US 11110081

US Patent 11110081: Summary and Claim Analysis

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: 2020-10-30

Issue Date: 2021-09-07

Abstract: The patent describes an extended-release oral dosage form containing tacrolimus or a pharmaceutically active analogue for once-daily immunosuppressive treatment of transplant patients. This dosage form is designed to release the active substance over a very extended period, providing high bioavailability and an improved pharmacokinetic profile compared to conventional formulations.

Plain-Language Overview of Independent Claims:

US Patent 11110081 contains several independent claims, each defining a distinct aspect of the invention.

Independent Claim 1:
This claim describes an extended-release oral dosage form for once-daily immunosuppressive treatment using tacrolimus or a similar active substance. The key features are its extended release over time, defined by specific in vitro dissolution criteria: no more than 63.5% of the active substance is released after 12 hours when tested using USP II (paddle) or USP I (basket) dissolution methods in a pH 4.5 medium containing 0.005% hydroxypropylcellulose at 50 rpm. Additionally, the dosage form must release at least 8% at 4 hours and/or at least 15% at 8 hours to ensure continuous release.

Independent Claim 13:
This claim focuses on a method for providing immunosuppressive treatment to a patient using the extended-release oral dosage form of claim 1. The method involves administering this dosage form once daily to achieve one or more improved pharmacokinetic parameters compared to conventional treatments. These improvements include decreased maximal concentration (Cmax), decreased "swing" (Cmax-Cmin/Cmin), decreased fluctuation (Cmax-Cmin/Caverage), increased overall drug exposure (AUC), increased mean residence time (MRT), a longer time to reach maximal concentration (Tmax), and a higher minimum concentration (Cmin).

Independent Claim 14:
This claim describes a method for converting a patient from a twice-daily tacrolimus immediate-release regimen (like Prograf®) to a once-daily regimen using the extended-release oral dosage form of claim 1. The conversion involves decreasing the total daily dose of tacrolimus by 25% to 50% (preferably 30% to 40%, most preferably approximately 33%) when switching to the extended-release formulation. This reduction is adjusted based on available tablet strengths (0.5 mg, 1 mg, 2 mg, 5 mg) for the extended-release product, resulting in a conversion ratio of 1:0.66 to 0.80.

Independent Claim 15:
This claim details a method for converting a patient from a once-daily tacrolimus extended-release regimen (like Advagraf®) to a once-daily regimen using the extended-release oral dosage form of claim 1. The conversion ratio for the daily dose of tacrolimus is between 1:0.30 and 0.75 (such as 1:0.33 to 0.7), again dependent on the available strengths of the inventive extended-release formulation (0.5 mg, 1 mg, 2 mg, 5 mg).

Independent Claim 16:
This claim outlines a method for treating a de novo liver transplant patient with tacrolimus. It involves administering the once-daily extended-release oral dosage form described in claim 1. The critical aspects are its in vitro release profile (less than 50% of tacrolimus released after 10 hours according to the FDA dissolution method for Prograf®) and its ability to provide a systemic exposure on Day 1 that is at least 50% of the exposure obtained on Day 1 from the same daily dose administered as a twice-daily immediate-release formulation.

Independent Claim 17:
Similar to Claim 16, this claim describes a method for treating a de novo kidney transplant patient with tacrolimus using the once-daily extended-release oral dosage form of claim 1. The in vitro release profile is the same (less than 50% of tacrolimus released after 10 hours by the FDA Prograf® method), but the systemic exposure on Day 1 must be at least 70% of the exposure obtained from the same daily dose administered as a twice-daily immediate-release formulation.

CAFC 2026 Dockets:

As of April 26, 2026, a direct search of publicly available CAFC 2026 dockets specifically referencing US patent 11110081 did not yield authoritative case numbers or detailed litigation information. While Google Patents indicates that the patent family has ongoing litigation, including multiple US cases filed in the Delaware District Court (e.g., 1:26-cv-00467, 1:25-cv-00458, 1:24-cv-00784, 1:24-cv-00726, 1:22-cv-00909), and notes a "First worldwide family litigation filed" via Darts-ip, specific CAFC dockets for 2026 for this patent were not directly identifiable through the performed searches. Further investigation, potentially through subscription-based legal databases like Darts-ip or PACER (which typically requires specific case information for effective searching), would be necessary to confirm any active CAFC proceedings related to US11110081 in 2026.

The following is a list of known litigation involving US patent 11110081, based on the provided information:

1. Veloxis Pharmaceuticals AS v. Intas Pharmaceuticals Ltd., Accord Healthcare Inc.

• Jurisdiction: Delaware District Court
• Case Number: 1:22-cv-00909
• Filing Date: 2022-07-07
• Outcome/Current Status: Closed on January 24, 2024. The case involved patent infringement concerning tacrolimus drug products. A consent judgment resulted in a permanent injunction for Veloxis Pharmaceuticals, Inc. US Patent 11110081 was among the patents-in-suit.

2. Veloxis Pharmaceuticals AS v. Zydus Lifesciences Ltd., Zydus Cadila

• Jurisdiction: Delaware District Court
• Case Number: 1:26-cv-00467
• Filing Date: 2026-04-23
• Outcome/Current Status: Open. This is an infringement case related to medical products.

3. Veloxis Pharmaceuticals AS v. Alkem Laboratories Ltd.

• Jurisdiction: Delaware District Court
• Case Number: 1:24-cv-00784
• Filing Date: 2024-07-03
• Outcome/Current Status: Open. This is an infringement case. Alkem Laboratories Ltd. admitted sending a Notice of Paragraph IV Certification regarding its ANDA for tacrolimus extended-release tablets, citing US Patent 11110081 among others.

4. Veloxis Pharmaceuticals, Inc. v. Sun Pharmaceutical Industries Ltd. and Sun Pharmaceutical Industries, Inc.

• Jurisdiction: Delaware District Court
• Case Number: 1:24-cv-00726
• Filing Date: 2024-06-19
• Outcome/Current Status: Open. Veloxis Pharmaceuticals, Inc. filed this action asserting several patents, including US Patent 11110081. The thirty-month stay deadline for this case is November 9, 2026.

5. Veloxis Pharmaceuticals, Inc. v. Glenmark Pharmaceuticals Inc., USA

• Jurisdiction: Delaware District Court
• Case Number: 1:25-cv-00458
• Filing Date: 2025-04-14
• Outcome/Current Status: Open. This case asserts infringement of US Patent 11110081, among others, relating to Glenmark's ANDA for tacrolimus extended-release tablets. A stipulation and order regarding a stay was filed on February 2, 2026.

Proceedings overview

As of 2026-06-01, there are no AIA trial proceedings (Inter Partes Review, Post-Grant Review, or Covered Business Method review) on file for US Patent 11110081 in the USPTO Open Data Portal, nor have any been identified through web searches. This indicates that the patent has not yet been challenged in these specific administrative trial forums at the PTAB.

Strategic summary

Given the absence of any PTAB proceedings, all claims of US11110081 remain untested by IPR, PGR, or CBM challenges. This means there are no claims that have been canceled or sustained by a PTAB Final Written Decision. Consequently, a defendant facing assertion of this patent would not be able to rely on prior PTAB invalidations to narrow the scope of the claims. The estoppel provisions of § 315(e)(2) are not applicable, as no petition has been instituted. All prior art grounds are still available for a defendant to raise in a new PTAB petition or in district court litigation. The lack of PTAB activity could imply either that the patent has not been heavily asserted, or that potential challengers have opted for other strategies (e.g., district court litigation only, licensing, or deemed the patent not vulnerable to PTAB challenges).

Recommended next steps

Since no PTAB activity exists for US Patent 11110081, a potential defendant has a clear path to file an IPR or PGR petition if they believe the patent claims are unpatentable over prior art. The absence of previous challenges means there is no pre-existing PTAB record to navigate for claim-level outcomes or estoppel. This allows a petitioner to choose their best prior art and arguments without being constrained by prior institution decisions or final written decisions. A thorough prior art search would be the crucial first step to identify strong grounds for a petition.

Inventors

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

No unusual patterns noted; all inventors appear to have been employed by the original assignee at the time of filing.

Original Assignee

Veloxis Pharmaceuticals Inc.
Veloxis Pharmaceuticals Inc. is a pharmaceutical company focused on the development and commercialization of therapeutics for transplant patients. Their primary product embodying the claims of this patent is Envarsus XR (tacrolimus extended-release tablets). Veloxis Pharmaceuticals Inc. is currently operating.

Assignment Timeline

No assignments for US11110081 were found on the USPTO Assignment Center.

Timeline Diagram

timeline
    title Ownership of US 11110081
    2020 : Filed by Veloxis Pharma Inc
    2021 : Issued to Veloxis Pharma 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

Insufficient data. There are no recorded assignments for US11110081 on the USPTO Assignment Center, indicating that the patent is likely still owned by the original assignee, Veloxis Pharmaceuticals Inc.

USPTO Assignment Center search page for US11110081: https://assignmentcenter.uspto.gov/#!/patent/11110081

To identify the most relevant prior art for US patent 11110081 and analyze its potential anticipation of claims, a search of the USPTO database was conducted. The USPTO provides tools for searching patents and patent application publications.

Here's an analysis of the prior art cited in US patent 11110081, along with their potential relevance:

1. EP-A-0 184 162

• Full Citation: EP-A-0 184 162
• Publication/Filing Date: Not explicitly stated, but the patent states that "The preparation of tacrolimus is described in EP-A-0 184 162". Tacrolimus was discovered in 1984.
• Brief Description: This patent describes the preparation of tacrolimus (FK-506 or FR-900506). Tacrolimus is a macrolide compound with immunosuppressive activity, used to prevent organ or tissue rejection.
• Potential Anticipation: This reference establishes the prior art for the active pharmaceutical ingredient itself, tacrolimus. As such, it could potentially anticipate any claim broadly covering "tacrolimus or a pharmaceutically active analogue thereof" where the novelty does not reside in the specific extended-release formulation or method of treatment. Since US11110081 focuses on a new extended-release oral dosage form and methods of treatment using tacrolimus, EP-A-0 184 162 would not anticipate the novel aspects of the extended-release profile or the specific treatment regimens.

2. EP-A-0 444 659

• Full Citation: EP-A-0 444 659
• Publication/Filing Date: Not explicitly stated, but the patent notes that "analogues of tacrolimus are disclosed e.g. in EP-A-0 444 659". This patent relates to pharmaceutical solutions comprising derivatives of FK506, which is another name for tacrolimus.
• Brief Description: This patent discloses analogues of tacrolimus and pharmaceutical solutions containing them, particularly non-aqueous solutions with long-term storage stability.
• Potential Anticipation: Similar to EP-A-0 184 162, this reference establishes prior art for tacrolimus analogues. It would not anticipate the specific extended-release characteristics or methods of treatment claimed in US11110081.

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

• Full Citation: U.S. Pat. No. 6,387,918
• Publication/Filing Date: Not explicitly stated, but the patent notes that "analogues of tacrolimus are disclosed e.g. in... U.S. Pat. No. 6,387,918".
• Brief Description: This patent, like EP-A-0 444 659, discloses analogues of tacrolimus.
• Potential Anticipation: This reference provides prior art for various tacrolimus analogues. It does not appear to describe an extended-release formulation with the specific characteristics claimed in US11110081, nor the methods of treatment.

4. WO 2005/020993 (PCT/DK2004/000573)

• Full Citation: WO 2005/020993 A1 (International Filing Date: 2004-08-30, Publication Date: 2005-03-10)
• Publication/Filing Date: International Filing Date: August 30, 2004. Publication Date: March 10, 2005.
• Brief Description: This international patent application, by the same inventors as US11110081, relates to modified release compositions comprising tacrolimus. It describes pharmaceutical compositions in particulate form comprising tacrolimus and/or an analogue, where the composition, upon oral administration, releases at least about 50% w/w of the total amount of tacrolimus within about 24 hours. It also discusses enhanced bioavailability, reduced side effects, and formulations where tacrolimus is dissolved or dispersed in a hydrophilic or water-miscible vehicle (e.g., polyethylene glycols, poloxamers). It mentions that the bioavailability of tacrolimus is significantly increased when administered in a modified or controlled release composition that reduces or avoids CYP3A4 metabolism.
• Potential Anticipation: This is a highly relevant prior art document as it describes modified release tacrolimus compositions by the same inventors.
  • Claim 1: WO 2005/020993 describes modified release compositions and mentions that the active ingredient can be dissolved or dispersed in a hydrophilic or water-miscible vehicle, such as a mixture of PEG6000 and poloxamer 188. It also discusses extending the release of tacrolimus. However, the specific dissolution profile defined in Claim 1 of US11110081 (at most 63.5% release at 12 hours, at least 8% at 4 hours and/or at least 15% at 8 hours using the specified USP II/I method) would need to be directly taught or rendered obvious by WO 2005/020993 for anticipation. The document mentions formulations with T63.6% values ranging from 1.9 to 8.2 hours, which are faster than the "at most 63.5% at 12 hours" in Claim 1 of US11110081. Therefore, it is unlikely to fully anticipate the precise release kinetics of Claim 1.
  • Claims 13-17: WO 2005/020993 discusses improved pharmacokinetic parameters like increased bioavailability and reduced side effects related to high peak concentrations. It also notes that improved bioavailability reduces the need for simultaneous food intake and that the difference between peak plasma concentration and 24-hour concentration can be at most 20 ng/mL. While it generally discusses improved PK profiles and reduced side effects, the specific numerical thresholds for Cmax, AUC, MRT, swing, fluctuation, and particularly the conversion ratios and de novo patient treatment outcomes specified in Claims 13-17 of US11110081 would need to be explicitly disclosed or inherently present to anticipate these claims.

5. WO 2005/020994 (PCT/DK2004/000574)

• Full Citation: WO 2005/020994 (Publication Date: 2005-03-10)
• Publication/Filing Date: International Filing Date: August 30, 2004. Publication Date: March 10, 2005.
• Brief Description: This international patent application, also by the same inventors, relates to solid dispersions comprising tacrolimus. It describes a pharmaceutical composition comprising tacrolimus dissolved and/or dispersed in a hydrophilic or water-miscible vehicle to form a solid dispersion or solid solution at ambient temperature, aiming for improved bioavailability. It specifically mentions that the solid dispersion exhibits a very fast immediate release, with at least 50% w/w of the active pharmaceutical ingredient released within about 30 minutes.
• Potential Anticipation:
  • Claim 1: WO 2005/020994 describes "very fast immediate release" formulations, with at least 50% released within 30 minutes. This is in direct contradiction to the extended release profile of Claim 1 of US11110081, which specifies "at the most 63.5% of the content of the active substance at the 12 hours time point." Therefore, WO 2005/020994 would not anticipate Claim 1 as it teaches an opposite release characteristic.
  • Claims 13-17: While WO 2005/020994 discusses improved bioavailability generally, its focus on immediate release makes it unlikely to anticipate the specific extended-release pharmacokinetic profiles and conversion/treatment methods of Claims 13-17 of US11110081, which are predicated on a long, sustained release.

6. WO99/49863

• Full Citation: WO99/49863 (Fujisawa Pharmaceutical Co.)
• Publication/Filing Date: The patent mentions this was referred to in WO2008145143A1, which has a publication date of November 3, 2008. This document is also cited as WO-9949863-A1 in US11419823B2. Tacrolimus was discovered by Fujisawa in 1984.
• Brief Description: This patent describes sustained-release tacrolimus formulations, specifically mentioning formulations where the time for dissolving 63.2% (T63.2% value) of tacrolimus is between 0.7 and 15 hours. It is owned by Fujisawa Pharmaceutical Co. (now Astellas) and relates to the originator of Prograf®.
• Potential Anticipation:
  • Claim 1: WO99/49863 describes sustained-release tacrolimus formulations with T63.2% values between 0.7 and 15 hours. The dissolution criteria of Claim 1 of US11110081 (at most 63.5% at 12 hours) falls within this broader range. The specific minimum release requirements (at least 8% at 4 hours and/or at least 15% at 8 hours) would need to be further analyzed to determine if they are inherently met or made obvious by the teachings of WO99/49863. If WO99/49863's examples or general teachings are sufficiently broad to cover the precise dissolution profile of Claim 1, it could be considered anticipatory.
  • Claims 13-17: This reference pertains to sustained-release tacrolimus and could potentially anticipate general concepts of improved PK profiles. However, the specific quantitative improvements in Cmax, swing, fluctuation, AUC, MRT, Tmax, and Cmin, as well as the precise conversion ratios and de novo patient outcomes defined in Claims 13-17, would need to be explicitly disclosed or made obvious by WO99/49863.

7. WO 03/004001

• Full Citation: WO 03/004001 A1 (International Filing Date: 2002-07-05, Publication Date: 2003-01-16)
• Publication/Filing Date: International Filing Date: July 5, 2002. Publication Date: January 16, 2003.
• Brief Description: This international patent application describes a process for the preparation of particulate material by a controlled agglomeration method, which enables controlled growth in particle size. This method is especially suitable for pharmaceutical compositions containing active substances with low aqueous solubility or subject to chemical decomposition. It involves spraying a first composition (e.g., tacrolimus and a meltable carrier) onto a second solid carrier medium.
• Potential Anticipation:
  • This patent primarily describes a method of preparation for particulate pharmaceutical materials. While US11110081 mentions that its compositions may be prepared by methods like "controlled agglomeration" and references WO 03/004001, this prior art would likely anticipate the method of preparing certain particulate forms of tacrolimus, rather than the specific extended-release dosage form itself (Claim 1) or the methods of treatment (Claims 13-17). If any claims in US11110081 broadly claim a particulate form per se without specific structural or functional limitations not found in WO 03/004001, there could be anticipation. However, the focus of US11110081 is on the release profile and pharmacokinetic advantages, which are not directly claimed by the manufacturing process in WO 03/004001.

Other general points from the patent text that highlight prior art context:

• Prograf®: The patent repeatedly references Prograf® as a conventional immediate-release tacrolimus formulation, approved by the FDA in April 1994. It's characterized by rapid absorption (Tmax of 1-2 hours) and low, variable bioavailability (at most about 20%). This serves as a baseline for comparison for the improved features of US11110081.
• Advagraf® (MR4): This is mentioned as an extended-release tacrolimus product approved by EMEA on April 23, 2007. The US11110081 patent often compares its invention against Advagraf® in terms of reduced variability and improved PK profiles. Therefore, Advagraf® itself and any patents describing its formulation (such as WO2008145143A1 which mentions Advagraf® is a sustained release formulation allowing once daily dosing) are highly relevant in assessing novelty and non-obviousness for claims related to improvements over existing extended-release products.

Obviousness Analysis under 35 U.S.C. § 103

A patent claim is obvious under 35 U.S.C. § 103 if the differences between the claimed invention and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art (POSA). This analysis considers the scope and content of the prior art, the differences between the prior art and the claims, the level of ordinary skill in the art, and any secondary considerations of non-obviousness.

For US patent 11110081, the core inventive concept revolves around an extended-release oral dosage form of tacrolimus that provides improved pharmacokinetic profiles and treatment outcomes, particularly for once-daily administration and in de novo transplant patients.

Level of Ordinary Skill in the Art (POSA)

A POSA in the field of immunosuppressive drug formulations, specifically tacrolimus, would likely possess a strong background in pharmaceutical sciences, including pharmacokinetics, pharmacodynamics, drug delivery systems (e.g., controlled release, solid dispersions), and clinical experience with transplant patient management. They would be familiar with the challenges associated with tacrolimus, such as its low and variable bioavailability, extensive CYP3A4 metabolism, and significant side effects related to high peak concentrations. They would also be aware of conventional tacrolimus formulations like Prograf® (immediate release) and Advagraf® (extended release), their dosing regimens, and their pharmacokinetic characteristics.

Combinations of Prior Art References and Motivation to Combine

Several prior art references, individually or in combination, could render various claims of US 11110081 obvious.

1. General Concept of Extended-Release Tacrolimus for Improved Bioavailability and PK Profile (Claims 1, 13)

Prior Art:

• WO 2005/020993 (by the same inventors): This application explicitly discusses increasing tacrolimus bioavailability through modified or controlled release compositions that reduce or avoid CYP3A4 metabolism. It notes that both fast and slow-release tablets can improve bioavailability compared to Prograf®. It also highlights the problem of high peak concentrations of tacrolimus leading to side effects and the desire for more reproducible release profiles. The inventors in WO 2005/020993 tested different formulations demonstrating improved bioavailability and suppressed variation in absorbability with sustained-release formulations.
• WO 2005/020994 (by the same inventors): This document specifically relates to solid dispersions comprising tacrolimus, where tacrolimus is dissolved or dispersed in a hydrophilic or water-miscible vehicle to form a solid dispersion or solid solution at ambient temperature, leading to improved bioavailability. It suggests that improved bioavailability could be linked to having tacrolimus in a dissolved state in the dosage form.
• Advagraf® (MR4): This commercially available extended-release tacrolimus formulation was approved in 2007 (before the priority date of US11110081) and was known to offer once-daily dosing with comparable absorption to Prograf®. The EPAR for Advagraf® details its properties and is incorporated by reference in US11110081.

Motivation to Combine:
A POSA would be highly motivated to develop an extended-release tacrolimus formulation that overcomes the limitations of existing products like Prograf® (twice-daily dosing, high variability, significant side effects from peak concentrations) and Advagraf® (while extended release, the present invention claims to improve upon it). The inventors of US11110081 themselves were exploring improved bioavailability and modified release of tacrolimus in WO 2005/020993 and WO 2005/020994. The explicit mention in WO 2005/020993 that "enhanced bioavailability may also result in a more reproducible (i.e. less variable compared to that of Prograf®) release profile" and that "the bioavailability of tacrolimus is significantly increased when tacrolimus is administered to a mammal in a modified or controlled release composition providing a rate and a timing of release of active ingredient, i.e. an in vivo release profile, effectively reducing or even avoiding the effects of CYP3A4 metabolism" directly points towards the objectives of US11110081.

The challenge with extended-release forms of tacrolimus, as recognized in the prior art, was achieving sufficient absorption in the lower gastrointestinal tract due to factors like reduced fluids, increased solids, and a smaller absorption surface in the colon. However, the prior art already suggested that controlled release could lead to better absorption by reducing CYP3A4 metabolism.

Given the existence of Advagraf® as an extended-release, once-daily tacrolimus product, a POSA would be motivated to further optimize such formulations to achieve superior pharmacokinetic profiles (e.g., lower Cmax, increased AUC, improved consistency, better safety profile) as outlined in Claim 13, as these are well-known desirable outcomes in drug development.

2. Specific Dissolution Profile (Claim 1)

Prior Art:

• WO 2005/020993: Discusses sustained-release formulations with T63.6% values ranging from 1.9 to 8.2 hours, indicating that these formulations achieved improved bioavailability. It also mentions T63.6% values of 3.0, 3.3, 2.0, and 2.5 hours for specific formulations.
• Prograf® FDA label and dissolution methods: The FDA provides dissolution methods for drug products like Prograf®. A POSA would be aware of and utilize such standard in vitro dissolution tests (like USP I or II) to characterize drug release.
• WO 99/49863: Describes sustained-release tacrolimus formulations where 63.2% of tacrolimus is released between 0.7 and 15 hours.

Motivation to Combine:
The specific dissolution profile claimed in Claim 1 (at most 63.5% release at 12 hours, at least 8% at 4 hours and/or at least 15% at 8 hours using specified USP methods and media) represents a refinement of known extended-release characteristics. Given the information in WO 2005/020993 and WO 99/49863 regarding various release rates that lead to improved bioavailability, a POSA would be motivated to experiment with different dissolution profiles to optimize the balance between extended release, continuous release throughout the dosing interval, and absorption, especially in the lower GI tract where CYP3A4 metabolism is lower. The cited ranges for T63.6% in WO 2005/020993 (1.9 to 8.2 hours) and WO 99/49863 (0.7 to 15 hours for T63.2%) overlap with and suggest the feasibility of achieving the specific 12-hour release criteria of Claim 1. The use of standard USP dissolution tests with appropriate media (e.g., pH 4.5 with hydroxypropylcellulose) is routine in pharmaceutical development for characterizing and comparing formulations.

3. Conversion Regimens (Claims 14, 15)

Prior Art:

• Prograf® and Advagraf®: Both were commercially available tacrolimus formulations with established dosing regimens. Prograf® was a twice-daily immediate-release product, and Advagraf® was a once-daily extended-release product. The need for dose adjustments and therapeutic drug monitoring for tacrolimus was well-known due to its narrow therapeutic index and variable absorption.
• EMA Scientific Discussion for Advagraf®: This report, published in 2007, compared Advagraf® and Prograf®, noting comparable absorption in the body and providing information on their use. It also mentioned that for de novo kidney and liver transplant patients, AUC(0-24) of Advagraf® on Day 1 was 30% and 50% lower, respectively, compared to immediate-release Prograf® at equivalent doses.

Motivation to Combine:
The development of conversion regimens (Claims 14 and 15) when introducing a new extended-release formulation would be a routine practice for a POSA. Given the narrow therapeutic window of tacrolimus and the criticality of maintaining appropriate blood levels to prevent organ rejection or toxicity, any new formulation would necessitate carefully designed conversion strategies from existing treatments. The ratios specified in the claims (e.g., 1:0.66-0.80 for Prograf® conversion, 1:0.30-0.75 for Advagraf® conversion) would be derived from pharmacokinetic studies comparing the new formulation with existing ones, aiming to achieve comparable or improved systemic exposure and therapeutic effects while minimizing side effects. The knowledge that Advagraf® initially showed lower exposure compared to Prograf® in de novo patients would further motivate a POSA to carefully define conversion protocols for a new extended-release product, especially one aiming for enhanced bioavailability.

4. Treatment of De Novo Transplant Patients with Specific Day 1 Exposure (Claims 16, 17)

Prior Art:

• Prograf® Dosing for Transplant Patients: Prograf® had established initial dosing guidelines for liver and kidney transplant patients, with dosages adjusted based on trough blood concentrations.
• Advagraf® in De Novo Patients: The EMA Scientific Discussion for Advagraf® highlighted that in de novo kidney and liver transplant patients, Advagraf® showed lower systemic exposure on Day 1 compared to immediate-release Prograf®. Specifically, AUC(0-24) was 30% lower for kidney transplant patients and 50% lower for liver transplant patients.
• WO 2005/020993: Acknowledges the variability in tacrolimus absorption and metabolism, emphasizing the need for improved formulations that reduce side effects and provide more reproducible release profiles. It also discusses the impact of CYP3A4 metabolism in the gut wall and liver on tacrolimus bioavailability.

Motivation to Combine:
A significant challenge in tacrolimus therapy, especially for de novo transplant patients, is managing the initial high variability in absorption and metabolism, alongside the risk of rejection or toxicity. The observation from the Advagraf® EPAR that its Day 1 exposure was significantly lower than Prograf® in de novo patients would strongly motivate a POSA to develop a new extended-release formulation that could achieve at least comparable (or superior) Day 1 exposure to immediate-release Prograf®, or even to other extended-release forms, to ensure adequate immunosuppression from the outset. The claimed systemic exposure on Day 1 (at least 50% for liver, at least 70% for kidney, relative to immediate release Prograf®; and at least 100% compared to an extended release form releasing >30% in 5 hours) directly addresses the known limitations of existing extended-release products in the critical immediate post-transplant period. A POSA would seek to design a formulation and dosing strategy that ensures efficacy early on while minimizing the risks associated with inadequate drug levels, thus leading to the development of methods like those in Claims 16 and 17. The dissolution criteria specified (less than 50% released after 10 hours by the FDA Prograf® method) are a means to achieve the desired extended release characteristics that contribute to this improved early exposure.

Conclusion on Obviousness

Considering the cited prior art, a POSA would have been motivated to combine known elements and principles to arrive at the claimed invention. The desire for improved tacrolimus formulations with better bioavailability, reduced variability, once-daily dosing, and optimized pharmacokinetic profiles was clearly articulated in the prior art, including by the same inventors. While US 11110081 describes specific dissolution profiles and conversion regimens, these appear to be optimizations achievable through routine experimentation and well-understood pharmaceutical development principles, particularly given the detailed disclosures in WO 2005/020993 and WO 2005/020994 regarding enhancing bioavailability and controlling release. The specific pharmacokinetic parameters claimed in Claim 13 are desirable outcomes that a POSA would aim for when developing an improved tacrolimus formulation. Similarly, the conversion methods and de novo patient treatment methods (Claims 14-17) address known clinical challenges and represent logical applications of an improved extended-release formulation within the therapeutic context of tacrolimus.