US 10864199

Here is a concise summary of US Patent 10864199, including information from the USPTO and CAFC dockets.

US Patent 10864199 Summary

• Title: Tacrolimus for improved treatment of transplant patients
• Current Assignee: Veloxis Pharmaceuticals Inc.
• Original Assignee: Veloxis Pharmaceuticals AS
• Inventors: Robert D. Gordon, Per Holm, Anne-Marie Lademann, Tomas Norling
• Filing Date: 2016-02-11
• Issue Date: 2020-12-15
• Abstract: An extended release oral dosage form comprising tacrolimus or a pharmaceutically active analogue thereof for once-daily immunosuppressive treatment of transplant patients. This dosage form releases the active substance over a very extended period, providing high bioavailability and an improved pharmacokinetic profile compared to conventional dosage forms.

Plain-Language Overview of Independent Claims:

• Claim 1: This claim describes an extended-release oral dosage form containing tacrolimus (or a similar active drug) for once-daily immunosuppressive treatment. The key feature is its slow release profile: when tested in a specific lab setup (USP II paddle or USP I basket test at pH 4.5 with 0.005% hydroxypropylcellulose and 50 rpm rotation), no more than 63.5% of the drug is released after 12 hours.
• Claim 26: This claim covers a pharmaceutical composition in particulate form (like a powder or granules) that contains tacrolimus (or a similar drug) and other standard pharmaceutical ingredients. When given orally, this composition results in an Area Under the Curve (AUC) in the body that is at least 1.3 times higher than that of Prograf® (a commercially available tacrolimus product) under similar conditions, indicating improved drug absorption.
• Claim 27: This claim describes a pharmaceutical composition in particulate form with tacrolimus and other ingredients that, when taken orally, releases tacrolimus in a controlled way. This controlled release leads to a maximum drug concentration (Cmax) in the body that is no more than about 80% of the Cmax achieved with Prograf® tablets.
• Claim 37: This claim focuses on a pharmaceutical composition in particulate form containing tacrolimus (or an analogue) and other ingredients. When administered orally, this composition releases the drug in a controlled manner and reduces side effects compared to Prograf® when both provide an equivalent therapeutic effect.
• Claim 49: This claim describes the extended-release oral dosage form of Claim 1 for use in an immunosuppressive treatment method. This method involves once-daily administration and provides one or more improved pharmacokinetic outcomes such as a lower maximum concentration (Cmax), reduced "swing" (fluctuation between max and min concentrations), increased total drug exposure (AUC), longer mean residence time (MRT), later time to maximum concentration (Tmax), or a higher minimum concentration (Cmin).
• Claim 50: This claim describes a method of providing once-daily immunosuppressive treatment using the extended-release formulation. A key aspect is that the minimum drug concentration (Cmin) in the blood highly correlates with the overall drug availability (bioavailability), with a correlation factor of at least 0.75 (and preferably higher).
• Claim 51: This claim describes a method of providing once-daily immunosuppressive treatment using the extended-release formulation, where the bioavailability of the drug is largely unaffected by the time of day it is taken. This allows for flexible dosing, including at bedtime or in the evening.
• Claim 52: This claim describes a method for converting a patient from an immediate-release tacrolimus regimen (like Prograf®) to the once-daily extended-release regimen. The method involves reducing the daily tacrolimus dosage by 25% to 50% (preferably around 33%) during this conversion.
• Claim 53: This claim describes a method for converting a patient from an Advagraf® regimen to the once-daily extended-release regimen. The conversion ratio from Advagraf® to the new formulation is between 1:0.30 and 1:0.75, depending on available dosage strengths (0.5 mg, 1 mg, 2 mg, and 5 mg).
• Claim 54: This claim describes a method of providing once-daily immunosuppressive treatment using the extended-release formulation specifically to reduce side effects related to high peak drug concentrations, such as neurological side effects like tremor and headache.
• Claim 55: This claim describes a method for treating patients at risk of organ toxicity from tacrolimus, specifically targeting organs known to accumulate the drug, including the adrenal gland, lung, heart, liver, gastrointestinal tract, and kidney.
• Claim 58: This claim describes a method for the initial treatment of a new liver transplant patient with tacrolimus. It involves administering the once-daily extended-release oral dosage form which, in an in vitro dissolution test (FDA method for Prograf®), releases less than 50% of tacrolimus after 10 hours. This dosage form must provide a systemic drug exposure on day 1 that is at least 50% of the exposure obtained on day 1 from an immediate-release tacrolimus form given twice a day.
• Claim 59: This claim describes a method for the initial treatment of a new kidney transplant patient with tacrolimus. It involves administering the once-daily extended-release oral dosage form which, in an in vitro dissolution test (FDA method for Prograf®), releases less than 50% of tacrolimus after 10 hours. This dosage form must provide a systemic drug exposure on day 1 that is at least 70% of the exposure obtained on day 1 from an immediate-release tacrolimus form given twice a day.
• Claim 60: This claim describes a method for the initial treatment of a new liver transplant patient with tacrolimus. It involves administering the once-daily extended-release oral dosage form which, in an in vitro dissolution test (FDA method for Prograf®), releases less than 50% of tacrolimus after 10 hours. This dosage form must provide a systemic drug exposure on day 1 that is at least 100% of the exposure obtained on day 1 from an extended-release oral dosage form that releases more than 30% of tacrolimus within 5 hours.
• Claim 61: This claim describes a method for the initial treatment of a new kidney transplant patient with tacrolimus. It involves administering the once-daily extended-release oral dosage form which, in an in vitro dissolution test (FDA method for Prograf®), releases less than 50% of tacrolimus after 10 hours. This dosage form must provide a systemic drug exposure on day 1 that is at least 100% of the exposure obtained on day 1 from an extended-release oral dosage form that releases more than 30% of tacrolimus within 5 hours.

USPTO and CAFC Docket Search for US10864199

As of April 26, 2026, the provided Google search results for USPTO and CAFC dockets for patent US10864199 did not specifically identify any active cases or dockets related to this patent in the CAFC in 2026. The search results provided general information about CAFC operations and other unrelated patent cases. There is no authoritative information from the provided search results to indicate any ongoing litigation specifically for US10864199 at the CAFC in 2026.

US patent 10864199 has been involved in litigation. Here's a summary of known cases:

• Plaintiff(s): Veloxis Pharmaceuticals, Inc.
• Defendant(s): Accord Healthcare & Intas
• Jurisdiction: Delaware District Court
• Case Number: 1:22-cv-00909
• Filing Date: The consent judgment was filed on January 24, 2024.
• Current Status/Outcome: Dismissed with prejudice via a consent judgment. This means Veloxis cannot refile these specific claims, and Accord loses the right to relitigate its invalidity and non-infringement counterclaims in Delaware on these patents against this ANDA product. The consent judgment enjoins Accord and Intas from infringement until the expiration of the patents-in-suit.

It's important to note that US patent 10864199 is part of a larger patent family related to extended-release tacrolimus formulations, and Veloxis has asserted multiple patents in its portfolio in litigation against generic challengers.

Proceedings overview

There are no AIA trial proceedings on file for US Patent 10864199 as of 2026-06-01. This indicates that the patent has not been subjected to challenges at the Patent Trial and Appeal Board (PTAB), meaning all claims remain untested by this adversarial review process.

Strategic summary

All claims of US10864199 are currently UNTESTED by any AIA trial proceeding before the PTAB. There are no records of Inter Partes Reviews (IPRs), Post-Grant Reviews (PGRs), or Covered Business Method (CBM) reviews having been filed against this patent. Consequently, there is no estoppel landscape established through PTAB proceedings, and all prior-art grounds remain potentially available for a defendant to assert, for instance, in district court litigation or a future PTAB challenge. The absence of PTAB activity suggests that the patent owner has not yet faced a direct validity challenge in this forum, or if challenges were considered, they were not formally filed or did not progress to institution.

Recommended next steps

Since there is no PTAB activity on file for US10864199, the recommended next steps are as follows:

• For a defendant facing assertion of this patent: Consider initiating an AIA trial proceeding (e.g., IPR or PGR, depending on the patent's effective filing date and available prior art) if a strong invalidity case can be built. The absence of prior PTAB challenges means there's no "hardened" claims to contend with, nor any estoppel on prior art grounds.
• Monitor for future filings: As the patent is active and has ongoing litigation, regularly check the USPTO PTAB E2E system for any newly filed petitions against US10864199.
• Analyze patent strength: Given the lack of PTAB review, a thorough prior art search and analysis of the patent's claims against the found art would be crucial to assess its vulnerability to future challenges.

Inventors

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

All named inventors were likely employed by Veloxis Pharmaceuticals AS at the time of the patent application's filing, which is a common practice for corporate patent ownership.

Original assignee

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

Veloxis Pharmaceuticals AS (now part of Veloxis Pharmaceuticals Inc.) developed and markets an extended-release tacrolimus formulation under the brand name Envarsus XR (known as LCP-Tacro in clinical development) for the improved treatment of transplant patients. This product embodies the claims of US 10864199.

Veloxis Pharmaceuticals AS was acquired by Asahi Kasei Pharma Corporation in 2020. Veloxis Pharmaceuticals Inc., the current assignee, continues to operate as a specialty pharmaceutical company focused on immunosuppressive treatments.

Assignment timeline

• 2016-02-11 (executed) / recorded N/A (implied)

  • Conveyance: Assignment (implied by initial application filing)
  • Assignor: Robert D. Gordon, Per Holm, Anne-Marie Lademann, Tomas Norling (Inventors)
  • Assignee: Veloxis Pharmaceuticals A/S
  • Context: Initial assignment of patent rights from inventors to the corporate entity at the time of filing the patent application.

• 2018-02-15 (executed) / recorded 2018-02-15 — Reel 041170/0411

  • Conveyance: SECURITY INTEREST
  • Assignor: VELOXIS PHARMACEUTICALS A/S
  • Assignee: ATHYRIUM OPPORTUNITIES III ACQUISITION LP
  • Correspondent: COOLEY LLP, 1290 AVENUE OF THE AMERICAS, NEW YORK, NY 10104-3300.
  • Context: Securitization of assets, likely in conjunction with a loan or financing agreement using patents as collateral.

• 2020-01-23 (executed) / recorded 2020-01-23 — Reel 048743/0116

  • Conveyance: RELEASE BY SECURED PARTY
  • Assignor: ATHYRIUM OPPORTUNITIES III ACQUISITION LP
  • Assignee: VELOXIS PHARMACEUTICALS A/S
  • Correspondent: COOLEY LLP, 1290 AVENUE OF THE AMERICAS, NEW YORK, NY 10104-3300. (This correspondent recurs in this chain.)
  • Context: Release of the security interest, returning unencumbered patent rights to Veloxis Pharmaceuticals A/S.

• 2021-03-17 (executed) / recorded 2021-03-17 — Reel 055740/0173

  • Conveyance: Assignment of Assignors Interest
  • Assignor: VELOXIS PHARMACEUTICALS A/S
  • Assignee: VELOXIS PHARMACEUTICALS INC.
  • Correspondent: KUTAK ROCK LLP, 1650 ARCHER PARK DR, OMAHA, NE 68102.
  • Context: Corporate restructuring or transfer of US patent assets from the Danish parent company to its US subsidiary.

• 2021-04-02 (executed) / recorded 2021-04-02 — Reel 055800/0073

  • Conveyance: Assignment of Assignors Interest
  • Assignor: VELOXIS PHARMACEUTICALS A/S
  • Assignee: VELOXIS PHARMACEUTICALS INC.
  • Correspondent: KUTAK ROCK LLP, 1650 ARCHER PARK DR, OMAHA, NE 68102. (This correspondent recurs in this chain.)
  • Context: Supplemental or clarifying transfer of patent rights from the Danish parent to its US subsidiary.

• 2024-03-25 (executed) / recorded 2024-03-25 — Reel 062638/0048

  • Conveyance: Assignment of Assignors Interest
  • Assignor: LADEMANN, ANNE-MARIE; HOLM, PER; GORDON, ROBERT D
  • Assignee: LIFECYCLE PHARMA A/S
  • Correspondent: MCDERMOTT WILL & EMERY LLP, 1850 K STREET NW SUITE 1100, WASHINGTON, DC 20006.
  • Context: Assignment of individual inventor rights, potentially a corrective or clarifying action to perfect the chain of title.

• 2024-03-25 (executed) / recorded 2024-03-25 — Reel 062638/0049

  • Conveyance: Assignment of Assignors Interest
  • Assignor: NORLING, TOMAS
  • Assignee: LIFECYCLE PHARMA A/S
  • Correspondent: MCDERMOTT WILL & EMERY LLP, 1850 K STREET NW SUITE 1100, WASHINGTON, DC 20006. (This correspondent recurs in this chain.)
  • Context: Assignment of individual inventor rights, likely a concurrent corrective or clarifying action.

• 2024-03-25 (executed) / recorded 2024-03-25 — Reel 062638/0050

  • Conveyance: Assignment of Assignors Interest
  • Assignor: LIFECYCLE PHARMA A/S
  • Assignee: VELOXIS PHARMACEUTICALS A/S
  • Correspondent: MCDERMOTT WILL & EMERY LLP, 1850 K STREET NW SUITE 1100, WASHINGTON, DC 20006. (This correspondent recurs in this chain.)
  • Context: Transfer of the inventor-assigned rights from an intermediate entity (Lifecycle Pharma A/S, which was an earlier name for Veloxis's Danish parent) back to Veloxis Pharmaceuticals A/S, likely to ensure a complete and perfect chain of title for the ultimate owner, Veloxis Pharmaceuticals Inc.

Timeline diagram

timeline
    title Ownership of US 10864199
    2016 : Filed by Veloxis Pharma A/S
    2018 : Security interest to Athyrium LP
    2020 : Security interest released
    2020 : Veloxis Pharma A/S acquired
    2021 : Assigned to Veloxis Pharma Inc
    2024 : Inventors assign to Lifecycle Pharma A/S
         : Lifecycle Pharma A/S to Veloxis Pharma A/S

NPE / troll-pattern signals

1. Shell-entity transfer — Not present. The assignees are either operating companies (Veloxis Pharmaceuticals AS/Inc.), an investment firm involved in a security interest (Athyrium), or an historical entity related to the operating company (Lifecycle Pharma A/S). There are no indications of licensing-only LLCs or registered-agent addresses without operations.
2. Known asserter in the chain — Not present. None of the assignees (Veloxis Pharmaceuticals AS/Inc., Athyrium Opportunities III Acquisition LP, Lifecycle Pharma A/S) are identified as known NPEs or high-frequency plaintiffs by public lists. Veloxis Pharmaceuticals Inc. is an operating company.
3. Repeat correspondent across the chain — Present. Cooley LLP appears as correspondent for the 2018-02-15 security interest and 2020-01-23 release (Reel 041170/0411, 048743/0116). Kutak Rock LLP appears for the 2021-03-17 and 2021-04-02 assignments (Reel 055740/0173, 055800/0073). McDermott Will & Emery LLP appears for all three 2024-03-25 assignments (Reel 062638/0048, 062638/0049, 062638/0050). While this indicates consistency within specific transactions, the firms are known full-service law firms, and the assignments are between related operating entities or a lender, not disparate shell entities.
4. Cascading transfers — Not present as an NPE pattern. The three assignments on 2024-03-25 (Reel 062638/0048, 062638/0049, 062638/0050) are consecutive, but they appear to be a coordinated effort to perfect title within the Veloxis corporate family, rather than a rapid transfer through unrelated shell entities for assertion purposes.
5. Pre-litigation transfer — Not present. The primary transfer to the current asserting entity, Veloxis Pharmaceuticals Inc., occurred in March/April 2021 (Reel 055740/0173, 055800/0073). The first infringement suit (1:22-cv-00909) was filed in 2022, well over 6 months after this transfer.
6. Bankruptcy fire-sale — Not present. There is no indication of bankruptcy proceedings for any entity in the chain. The 2018 security interest and 2020 release reflect financing activity, not a distress sale.
7. Privateering — Not present. Veloxis Pharmaceuticals Inc. is an operating company that directly manufactures and sells a product embodying the patent claims, and it is asserting the patent against generic competitors.
8. Defensive aggregator (anti-NPE) — Not present. The chain ends with Veloxis Pharmaceuticals Inc., an operating company. No defensive aggregators are involved.

Verdict

Operating-company assertion

The assignment timeline consistently shows ownership within the Veloxis Pharmaceuticals corporate family, with a temporary security interest from a legitimate investment firm. Veloxis Pharmaceuticals Inc. is an operating company that develops and markets a product (Envarsus XR) embodying the patent claims and is suing direct competitors (Accord Healthcare & Intas) over alleged infringement. The 2024 assignments appear to be corrective measures to perfect the chain of title rather than indicative of an NPE strategy.

USPTO Assignment Center search for US10864199.

The following prior art documents have been identified as cited against US patent 10864199:

Due to the absence of explicit claims for US10864199 in the provided patent text, the potential anticipation under 35 U.S.C. § 102 is assessed based on a comparison of the cited prior art's abstract/description with the general inventive concepts and advantages described in US10864199, such as extended release, improved bioavailability, reduced Cmax, increased Tmax, reduced variability, and specific pharmaceutical formulations involving tacrolimus or its analogues.

Here are the details for each cited patent:

1. WO2005020994A1 - Solid dispersions of tacrolimus

• Full Citation: WO2005020994A1, "Solid dispersions of tacrolimus", published March 10, 2005.
• Publication/Filing Date: Publication date: March 10, 2005. Priority date: August 27, 2003.
• Brief Description: This international patent application describes solid dispersions comprising tacrolimus and/or its analogues, along with a hydrophilic or water-miscible vehicle. The invention aims to improve the bioavailability of tacrolimus by formulating it in a solid dispersion or solid solution.
• Potential Anticipation: This reference potentially anticipates the inventive concept of US10864199 relating to compositions where tacrolimus is present as a solid dispersion or solid solution in a hydrophilic or water-miscible vehicle, specifically aiming for improved bioavailability. The US10864199 patent text explicitly references WO 2005/020994 by the same inventors relating to solid dispersions comprising tacrolimus, indicating a strong foundational relationship.

2. WO2005020993A1 - Tacrolimus formulations with improved bioavailability

• Full Citation: WO2005020993A1, "Tacrolimus formulations with improved bioavailability", published March 10, 2005.
• Publication/Filing Date: Publication date: March 10, 2005. Priority date: August 27, 2003.
• Brief Description: This international patent application discloses pharmaceutical compositions of tacrolimus designed to enhance its bioavailability upon oral administration. The formulations are tested in animal models, demonstrating improved bioavailability compared to conventional tacrolimus products. The patent also describes various controlled release formulations.
• Potential Anticipation: This document is highly relevant as US10864199 explicitly states that its inventors also tested different tacrolimus formulations in WO 2005/020993, demonstrating improved bioavailability compared to Prograf®. This suggests that the core inventive concept of achieving improved bioavailability for tacrolimus through specific formulations is at least partially anticipated or built upon this prior work.

3. WO2003004001A1 - Particulate material

• Full Citation: WO2003004001A1, "Particulate material", published January 16, 2003.
• Publication/Filing Date: Publication date: January 16, 2003. Priority date: July 9, 2001.
• Brief Description: This international patent application describes a process for preparing particulate material by a controlled agglomeration method, involving spraying a first composition (comprising an active substance and a melted carrier) onto a second solid carrier medium. This method is noted as useful for incorporating relatively large amounts of oil or oily-like material in solid compositions.
• Potential Anticipation: US10864199 describes a method of preparation for its pharmaceutical compositions that is "a particularly useful method... described in WO 03/004001", specifically mentioning the controlled agglomeration method involving spraying a melted first composition onto a second solid carrier. This directly anticipates the manufacturing process aspect described in US10864199.

4. US6468565B1 - Extended release pharmaceutical compositions

• Full Citation: US6468565B1, "Extended release pharmaceutical compositions", granted October 22, 2002.
• Publication/Filing Date: Publication date: October 22, 2002. Filing date: January 16, 2001.
• Brief Description: This patent describes extended-release pharmaceutical compositions designed to provide controlled release of an active agent over an extended period. The compositions often involve a core matrix or coating for controlled release.
• Potential Anticipation: This patent broadly anticipates the concept of extended-release pharmaceutical compositions for oral administration, which is a fundamental aspect of US10864199. Depending on the specific active agents and release profiles claimed in US6468565B1, it could potentially anticipate the general formulation strategy for achieving extended release, though not necessarily with tacrolimus or the specific pharmacokinetic improvements outlined in US10864199.

5. US6472429B1 - Controlled release pharmaceutical composition

• Full Citation: US6472429B1, "Controlled release pharmaceutical composition", granted October 29, 2002.
• Publication/Filing Date: Publication date: October 29, 2002. Filing date: July 19, 2001.
• Brief Description: This patent details a controlled-release pharmaceutical composition comprising a drug, a water-insoluble or sparingly water-soluble polymer, and a water-soluble excipient. The composition aims to provide a prolonged release of the drug.
• Potential Anticipation: Similar to US6468565B1, this patent generally anticipates the concept of a controlled-release pharmaceutical composition. If the composition's characteristics (e.g., use of specific polymers, release kinetics) overlap with the generic aspects of extended-release formulations in US10864199, it could be seen as anticipating broad elements of the invention.

6. US6387918B1 - FK506-like compounds

• Full Citation: US6387918B1, "FK506-like compounds", granted May 14, 2002.
• Publication/Filing Date: Publication date: May 14, 2002. Filing date: January 18, 2001.
• Brief Description: This patent describes novel FK506-like compounds and their use as immunosuppressants. FK506 is another name for tacrolimus.
• Potential Anticipation: US10864199 explicitly cites US6387918 for disclosing analogues of tacrolimus. This patent is relevant for the active substance itself or its analogues, rather than the extended-release formulation technology. It would anticipate aspects of US10864199 that claim the use of tacrolimus or its pharmaceutically active analogues broadly, but not necessarily the specific formulation or pharmacokinetic profile improvements.

7. WO2000050007A1 - Self-emulsifying pharmaceutical formulation

• Full Citation: WO2000050007A1, "Self-emulsifying pharmaceutical formulation", published August 31, 2000.
• Publication/Filing Date: Publication date: August 31, 2000. Priority date: February 25, 1999.
• Brief Description: This international patent application describes self-emulsifying pharmaceutical formulations containing an active agent, particularly amphiphilic surfactants, to improve the bioavailability of poorly water-soluble drugs.
• Potential Anticipation: US10864199 mentions the inclusion of surfactants, specifically referencing "amphiphillic surfactants as those disclosed in WO 00/50007 in the name of Lipocine, Inc." This directly anticipates the use of certain surfactant types in tacrolimus formulations to aid solubility and potentially improve absorption.

8. WO9949863A1 - Pharmaceutical preparation containing tacrolimus

• Full Citation: WO9949863A1, "Pharmaceutical preparation containing tacrolimus", published October 7, 1999.
• Publication/Filing Date: Publication date: October 7, 1999. Priority date: March 31, 1998.
• Brief Description: This international patent application describes pharmaceutical preparations containing tacrolimus, focusing on formulations that improve stability and bioavailability. It is relevant to the fast-release conventional product Prograf®.
• Potential Anticipation: US10864199 explicitly refers to WO99/49863 as describing the formulation of the fast release conventional product Prograf®, owned by Fujisawa Pharmaceutical Co. This document serves as a baseline or comparison point for the improved bioavailability and pharmacokinetic profiles claimed by US10864199, rather than directly anticipating the extended-release features. However, it does anticipate the use of tacrolimus in pharmaceutical preparations and might contain elements of excipients or general formulation strategies that US10864199 builds upon or differentiates itself from.

9. WO9940902A1 - Controlled release pharmaceutical preparations for oral administration

• Full Citation: WO9940902A1, "Controlled release pharmaceutical preparations for oral administration", published August 19, 1999.
• Publication/Filing Date: Publication date: August 19, 1999. Priority date: February 12, 1998.
• Brief Description: This international patent application describes controlled-release pharmaceutical preparations intended for oral administration, aiming to provide a prolonged therapeutic effect.
• Potential Anticipation: This broadly anticipates the concept of controlled-release oral pharmaceutical preparations. The general goal of providing prolonged release is shared with US10864199. Specifics of the formulation, active ingredient, and achieved pharmacokinetic benefits would determine the degree of anticipation.

10. US5980942A - Sustained release oral dosage formulation comprising a highly water soluble drug

• Full Citation: US5980942A, "Sustained release oral dosage formulation comprising a highly water soluble drug", granted November 9, 1999.
• Publication/Filing Date: Publication date: November 9, 1999. Filing date: February 28, 1997.
• Brief Description: This patent describes sustained-release oral dosage formulations, particularly for highly water-soluble drugs, using a specific combination of release-controlling polymers.
• Potential Anticipation: While US10864199 deals with tacrolimus, which is practically insoluble in water, the general principles of sustained-release oral dosage formulations and the use of release-controlling polymers could be broadly anticipated by this patent.

11. US5891472A - Controlled release pharmaceutical preparations for oral administration

• Full Citation: US5891472A, "Controlled release pharmaceutical preparations for oral administration", granted April 6, 1999.
• Publication/Filing Date: Publication date: April 6, 1999. Filing date: October 23, 1996.
• Brief Description: This patent describes controlled-release oral pharmaceutical preparations, which may involve matrix systems or coated particles to achieve prolonged drug release.
• Potential Anticipation: Similar to WO9940902A1 and US6468565B1, this patent broadly anticipates the concept of controlled-release oral pharmaceutical preparations.

12. WO9706791A1 - Pharmaceutical compositions containing 2-substituted cephalosporins

• Full Citation: WO9706791A1, "Pharmaceutical compositions containing 2-substituted cephalosporins", published February 27, 1997.
• Publication/Filing Date: Publication date: February 27, 1997. Priority date: August 19, 1995.
• Brief Description: This international patent application describes pharmaceutical compositions containing 2-substituted cephalosporins, which are a class of antibiotics.
• Potential Anticipation: This document is unlikely to directly anticipate any core inventive concepts of US10864199, as it concerns a completely different active pharmaceutical ingredient (cephalosporins vs. tacrolimus). It might be cited for very general formulation techniques or excipients common across pharmaceutical compositions, but not for the specific extended-release tacrolimus formulation or its pharmacokinetic advantages.

13. US5554388A - Controlled-release composition of FK506

• Full Citation: US5554388A, "Controlled-release composition of FK506", granted September 10, 1996.
• Publication/Filing Date: Publication date: September 10, 1996. Filing date: February 15, 1995.
• Brief Description: This patent specifically describes a controlled-release composition for FK506 (tacrolimus), which is directly relevant to US10864199. It aims to achieve sustained release of tacrolimus.
• Potential Anticipation: This patent is highly significant as it directly addresses controlled-release formulations of tacrolimus (FK506). It potentially anticipates the broad concept of an extended-release tacrolimus oral dosage form for immunosuppressive treatment. The novelty of US10864199 would then lie in the specific extended release profile, improved bioavailability parameters (e.g., lower Cmax, higher AUC, reduced variability, sustained Cmin), formulation components, or methods that differentiate it from the teaching of US5554388A.

14. US5503848A - Controlled-release pharmaceutical compositions

• Full Citation: US5503848A, "Controlled-release pharmaceutical compositions", granted April 2, 1996.
• Publication/Filing Date: Publication date: April 2, 1996. Filing date: May 11, 1994.
• Brief Description: This patent describes controlled-release pharmaceutical compositions, often involving a matrix system, to provide a sustained therapeutic effect.
• Potential Anticipation: This broadly anticipates the general concept of controlled-release pharmaceutical compositions, similar to other general controlled-release patents cited.

15. US5260082A - ENTERIC DOSAGE FORMS

• Full Citation: US5260082A, "ENTERIC DOSAGE FORMS", granted November 9, 1993.
• Publication/Filing Date: Publication date: November 9, 1993. Filing date: April 1, 1992.
• Brief Description: This patent describes enteric dosage forms designed to prevent drug release in the stomach and release it in the intestines, often using pH-sensitive coatings.
• Potential Anticipation: US10864199 mentions that its release "may be pH dependent, i.e., the release predominantly takes place after passage of the stomach," and that "Such a pH dependent release is mainly provided by means of enteric coating material." This patent directly anticipates the use of enteric coatings for delayed, pH-dependent release.

16. US5202128A - Extended-release compositions

• Full Citation: US5202128A, "Extended-release compositions", granted April 13, 1993.
• Publication/Filing Date: Publication date: April 13, 1993. Filing date: August 14, 1992.
• Brief Description: This patent describes extended-release compositions, often involving matrix systems, for prolonged drug delivery.
• Potential Anticipation: This broadly anticipates the general concept of extended-release compositions, similar to other general controlled-release patents cited.

17. US5128143A - Enteric-coated sustained-release pharmaceutical compositions

• Full Citation: US5128143A, "Enteric-coated sustained-release pharmaceutical compositions", granted July 7, 1992.
• Publication/Filing Date: Publication date: July 7, 1992. Filing date: February 13, 1991.
• Brief Description: This patent describes pharmaceutical compositions combining enteric coating with sustained-release mechanisms.
• Potential Anticipation: This patent combines the concepts of enteric coating and sustained release, both of which are discussed in US10864199 as potential mechanisms for achieving its desired release profile. Thus, it potentially anticipates aspects relating to combined delayed and extended release.

18. US5019397A - Controlled release pharmaceutical compositions

• Full Citation: US5019397A, "Controlled release pharmaceutical compositions", granted May 28, 1991.
• Publication/Filing Date: Publication date: May 28, 1991. Filing date: April 17, 1989.
• Brief Description: This patent describes various controlled-release pharmaceutical compositions designed for prolonged drug delivery.
• Potential Anticipation: This broadly anticipates the general concept of controlled-release pharmaceutical compositions.

19. US4871549A - Dosage forms for providing biphasic release

• Full Citation: US4871549A, "Dosage forms for providing biphasic release", granted October 3, 1989.
• Publication/Filing Date: Publication date: October 3, 1989. Filing date: January 17, 1986.
• Brief Description: This patent describes dosage forms that provide a biphasic release profile (e.g., immediate release followed by sustained release).
• Potential Anticipation: While US10864199 focuses on extended release, the general concept of tailoring release profiles, including initial release characteristics, could be broadly anticipated by this patent.

20. EP-A-0 184 162 - Preparation of tacrolimus

• Full Citation: EP-A-0 184 162 (European Patent Application), "Macrolide Compounds and Process for Their Production and Use", published June 11, 1986. (Equivalent to US4894366A)
• Publication/Filing Date: Publication date: June 11, 1986. Filing date: October 22, 1985.
• Brief Description: This European patent application describes the preparation of tacrolimus (FK506) itself.
• Potential Anticipation: US10864199 explicitly states, "The preparation of tacrolimus is described in EP-A-0 184 162". This patent anticipates the method of synthesizing the active pharmaceutical ingredient, tacrolimus, but not the specific extended-release formulations or their pharmacokinetic advantages.

21. US4606909A - PHARMACEUTICAL COMPOSITION FOR ORAL ADMINISTRATION

• Full Citation: US4606909A, "PHARMACEUTICAL COMPOSITION FOR ORAL ADMINISTRATION", granted August 19, 1986.
• Publication/Filing Date: Publication date: August 19, 1986. Filing date: June 20, 1985.
• Brief Description: This patent describes general pharmaceutical compositions for oral administration.
• Potential Anticipation: This is a very broad citation, likely anticipating the general concept of pharmaceutical compositions for oral administration, but not the specific extended-release features, active ingredient (tacrolimus), or pharmacokinetic benefits.

22. US4476107A - Controlled release pharmaceutical compositions

• Full Citation: US4476107A, "Controlled release pharmaceutical compositions", granted October 9, 1984.
• Publication/Filing Date: Publication date: October 9, 1984. Filing date: September 1, 1982.
• Brief Description: This patent describes early forms of controlled-release pharmaceutical compositions using various matrix materials.
• Potential Anticipation: This broadly anticipates the general concept and basic mechanisms of controlled-release pharmaceutical compositions, providing a foundation upon which later, more specific extended-release technologies (like those for tacrolimus) were developed.

23. EP-A-0 444 659 - Analogues of tacrolimus

• Full Citation: EP-A-0 444 659 (European Patent Application), "Macrolactam compounds, their preparation and use", published September 4, 1991. (Equivalent to US5250678A)
• Publication/Filing Date: Publication date: September 4, 1991. Filing date: February 28, 1991.
• Brief Description: This European patent application discloses various macrolactam compounds, including analogues of tacrolimus, with immunosuppressive properties.
• Potential Anticipation: US10864199 explicitly states that "analogues of tacrolimus are disclosed e.g. in EP-A-0 444 659". Similar to US6387918B1, this patent anticipates the existence and chemical structure of certain tacrolimus analogues, which are defined as part of the active substance in US10864199, but not the specific extended-release formulation or its pharmacokinetic advantages.

Summary of Most Relevant Prior Art:

The most relevant prior art documents appear to be those directly related to tacrolimus formulations or methods that US10864199 explicitly builds upon or differentiates itself from:

• US5554388A (Controlled-release composition of FK506): Directly addresses controlled-release formulations of tacrolimus.
• WO2005020993A1 (Tacrolimus formulations with improved bioavailability) and WO2005020994A1 (Solid dispersions of tacrolimus): These are by the same inventors and are explicitly referenced in US10864199 as foundational for improved bioavailability and solid dispersion technology.
• WO2003004001A1 (Particulate material): Explicitly referenced for the manufacturing process of the particulate material.
• WO9949863A1 (Pharmaceutical preparation containing tacrolimus): Describes the conventional Prograf® formulation, which US10864199 aims to improve upon.
• EP-A-0 184 162 and EP-A-0 444 659: These anticipate the existence and preparation of tacrolimus and its analogues, respectively, which are the active ingredients of US10864199.

Other patents provide more general background on controlled-release technologies or pharmaceutical excipients that are not specific to tacrolimus.

Obviousness Analysis under 35 U.S.C. § 103 for US10864199

This analysis identifies combinations of prior art references that would render claims of US patent 10864199 obvious to a person having ordinary skill in the art (PHOSITA), along with the motivations for such combinations. A PHOSITA in this field would be a pharmaceutical scientist or formulation chemist with experience in developing oral dosage forms for immunosuppressants, particularly those with poor solubility and variable absorption, and familiarity with extended-release technologies and pharmacokinetic principles.

The Invention of US10864199

US10864199 describes an extended-release oral dosage form comprising tacrolimus (or an active analogue) for once-daily immunosuppressive treatment. Key aspects of the invention include:

• Release of the active substance over a very extended period, characterized by a substantial zero-order release for a majority of the release.
• Specific in vitro dissolution profile: at most 63.5% release at 12 hours, with at least 8% at 4 hours and/or at least 15% at 8 hours (using USP II paddle or USP I basket, pH 4.5, 0.005% hydroxypropylcellulose, 50 rpm).
• Improved pharmacokinetic (PK) profile compared to conventional dosage forms (e.g., Prograf®) and existing extended-release forms (e.g., Advagraf®), including:
  • Substantially extended time to reach maximal concentration (Tmax).
  • Lower maximal concentrations (Cmax).
  • Higher minimal concentrations (Cmin).
  • Extended mean residence times (MRT).
  • Surprisingly high bioavailability and excellent correlation between Cmin and bioavailability.
  • Reduced intra- and inter-subject variability in Tmax, Cmax, and AUC (0-∞) compared to Advagraf® and Prograf®.
  • Increased bioavailability (AUC(0-∞)) of at least 20% compared to Advagraf® and at least 10% compared to Prograf®.
  • Bioavailability substantially independent of dosing time.
• Reduced side effects related to high peak concentrations (e.g., nephro-/neuro-toxicity, GI side effects).
• Substantial absorption in the colon.
• Possible reduced daily dosage compared to Prograf® (e.g., 25-50% reduction) or Advagraf® (e.g., 1:0.30 to 0.75 ratio).
• The active ingredient is preferably present as a solid dispersion or solid solution in a hydrophilic or water-miscible vehicle.
• A particularly useful preparation method is controlled agglomeration (spraying a melted first composition onto a solid second carrier).

Prior Art References

The patent text references the following prior art:

• Prograf® (NDA no 50708, FDA approved April 27, 2006): A conventional, immediate-release tacrolimus formulation, administered twice daily. Known for rapid absorption (Tmax 1-2 hours), incomplete and variable bioavailability (at most about 20%), and significant inter- and intra-individual variability. It is extensively metabolized by CYP3A4 in the gut wall and liver, and associated with significant side effects including nephro- and neurotoxicity.
• Advagraf® (MR4, EMEA approved April 23, 2007): An existing commercial extended-release tacrolimus product, administered once daily. The present invention claims to provide an improved PK profile compared to Advagraf®, including decreased Cmax and increased bioavailability.
• WO 2005/020993 (by the present inventors): Demonstrated that both fast-release and slow-release tacrolimus tablets could result in improved bioavailability compared to Prograf®. This publication suggested a link between improved bioavailability and tacrolimus being in a dissolved state in the dosage form.
• WO 2005/020994 (by the present inventors): Relates to solid dispersions comprising tacrolimus, further supporting the link between improved bioavailability and the dissolved state of tacrolimus.
• WO 03/004001: Describes a method for preparing particulate material by controlled agglomeration, which the present patent explicitly identifies as a "particularly useful method" for its compositions.
• WO 00/50007 (Lipocine, Inc.): Discloses amphiphilic surfactants as suitable excipients.
• EP-A-0 184 162, EP-A-0 444 659, U.S. Pat. No. 6,387,918: Describe tacrolimus preparation and analogues.

Obviousness Combinations and Motivations

A strong argument for obviousness can be made by combining the knowledge derived from Prograf®, Advagraf®, the inventors' own prior applications (WO 2005/020993, WO 2005/020994, WO 03/004001), and general pharmaceutical formulation principles.

Combination 1: Prograf® + WO 2005/020993 + WO 2005/020994 + WO 03/004001 + General ER Knowledge

1. Motivation to develop an extended-release (ER) formulation:

   • Prograf®'s limitations: A PHOSITA would be acutely aware of Prograf®'s significant drawbacks: low and variable bioavailability, rapid Tmax (1-2 hours), the need for twice-daily (BID) dosing, and associated peak-concentration-related toxicities (nephro-, neuro-toxicity, GI side effects).
   • Patient compliance and therapeutic benefits: The motivation to convert to a once-daily (QD) regimen for improved patient compliance and to reduce dose fluctuations (lower Cmax, higher Cmin) to mitigate side effects and maintain efficacy throughout the dosing interval is a well-established objective in pharmaceutical development for drugs like tacrolimus.
   • Improved bioavailability: The inventors themselves, in WO 2005/020993, had already demonstrated that slow-release tablets could result in improved bioavailability compared to Prograf®. This explicitly points towards the viability of extended release for tacrolimus.

2. Motivation to use solid dispersions/solutions for improved bioavailability:

   • Poor solubility and metabolism: Tacrolimus is practically insoluble in water and extensively metabolized by CYP3A4 in the gut wall and liver. A PHOSITA knows that formulating poorly soluble drugs in a dissolved or finely dispersed state (e.g., solid dispersions or solutions) can significantly enhance dissolution and, consequently, bioavailability by overcoming solubility limitations.
   • Inventors' own guidance: WO 2005/020993 explicitly states that improved bioavailability might be linked to "having tacrolimus in a dissolved state". This is directly supported by WO 2005/020994 (by the same inventors), which relates to solid dispersions comprising tacrolimus and their connection to improved bioavailability. Thus, a PHOSITA would be strongly motivated by the inventors' own prior work to utilize solid dispersion technology.

3. Motivation to use controlled agglomeration for preparation:

   • Known method for solid dispersions: WO 03/004001 (also by the present inventors) details a controlled agglomeration method for preparing particulate material by spraying a melted composition onto a solid carrier. The current patent itself states this is a "particularly useful method" for its compositions, especially when tacrolimus is present as a solid dispersion. This method offers a practical and effective way to manufacture solid dispersions.

Conclusion on Obviousness of Combination 1:
A PHOSITA, faced with the known limitations of Prograf® (low bioavailability, high Cmax, BID dosing, high variability, metabolism), and informed by the inventors' own earlier work demonstrating improved bioavailability through slow-release formulations and solid dispersions of tacrolimus (WO 2005/020993, WO 2005/020994), would have a clear motivation to develop an optimized once-daily extended-release formulation. Employing the controlled agglomeration method taught in WO 03/004001 to create a solid dispersion of tacrolimus would be a logical and predictable choice for achieving enhanced dissolution and sustained release. The specific in vitro dissolution profiles and PK parameters claimed in US10864199, while precise, represent the results of routine optimization of an extended-release formulation employing known technologies (solid dispersions, matrix systems, coatings) for a drug with known absorption challenges, rather than an unpredictable invention. The goal of achieving a flatter PK profile (lower Cmax, higher Cmin, reduced swing/fluctuation) to mitigate toxicity and improve efficacy, as well as extending release to the colon to bypass upper GI metabolism, would be obvious to try with a reasonable expectation of success.

Combination 2: Advagraf® + General ER Optimization Principles

1. Motivation to improve upon Advagraf®:

   • Existing ER, but with room for improvement: Advagraf® was already an extended-release, once-daily tacrolimus product. However, the present patent explicitly highlights areas for improvement, stating it provides a "decreased Cmax value relative to that obtained by administration of the commercial product Advagraf® (MR4)... of at least about 10%... or at least about 55%" and an "increased bioavailability relative to that obtained by administration of the commercially product Advagraf® (MR4)... of at least about 20%... or at least about 65%". It also claims reduced variability compared to Advagraf®.
   • De novo patient issues: The patent notes Advagraf®'s "reduced bioavailability" in de novo transplant patients, attributing it partly to "a relative higher impact of the gastrointestinal metabolism possibly in combination with a lower absorption rate which facilitates a higher first passage extraction fraction by the liver." This would strongly motivate a PHOSITA to develop an even more extended and colon-targeting release to further bypass first-pass metabolism and improve initial exposure and predictability. The patent states that its formulation "primarily releases tacrolimus in the lower ileum and colon where metabolism is less."

2. Means for further optimization:

   • Refined extended release: A PHOSITA would routinely attempt to modify the release characteristics of an existing ER product, such as Advagraf®, to achieve better PK profiles. This involves adjusting the type and amount of matrix-forming polymers (e.g., cellulose derivatives like HPC, HPMC) or coating materials (e.g., acrylic polymers, ethylcellulose) and employing techniques like solid dispersions to ensure adequate drug release over a prolonged period, especially in the less fluid-rich environment of the colon. The selection of specific excipients to control release is within the ordinary skill in the art.
   • Targeting colon absorption: Given the known CYP3A4 metabolism in the upper GI, a PHOSITA would be motivated to design an ER formulation that delivers a substantial portion of the drug to the lower GI tract (colon) for absorption, thereby reducing metabolism and increasing bioavailability. While challenging, the concept of colon-targeting drug delivery is known.

Conclusion on Obviousness of Combination 2:
Starting from Advagraf® as an existing once-daily ER tacrolimus formulation, a PHOSITA would be motivated to further optimize its release profile to achieve superior PK benefits (lower Cmax, higher bioavailability, reduced variability, better initial exposure for de novo patients) and address the recognized limitations, particularly the impact of upper GI metabolism. The pursuit of a more extended and colon-targeted release through routine formulation adjustments and the application of known technologies like solid dispersions (as taught in WO 2005/020994) would be an obvious path with a reasonable expectation of success for improving existing ER tacrolimus therapy. The specific in vitro dissolution characteristics and achieved PK parameters, while advantageous, would likely be seen as the result of such routine optimization efforts.