US 12403095

Analysis of U.S. Patent 12,403,095: Stabilized Tacrolimus Composition

Date of Analysis: May 1, 2026

A detailed review of U.S. Patent 12,403,095 has been conducted. This document, titled "Stabilized tacrolimus composition," was issued on September 2, 2025, and is assigned to Veloxis Pharmaceuticals Inc. The inventors are listed as Nikolaj Skak and Per Holm. The patent application was filed on July 5, 2022.

No litigation concerning this patent has been identified in the CAFC dockets for 2026.

Abstract:

The invention relates to a stable pharmaceutical composition comprising a solid dispersion of tacrolimus in a vehicle. The composition further includes a stabilizing agent capable of providing a pH below 7 in the composition, as measured after re-dispersion in water. This stabilization is aimed at preventing or reducing the formation of major degradation products of tacrolimus, particularly 8-epitacrolimus, upon storage.

Summary of Independent Claims:

The patent asserts two independent claims, which are foundational to the intellectual property protection sought.

Independent Claim 1:

This claim defines a pharmaceutical composition that is a solid dispersion of the immunosuppressive drug tacrolimus. Key limitations of this claim are:

• Active Ingredient: Tacrolimus is the sole active ingredient.
• Formulation: It is a solid dispersion in a mixture of a vehicle and a stabilizing agent.
• Stabilizing Agent: The agent must be a metal chelating agent and must result in a pH below 7 for the composition.
• Tacrolimus Concentration: The composition must contain between approximately 0.5% and 5% of tacrolimus by total weight.
• Stability Requirement: When stored at 40°C and 75% relative humidity for 5 weeks, the amount of the degradation product 8-epitacrolimus must not increase by more than 0.5% of the total weight of tacrolimus.
• Vehicle Exclusion: The vehicle used in the formulation cannot include a cyclo-dextrin.

In essence, this claim protects a specific formulation of tacrolimus that is stabilized against degradation under defined stress conditions, with particular compositional and functional requirements.

Independent Claim 11:

Similar to the first independent claim, this claim also describes a stabilized solid dispersion of tacrolimus where it is the only active ingredient and the vehicle does not contain a cyclo-dextrin. The primary distinctions and key features are:

• Active Ingredient & Formulation: Tacrolimus is the sole active ingredient in a solid dispersion with a vehicle and a metal-chelating stabilizing agent that provides a pH below 7.
• Tacrolimus Concentration: The concentration of tacrolimus is also set between approximately 0.5% and 5% by total weight.
• Stability Requirement: This claim sets a different stability standard. After storage at 25°C and 60% relative humidity for 5 weeks, the amount of 8-epitacrolimus should not increase by more than 0.2% of the total tacrolimus weight.

This claim provides protection for a tacrolimus formulation that demonstrates stability under more standard storage conditions, with a stricter limit on the formation of the specified degradation product.

Litigation Status of U.S. Patent 12,403,095

As of May 1, 2026, U.S. Patent 12,403,095 is involved in at least two known litigations, both of which are Abbreviated New Drug Application (ANDA) cases filed in the U.S. District Court for the District of Delaware. These cases typically arise when a generic drug manufacturer seeks FDA approval to market a generic version of a branded drug before the expiration of patents covering that drug.

Details of the cases are as follows:

Case 1

• Plaintiff(s): Veloxis Pharmaceuticals, Inc.
• Defendant(s): Glenmark Pharmaceuticals Inc., USA
• Jurisdiction: U.S. District Court for the District of Delaware
• Case Number: 1:26-cv-00305
• Filing Date: March 20, 2026
• Outcome or Current Status: The case is currently open.

Case 2

• Plaintiff(s): Veloxis Pharmaceuticals, Inc.
• Defendant(s): Zydus Pharmaceuticals (USA) Inc. and Zydus Lifesciences Ltd.
• Jurisdiction: U.S. District Court for the District of Delaware
• Case Number: 1:26-cv-00467
• Filing Date: April 23, 2026
• Outcome or Current Status: The case is currently open. In this case, the '095 patent is listed among several others with an anticipated expiration date of May 30, 2028, and a thirty-month stay deadline of September 12, 2028.

Proceedings overview

There are no AIA trial proceedings on file for U.S. Patent 12,403,095. This indicates that the patent has not yet been challenged in an IPR, PGR, or CBM proceeding at the USPTO's Patent Trial and Appeal Board.

Strategic summary

As of May 30, 2026, all claims of U.S. Patent 12,403,095 (claims 1-21) remain untested by the PTAB. There is no estoppel landscape to consider as no AIA trials have been initiated. The absence of PTAB activity might suggest that the patent has not yet been heavily asserted in a manner that would provoke an IPR filing, or potential challengers have not yet identified strong grounds for invalidation under the AIA trial standards.

Recommended next steps

Since no PTAB activity exists for U.S. Patent 12,403,095, any defendant currently facing assertion of this patent has a full range of prior-art grounds available for potential IPR or PGR challenges. If considering such a challenge, it would be prudent to conduct a thorough prior art search, focusing on the novelty and obviousness of claims 1 and 11 (the independent claims), as well as their dependent claims. The absence of PTAB challenges to date could be a signal, but it does not preclude the possibility of successful challenges in the future.

Inventors

• Nikolaj Skak: Veloxis Pharmaceuticals Inc. (at time of filing)
• Per Holm: Veloxis Pharmaceuticals Inc. (at time of filing)

Original assignee

Veloxis Pharmaceuticals Inc. (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.) is a pharmaceutical company that develops and commercializes immunosuppressive drugs. They market products such as Envarsus XR (tacrolimus extended-release tablets) for the prevention of organ rejection in adult kidney transplant patients. Veloxis Pharmaceuticals Inc. is currently operating as a subsidiary of Asahi Kasei Pharma.

Assignment timeline

The USPTO Patent Assignment Search database does not currently show any assignment records for US12403095. The current assignee, Veloxis Pharmaceuticals Inc., is the original assignee as shown on the patent document.

Timeline diagram

timeline
    title Ownership of US 12403095
    2008 : Priority date
    2022 : Application filed by Veloxis Pharmaceuticals Inc
    2025 : Application granted, published to Veloxis Pharmaceuticals Inc

NPE / troll-pattern signals

1. Shell-entity transfer — not present
2. Known asserter in the chain — not present
3. Repeat correspondent across the chain — not present
4. Cascading transfers — not present
5. Pre-litigation transfer — not present
6. Bankruptcy fire-sale — not present
7. Privateering — not present
8. Defensive aggregator (anti-NPE) — not present

Verdict

Operating-company assertion

There are no assignment records for US12403095 in the USPTO database, indicating that the patent remains with its original assignee, Veloxis Pharmaceuticals Inc. Veloxis Pharmaceuticals Inc. is a pharmaceutical company that manufactures and sells products related to tacrolimus. The litigation cases initiated by Veloxis Pharmaceuticals Inc. against Glenmark Pharmaceuticals Inc., USA (1:26-cv-00305) and Zydus Pharmaceuticals (USA) Inc. (1:26-cv-00467) appear to be typical operating-company assertions against generic drug manufacturers.

USPTO Assignment Center search: https://assignmentcenter.uspto.gov/

Analysis of Prior Art for U.S. Patent 12,403,095

An evaluation of the prior art cited in U.S. Patent 12,403,095 has been performed to determine its relevance to the patent's claims under 35 U.S.C. § 102. The following references are considered the most pertinent.

U.S. Patent Application Publication No. 2008/0132533 A1 (Yeom et al.)

• Full Citation: US 2008/0132533 A1
• Publication Date: June 5, 2008
• Filing Date: November 29, 2007
• Brief Description: Yeom discloses a solid dispersion formulation of tacrolimus with an enteric polymer to enhance stability by reducing recrystallization, particularly under high temperature and humidity. The formulation is designed to release tacrolimus quickly in aqueous media to improve bioavailability.
• Potential Anticipation of Claims:
  • Claims 1 and 11: Yeom teaches the use of a solid dispersion of tacrolimus to improve stability, which is a core concept of the '095 patent. Specifically, it mentions conducting stability tests at 40°C and 75% relative humidity, directly relevant to the conditions specified in claim 1. However, Yeom's focus is on using enteric polymers to prevent recrystallization rather than a metal-chelating stabilizing agent to prevent chemical degradation (specifically the formation of 8-epitacrolimus) by controlling pH. Yeom does not appear to disclose a stabilizing agent that is a metal chelator or one that provides a pH below 7. Furthermore, it does not specify limitations on the formation of 8-epitacrolimus.

U.S. Patent No. 7,994,214 B2 (Holm et al.)

• Full Citation: US 7,994,214 B2
• Publication Date: August 9, 2011
• Filing Date: July 7, 2009
• Brief Description: This patent, which shares an inventor with the '095 patent, describes solid dispersions of tacrolimus in a hydrophilic or water-miscible vehicle. The concentration of tacrolimus is specified to be between approximately 0.01% and 15% w/w. The invention aims to prepare solid oral dosage forms like tablets and capsules.
• Potential Anticipation of Claims:
  • Claims 1 and 11: Holm '214 discloses a solid dispersion of tacrolimus in a vehicle at concentrations that overlap with the ranges claimed in the '095 patent. It also mentions that stabilizing agents may be added to ensure the stability of the solid dispersion. However, it does not specifically require a metal-chelating agent that provides a pH below 7, nor does it set forth the specific stability requirements concerning the limited formation of 8-epitacrolimus under the precise conditions laid out in claims 1 and 11 of the '095 patent.

U.S. Patent Application Publication No. 2006/0177500 A1 (Shin et al.)

• Full Citation: US 2006/0177500 A1
• Publication Date: August 10, 2006
• Filing Date: August 26, 2005
• Brief Description: Shin discloses a solid dispersion of tacrolimus prepared by dissolving tacrolimus and a solid carrier in an organic solvent and then drying the mixture. The solid carriers mentioned include sucrose fatty acid esters and sodium lauryl sulfate. The goal is to increase the dissolution rate of tacrolimus.
• Potential Anticipation of Claims:
  • Claims 1 and 11: While Shin teaches a solid dispersion of tacrolimus, it relies on a solvent-based method for preparation. The '095 patent focuses on a melt-based dispersion. More importantly, Shin does not mention the use of a stabilizing agent that is a metal chelator, the control of pH to below 7, or the specific stability limitations regarding 8-epitacrolimus formation. The carriers disclosed are for improving dissolution and are not described as having stabilizing or pH-modifying properties.

European Patent No. 2575769 B1 (Veloxis Pharmaceuticals A/S)

• Full Citation: EP 2575769 B1
• Publication Date: April 3, 2013
• Filing Date: February 17, 2011
• Brief Description: This European patent, from the same assignee as the '095 patent, is highly relevant as it explicitly discloses stabilized pharmaceutical compositions of tacrolimus. It describes a solid dispersion of tacrolimus with a stabilizing agent to prevent the formation of degradation products, including 8-epitacrolimus. It mentions using organic acids like tartaric acid as stabilizing agents and provides examples of compositions with PEG 6000 and poloxamer 188 as the vehicle. It also discloses stability data after storage at 25°C/60% RH.
• Potential Anticipation of Claims:
  • Claims 1 and 11: This reference appears to be the most relevant prior art. It discloses many key elements of the '095 patent's claims, including a solid dispersion of tacrolimus, the use of a stabilizing agent to reduce the formation of 8-epitacrolimus, and stability testing under conditions similar to those in claim 11. The disclosure of tartaric acid (a known metal chelator and acid) and a vehicle of PEG and poloxamer is also significant. A detailed analysis would be required to determine if this European patent discloses all the limitations of the independent claims of the '095 patent, particularly the precise percentage increase limits for 8-epitacrolimus under the specified storage conditions and the explicit limitation that tacrolimus is the sole active ingredient. It is highly likely that this reference would be a key piece of prior art in any validity challenge.

Analysis of Obviousness for U.S. Patent 12,403,095 under 35 U.S.C. § 103

An analysis of U.S. Patent 12,403,095 for obviousness under 35 U.S.C. § 103 reveals that claims 1 and 11, the independent claims, appear to be rendered obvious by a combination of the prior art, primarily European Patent No. 2575769 B1 (EP '769), in conjunction with a person having ordinary skill in the art's (POSITA) general knowledge of pharmaceutical formulation and regulatory requirements.

Identified Combinations and Rationale for Obviousness

The most potent combination for challenging the obviousness of claims 1 and 11 is EP 2575769 B1 alone, or in combination with general pharmaceutical knowledge.

EP 2575769 B1 (Veloxis Pharmaceuticals A/S)

• Relevance: This European patent, from the same assignee as US 12,403,095, is highly relevant as it explicitly discloses stabilized pharmaceutical compositions of tacrolimus. It describes a solid dispersion of tacrolimus with a stabilizing agent to prevent the formation of degradation products, including 8-epitacrolimus. It also mentions using organic acids like tartaric acid as stabilizing agents and provides examples of compositions with polyethylene glycol (PEG) 6000 and poloxamer 188 as the vehicle. Crucially, it discloses stability data after storage at 25°C/60% RH.

Addressing Limitations of Claims 1 and 11 with EP '769:

1. Solid Dispersion of Tacrolimus in a Vehicle with a Stabilizing Agent: EP '769 explicitly teaches this core concept.
2. Stabilizing Agent is a Metal Chelating Agent and Provides a pH Below 7: EP '769 discloses the use of organic acids, specifically tartaric acid, as a stabilizing agent. A POSITA would readily know that tartaric acid is a dicarboxylic acid, capable of lowering pH and acting as a metal chelating agent. The US 12,403,095 patent itself notes that "tartaric acid has a chelating effect. It is contemplated that a chelator stabilizing agent is preferred in order to prevent or reduce formation of C8-epimer tacrolimus degradation product." Furthermore, the '095 patent states that "the pH may be provided by the stabilizing agent and/or be adjusted by an inorganic or organic acid or a mixture thereof," and explicitly shows tartaric acid providing a pH of 3.5. This demonstrates that the pH-lowering and chelating properties are inherent or well-known aspects of using tartaric acid for stabilization against 8-epitacrolimus.
3. Tacrolimus Concentration (0.5% to 5% w/w): US 7,994,214 B2 (Holm et al.), which shares an inventor with the '095 patent, discloses tacrolimus concentrations from 0.01% to 15% w/w in solid dispersions, encompassing the claimed range. This range would be well within the knowledge of a POSITA, especially one working for Veloxis Pharmaceuticals.
4. Tacrolimus is the Sole Active Ingredient: When formulating a specific drug like tacrolimus for its known immunosuppressive purpose, it is standard pharmaceutical practice to develop formulations where it is the sole active ingredient, unless a specific combination therapy is explicitly intended. EP '769's disclosure of "stabilized pharmaceutical compositions of tacrolimus" would inherently imply such formulations.
5. Vehicle Does Not Include a Cyclo-dextrin: EP '769 provides examples of vehicles such as PEG 6000 and poloxamer 188. These are not cyclodextrins. The '095 patent itself lists cyclodextrins as other useful hydrophilic or water-miscible vehicles, indicating they are not universally required. Thus, excluding cyclodextrins would not represent an inventive step if the core stabilization mechanism relies on other vehicle components.
6. Specific Quantitative Stability Limits for 8-epitacrolimus: This is the most specific limitation. The '095 patent defines limits such as "no more than 0.5% more 8-epitacrolimus after storage at 40° C. at 75% relative humidity for 5 weeks" (Claim 1) or "no more than 0.2% more 8-epitacrolimus after storage at 25° C. at 60% relative humidity for 5 weeks" (Claim 11).
   • The '095 patent highlights that the International Conference of Harmonization (ICH) guidelines set a limit of 0.5% for a single degradation product for daily dosages between 10 to 100 mg. A POSITA would be strongly motivated to achieve stability profiles that meet these known regulatory standards.
   • EP '769 already discloses stability data at 25°C/60% RH, one of the storage conditions. If the data in EP '769 demonstrates improved stability of tacrolimus and reduced 8-epitacrolimus, a POSITA would find it obvious to optimize the concentration of the stabilizing agent (e.g., tartaric acid) to meet or exceed these regulatory thresholds. Example 8 of the '095 patent itself demonstrates the routine optimization of tartaric acid concentration to achieve "long term stability" and identifies an "optimum" range of 0.10% to 0.20% w/w for the highest stabilizing effect. Such optimization would be considered routine experimentation for a formulator seeking to enhance product shelf-life and regulatory compliance.

Motivation to Combine:

A POSITA, particularly one associated with Veloxis Pharmaceuticals (due to the shared assignee and inventors between EP '769 and US 12,403,095), would be well aware of the challenges in stabilizing tacrolimus and the problem of 8-epitacrolimus formation. EP '769 directly addresses this by teaching a solution: using organic acid chelators in a solid dispersion to prevent 8-epitacrolimus. The motivation to further develop or optimize these formulations to meet specific, known regulatory impurity limits (like those from ICH guidelines) would be high. The adjustments to the concentration of the stabilizing agent to achieve precise stability outcomes, as well as the selection of commonly known vehicles (like PEG and poloxamer) without adding non-essential components (like cyclodextrins), would be considered within the ordinary skill of a formulator.

Therefore, the combination of the specific teachings of EP 2575769 B1 regarding tacrolimus solid dispersions, stabilizing agents (e.g., tartaric acid), and their effect on 8-epitacrolimus, with the general knowledge of pharmaceutical formulation and the goal of meeting established regulatory stability criteria, would have made claims 1 and 11 of US 12,403,095 obvious to a POSITA.