimus Composition,” Issued January 24, 2017.
  • Technology Synopsis: This patent, part of the same family as the ’190 Patent, addresses the chemical instability of tacrolimus in pharmaceutical formulations. The invention stabilizes tacrolimus by incorporating a stabilizing agent, such as an organic acid, to maintain an acidic environment and prevent the formation of degradation products upon storage. (Compl. ¶16; '190 Patent, Abstract).
  • Asserted Claims: At least claim 1. (Compl. ¶47).
  • Accused Features: The composition of Defendants' ANDA Products is alleged to contain a solid dispersion of tacrolimus with a stabilizer that infringes the claims. (Compl. ¶¶47-48).

U.S. Patent No. 10,864,199 - “Tacrolimus for Improved Treatment of Transplant Patients”

  • Patent Identification: U.S. Patent No. 10864199, “Tacrolimus for Improved Treatment of Transplant Patients,” Issued December 15, 2020.
  • Technology Synopsis: This patent, part of the same family as the ’998 Patent, is directed to methods of treating transplant patients with an extended-release tacrolimus formulation. The invention claims specific pharmacokinetic profiles and in vitro dissolution rates that provide for improved, once-daily dosing with reduced variability compared to conventional formulations. (Compl. ¶18; '199 Patent, Abstract).
  • Asserted Claims: At least claim 14. (Compl. ¶69).
  • Accused Features: The use of Defendants' ANDA Products according to their proposed label is alleged to result in the claimed pharmacokinetic and dissolution profiles for treating transplant patients. (Compl. ¶¶69-70).

U.S. Patent No. 11,110,081 - “Tacrolimus for Improved Treatment of Transplant Patients”

  • Patent Identification: U.S. Patent No. 11110081, “Tacrolimus for Improved Treatment of Transplant Patients,” Issued September 7, 2021.
  • Technology Synopsis: This patent is also part of the family including the ’998 and ’199 Patents. It covers methods for treating transplant patients with a once-daily, extended-release tacrolimus formulation designed to achieve a more consistent and safer pharmacokinetic profile than immediate-release versions. (Compl. ¶19; '199 Patent, Abstract).
  • Asserted Claims: At least claim 1. (Compl. ¶79).
  • Accused Features: The administration of Defendants' ANDA Products as instructed on their proposed labeling is alleged to infringe the claimed methods of treatment. (Compl. ¶¶79-80).

U.S. Patent No. 11,123,331 - “Tacrolimus for Improved Treatment of Transplant Patients”

  • Patent Identification: U.S. Patent No. 11123331, “Tacrolimus for Improved Treatment of Transplant Patients,” Issued September 21, 2021.
  • Technology Synopsis: As another member of the extended-release profile family, this patent claims methods of treating transplant patients with a once-daily tacrolimus dosage form that provides improved pharmacokinetic parameters, such as reduced peak-to-trough fluctuation, over a 24-hour dosing interval. (Compl. ¶20; '199 Patent, Abstract).
  • Asserted Claims: At least claim 1. (Compl. ¶89).
  • Accused Features: The intended use of Defendants' ANDA Products for treating transplant patients is alleged to meet the specific method limitations claimed in the patent. (Compl. ¶¶89-90).

U.S. Patent No. 11,419,823 - “Stabilized Tacrolimus Composition”

  • Patent Identification: U.S. Patent No. 11419823, “Stabilized Tacrolimus Composition,” Issued August 23, 2022.
  • Technology Synopsis: This patent, in the same family as the ’190 and ’918 Patents, is directed to stabilizing tacrolimus in a solid dispersion. It claims a composition containing a stabilizing agent, such as a metal-chelating organic acid, to provide an acidic microenvironment that inhibits the formation of degradation products during the product's shelf life. (Compl. ¶21; '190 Patent, Abstract).
  • Asserted Claims: At least claim 1. (Compl. ¶99).
  • Accused Features: The formulation of Defendants' ANDA Products is alleged to inherently contain the claimed combination of a tacrolimus dispersion and a stabilizing agent. (Compl. ¶¶99-100).

III. The Accused Instrumentality

Product Identification

  • The accused instrumentalities are Defendants' generic 0.75 mg, 1 mg, and 4 mg extended-release tablets containing tacrolimus, for which Defendants have filed ANDA No. 215836 with the FDA (the "ANDA Products"). (Compl. ¶1).

Functionality and Market Context

  • The ANDA Products are designed to be generic versions of Plaintiff's ENVARSUS XR® tablets. (Compl. ¶2). As such, they are intended to have the same active ingredient, dosage form, strengths, and route of administration, and to be bioequivalent to ENVARSUS XR®. (Compl. ¶27). Their function is to provide an extended release of tacrolimus over a 24-hour period for once-daily administration to prevent organ rejection in kidney transplant patients. (Compl. ¶¶23, 27). The complaint alleges that Defendants seek approval to market these generic products prior to the expiration of the patents-in-suit. (Compl. ¶26). No probative visual evidence provided in complaint.

IV. Analysis of Infringement Allegations

The complaint does not provide claim charts or specific factual allegations mapping elements of the asserted claims to features of the accused products. Instead, it makes general allegations that the ANDA Products and their use will satisfy each element of at least one claim of each patent-in-suit. (Compl. ¶¶37, 48, 59, 70, 80, 90, 100).

The central theory of infringement for the method patents (e.g., the ’998 Patent family) is that Defendants' ANDA Products are extended-release tacrolimus tablets intended for once-daily use, and their proposed product label will instruct medical professionals and patients to administer them in a way that directly infringes the claimed methods of treatment, which are defined by specific pharmacokinetic and release profiles. (Compl. ¶¶36-37).

The theory of infringement for the composition patents (e.g., the ’190 Patent family) is that the formulation of the ANDA Products themselves will meet the claim limitations requiring a solid dispersion of tacrolimus combined with a specific type of stabilizing agent. (Compl. ¶¶58-59).

  • Identified Points of Contention:
    • Technical Questions (Composition Patents): A primary factual question will be whether the specific excipients used in Defendants' ANDA Products, as disclosed confidentially in the ANDA, fall within the scope of the claimed "stabilizing agent," which the ’190 Patent defines as a "metal chelating agent that is an organic acid." The case may turn on whether Defendants' formulation uses such an agent to achieve stability or relies on an alternative, non-infringing method.
    • Scope Questions (Method Patents): A central dispute for the method patents, such as the ’998 Patent and its family members, will be whether the pharmacokinetic and in vitro dissolution profiles of Defendants' ANDA Products, as established by the data in their ANDA, meet the specific numerical limitations recited in the asserted claims. This will likely involve a competing analysis of bioequivalence data by technical experts.

V. Key Claim Terms for Construction

  • The Term: "a metal chelating agent that is an organic acid" (from claim 1 of the ’190 Patent)
  • Context and Importance: This term is central to the infringement analysis for the family of composition patents (’918, ’190, ’823). Infringement depends entirely on whether Defendants' formulation contains an excipient that meets this definition. Practitioners may focus on this term because if Defendants achieve stability through a non-chelating agent or an inorganic acid, they would have a strong non-infringement argument.
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: The specification provides a non-limiting list of "useful organic acids," including "acetic acid, succinic acid, citric acid, tartaric acid, acrylic acid, benzoic acid, malic acid, maleic acid, oxalic acid and sorbic acid; and mixtures thereof." (’190 Patent, col. 7:40-44). Plaintiff may argue this broad list indicates the term should encompass a wide variety of common pharmaceutical organic acids.
    • Evidence for a Narrower Interpretation: The specification repeatedly emphasizes the "metal chelating agent" aspect, explaining that the "formation of the major degradation product 8-epitacrolimus is decreased in the presence in the composition of a metal chelating agent." (’190 Patent, col. 8:5-8). Defendants may argue that the term should be construed to require an organic acid that has a demonstrated metal-chelating capability sufficient to stabilize tacrolimus in the manner described by the patent, potentially excluding acids with weak or no relevant chelating properties.

VI. Other Allegations

  • Indirect Infringement: The complaint alleges both induced and contributory infringement for all seven patents. (Compl. ¶¶40-41, 51-52, 62-63, 72-73, 82-83, 92-93, 100-101 [by repetition]). Inducement is based on the allegation that Defendants' proposed product labeling will instruct users to administer the ANDA Products in an infringing manner. (Compl. ¶40). Contributory infringement is based on the allegation that the ANDA Products are especially adapted for an infringing use and have no substantial non-infringing use. (Compl. ¶41).
  • Willful Infringement: While the complaint does not use the word "willful," it alleges that Defendants had knowledge of each patent prior to filing their ANDA. (Compl. ¶¶44, 55, 66, 76, 86, 96, 104). It further alleges that the case is "exceptional" and requests attorneys' fees under 35 U.S.C. § 285, which is the statutory basis for seeking enhanced damages or fees in cases of egregious infringement. (Compl. ¶¶45, 56, 67, 77, 87, 97, 105).

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

  • A core issue will be one of compositional identity: does the accused generic product, as formulated in its confidential ANDA, contain the specific type of "stabilizing agent"—a metal-chelating organic acid—required by the composition patents, or does it employ a different, non-infringing stabilization technology?
  • A key evidentiary question will be one of profile matching: does the data within Defendants' ANDA demonstrate that their product will exhibit the specific in vitro dissolution rates and in vivo pharmacokinetic profiles (e.g., Cmax, AUC ratios) that are explicitly recited as limitations in the asserted method of treatment patents?
  • A third area of focus, although not detailed in the complaint, will be validity: will Defendants be able to demonstrate, with clear and convincing evidence, that the claimed compositions and treatment methods were obvious improvements over prior art tacrolimus formulations and extended-release technologies known at the time of the invention?