DCT

1:24-cv-00784

Veloxis Pharma Inc v. Alkem Laboratories Ltd

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I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 1:24-cv-00784, D. Del., 05/16/2025
  • Venue Allegations: Plaintiff alleges venue is proper because Defendant is a foreign corporation subject to personal jurisdiction in the district.
  • Core Dispute: Plaintiff alleges that Defendant's filing of an Abbreviated New Drug Application (ANDA) seeking approval to market generic extended-release tacrolimus tablets constitutes an act of infringement of eight U.S. patents related to Plaintiff’s branded drug, ENVARSUS XR®.
  • Technical Context: The technology concerns pharmaceutical formulations of tacrolimus, an immunosuppressant drug critical for preventing organ rejection in transplant patients, focusing on improving its stability and pharmacokinetic profile.
  • Key Procedural History: The litigation was initiated under the Hatch-Waxman Act following Defendant's notification to Plaintiff, via a Paragraph IV certification letter, of its ANDA filing with the U.S. Food and Drug Administration (FDA).

Case Timeline

Date Event
2008-07-08 Priority Date for ’998, ’199, ’081, ’331, ’103 Patents
2010-02-18 Priority Date for ’918, ’190, ’823 Patents
2014-04-01 U.S. Patent No. 8,685,998 Issues
2017-01-24 U.S. Patent No. 9,549,918 Issues
2019-01-01 U.S. Patent No. 10,166,190 Issues
2020-12-15 U.S. Patent No. 10,864,199 Issues
2021-09-07 U.S. Patent No. 11,110,081 Issues
2021-09-21 U.S. Patent No. 11,123,331 Issues
2022-08-23 U.S. Patent No. 11,419,823 Issues
2024-05-23 Date of Defendant’s Notice Letter
2024-09-10 U.S. Patent No. 12,083,103 Issues
2025-05-16 Amended Complaint Filing Date

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 oral administration of tacrolimus results in incomplete and variable bioavailability, with high peak blood concentrations (Cmax) that are associated with significant side effects of nephro- or neuro-toxic origin (U.S. Patent No. 8,685,998, col. 2:21-42).
  • The Patented Solution: The invention is an extended-release oral dosage form of tacrolimus designed for once-daily administration. This formulation releases the drug over an extended period, which is intended to provide improved bioavailability while simultaneously reducing the peak blood concentration compared to conventional immediate-release products (U.S. Patent No. 8,685,998, Abstract; col. 3:36-44). The technology achieves this through a solid dispersion of tacrolimus in a hydrophilic or water-miscible vehicle, such as a polyethylene glycol (U.S. Patent No. 8,685,998, col. 12:15-25).
  • Technical Importance: This approach allows for a once-daily dosing regimen that may reduce the risk of peak-concentration-related toxicities, enhance patient compliance, and provide a more stable and predictable therapeutic effect for transplant patients (’998 Patent, col. 13:11-20).

Key Claims at a Glance

  • The complaint asserts at least independent claim 1 (Compl. ¶33).
  • The essential elements of claim 1, a method claim, are:
    • Providing immunosuppressive treatment to a patient in a once daily regimen.
    • Orally administering an extended release oral dosage form comprising tacrolimus.
    • Wherein the dosage form provides a Cmax that is at most about 80% of the Cmax for a tacrolimus dosage form approved under U.S. New Drug Application No. 050708 (Prograf®).
    • With the Cmax comparison being made under similar conditions and with similar molecular daily dosages.

U.S. Patent No. 9,549,918 - "Stabilized Tacrolimus Composition," issued January 24, 2017.

The Invention Explained

  • Problem Addressed: The patent background explains that tacrolimus is susceptible to chemical degradation, particularly when formulated as a molecular dispersion, which can increase the risk of forming impurities and degradation products during manufacturing and storage (’918 Patent, col. 3:5-15, 51-57). One major degradation product identified is 8-epitacrolimus (’918 Patent, col. 4:20-23).
  • The Patented Solution: The invention is a stable pharmaceutical composition comprising a solid dispersion of tacrolimus in a vehicle, further including a stabilizing agent. This agent, preferably an organic acid like tartaric acid, is capable of providing a pH below 7 in the composition, which prevents or reduces the formation of degradation products upon storage (’918 Patent, Abstract; col. 3:20-41).
  • Technical Importance: By improving the chemical stability and shelf-life of extended-release tacrolimus formulations, the invention helps ensure the safety, potency, and regulatory compliance of the drug product, which is critical for a narrow therapeutic index drug used in a chronic setting (’918 Patent, col. 3:55-62).

Key Claims at a Glance

  • The complaint asserts at least independent claim 1 (Compl. ¶45).
  • The essential elements of claim 1, a composition claim, are:
    • A solid sustained release oral dosage form.
    • Comprising a solid dispersion of tacrolimus in a mixture of a vehicle and tartaric acid.
    • Wherein the vehicle comprises polyethylene glycol and poloxamer.

U.S. Patent No. 10,166,190 - "Stabilized Tacrolimus Composition," issued January 1, 2019.

  • Technology Synopsis: This patent addresses the same technical problem as the ’918 Patent: the chemical degradation of tacrolimus in pharmaceutical formulations. The patented solution is a sustained release tablet containing tacrolimus, its degradation product 8-epitacrolimus, and a metal chelating agent (an organic acid), where the formulation is stable enough to comprise less than 0.5% by weight of 8-epitacrolimus after a specified storage period (U.S. Patent No. 10,166,190, claim 1).
  • Asserted Claims: At least claim 1 (Compl. ¶56).
  • Accused Features: The Defendant's ANDA Products are alleged to be sustained release tablets that meet the claimed compositional and stability requirements (Compl. ¶56).

U.S. Patent No. 10,864,199 - "Tacrolimus for Improved Treatment of Transplant Patients," issued December 15, 2020.

  • Technology Synopsis: This patent addresses the problem of variable tacrolimus bioavailability and peak-related side effects, similar to the ’998 Patent. The claimed solution is an extended release oral dosage form that, when administered once daily, exhibits a specific Cmax/Cmin ratio that is less than the ratio observed with the immediate-release Prograf® product under similar conditions (U.S. Patent No. 10,864,199, claim 14).
  • Asserted Claims: At least claim 14 (Compl. ¶67).
  • Accused Features: The Defendant’s ANDA Products, when used according to their label, are alleged to provide the claimed pharmacokinetic Cmax/Cmin ratio (Compl. ¶67).

U.S. Patent No. 11,110,081 - "Tacrolimus for Improved Treatment of Transplant Patients," issued September 7, 2021.

  • Technology Synopsis: This patent also addresses the problem of optimizing the tacrolimus release profile to improve bioavailability and reduce side effects. The solution is an extended release oral dosage form characterized by a specific in vitro dissolution profile, namely releasing at most 63.5% of its tacrolimus content at the 12-hour time point under specified test conditions (U.S. Patent No. 11,110,081, claim 1).
  • Asserted Claims: At least claim 1 (Compl. ¶77).
  • Accused Features: The Defendant's ANDA Products are alleged to have the dissolution profile required by the claims (Compl. ¶77).

U.S. Patent No. 11,123,331 - "Tacrolimus for Improved Treatment of Transplant Patients," issued September 21, 2021.

  • Technology Synopsis: This patent addresses the problem of suboptimal bioavailability of conventional tacrolimus formulations. The invention is an extended release tacrolimus composition that provides an improved area-under-the-curve (AUC)—a measure of total drug exposure—that is at least 1.3 times the AUC provided by Prograf® under similar conditions (U.S. Patent No. 11,123,331, claim 1).
  • Asserted Claims: At least claim 1 (Compl. ¶87).
  • Accused Features: Defendant's ANDA Products are alleged to provide the claimed enhanced bioavailability and AUC profile relative to Prograf® (Compl. ¶87).

U.S. Patent No. 11,419,823 - "Stabilized Tacrolimus Composition," issued August 23, 2022.

  • Technology Synopsis: This patent, related to the ’918 Patent, addresses the degradation of tacrolimus into 8-epitacrolimus during storage. The solution is a sustained release tablet containing a solid dispersion of tacrolimus, a vehicle with polyethylene glycol and poloxamer, and a metal chelating agent, which exhibits a specific level of stability defined as accumulating no more than 0.5% more 8-epitacrolimus after storage (U.S. Patent No. 11,419,823, claim 1).
  • Asserted Claims: At least claim 1 (Compl. ¶97).
  • Accused Features: The Defendant's ANDA Products are alleged to be tablets meeting the claimed compositional and stability limitations (Compl. ¶97).

U.S. Patent No. 12,083,103 - "Tacrolimus for Improved Treatment of Transplant Patients," issued September 10, 2024.

  • Technology Synopsis: This patent claims a method for the prophylaxis of organ rejection in a de novo kidney transplant patient. The method involves once-daily oral administration of an extended-release tacrolimus composition that provides a time to maximum concentration (Tmax) on day 1 of treatment of between 4 and 24 hours (U.S. Patent No. 12,083,103, claim 1).
  • Asserted Claims: At least claim 1 (Compl. ¶108).
  • Accused Features: The use of Defendant's ANDA Products according to their label for prophylaxis of organ rejection in de novo kidney transplant patients is alleged to meet the claimed pharmacokinetic (Tmax) requirements (Compl. ¶108).

III. The Accused Instrumentality

Product Identification

  • Defendant Alkem Laboratories Ltd.’s proposed 0.75 mg, 1 mg, and 4 mg extended-release tablets of tacrolimus, which are the subject of ANDA No. 219575 submitted to the FDA (Compl. ¶1).

Functionality and Market Context

  • The complaint alleges that the accused ANDA Products are generic versions of Plaintiff’s ENVARSUS XR® product (Compl. ¶2). By filing the ANDA, Defendant has represented to the FDA that its products have the same active ingredient, dosage form, strengths, and route of administration as ENVARSUS XR® (Compl. ¶24). The ANDA Products are also represented as being bioequivalent to ENVARSUS XR® and are intended for the same indications, namely the prophylaxis of organ rejection in kidney transplant patients (Compl. ¶20, ¶24).

IV. Analysis of Infringement Allegations

The complaint alleges infringement but does not provide claim charts or detailed factual support for how the accused products meet specific claim limitations. The infringement theory is predicated on the allegation that by seeking approval for a generic equivalent of ENVARSUS XR®, the accused ANDA Products will necessarily have the composition, stability, and pharmacokinetic properties claimed in the patents-in-suit.

No probative visual evidence provided in complaint.

8,685,998 Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
A method of providing immunosuppressive treatment of a patient in need thereof in a once daily regimen, the method comprising orally administering an extended release oral dosage form comprising tacrolimus... Use of Defendant's ANDA Product according to its FDA-approved label, which will instruct for once-daily administration for immunosuppressive treatment. ¶34 col. 28:5-9
wherein the dosage form provides a Cmax that is at the most about 80% of the Cmax for a tacrolimus dosage form approved under U.S. New Drug Application No. 050708... The bioequivalence data submitted in Defendant's ANDA will demonstrate that its product, when administered, results in a Cmax profile that meets this limitation relative to the reference drug (Prograf®). ¶34 col. 28:10-17

9,549,918 Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
A solid sustained release oral dosage form comprising a solid dispersion of tacrolimus in a mixture of a vehicle and tartaric acid... The formulation described in Defendant's ANDA contains tacrolimus as a solid dispersion stabilized with tartaric acid. ¶45 col. 21:5-8
wherein the vehicle comprises polyethylene glycol and poloxamer. The vehicle or carrier system for the tacrolimus in Defendant's ANDA product is composed of polyethylene glycol and poloxamer. ¶45 col. 21:9-11

Identified Points of Contention

  • Scope Questions: A central question for the method claims (e.g., in the ’998 Patent) will be whether the data in Alkem’s ANDA, generated to prove bioequivalence to ENVARSUS XR®, also necessarily proves infringement of claims defined by pharmacokinetic parameters relative to a different drug, Prograf®. For the composition claims (e.g., in the ’918 Patent), a question is whether the term "solid dispersion" requires a complete molecular dispersion of tacrolimus, or if it can be construed to cover other solid-state forms that may be present in the accused product.
  • Technical Questions: What evidence does the complaint provide that Alkem's formulation uses tartaric acid specifically as the stabilizing agent, as required by claim 1 of the ’918 Patent, versus another pharmaceutically acceptable acid? Further, what is the precise definition of "about 80%" in the ’998 Patent's claim, and what statistical methodology will be used to determine if the accused product's Cmax falls within this range?

V. Key Claim Terms for Construction

The Term: "a Cmax that is at the most about 80% of the Cmax for a tacrolimus dosage form approved under U.S. New Drug Application No. 050708" (’998 Patent, claim 1)

  • Context and Importance: This term is the central limitation of the primary asserted method claim and defines the invention's pharmacokinetic profile. The entire infringement analysis for this claim will depend on how "Cmax" is measured and how "about 80%" is statistically interpreted. Practitioners may focus on this term because infringement hinges on a comparison of clinical data that can vary based on patient populations and test conditions.
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: The claim language is broad, referring generally to "similar conditions," which could be argued to cover any standard bioequivalence testing protocol (’998 Patent, col. 28:15-17).
    • Evidence for a Narrower Interpretation: The specification provides specific examples of clinical studies with defined patient populations (e.g., healthy subjects, fasted state) and graphical data (e.g., ’998 Patent, FIG. 3). A defendant may argue that "similar conditions" should be limited to the specific conditions disclosed in these preferred embodiments.

The Term: "solid dispersion" (’918 Patent, claim 1)

  • Context and Importance: This term defines the physical form of the active pharmaceutical ingredient. The infringement analysis for the composition claims depends on whether Alkem's formulation contains tacrolimus in this specific state. A dispute may arise if Alkem achieves stability using a different physical form that it argues is not a "solid dispersion."
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: The patent does not provide an explicit definition in the claims, which may support giving the term its plain and ordinary meaning to one of skill in the art, potentially covering a range of non-crystalline states.
    • Evidence for a Narrower Interpretation: The background section contrasts poorly soluble crystalline tacrolimus with the solid solutions/dispersions used in the invention, suggesting the term is meant to exclude crystalline forms (’918 Patent, col. 3:29-44). The specification also notes that the downside of molecular dispersions is increased motility and risk of chemical degradation, linking the term "solid dispersion" to a molecular-level distribution of the drug (’918 Patent, col. 3:51-57).

VI. Other Allegations

  • Indirect Infringement: The complaint alleges inducement of infringement for all asserted patents. This is based on the allegation that Defendant's product labeling will instruct physicians and patients to administer the ANDA Products in a manner that directly infringes the asserted method claims (e.g., once-daily dosing for immunosuppression) (Compl. ¶37, ¶48, ¶59, ¶69, ¶79, ¶89, ¶100, ¶110).
  • Willful Infringement: The complaint alleges that Defendant had knowledge of the patents-in-suit prior to filing its ANDA (Compl. ¶41, ¶52, ¶63, ¶73, ¶83, ¶93, ¶104, ¶114). The complaint also asserts that the case is "exceptional" under 35 U.S.C. § 285, seeking an award of attorneys' fees (Compl. ¶42, ¶53, ¶64, ¶74, ¶84, ¶94, ¶105, ¶115).

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

  • A core issue will be one of compositional identity: Does the specific formulation detailed in Alkem's confidential ANDA submission contain a "solid dispersion of tacrolimus" stabilized by "tartaric acid" in a "polyethylene glycol and poloxamer" vehicle, as required by the claims of the ’918 patent family, or does it employ a chemically distinct, non-infringing formulation to achieve bioequivalence?
  • A key evidentiary question will be one of infringement by bioequivalence: Will the clinical data Alkem submitted to the FDA to prove its product is bioequivalent to ENVARSUS XR® also be sufficient to prove, by a preponderance of the evidence, that its product meets the distinct pharmacokinetic limitations of the ’998 patent family, which are defined relative to a different reference drug (Prograf®)? The case will likely involve significant disputes over the proper statistical analysis and comparison of these clinical datasets.