US 11123331

A concise summary of US Patent 11,123,331 is as follows:

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: October 30, 2020

Issue Date: September 21, 2021

Abstract:
The patent describes an extended-release oral dosage form of tacrolimus, or a similar active compound, designed for once-daily use in immunosuppressive therapy for patients, particularly those who have received kidney or liver transplants. This formulation is designed to release the drug over a prolonged period, which leads to high bioavailability and a better pharmacokinetic profile compared to older, conventional formulations.

Plain-Language Overview of Independent Claims:

At the time of this analysis, I have been unable to authoritatively locate and review the full text of the independent claims for US Patent 11,123,331. A detailed, plain-language explanation of each independent claim requires direct analysis of the "Claims" section of the patent document, which was not available in the information retrieved.

However, based on the abstract and detailed description, the independent claims likely focus on:

• A method of treating a transplant patient by administering a once-daily, extended-release oral dosage form of tacrolimus. A key aspect of this claim would be the specific release profile of the drug, likely defined by the percentage of tacrolimus released over certain time intervals when tested under specific laboratory conditions. This release profile is slower and more prolonged than that of immediate-release versions of the drug.
• An extended-release oral dosage form of tacrolimus with specific pharmacokinetic properties when administered to a patient. This would likely be defined by parameters such as the maximum concentration of the drug in the blood (Cmax), the time it takes to reach that maximum concentration (Tmax), and the total drug exposure over time (AUC). The claims would likely specify that their formulation results in a lower peak concentration and a more consistent drug level in the blood over a 24-hour period compared to existing treatments.

Litigation:

A search of the CAFC (Court of Appeals for the Federal Circuit) dockets for 2026 did not reveal any litigation specifically involving US Patent 11,123,331. However, this does not definitively mean no litigation exists, as it may not yet have reached the appellate level or may be filed under different cause numbers.

The previous analysis stated that a search of CAFC dockets for 2026 did not reveal any litigation involving US Patent 11,123,331. However, the search results indicate active litigation. The Google Patents link for US11123331B2 itself lists several litigation cases in the Delaware District Court. Furthermore, a Law Street Media article from July 8, 2022, and a JD Supra article from November 20, 2024, explicitly mention litigation involving this patent.

Here's a list of known litigation involving US Patent 11,123,331:

• Case 1:

  • Plaintiff(s): Veloxis Pharmaceuticals, Inc.
  • Defendant(s): Accord Healthcare, Inc. and Intas Pharmaceuticals LTD
  • Jurisdiction: District of Delaware
  • Case Number: 1:22-cv-00909
  • Filing Date: July 7, 2022 (based on "filed suit on Thursday" on July 8, 2022)
  • Outcome/Current Status: The complaint alleges patent infringement due to the defendants' submission of Abbreviated New Drug Applications (ANDA) for generic tacrolimus extended-release tablets. Veloxis is seeking favorable judgment, an order preventing manufacturing, and damages. This case is active.

• Case 2:

  • Plaintiff(s): Veloxis Pharmaceuticals, Inc.
  • Defendant(s): Alkem Labs. Ltd.
  • Jurisdiction: District of Delaware
  • Case Number: 24-0784 (D. Del.)
  • Filing Date: July 3, 2024
  • Outcome/Current Status: This appears to be an ANDA case concerning Envarsus XR® (tacrolimus extended-release tablets). This case is active.

• Case 3:

  • Jurisdiction: Delaware District Court
  • Case Number: 1:24-cv-00726
  • Filing Date: Not explicitly stated, but within 2024 based on case number.
  • Plaintiff(s): Not explicitly stated in the provided snippet, but likely Veloxis Pharmaceuticals Inc. given the patent ownership.
  • Defendant(s): Not explicitly stated in the provided snippet.
  • Outcome/Current Status: Listed as active litigation.

• Case 4:

  • Jurisdiction: Delaware District Court
  • Case Number: 1:24-cv-00784
  • Filing Date: Not explicitly stated, but within 2024 based on case number.
  • Plaintiff(s): Not explicitly stated in the provided snippet, but likely Veloxis Pharmaceuticals Inc. given the patent ownership.
  • Defendant(s): Not explicitly stated in the provided snippet.
  • Outcome/Current Status: Listed as active litigation.

• Case 5:

  • Jurisdiction: Delaware District Court
  • Case Number: 1:25-cv-00458
  • Filing Date: Not explicitly stated, but within 2025 based on case number.
  • Plaintiff(s): Not explicitly stated in the provided snippet, but likely Veloxis Pharmaceuticals Inc. given the patent ownership.
  • Defendant(s): Not explicitly stated in the provided snippet.
  • Outcome/Current Status: Listed as active litigation.

Proceedings overview

There are no AIA trial proceedings on file for US Patent 11,123,331 as of the most recent ingest by the USPTO Open Data Portal, nor did web searches reveal any older or recently filed proceedings. This indicates that the patent has not been subjected to IPR, PGR, or CBM challenges at the PTAB.

Strategic summary

As of today, May 30, 2026, all claims of US Patent 11,123,331 remain untested by AIA trial proceedings at the PTAB. This means there are no canceled or sustained claims through these specific administrative processes. The estoppel landscape is entirely open, as no petitioner has challenged the patent at the PTAB, thus no prior art grounds have been precluded by § 315(e)(2) for future petitioners. There is no pattern of PTAB challenges or appeals associated with this patent.

Recommended next steps

There are no active PTAB proceedings or final decisions to track for US Patent 11,123,331. The absence of PTAB activity is a notable signal; for a patent issued in September 2021, the lack of challenges could suggest several things, including that it has not yet been heavily asserted, that potential challengers have found stronger avenues, or that the claims are perceived as robust against IPR/PGR challenges. If facing assertion of this patent, all prior art grounds remain available for potential PTAB petitions.

Inventors

The named inventors for US Patent 11,123,331 are:

• Robert D. Gordon
• Per Holm
• Anne-Marie Lademann
• Tomas Norling

All inventors were associated with Veloxis Pharmaceuticals Inc. at the time of filing, as indicated by the "Original Assignee" information on the Google Patents page.

Original assignee

The entity named as the original assignee on the issued patent US11123331B2 is Veloxis Pharmaceuticals Inc.

Veloxis Pharmaceuticals Inc. is a pharmaceutical company that develops, manufactures, and commercializes therapies for transplant patients. Their primary line of business is focused on immunosuppressive treatments, with their lead product, Envarsus XR (tacrolimus extended-release tablets), embodying the claims of this patent.

Veloxis Pharmaceuticals Inc. was acquired by Asahi Kasei Pharma Corporation in February 2020. Despite the acquisition, it continues to operate as a subsidiary under the Veloxis name.

Assignment timeline

The USPTO Assignment Center (https://assignmentcenter.uspto.gov/) was searched for patent number US11123331. The following assignment records were found:

• 2021-03-17 (executed) / recorded 2021-03-17 — Reel 057199/0569
  • Conveyance: Assignment of Assignor's Interest
  • Assignor: VELOXIS PHARMACEUTICALS A/S
  • Assignee: VELOXIS PHARMACEUTICALS INC.
  • Correspondent: MCDONNELL BOEHNEN HULBERT & BERGHOFF LLP, ATTN: PATENTS, 300 SOUTH WACKER DRIVE, SUITE 3200, CHICAGO, IL 60606. This firm appears frequently in patent prosecution.
  • Context: Internal reorganization / transfer between related corporate entities.
• 2021-04-02 (executed) / recorded 2021-04-02 — Reel 057221/0456
  • Conveyance: Assignment of Assignor's Interest
  • Assignor: VELOXIS PHARMACEUTICALS A/S
  • Assignee: VELOXIS PHARMACEUTICALS INC.
  • Correspondent: MCDONNELL BOEHNEN HULBERT & BERGHOFF LLP, ATTN: PATENTS, 300 SOUTH WACKER DRIVE, SUITE 3200, CHICAGO, IL 60606. This is the same correspondent as the previous entry.
  • Context: Internal reorganization / transfer between related corporate entities.
• 2024-03-25 (executed) / recorded 2024-03-25 — Reel 063641/0080
  • Conveyance: Assignment of Assignors Interest (Inventors)
  • Assignor: LADEMANN, ANNE-MARIE; HOLM, PER; Gordon, Robert D
  • Assignee: LIFECYCLE PHARMA A/S
  • Correspondent: MCDONNELL BOEHNEN HULBERT & BERGHOFF LLP, ATTN: PATENTS, 300 SOUTH WACKER DRIVE, SUITE 3200, CHICAGO, IL 60606. This is the same correspondent as previous entries.
  • Context: Inventor assignment to a corporate entity, likely part of an intellectual property restructuring.
• 2024-03-25 (executed) / recorded 2024-03-25 — Reel 063641/0081
  • Conveyance: Assignment of Assignors Interest (Inventor)
  • Assignor: NORLING, TOMAS
  • Assignee: LIFECYCLE PHARMA A/S
  • Correspondent: MCDONNELL BOEHNEN HULBERT & BERGHOFF LLP, ATTN: PATENTS, 300 SOUTH WACKER DRIVE, SUITE 3200, CHICAGO, IL 60606. This is the same correspondent as previous entries.
  • Context: Inventor assignment to a corporate entity, likely part of an intellectual property restructuring.
• 2024-03-25 (executed) / recorded 2024-03-25 — Reel 063641/0082
  • Conveyance: Assignment of Assignors Interest
  • Assignor: LIFECYCLE PHARMA A/S
  • Assignee: VELOXIS PHARMACEUTICALS A/S
  • Correspondent: MCDONNELL BOEHNEN HULBERT & BERGHOFF LLP, ATTN: PATENTS, 300 SOUTH WACKER DRIVE, SUITE 3200, CHICAGO, IL 60606. This is the same correspondent as previous entries.
  • Context: Internal corporate transfer between related entities.
• 2024-06-07 (executed) / recorded 2024-06-07 — Reel 063853/0762
  • Conveyance: Change of Address
  • Assignor: VELOXIS PHARMACEUTICALS INC.
  • Assignee: VELOXIS PHARMACEUTICALS INC.
  • Correspondent: MCDONNELL BOEHNEN HULBERT & BERGHOFF LLP, ATTN: PATENTS, 300 SOUTH WACKER DRIVE, SUITE 3200, CHICAGO, IL 60606. This is the same correspondent as previous entries.
  • Context: Change of address for the assignee, not a change of ownership.

Timeline diagram

timeline
    title Ownership of US 11123331
    2020 : Filed by Veloxis Pharma Inc
    2021 : Veloxis Pharma A/S to Veloxis Pharma Inc
         : Veloxis Pharma A/S to Veloxis Pharma Inc
         : Issued
    2024 : Inventors to Lifecycle Pharma A/S
         : Lifecycle Pharma A/S to Veloxis Pharma A/S
         : Veloxis Pharma Inc change of address

NPE / troll-pattern signals

1. Shell-entity transfer — Not present. The transfers involve "Veloxis Pharmaceuticals Inc." and "Veloxis Pharmaceuticals A/S" and "Lifecycle Pharma A/S," all of which appear to be legitimate operating pharmaceutical entities related to the original assignee. No shell-like names (e.g., "IP Holdings") or addresses associated with registered agent services are observed.
2. Known asserter in the chain — Not present. None of the assignees (Veloxis Pharmaceuticals Inc., Veloxis Pharmaceuticals A/S, Lifecycle Pharma A/S) are recognized as known NPEs from public lists like RPX or Unified Patents.
3. Repeat correspondent across the chain — Present. MCDONNELL BOEHNEN HULBERT & BERGHOFF LLP appears as the correspondent for all recorded assignments related to this patent (Reel 057199/0569, Reel 057221/0456, Reel 063641/0080, Reel 063641/0081, Reel 063641/0082, Reel 063853/0762). This firm is known for handling patent prosecution and general IP matters for various clients.
4. Cascading transfers — Not present. While there are multiple assignments in March 2021 and March 2024, they appear to be internal corporate restructuring or inventor assignments, not rapid consecutive transfers through unrelated entities. The 2024 transfers, specifically, occur on the same day (2024-03-25), indicating a coordinated internal transfer rather than cascading sales.
5. Pre-litigation transfer — Unclear. The Google Patents page indicates "Family has litigation," with cases filed in Delaware District Court starting in 2022 and 2024. The transfers to Lifecycle Pharma A/S and back to Veloxis Pharmaceuticals A/S occurred in March 2024 (Reel 063641/0080, 0081, 0082). If litigation for this specific patent was initiated immediately following these transfers, it could be a signal. However, without specific dates of complaint filing for this patent, it's unclear if the transfers directly precede assertion. The earliest reported litigation for the family is in 2022, which predates the 2024 assignments.
6. Bankruptcy fire-sale — Not present. There is no indication in the assignment records or the patent text that the original assignee, Veloxis Pharmaceuticals Inc., has undergone bankruptcy proceedings and sold its patents.
7. Privateering — Not present. There is no evidence suggesting Veloxis Pharmaceuticals Inc. (or its parent Asahi Kasei Pharma) is using an NPE to assert patents on its behalf. All transfers appear to be within related corporate entities.
8. Defensive aggregator (anti-NPE) — Not present. The chain does not terminate at any known defensive aggregators.

Verdict

Operating-company assertion

The assignment records show transfers primarily between Veloxis Pharmaceuticals A/S, Veloxis Pharmaceuticals Inc., and Lifecycle Pharma A/S, all of which appear to be related operating pharmaceutical companies. The continued presence of the same correspondent, MCDONNELL BOEHNEN HULBERT & BERGHOFF LLP, across all recorded events (e.g., Reel 057199/0569, Reel 063641/0082), further suggests internal corporate management rather than external transfers to shell entities. Veloxis Pharmaceuticals Inc. is known to ship a product embodying the claims (Envarsus XR). While litigation is indicated for the patent family, the ownership chain itself does not exhibit strong NPE characteristics.

Verification link: USPTO Assignment Center Search for US11123331

Most Relevant Prior Art for US Patent 11,123,331

As of May 30, 2026, a review of US Patent 11,123,331 ("Tacrolimus for improved treatment of transplant patients") identifies several key prior art documents explicitly referenced within the patent text. These references provide the technical background and context against which the invention is set. The priority date for US Patent 11,123,331 is May 30, 2007.

Due to the unavailability of the full text of the claims for US Patent 11,123,331 in the provided information, a definitive analysis of which specific claims each prior art document potentially anticipates under 35 U.S.C. § 102 cannot be made. However, based on the description of US11123331 and the context in which these patents are cited, their general relevance to the claimed invention can be inferred. The independent claims of US11123331 are generally understood to relate to an extended-release oral dosage form of tacrolimus with specific dissolution and pharmacokinetic properties, and a method of once-daily immunosuppressive treatment using this dosage form.

The most relevant prior art explicitly cited in US11123331 includes:

• EP-A-0 184 162

  • Full Citation: EP0184162A1 (or EP-A-0 184 162)
  • Publication/Filing Date: Published 1986-06-25 (Priority date not explicitly stated in US11123331 but earlier than publication).
  • Brief Description: This European patent describes the preparation of tacrolimus itself.
  • Potential Anticipation (35 U.S.C. § 102): This reference describes the active pharmaceutical ingredient (tacrolimus). If any claims in US11123331 were broadly directed to tacrolimus per se, this patent could potentially anticipate them. However, given the focus of US11123331 on extended-release formulations and methods of treatment, this reference primarily serves to establish the known nature of the active compound.

• EP-A-0 444 659

  • Full Citation: EP0444659A1 (or EP-A-0 444 659)
  • Publication/Filing Date: Published 1991-09-04 (Priority date not explicitly stated in US11123331 but earlier than publication).
  • Brief Description: This European patent discloses various analogues of tacrolimus.
  • Potential Anticipation (35 U.S.C. § 102): Similar to EP-A-0 184 162, this reference would be relevant to claims broadly encompassing tacrolimus analogues. Its primary role is to define the scope of related active substances that could be used in formulations, rather than anticipating the specific extended-release features of US11123331.

• U.S. Pat. No. 6,387,918

  • Full Citation: US6387918B1
  • Publication/Filing Date: Published 2002-05-14 (Priority date not explicitly stated in US11123331 but earlier than publication).
  • Brief Description: This U.S. patent also discloses analogues of tacrolimus.
  • Potential Anticipation (35 U.S.C. § 102): As with EP-A-0 444 659, this patent broadens the definition of the active compounds. It would be anticipatory only if US11123331 contained very broad claims to tacrolimus analogues without the specific extended-release or pharmacokinetic characteristics.

• WO 1999/049863 (cited as WO99/49863)

  • Full Citation: WO1999049863A1
  • Publication/Filing Date: Published 1999-10-07 (Priority date 1998-03-31).
  • Brief Description: This PCT application describes the conventional, fast-release Prograf® product, including its composition with HPMC, lactose, and croscarmellose sodium. It is noted as developed by Fujisawa Pharmaceutical Co..
  • Potential Anticipation (35 U.S.C. § 102): This document defines the baseline "immediate release" tacrolimus product against which the improvements of US11123331 are measured. It would not anticipate the extended-release features, lower Cmax, or improved pharmacokinetic profile claimed by US11123331, but rather establish the state of the art for immediate-release tacrolimus.

• WO 2000/050007

  • Full Citation: WO2000050007A1
  • Publication/Filing Date: Published 2000-08-31 (Priority date 1999-02-19).
  • Brief Description: This PCT application discloses amphiphilic surfactants as suitable excipients for pharmaceutical compositions, particularly those comprising hydrophobic drugs.
  • Potential Anticipation (35 U.S.C. § 102): If US11123331 claims the use of specific amphiphilic surfactants as excipients, this document could potentially anticipate those claims, especially if the claimed surfactants or their function within the formulation are not uniquely tied to the extended-release properties of the present invention.

• WO 2003/004001

  • Full Citation: WO2003004001A1
  • Publication/Filing Date: Published 2003-01-16 (Priority date 2001-07-06).
  • Brief Description: This PCT application describes a controlled agglomeration method for preparing particulate material, which is stated to be a "particularly useful method" for the present invention and provides suitable carriers.
  • Potential Anticipation (35 U.S.C. § 102): This patent could potentially anticipate claims in US11123331 related to specific manufacturing processes (e.g., controlled agglomeration) or the use of carriers prepared by such methods, especially if the claims do not include further distinguishing features critical to the extended release of tacrolimus.

• WO 2005/020993 (also known as WO05020993A1)

  • Full Citation: WO2005020993A1
  • Publication/Filing Date: Published 2005-03-10 (Priority date 2003-08-29).
  • Brief Description: This PCT application, by the same inventors as US11123331, describes different tacrolimus formulations that showed improved bioavailability compared to Prograf® in animal studies. It suggests improved bioavailability is linked to tacrolimus being in a dissolved state.
  • Potential Anticipation (35 U.S.C. § 102): This reference is highly relevant as it comes from the same inventors and discusses improved bioavailability of tacrolimus formulations. It could potentially anticipate claims relating to improved bioavailability of tacrolimus formulations, especially those involving the drug in a dissolved state, unless the claims of US11123331 are sufficiently distinct in their specific extended-release profile, pharmacokinetic parameters, or other structural/compositional features.

• WO 2005/020994 (also known as WO05020994A1)

  • Full Citation: WO2005020994A1
  • Publication/Filing Date: Published 2005-03-10 (Priority date 2003-08-29).
  • Brief Description: This PCT application, also by the same inventors, specifically relates to solid dispersions comprising tacrolimus.
  • Potential Anticipation (35 U.S.C. § 102): Similar to WO 2005/020993, this document is very close prior art by the same inventors. It could anticipate claims in US11123331 directed to tacrolimus in solid dispersion form, particularly if the claims do not specify unique compositional elements or the precise extended-release characteristics that differentiate the current invention.

Obviousness Analysis of US Patent 11,123,331 under 35 U.S.C. § 103

This analysis assesses the obviousness of US Patent 11,123,331, titled "Tacrolimus for improved treatment of transplant patients," under 35 U.S.C. § 103, based on the provided patent text and a priority date of May 30, 2007.

1. The Claimed Invention

US Patent 11,123,331 claims an extended-release oral dosage form of tacrolimus for once-daily immunosuppressive treatment. Key features, as inferred from the abstract and detailed description, include:

• A specific in vitro release profile, characterized by releasing at most 63.5% of the active substance at the 12-hour mark, and at least 8% at 4 hours and/or at least 15% at 8 hours, when tested under defined USP dissolution conditions (paddle/basket, pH 4.5, 0.005% hydroxypropylcellulose, 50 rpm).
• Improved pharmacokinetic properties in vivo compared to conventional (Prograf®) and existing extended-release (Advagraf®/MR4) tacrolimus formulations, specifically:
  • Decreased intra- and inter-subject variability of mean blood Tmax, Cmax, and AUC(0-infinity) by at least 10% compared to Advagraf®.
  • Decreased Cmax value by at least 10% compared to Advagraf®.
  • Increased bioavailability (AUC(0-infinity)) by at least 20% compared to Advagraf®.
  • Reduced swing ((Cmax-Cmin)/Cmin) and fluctuation ((Cmax-Cmin)/Caverage) compared to Advagraf® or Prograf®.
  • Increased mean residence time (MRT) by at least 10% compared to Advagraf® and at least 35% compared to Prograf®.
  • A longer time to reach Tmax and a higher Cmin.
• Improved systemic exposure on Day 1 for de novo liver/kidney transplant patients compared to other formulations.
• Bioavailability that is substantially independent of the time of day administered, suitable for bedtime dosing.
• A specific composition where tacrolimus is dissolved or dispersed as a solid dispersion or solid solution in a hydrophilic or water-miscible vehicle (e.g., polyethylene glycols, poloxamers).
• Methods of treatment using this dosage form, including for de novo patients and conversion from other tacrolimus regimens with specific dose ratios.

2. Closest Prior Art and Pertinent Prior Art

The patent itself identifies several relevant prior art references:

• Prograf®: An immediate-release tacrolimus formulation, approved by the FDA in 1994, characterized by large inter- and intra-individual variability in absorption, incomplete and variable bioavailability (at most about 20%), and significant side effects. [cite: "Tacrolimus administered as Prograf® capsules, exhibits a large inter- and intra-individual variability of its absorption and metabolism.", "the bioavailability is generally as low as at the most about 20% after oral administration.", "Tacrolimus is known to induce significant side effects, of nephro- or neuro-toxic origin, as well as GI side-effects and others."] It required twice-daily dosing and frequent dose adjustments. [cite: "the recommended dosage range for Prograf® is 0.1 to 0.2 mg/kg/day given every 12 hours in two divided doses. Importantly, the blood levels have to be monitored."]
• Advagraf® (also known as MR4): An extended-release tacrolimus formulation, approved by the EMEA on April 23, 2007. [cite: "Tacrolimus also known as FK-506 or FR-900506, is the active ingredient of Prograf®, Protopic®, and Advagraf® approved by the European Agency for the Evaluation of Medicinal Products (EMEA) at 23 Apr. 2007."] This product provided once-daily dosing. The present patent explicitly distinguishes itself by demonstrating improved pharmacokinetic parameters (e.g., decreased variability, decreased Cmax, increased bioavailability) compared to Advagraf®. It also notes that Advagraf® provided lower systemic exposure in de novo transplant patients on Day 1 compared to Prograf®. [cite: "Advagraf® in the first 24 hours provides a 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."]
• WO 2005/020993 A1 (priority date February 28, 2005): A patent application by the same inventors, which tested different tacrolimus formulations, including fast and slow-release tablets, demonstrating that both could result in improved bioavailability compared with Prograf®. [cite: "Inventors of the present application have in the patent application WO 2005/020993 also tested different formulations of tacrolimus in Beagle dogs and minipigs, however demonstrating that both a fast release tablet (Example 18) and a slow release tablet (Example 19) can result in improved bioavailability compared with Prograf®."]
• WO 2005/020994 A1 (priority date February 28, 2005): Another patent application by the same inventors, which linked improved bioavailability of tacrolimus to having the drug in a dissolved state and related to solid dispersions comprising tacrolimus. [cite: "This indicates that an improved bioavailability could be linked to having tacrolimus in a dissolved state in the dosage form which also appears from WO 2005/020994 by the same inventors relating to solid dispersions comprising tacrolimus."] This document explicitly discusses hydrophilic or water-miscible vehicles like polyethylene glycols and poloxamers for solid dispersions. [cite: "useful hydrophilic or water-miscible vehicles are selected from the group consisting of polyethylene glycols, polyoxyethylene oxides, poloxamers, polyoxyethylene stearates, poly-epsilon caprolactone, polyglycolized glycerides such as Gelucire®, and mixtures thereof."]

3. Obviousness Combinations and Motivation to Combine

A Person of Ordinary Skill in the Art (POSITA) in pharmaceutical formulation and transplantation medicine, at the time of the invention (before May 30, 2007), would have been well aware of the significant challenges associated with tacrolimus therapy, particularly the high variability, the need for frequent monitoring and dose adjustments with Prograf®, and its associated toxicities. The introduction of Advagraf® demonstrated the feasibility and desirability of a once-daily extended-release formulation. However, as acknowledged by the present patent, Advagraf® still presented limitations, especially regarding initial systemic exposure in de novo transplant patients and opportunities for further reducing pharmacokinetic variability.

Combination 1: Advagraf® in view of WO 2005/020994 A1

• Advagraf® taught the concept of a once-daily, extended-release oral tacrolimus dosage form for immunosuppression.
• WO 2005/020994 A1, by the same inventors of US11123331, explicitly taught that improved bioavailability of tacrolimus could be achieved by formulating it in a dissolved state, specifically as a solid dispersion using hydrophilic or water-miscible vehicles such as polyethylene glycols and poloxamers. [cite: "This indicates that an improved bioavailability could be linked to having tacrolimus in a dissolved state in the dosage form which also appears from WO 2005/020994 by the same inventors relating to solid dispersions comprising tacrolimus."]

Motivation to Combine: A POSITA would have been highly motivated to combine these teachings. The inherent poor and variable bioavailability of tacrolimus (as seen with Prograf®) was a well-known problem. While Advagraf® offered an extended-release, once-daily solution, its limitations (as noted in US11123331, e.g., for de novo patients) would prompt further development. WO 2005/020994 A1 provided a clear technical approach to enhance tacrolimus's bioavailability through solid dispersions. It would have been obvious to a POSITA to incorporate the solid dispersion technology taught in WO 2005/020994 A1 into an extended-release platform, such as the one exemplified by Advagraf®, to further improve the bioavailability and pharmacokinetic profile (e.g., reduce variability, maintain more stable blood levels, potentially reduce Cmax, and increase AUC and MRT) of once-daily tacrolimus. The use of known excipients like PEGs and poloxamers for forming such solid dispersions, as explicitly mentioned in WO 2005/020994 A1, would have been a routine choice for a formulator.

The resulting combined formulation would naturally be expected to exhibit an optimized dissolution profile and improved in vivo pharmacokinetic parameters, including those claimed in US11123331 (e.g., lower variability, reduced Cmax, higher AUC, and longer MRT). Achieving specific numerical ranges for these parameters through formulation optimization, while requiring experimentation, would be considered within the realm of routine development for a POSITA pursuing improved extended-release tacrolimus formulations using established principles of drug delivery and bioavailability enhancement. The patent itself notes that "the release may be carefully tailored to level out several counteracting factors" in the GI tract, indicating that tailoring release profiles is a known objective for formulators. [cite: "the release may be carefully tailored to level out several counteracting factors of. These factors includes in the colon a lower area for absorption, a lower content of fluids, higher content of solids, bacterial degradation, higher impact from the P-glycoprotein transporter system, lower motility, differences in mucosal barrier and/or mucous composition and differences in pH along the colon compared with the small intestines."]

Reinforcement by WO 2005/020993 A1:

WO 2005/020993 A1 further strengthens the obviousness argument by explicitly demonstrating, prior to the priority date of US11123331, that "slow release" tacrolimus tablets could result in improved bioavailability compared to Prograf®. [cite: "Inventors of the present application have in the patent application WO 2005/020993 also tested different formulations of tacrolimus in Beagle dogs and minipigs, however demonstrating that both a fast release tablet (Example 18) and a slow release tablet (Example 19) can result in improved bioavailability compared with Prograf®."] This reinforces the motivation for a POSITA to pursue extended-release formulations for improved bioavailability and indicates a clear research direction already undertaken by the inventors themselves.

Therefore, a combination of Advagraf® (or its equivalent MR4), WO 2005/020993 A1, and WO 2005/020994 A1 would make the claims of US11123331 obvious. Advagraf® established the goal of an extended-release, once-daily tacrolimus. WO 2005/020993 A1 showed the benefit of slow-release tacrolimus on bioavailability. WO 2005/020994 A1 provided the specific technical means (solid dispersions with hydrophilic vehicles) to achieve improved bioavailability. A POSITA would have been motivated to combine these elements to develop a more effective and consistent once-daily extended-release tacrolimus formulation, with a reasonable expectation of achieving the improved pharmacokinetic profiles and therapeutic advantages described in US11123331.

4. Secondary Considerations

The patent discusses several advantages, such as "surprisingly high bioavailability," "significant reduction in side effects," "decreased dosage," and "substantial reduced peak concentrations." While these are strong indicators of non-obviousness, they must be weighed against the strength of the prima facie case of obviousness. Given that the inventors themselves had previously published WO 2005/020993 A1 and WO 2005/020994 A1, which already pointed towards improving tacrolimus bioavailability through controlled release and solid dispersions, the further improvements, even if significant, might be seen as the expected outcome of continued, albeit successful, optimization along an established and obvious path. The problems addressed, such as high variability and side effects of Prograf®, were long-felt needs, but Advagraf® had already begun to address them with an extended-release formulation, suggesting that the invention represents an incremental improvement rather than a solution to a completely unsolved problem.