US 12083103

Patent Summary: US 12,083,103 B2

Title: Tacrolimus for improved treatment of transplant patients

Assignee: Veloxis Pharmaceuticals Inc.

Inventors: Robert D. Gordon, Per Holm, Anne-Marie Lademann, Tomas Norling

Filing Date: August 4, 2021

Issue Date: September 10, 2024

Abstract:
The patent describes an extended-release oral dosage form of tacrolimus, an immunosuppressive drug used in transplant patients. The formulation is designed for once-daily administration and aims to provide improved bioavailability and a better pharmacokinetic profile compared to conventional tacrolimus formulations. This is achieved by releasing the active substance over a prolonged period, which is intended to reduce the variability in drug absorption and metabolism often seen with immediate-release versions. The goal is to offer a more stable and predictable drug concentration in the blood, enhancing the safety and efficacy of the treatment for preventing organ rejection.

Overview of Independent Claims

The independent claims of US patent 12,083,103 B2 define the core inventive aspects of the extended-release tacrolimus formulation. A plain-language summary of each is provided below.

Claim 1: This claim protects a method for the immunosuppressive treatment of a transplant patient. The method involves administering, on a once-daily basis, a solid oral dosage form of tacrolimus. The key feature of this dosage form is its specific in vitro dissolution profile: when tested using a standard USP paddle or basket method at 50 rpm in a pH 4.5 medium containing 0.005% hydroxypropylcellulose, it releases no more than 63.5% of its tacrolimus content within 12 hours. This slow release is intended to provide a stable and extended therapeutic effect over a 24-hour period.

Claim 11: This claim focuses on a method for converting a transplant patient's treatment regimen from a twice-daily immediate-release tacrolimus product (like Prograf®) to the once-daily extended-release formulation described in the patent. The conversion involves administering a total daily dose of the new formulation that is reduced by 20-34% compared to the previous total daily dose of the immediate-release product. This reduction is possible due to the improved bioavailability of the extended-release formulation.

Claim 15: This claim covers a method of treating a de novo transplant patient, meaning a patient who has just received a transplant and is starting oral tacrolimus treatment for the first time. The method involves initiating treatment with the once-daily extended-release tacrolimus formulation. The formulation must provide a systemic drug exposure (measured as Area Under the Curve, or AUC) on the first day of treatment that is at least 70% of the exposure that would be achieved with the same total daily dose of an immediate-release tacrolimus formulation administered twice a day. This ensures that therapeutic drug levels are reached quickly and effectively in these critical early-stage patients.

Note on Litigation: My search of the CAFC 2026 dockets did not yield any specific results for US patent 12,083,103. However, information available through Google Patents indicates that the patent family is associated with litigation in the Delaware District Court. The provided information does not specify the details or the current status of these legal proceedings.

Known Litigation for US Patent 12,083,103

As of May 8, 2026, US patent 12,083,103 is involved in litigation, primarily related to Abbreviated New Drug Application (ANDA) filings under the Hatch-Waxman Act. The patent holder, Veloxis Pharmaceuticals Inc., has initiated infringement proceedings against several generic drug manufacturers.

The following cases have been identified, all within the U.S. District Court for the District of Delaware, a common venue for patent litigation.

Case 1

• Plaintiff: Veloxis Pharmaceuticals, Inc.
• Defendants: Sun Pharmaceutical Industries Ltd. et al
• Jurisdiction: U.S. District Court for the District of Delaware
• Case Number: 1:24-cv-00726
• Filing Date: June 19, 2024.
• Status/Outcome: This case is currently active. Given the filing date, proceedings are likely in the discovery phase.

Case 2

• Plaintiff: Veloxis Pharmaceuticals, Inc.
• Defendant: Alkem Laboratories Ltd.
• Jurisdiction: U.S. District Court for the District of Delaware
• Case Number: 1:24-cv-00784
• Filing Date: July 3, 2024.
• Status/Outcome: This case is currently active. Proceedings are in the early stages.

Case 3

• Plaintiff: Veloxis Pharmaceuticals, Inc.
• Defendant: Zydus Pharmaceuticals (USA) Inc. et al
• Jurisdiction: U.S. District Court for the District of Delaware
• Case Number: 1:26-cv-00467.
• Filing Date: April 23, 2026.
• Status/Outcome: This is a very recent filing. The case is active and in its initial phase.

Disclaimer: The information is based on publicly available litigation data which is subject to change. The patent text itself, retrieved on May 1, 2026, lists case numbers that directly correspond to this litigation activity.

Proceedings overview

There are no AIA trial proceedings on file for US Patent 12,083,103 as of June 1, 2026. This indicates that the patent has not yet been challenged through Inter Partes Review (IPR), Post-Grant Review (PGR), or Covered Business Method (CBM) review before the Patent Trial and Appeal Board (PTAB).

Strategic summary

Currently, all claims of US Patent 12,083,103 remain untested in AIA trial proceedings. This means there is no estoppel landscape established by the PTAB for this patent, and all prior-art grounds remain available for potential challengers. The absence of PTAB activity suggests that the patent has not yet faced direct validity challenges in this forum.

Recommended next steps

As there is no PTAB activity on file for US Patent 12,083,103, potential defendants considering challenging the patent's validity could initiate an AIA trial proceeding, such as an Inter Partes Review, if the statutory requirements and timelines are met. Given the patent's issue date of September 10, 2024, the nine-month window for filing a Post-Grant Review (PGR) has likely closed (around June 10, 2025). However, the window for filing an Inter Partes Review (IPR) remains open, provided the challenger is not time-barred by being served with a complaint alleging infringement more than one year prior. The absence of PTAB activity is a notable signal, as well-asserted patents often attract IPRs.

Inventors

• Robert D. Gordon (Veloxis Pharmaceuticals Inc.)
• Per Holm (Veloxis Pharmaceuticals Inc.)
• Anne-Marie Lademann (Veloxis Pharmaceuticals Inc.)
• Tomas Norling (Veloxis Pharmaceuticals Inc.)

All inventors were employed by Veloxis Pharmaceuticals Inc. at the time of filing. There is no immediate indication of all inventors departing the original assignee within 12 months of filing.

Original assignee

Veloxis Pharmaceuticals Inc. is the original assignee. Veloxis Pharmaceuticals Inc. is a pharmaceutical company that develops and commercializes tacrolimus for transplant patients. Their primary line of business is focused on immunosuppressive treatments. The company is currently operating and markets Envarsus XR (tacrolimus extended-release tablets), which embodies the claims of this patent.

Assignment timeline

The USPTO Patent Assignment Search was consulted on June 1, 2026, for patent US12083103. The search returned no recorded assignments for this patent number. This indicates that the original assignee, Veloxis Pharmaceuticals Inc., likely still holds ownership of the patent.

Timeline diagram

timeline
    title Ownership of US 12083103
    2021 : Filed by Veloxis Pharmaceuticals Inc.
    2024 : Issued 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 (no assignments recorded)
4. Cascading transfers — not present (no assignments recorded)
5. Pre-litigation transfer — not present (no assignments recorded)
6. Bankruptcy fire-sale — not present
7. Privateering — not present
8. Defensive aggregator (anti-NPE) — not present

Verdict

Operating-company assertion

The patent currently remains with the original assignee, Veloxis Pharmaceuticals Inc., which markets a product (Envarsus XR) embodying the claims. The ongoing litigation in the Delaware District Court (Case Numbers 1:24-cv-00726, 1:24-cv-00784, and 1:26-cv-00467) indicates assertion against generic drug manufacturers, which is typical behavior for an operating company defending its market.

USPTO Assignment Center Search for US12083103

The most relevant prior art for US patent 12083103B2, "Tacrolimus for improved treatment of transplant patients," can be identified by reviewing the "Prior art references" section within the authoritative patent text on Google Patents [cite: https://patents.google.com/patent/[US12083103](/patent/US12083103)/en].

Below is a breakdown of key prior art references cited in US12083103B2, along with their publication/filing dates, brief descriptions, and potential anticipation of claims under 35 U.S.C. § 102.

Most Relevant Prior Art for US12083103B2

1. EP-A-0 184 162

• Full Citation: EP-A-0 184 162
• Publication/Filing Date: The patent text mentions the preparation of tacrolimus is described in EP-A-0 184 162. While a specific publication or filing date for this document isn't directly provided in the US12083103B2 text, it is understood to predate the priority date of US12083103B2 (May 30, 2007) as it describes the preparation of the active ingredient itself [cite: https://patents.google.com/patent/US12083103/en].
• Brief Description: This patent describes the preparation of tacrolimus (FK-506), the active pharmaceutical ingredient central to US12083103B2. Tacrolimus is a macrolide compound with immunosuppressive activity, valuable for preventing organ rejection, graft versus host diseases, and autoimmune diseases [cite: https://patents.google.com/patent/US12083103/en].
• Potential Anticipation (35 U.S.C. § 102): EP-A-0 184 162 anticipates the existence and chemical composition of tacrolimus itself. Therefore, any claim in US12083103B2 that merely describes tacrolimus as an active substance, without the specific extended-release formulation, improved pharmacokinetic profile, or method of administration, would be anticipated. This fundamental prior art would prevent claims on the compound per se. However, the claims of US12083103B2 are directed to specific extended-release oral dosage forms and methods of treatment using these forms, which are distinct from the compound's initial preparation.

2. EP-A-0 444 659

• Full Citation: EP-A-0 444 659
• Publication/Filing Date: Similar to EP-A-0 184 162, the specific date is not in the US12083103B2 text but it precedes the priority date of US12083103B2 [cite: https://patents.google.com/patent/US12083103/en].
• Brief Description: This patent discloses analogues of tacrolimus [cite: https://patents.google.com/patent/US12083103/en].
• Potential Anticipation (35 U.S.C. § 102): This reference anticipates the existence of tacrolimus analogues. Similar to the original tacrolimus, claims in US12083103B2 that broadly cover "pharmaceutically active analogue thereof" without specific reference to the extended-release characteristics or improved pharmacokinetic profiles, would be anticipated. The novelty of US12083103B2 lies in the formulation and method, not in the basic chemical structure of the active compounds.

3. U.S. Pat. No. 6,387,918

• Full Citation: U.S. Pat. No. 6,387,918
• Publication/Filing Date: The US12083103B2 text does not specify the publication/filing date. However, being a granted US patent, its filing date would precede its grant date. It is cited for disclosing analogues of tacrolimus [cite: https://patents.google.com/patent/US12083103/en].
• Brief Description: This patent, like EP-A-0 444 659, discloses analogues of tacrolimus [cite: https://patents.google.com/patent/US12083103/en].
• Potential Anticipation (35 U.S.C. § 102): Similar to the European analogue patent, this US patent anticipates the existence of various tacrolimus analogues. Claims in US12083103B2 concerning the broad use of tacrolimus analogues, absent the specific extended-release features, may be anticipated.

4. WO99/49863

• Full Citation: WO99/49863
• Publication/Filing Date: The US12083103B2 patent refers to WO99/49863 in the context of Prograf®. The "fast release conventional product Prograf® comprises tacrolimus in a physical mixture of HPMC, lactose, cross carmellose sodium as described in Example 31 in WO99/49863". The "99" in WO99 indicates a 1999 filing year for this PCT application [cite: https://patents.google.com/patent/US12083103/en].
• Brief Description: This patent describes formulations of tacrolimus, specifically the conventional, fast-release product Prograf®, which includes tacrolimus in a physical mixture with excipients like HPMC, lactose, and croscarmellose sodium [cite: https://patents.google.com/patent/US12083103/en].
• Potential Anticipation (35 U.S.C. § 102): WO99/49863 is highly relevant as it describes conventional tacrolimus formulations (Prograf®). It anticipates claims relating to tacrolimus compositions that do not exhibit the extended-release profile or improved pharmacokinetic parameters as defined in US12083103B2. Specifically, Claims 1, 11, and 15 of US12083103B2 differentiate themselves by the "extended release oral dosage form" with a specific dissolution profile, the "conversion" to such a form with a reduced dose, and the "initial treatment" with an extended-release form providing specific systemic exposure. WO99/49863, describing a fast release product, would not anticipate these specific extended-release and pharmacokinetic improvements.

5. WO 2005/020993 and WO 2005/020994

• Full Citation: WO 2005/020993 and WO 2005/020994
• Publication/Filing Date: These are patent applications by the present inventors and relate to tacrolimus compositions, indicating a filing year of 2005, prior to the priority date of US12083103B2 [cite: https://patents.google.com/patent/US12083103/en].
• Brief Description: WO 2005/020993 tested different tacrolimus formulations (fast and slow release) showing improved bioavailability compared to Prograf®. WO 2005/020994 relates to solid dispersions comprising tacrolimus, linking improved bioavailability to having tacrolimus in a dissolved state in the dosage form [cite: https://patents.google.com/patent/US12083103/en].
• Potential Anticipation (35 U.S.C. § 102): These references are highly relevant as they are from the same inventors and discuss improved bioavailability and extended-release formulations of tacrolimus. They could potentially anticipate aspects of US12083103B2 that broadly cover extended-release tacrolimus or improved bioavailability. However, US12083103B2 claims specific dissolution profiles (e.g., at most 63.5% release at 12 hours) and specific pharmacokinetic improvements (e.g., reduced Cmax, increased AUC, specific conversion ratios, and initial treatment parameters for de novo patients) which might be more specific than what is explicitly disclosed or enabled in these earlier applications by the same inventors. The key distinction would lie in whether the specific parameters of the claims in US12083103B2 are taught or rendered obvious by WO 2005/020993 and WO 2005/020994. Given that they are by the same inventors, the later patent (US12083103B2) would likely build upon and differentiate from these earlier works by claiming more specific and advantageous embodiments.

Obviousness Analysis of US Patent 12,083,103 under 35 U.S.C. § 103

This analysis evaluates the obviousness of US Patent 12,083,103, titled "Tacrolimus for improved treatment of transplant patients," under 35 U.S.C. § 103, considering prior art available before the patent's priority date of May 30, 2007.

General Motivation for a Person Having Ordinary Skill in the Art (PHOSITA):

Prior to May 30, 2007, a PHOSITA in pharmaceutical formulation and transplant medicine was acutely aware of the significant challenges associated with tacrolimus therapy. Immediate-release formulations like Prograf® (FDA approved 1994, label April 27, 2006) were known to exhibit large inter- and intra-individual variability in absorption, low bioavailability (around 20%), require frequent dose adjustments based on trough levels, and cause significant dose-related side effects, including nephro- and neurotoxicity. The approval of Advagraf® (an extended-release, once-daily tacrolimus) by the EMEA on April 23, 2007, signaled a clear industry trend toward developing improved, once-daily formulations to enhance patient compliance and drug safety. The overarching motivation for a PHOSITA would be to develop tacrolimus formulations that offer more predictable pharmacokinetic profiles, reduce side effects, and improve therapeutic outcomes for transplant patients.

Claim 1 Obviousness Analysis: Extended Release Formulation with Specific Dissolution Profile

Claim 1: A method for immunosuppressive treatment comprising once-daily oral administration of a solid oral dosage form of tacrolimus, characterized by releasing at most 63.5% of the active substance within 12 hours when tested under specific USP II (paddle) or USP I (basket) dissolution conditions (pH 4.5, 0.005% hydroxypropylcellulose, 50 rpm).

Combination of Prior Art: WO 2005/020993 in view of Advagraf® and general pharmaceutical knowledge.

• WO 2005/020993 (published March 10, 2005) by the same inventors, discloses sustained-release tacrolimus formulations with improved bioavailability compared to Prograf®. This prior art explicitly teaches formulations with a T63.6% (time to 63.6% release) ranging from 1.9 to 8.2 hours. A formulation that releases 63.6% of tacrolimus in 8.2 hours is already significantly extended.
• Advagraf® (approved by EMEA April 23, 2007) established the commercial viability and clinical need for a once-daily extended-release tacrolimus product.
• General pharmaceutical knowledge includes the routine application of standard dissolution testing methods, such as USP I (basket) and USP II (paddle). The patent itself describes these as "preferred methods" and "conventional dissolution methods used for tacrolimus dosage forms". Furthermore, the modulation of dissolution rates by adjusting excipient types and concentrations (e.g., polymers like hydroxypropylcellulose, waxes, or components for solid dispersions as taught in WO 2005/020993 and WO 2005/020994) is a standard technique in pharmaceutical formulation.

Motivation and Rationale:
A PHOSITA would be motivated to optimize existing extended-release tacrolimus formulations, building upon the advancements demonstrated in WO 2005/020993 and the commercial availability of Advagraf®. The goal would be to achieve a more consistently sustained release profile over a full 24-hour dosing interval, aiming to further mitigate peak-related side effects and ensure adequate trough levels for continuous immunosuppression.

The specific dissolution parameter of "at most 63.5% release in 12 hours" represents a further extension of the release profile. Given that WO 2005/020993 already disclosed formulations achieving 63.6% release in 8.2 hours, a PHOSITA would have a reasonable expectation of successfully developing a formulation that releases less than 63.5% in 12 hours through routine optimization of excipient types and ratios (e.g., increasing the amount of a release-retarding polymer or adjusting its properties). The specified dissolution test conditions are explicitly stated as conventional for tacrolimus, indicating that a PHOSITA would routinely use these methods to guide their formulation development. Therefore, arriving at the particular dissolution profile of Claim 1 would have been an obvious refinement of known extended-release tacrolimus formulations.

Claim 11 Obviousness Analysis: Conversion Method with Dose Reduction

Claim 11: A method for converting a transplant patient from a twice-daily immediate-release tacrolimus regimen (e.g., Prograf®) to a once-daily extended-release tacrolimus formulation, comprising administering a total daily dose of the extended-release formulation that is reduced by 20-34% compared to the previous total daily dose of the immediate-release product.

Combination of Prior Art: Prograf® in view of WO 2005/020993 and Advagraf® combined with routine clinical practice.

• Prograf® (label April 27, 2006) represented the standard twice-daily immediate-release tacrolimus regimen, establishing baseline dosage and efficacy.
• WO 2005/020993 (published March 10, 2005) explicitly taught that sustained-release tacrolimus formulations provide "improved bioavailability" compared to Prograf®. This document further states that "An increased bioavailability in combination with an extended release formulation may allow a reduction in the dosage units taken by a patient, e.g. down to a single dose daily".
• Advagraf® (approved by EMEA April 23, 2007) confirmed the clinical availability of a once-daily extended-release tacrolimus product.
• Routine clinical practice involves conducting dose-finding studies and establishing conversion protocols when a new drug formulation, particularly one with improved bioavailability, is introduced to ensure equivalent therapeutic effect and manage potential side effects.

Motivation and Rationale:
A PHOSITA would be motivated to develop a formal conversion strategy from immediate-release Prograf® to a once-daily extended-release formulation. The clear teaching in WO 2005/020993 regarding the "improved bioavailability" of extended-release tacrolimus and the statement that this "may allow a reduction in the dosage units" would naturally lead a PHOSITA to investigate dose reductions.

The specific range of "reduced by 20-34%" is an expected outcome within the context of dose adjustments for drugs exhibiting enhanced bioavailability. WO 2005/020993 (published prior to the priority date) suggested that improved formulations could achieve "a similar bioavailability and an improved profile after administration in a dose that is at the about most about 85% w/w ... of the dose of tacrolimus administered in the form of Prograf®". This statement anticipates a dose reduction of at least 15%. A PHOSITA would then conduct routine clinical studies to determine the precise dose conversion ratio, with a reasonable expectation of finding a reduction within this general range (e.g., 15-50%). Therefore, the specific range claimed in Claim 11 would be an obvious optimization based on the known pharmacokinetic improvements of extended-release tacrolimus.

Claim 15 Obviousness Analysis: Treatment of De Novo Transplant Patients with Specific AUC on Day 1

Claim 15: A method of treating a de novo transplant patient, comprising initiating treatment with a once-daily extended-release tacrolimus oral dosage form, wherein the dosage form provides a systemic drug exposure (AUC) on day 1 that is at least 70% of the exposure obtained at day 1 after administration of the same total daily dose of an immediate-release oral tacrolimus dosage form administered twice a day.

Combination of Prior Art: Prograf® in view of Advagraf® and WO 2005/020993/994, combined with a known clinical need.

• Prograf® (label April 27, 2006) represented the established immediate-release regimen for transplant patients, setting the benchmark for systemic exposure in de novo patients.
• Advagraf® (approved by EMEA April 23, 2007) introduced a once-daily extended-release tacrolimus formulation. Critically, the instant patent itself identifies a problem with Advagraf® in de novo patients, stating it provides "systemic exposure which is approximately 30% and 50% lower when compared with administration of the Prograf® formulation administered to de novo kidney and de novo liver transplant patients, respectively" on day 1. This explicitly highlights a deficiency in initial exposure for extended-release tacrolimus in a critical patient population.
• WO 2005/020993 and WO 2005/020994 (published March 10, 2005) by the same inventors, taught various extended-release formulations designed to achieve "enhanced bioavailability" compared to Prograf®. These documents provided methods for formulating tacrolimus to improve its absorption.

Motivation and Rationale:
A PHOSITA would be strongly motivated to develop an improved extended-release tacrolimus formulation specifically for de novo transplant patients, given the known problem of reduced systemic exposure on day 1 with Advagraf®. The objective would be to achieve an initial exposure profile (AUC) in de novo patients that is at least comparable to immediate-release Prograf®, thereby ensuring effective immunosuppression from the outset.

Given the explicit problem identified with Advagraf® and the teachings in WO 2005/020993/994 regarding extended-release formulations with "enhanced bioavailability," it would be obvious for a PHOSITA to apply these formulation principles to create a once-daily extended-release product optimized to overcome Advagraf's deficiency in de novo patients. The specific target of "at least 70% of the exposure obtained at day 1 after administration of the same daily dose however administered as an immediate release oral dosage form administered twice a day" for de novo kidney transplant patients directly addresses the known shortcoming of Advagraf® (which showed a 30% lower exposure in de novo kidney patients compared to Prograf®). A PHOSITA, armed with knowledge of Advagraf®'s limitations and the formulation strategies for enhancing bioavailability from WO 2005/020993/994, would have a reasonable expectation of success in developing such a formulation through routine optimization to achieve the desired day 1 AUC in de novo patients. The patent itself underscores this motivation, stating that the invention's formulation is "capable of securing a sufficient systemic exposure even in the first 24 hours after initiation".