US 8664239

Patent Summary: US 8,664,239 B2

Title: Tacrolimus for improved treatment of transplant patients

Assignee: Veloxis Pharmaceuticals Inc.

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

Filing Date: June 23, 2011

Issue Date: March 4, 2014

Abstract:
The patent describes an extended-release oral dosage form of tacrolimus, an immunosuppressant drug used in transplant patients. This formulation is designed for once-daily administration and aims to provide improved pharmacokinetic properties compared to conventional, immediate-release tacrolimus formulations. Key features of the invention include a release of the active substance over a prolonged period, leading to a higher bioavailability, a lower peak blood concentration (Cmax), and a more consistent therapeutic level of the drug over a 24-hour period. The claimed formulation is characterized by a specific in vitro dissolution profile, where at most 63.5% of the tacrolimus is released at the 12-hour mark under specified test conditions. The invention also covers methods of treatment using this formulation, including converting patients from other tacrolimus regimens.

Plain-Language Overview of Independent Claims:

At the time of its issuance, US Patent 8,664,239 included several independent claims. Here is a plain-language summary of their core concepts:

• Claim 1: This claim protects a method for the immunosuppressive treatment of a transplant patient by administering a once-daily, extended-release oral dosage form of tacrolimus. The key feature of this dosage form is its specific dissolution rate: when tested in a lab under conditions simulating the gastrointestinal tract (USP II paddle or USP I basket method at pH 4.5 with 0.005% hydroxypropylcellulose at 50 rpm), it releases no more than 63.5% of its tacrolimus content within 12 hours. This controlled release is intended to provide a stable and effective level of the drug in the patient's body over a full 24-hour period.

• Claim 11: This claim is also for a method of immunosuppressive treatment in a transplant patient using a once-daily, extended-release oral tacrolimus dosage form. This claim further specifies the in-vivo (in the body) performance of the drug. It requires that upon administration of a single 5 mg dose to healthy subjects who have fasted, the average maximum blood concentration (Cmax) of tacrolimus does not exceed 15 ng/mL, while the overall drug exposure (mean AUC(0-96 h)) is at least 45 ng·h/L. This ensures that the drug is released slowly to avoid high initial peaks (which can be associated with side effects) but is still well-absorbed over time.

• Claim 18: This claim focuses on a method for converting a transplant patient from a twice-daily immediate-release tacrolimus regimen (like Prograf®) to a once-daily regimen using the extended-release formulation. The method involves administering a total daily dose of the new formulation that is reduced by 20% to 34% compared to the patient's previous total daily dose of the immediate-release tacrolimus. This reduction is possible due to the improved bioavailability of the extended-release formulation.

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 8,664,239 as of April 26, 2026. However, the Google Patents page for this patent indicates that its family has been involved in litigation. Further investigation beyond the scope of this specific search would be required to determine the details of any past or ongoing legal disputes concerning this patent family.

Litigation involving US Patent 8,664,239 includes the following case:

1. Veloxis Pharmaceuticals, Inc. v. Accord Healthcare, Inc. and [Intas Pharmaceuticals LTD.](/litigations/by-defendant/Intas%20Pharmaceuticals%20LTD.)

• Plaintiff(s): Veloxis Pharmaceuticals, Inc.
• Defendant(s): Accord Healthcare, Inc. and Intas Pharmaceuticals LTD.
• Jurisdiction: District of Delaware
• Case Number: Not explicitly provided, but the article mentions it was filed in the District of Delaware. Further search would be needed to pinpoint the exact case number for this specific patent within the multi-patent lawsuit.
• Filing Date: July 7, 2022
• Outcome or Current Status: This case was filed in response to Accord Healthcare's submission of an Abbreviated New Drug Application (ANDA) to the FDA, seeking approval to market generic versions of Veloxis's ENVARSUS XR (tacrolimus extended-release tablets) prior to the expiration of several patents, including US 8,664,239. Veloxis alleges patent infringement, seeking to prevent the defendants from manufacturing their ANDA products and requesting damages if the products are launched. The case was ongoing as of the July 8, 2022, article.

Google Patents also indicates a US case filed in Delaware District Court with case number 1:26-cv-00467 that includes US8664239. While the plaintiff and defendant are not specified in the Google Patents listing, this indicates ongoing litigation related to the patent.

Proceedings overview

As of May 31, 2026, there are no AIA trial proceedings (Inter Partes Review, Post-Grant Review, or Covered Business Method) on file for US Patent 8,664,239. This indicates that the patent has not been subjected to challenges at the Patent Trial and Appeal Board (PTAB) through these specific mechanisms.

Strategic summary

Currently, all claims of US 8,664,239 remain unchallenged and, therefore, are neither canceled nor sustained by PTAB proceedings. Since no AIA trials have been initiated, there is no estoppel landscape established under 35 U.S.C. § 315(e)(2) for any potential petitioner or their privies. All prior-art grounds remain available for future challenges, whether in litigation or a new PTAB petition. The absence of PTAB activity suggests that the patent has not yet faced validity challenges in this forum, or that previous challenges, if any, were resolved prior to an AIA trial filing, or that potential challengers have not found suitable grounds or motivation to file.

Recommended next steps

Since there is no PTAB activity on file for US 8,664,239, a defendant currently facing assertion of this patent should consider the following:

• Evaluate potential IPR/PGR challenges: Assess the patent's claims against prior art to determine if strong grounds for an Inter Partes Review (IPR) or Post-Grant Review (PGR) exist. While no challenges have been filed to date, this does not preclude the existence of invalidating prior art.
• Monitor for future filings: Keep an eye on the USPTO's PTAB E2E system for any newly filed petitions against US 8,664,239. The absence of past filings does not guarantee future inaction.

Inventors

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

All inventors were employed by Veloxis Pharmaceuticals AS, the entity that filed the patent application. No unusual patterns, such as all inventors departing the original assignee within 12 months of filing, were detected.

Original assignee

The original assignee listed on the issued patent is Veloxis Pharmaceuticals AS.

Veloxis Pharmaceuticals Inc. (the successor entity) markets ENVARSUS XR® (tacrolimus extended-release capsules), which embodies the claims of US 8,664,239. The company is a fully integrated specialty pharmaceutical company focused on the global development and commercialization of medications utilized by transplant patients. Veloxis Pharmaceuticals A/S, the Danish predecessor, was acquired by Asahi Kasei in March 2020 and subsequently reorganized into Veloxis Pharmaceuticals Inc., headquartered in Cary, North Carolina, USA. The current status is operating.

Assignment timeline

• 2011-06-23 (executed) / recorded 2011-07-15 — Reel 016335/0536

  • Conveyance: ASSIGNMENT
  • Assignor: VELOXIS PHARMACEUTICALS AS
  • Assignee: LIFECYCLE PHARMA A/S
  • Correspondent: WOODCOCK WASHBURN LLP, CIRA CENTRE, 12TH FLOOR, 2929 ARCH STREET, PHILADELPHIA, PA 19104-2891. This firm recurs multiple times in this chain.
  • Context: Assignment from original applicant to an intermediate entity.

• 2011-06-28 (executed) / recorded 2011-07-15 — Reel 016335/0547

  • Conveyance: ASSIGNMENT (Change of Name)
  • Assignor: VELOXIS PHARMACEUTICALS A/S (Change of Name) LIFECYCLE PHARMA A/S
  • Assignee: VELOXIS PHARMACEUTICALS A/S
  • Correspondent: WOODCOCK WASHBURN LLP, CIRA CENTRE, 12TH FLOOR, 2929 ARCH STREET, PHILADELPHIA, PA 19104-2891. This firm recurs multiple times in this chain.
  • Context: Lifecycle Pharma A/S changed its name to Veloxis Pharmaceuticals A/S.

• 2011-06-28 (executed) / recorded 2011-07-15 — Reel 016335/0542

  • Conveyance: ASSIGNMENT
  • Assignor: VELOXIS PHARMACEUTICALS AS
  • Assignee: VELOXIS PHARMACEUTICALS A/S
  • Correspondent: WOODCOCK WASHBURN LLP, CIRA CENTRE, 12TH FLOOR, 2929 ARCH STREET, PHILADELPHIA, PA 19104-2891. This firm recurs multiple times in this chain.
  • Context: Concurrent assignment from original applicant to the newly named Veloxis Pharmaceuticals A/S.

• 2014-01-15 (executed) / recorded 2014-01-16 — Reel 016590/0734

  • Conveyance: ASSIGNMENT (Change of Address)
  • Assignor: VELOXIS PHARMACEUTICALS A/S
  • Assignee: VELOXIS PHARMACEUTICALS A/S
  • Correspondent: WOODCOCK WASHBURN LLP, CIRA CENTRE, 12TH FLOOR, 2929 ARCH STREET, PHILADELPHIA, PA 19104-2891. This firm recurs multiple times in this chain.
  • Context: Internal change of address for Veloxis Pharmaceuticals A/S.

• 2016-04-12 (executed) / recorded 2016-04-12 — Reel 018442/0834

  • Conveyance: SECURITY INTEREST
  • Assignor: VELOXIS PHARMACEUTICALS A/S
  • Assignee: NOVO A/S, LUNDBECKFOND INVEST A/S
  • Correspondent: GORRISSEN FEDERSPIEL, H. C. ANDERSENS BOULEVARD 12, COPENHAGEN V DK-1553, DENMARK.
  • Context: Veloxis Pharmaceuticals A/S granted a security interest to investors.

• 2018-02-14 (executed) / recorded 2018-02-15 — Reel 020896/0200

  • Conveyance: SECURITY INTEREST
  • Assignor: VELOXIS PHARMACEUTICALS A/S
  • Assignee: ATHYRIUM OPPORTUNITIES III ACQUISITION LP
  • Correspondent: LATHAM & WATKINS LLP, 885 THIRD AVENUE, NEW YORK, NY 10022-4834. This firm recurs multiple times in this chain.
  • Context: Veloxis Pharmaceuticals A/S granted a security interest to another investor.

• 2018-02-28 (executed) / recorded 2018-03-02 — Reel 020967/0056

  • Conveyance: RELEASE BY SECURED PARTY
  • Assignor: LUNDBECKFOND INVEST A/S, NOVO A/S
  • Assignee: VELOXIS PHARMACEUTICALS A/S
  • Correspondent: LATHAM & WATKINS LLP, 885 THIRD AVENUE, NEW YORK, NY 10022-4834. This firm recurs multiple times in this chain.
  • Context: Release of security interest from Novo A/S and Lundbeckfond Invest A/S.

• 2020-01-20 (executed) / recorded 2020-01-23 — Reel 022137/0308

  • Conveyance: RELEASE BY SECURED PARTY
  • Assignor: ATHYRIUM OPPORTUNITIES III ACQUISITION LP
  • Assignee: VELOXIS PHARMACEUTICALS A/S
  • Correspondent: LATHAM & WATKINS LLP, 885 THIRD AVENUE, NEW YORK, NY 10022-4834. This firm recurs multiple times in this chain.
  • Context: Release of security interest from Athyrium Opportunities III Acquisition LP.

• 2021-03-17 (executed) / recorded 2021-04-02 — Reels 023348/0919 and 023348/0927

  • Conveyance: ASSIGNMENT OF ASSIGNORS INTEREST
  • Assignor: VELOXIS PHARMACEUTICALS A/S
  • Assignee: VELOXIS PHARMACEUTICALS INC.
  • Correspondent: WOODCOCK WASHBURN LLP, CIRA CENTRE, 12TH FLOOR, 2929 ARCH STREET, PHILADELPHIA, PA 19104-2891. This firm recurs multiple times in this chain.
  • Context: Corporate restructuring/re-domiciliation from Danish A/S entity to US Inc. entity.

• 2024-03-13 (executed) / recorded 2024-03-25 — Reel 026601/0309

  • Conveyance: ASSIGNMENT OF ASSIGNORS INTEREST
  • Assignor: LADEMANN, ANNE-MARIE, HOLM, PER, Gordon, Robert D
  • Assignee: LIFECYCLE PHARMA A/S
  • Correspondent: MCDERMOTT WILL & EMERY LLP, 2000 AVENUE OF THE STARS, SUITE 400 NORTH, LOS ANGELES, CA 90067.
  • Context: Assignment of inventor rights from multiple inventors to Lifecycle Pharma A/S (likely confirmatory assignment).

• 2024-03-13 (executed) / recorded 2024-03-25 — Reel 026601/0303

  • Conveyance: ASSIGNMENT OF ASSIGNORS INTEREST
  • Assignor: NORLING, TOMAS
  • Assignee: LIFECYCLE PHARMA A/S
  • Correspondent: MCDERMOTT WILL & EMERY LLP, 2000 AVENUE OF THE STARS, SUITE 400 NORTH, LOS ANGELES, CA 90067.
  • Context: Assignment of inventor rights from an inventor to Lifecycle Pharma A/S (likely confirmatory assignment).

Timeline diagram

timeline
    title Ownership of US 8664239
    2011 : Filed by Veloxis AS
         : Assigned to Veloxis A/S
    2014 : Patent issued
         : Veloxis A/S address change
    2016 : Security interest to NOVO/LUNDBECK
    2018 : Security interest to ATHYRIUM
         : Security released by NOVO/LUNDBECK
    2020 : Security released by ATHYRIUM
    2021 : Assigned to Veloxis Inc
    2024 : Inventors assign to Lifecycle Pharma A/S

NPE / troll-pattern signals

1. Shell-entity transfer — Not present. The patent has consistently been held by Veloxis Pharmaceuticals A/S or Veloxis Pharmaceuticals Inc., which are operating companies developing and commercializing pharmaceutical products. Lifecycle Pharma A/S was a predecessor/related entity.
2. Known asserter in the chain — Not present. None of the assignees (Veloxis Pharmaceuticals AS, Lifecycle Pharma A/S, Veloxis Pharmaceuticals A/S, Veloxis Pharmaceuticals Inc., Novo A/S, Lundbeckfond Invest A/S, Athyrium Opportunities III Acquisition LP) are known NPEs. Veloxis Pharmaceuticals Inc. has been involved in patent litigation to protect its product, ENVARSUS XR®, against generic manufacturers (e.g., Accord Healthcare and Intas Pharmaceuticals).
3. Repeat correspondent across the chain — Present. WOODCOCK WASHBURN LLP appears as correspondent for multiple assignments from 2011 to 2021 (Reel 016335/0536, 016335/0547, 016335/0542, 016590/0734, 023348/0919, 023348/0927). LATHAM & WATKINS LLP also appears for multiple security-related transactions from 2018 to 2020 (Reel 020896/0200, 020967/0056, 022137/0308). This is typical for in-house counsel or a long-standing outside counsel relationship with an operating company.
4. Cascading transfers — Not present. The transfers involve corporate reorganizations or securing/releasing financing, not rapid consecutive assignments to different, potentially related, shell entities.
5. Pre-litigation transfer — Not present. The patent was issued in 2014. Litigation identified for this patent family (though not specifically this patent number in the snippet, but related to ENVARSUS XR patents) indicates a suit filed in July 2022. The last corporate assignment to Veloxis Pharmaceuticals Inc. was in April 2021 (Reel 023348/0919, 023348/0927), well over 6 months prior to the litigation. The inventor assignments in March 2024 were much later.
6. Bankruptcy fire-sale — Not present. Veloxis Pharmaceuticals A/S was acquired by Asahi Kasei, not dissolved or in bankruptcy.
7. Privateering — Not present. Veloxis Pharmaceuticals Inc. is the operating company asserting its own patents to protect its product from generic competition.
8. Defensive aggregator (anti-NPE) — Not present. The chain does not terminate at a known defensive aggregator.

Verdict

Operating-company assertion

The assignment records show a clear chain of title from the initial filing entity to Veloxis Pharmaceuticals Inc., an operating pharmaceutical company that markets ENVARSUS XR®, a product embodying the claims of this patent. The litigation activity observed is consistent with an operating company defending its commercialized product against generic competition. The recurring correspondents indicate a consistent legal relationship, not a series of disparate shell entities.

USPTO Assignment Center search page for 8664239: https://assignmentcenter.uspto.gov/patents/8664239

To identify the most relevant prior art for US Patent 8,664,239, I will access the patent information directly from the USPTO database. This will allow me to examine the patent's cited references, which are typically the most pertinent prior art considered during examination.

Once I have the list of cited prior art, I will analyze each reference to provide its full citation, publication/filing date, a brief description, and which claims of US 8,664,239 it potentially anticipates under 35 U.S.C. § 102. Anticipation under 35 U.S.C. § 102 means that a single prior art reference discloses every element of a claimed invention, either explicitly or inherently.

The USPTO website provides a Patent Public Search tool which can be used to search for patents and their citations. I will use this tool to retrieve the necessary information.
To identify the most relevant prior art for US Patent 8,664,239, I need to access the patent's full text and its cited references from the USPTO database. Since I cannot directly interact with a live database, I will rely on the provided patent text to extract the cited references. The patent text itself explicitly lists several prior art documents.

From the provided full patent text, the following prior art references are explicitly mentioned and incorporated by reference:

1. EP-A-0 184 162: Cited for the preparation of tacrolimus.
2. EP-A-0 444 659: Cited for analogues of tacrolimus.
3. U.S. Pat. No. 6,387,918: Cited for analogues of tacrolimus.
4. WO99/49863 (Fujisawa Pharmaceutical Co.): Described as sustained release tacrolimus formulations. This also mentions being granted as U.S. Pat. No. 6,440,458, U.S. Pat. No. 6,576,259, and U.S. Pat. No. 6,884,433.
5. WO 2005/020993 (by the present inventors): Discusses different tacrolimus formulations tested in Beagle dogs and minipigs, showing improved bioavailability.
6. WO 2005/020994 (by the same inventors): Relates to solid dispersions comprising tacrolimus.
7. WO 03/004001: Describes a method for preparing particulate material by controlled agglomeration.
8. WO 00/50007 (Lipocine, Inc.): Discloses amphiphillic surfactants.

Analysis of Prior Art and Potential Anticipation under 35 U.S.C. § 102:

Anticipation under 35 U.S.C. § 102 requires that a single prior art reference discloses every element of a claimed invention, either expressly or inherently.

Here's an analysis of the identified prior art documents:

1. EP-A-0 184 162

   • Full Citation: EP-A-0 184 162
   • Publication/Filing Date: Not explicitly stated in the provided text, but it predates the priority date of US8664239 (2007-05-30) as it describes the preparation of tacrolimus.
   • Brief Description: Describes the preparation of tacrolimus.
   • Potential Anticipation: This reference likely anticipates the mere compound "tacrolimus" itself. However, US8664239 claims extended release oral dosage forms of tacrolimus with specific dissolution profiles and pharmacokinetic properties, as well as methods of treatment and conversion using such forms. Therefore, EP-A-0 184 162, while fundamental to the existence of tacrolimus, would not anticipate the novel formulation or method claims of US8664239, as it does not disclose all elements of those claims.

2. EP-A-0 444 659

   • Full Citation: EP-A-0 444 659
   • Publication/Filing Date: Not explicitly stated, but predates US8664239.
   • Brief Description: Discloses analogues of tacrolimus.
   • Potential Anticipation: Similar to EP-A-0 184 162, this reference would anticipate the existence of certain tacrolimus analogues but would not anticipate the specific extended release formulations or methods claimed in US8664239.

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

   • Full Citation: U.S. Pat. No. 6,387,918
   • Publication/Filing Date: Not explicitly stated, but predates US8664239.
   • Brief Description: Discloses analogues of tacrolimus.
   • Potential Anticipation: Like the above, this patent would anticipate the existence of certain tacrolimus analogues but not the specific extended release formulations or methods claimed in US8664239.

4. WO99/49863 (Fujisawa Pharmaceutical Co.)

   • Full Citation: WO99/49863, also granted as U.S. Pat. No. 6,440,458, U.S. Pat. No. 6,576,259, and U.S. Pat. No. 6,884,433.
   • Publication/Filing Date: Not explicitly stated for WO99/49863, but the "Prior art keywords" for US8664239 list a "Prior art date" of 2007-05-30. Given the "WO99" in the publication number, its filing/publication would be in 1999.
   • Brief Description: Describes sustained release tacrolimus formulations with a T63.2% value between 0.7 and 15 hours. The most preferred embodiment has a T63.6 value of 2-5 hours. Example formulations have T63.6% values from 1.9 to 8.2 hours.
   • Potential Anticipation: This is a highly relevant reference as it specifically deals with sustained-release tacrolimus formulations.
     • Claim 1 of US8664239 requires a release of at most 63.5% of the active substance at the 12-hour time point under specified dissolution conditions. WO99/49863 describes formulations where the time for dissolving 63.2% (T63.2% value) is between 0.7 and 15 hours. While some formulations in WO99/49863 could fall within the "at most 63.5% at 12 hours" (e.g., a formulation that releases 63.2% at 15 hours would also release less than 63.5% at 12 hours), the stated "most preferred embodiment" has a T63.6 value of 2-5 hours, and example formulations range from 1.9 to 8.2 hours. These faster release profiles likely do not meet the "at most 63.5% at 12 hours" limitation of Claim 1. However, a detailed comparison of the specific dissolution curves and conditions would be required to definitively determine anticipation. The patent text of US8664239 itself distinguishes its "very extended period of time" release from WO99/49863, stating that a formulation with 63.2% released in 42 minutes "seems to be only marginally different from the conventional immediate release formulation of tacrolimus." This suggests that the invention believes its release profile is significantly slower than those generally preferred or exemplified in WO99/49863.
     • Claim 11 of US8664239 specifies pharmacokinetic parameters (Cmax at most 15 ng/mL and AUC(0-96 h) at least 45 ng·h/L for a 5mg dose in fasted healthy subjects). WO99/49863 discusses "improved bioavailability" but does not explicitly provide these specific Cmax and AUC values, making direct anticipation of Claim 11 less likely without further detailed analysis of the in vivo data in WO99/49863.
     • Claim 18 of US8664239 relates to a conversion method with a specific dose reduction. While WO99/49863 describes sustained release, it does not explicitly disclose this specific conversion ratio or method.

5. WO 2005/020993 (by the present inventors)

   • Full Citation: WO 2005/020993
   • Publication/Filing Date: Not explicitly stated, but "WO 2005" indicates a publication year of 2005, predating the priority date of US8664239.
   • Brief Description: Tested different tacrolimus formulations (fast and slow release) in Beagle dogs and minipigs, demonstrating improved bioavailability compared to Prograf®. This indicates improved bioavailability could be linked to tacrolimus being in a dissolved state.
   • Potential Anticipation: This reference, by the same inventors, focuses on improved bioavailability. While it generally discusses improved bioavailability for tacrolimus, it does not necessarily disclose the specific extended release profile of Claim 1 or the precise pharmacokinetic parameters of Claim 11. It also doesn't specify the conversion method of Claim 18. It serves as background art highlighting the challenge and general direction of research.

6. WO 2005/020994 (by the same inventors)

   • Full Citation: WO 2005/020994
   • Publication/Filing Date: Not explicitly stated, but "WO 2005" indicates a publication year of 2005, predating the priority date of US8664239.
   • Brief Description: Relates to solid dispersions comprising tacrolimus.
   • Potential Anticipation: This reference relates to the formulation type (solid dispersions) that could be used in an extended release product. However, it does not, by itself, disclose the specific release profile, pharmacokinetic parameters, or conversion methods claimed in US8664239. The invention states that solid dispersions "will contribute to a predictable and constant in vivo release of tacrolimus" and that "at least a part of tacrolimus ... is present in the composition in the form of a solid solution including a molecular dispersion and a solid dispersion." This suggests WO 2005/020994 teaches a component or a way of formulating that is used in US8664239, rather than anticipating the entire claimed invention.

7. WO 03/004001

   • Full Citation: WO 03/004001
   • Publication/Filing Date: "WO 03" indicates a publication year of 2003, predating the priority date of US8664239.
   • Brief Description: Describes a process for the preparation of particulate material by a controlled agglomeration method, involving spraying a melted first composition onto a second solid carrier medium. This method is described as "particularly useful" for preparing the pharmaceutical compositions of US8664239.
   • Potential Anticipation: This reference anticipates the method of preparing particulate material, which may be a component of the claimed dosage form. However, it does not anticipate the specific extended release profile, pharmacokinetic parameters, or treatment methods of US8664239. It teaches a process for making a component, not the final product with all its claimed characteristics.

8. WO 00/50007 (Lipocine, Inc.)

   • Full Citation: WO 00/50007 in the name of Lipocine, Inc.
   • Publication/Filing Date: "WO 00" indicates a publication year of 2000, predating the priority date of US8664239.
   • Brief Description: Discloses amphiphilic surfactants suitable for use in compositions.
   • Potential Anticipation: This reference anticipates the use of certain excipients (surfactants) that may be included in the dosage forms of US8664239. It does not anticipate the overall extended release formulation, its performance characteristics, or the methods of treatment.

Conclusion on Most Relevant Prior Art:

Based on the descriptions, WO99/49863 (Fujisawa Pharmaceutical Co.) appears to be the most relevant prior art. It specifically addresses sustained-release tacrolimus formulations, which is the core subject of US8664239. While US8664239 aims to distinguish itself by a more extended release profile and improved pharmacokinetic performance, WO99/49863's disclosure of sustained-release tacrolimus and its dissolution characteristics would be the closest reference for anticipation of the formulation claims, particularly Claim 1. A thorough comparison of the dissolution methodologies and results would be critical to determine if any specific embodiment within WO99/49863 explicitly or inherently meets the "at most 63.5% at 12 hours" criterion of Claim 1.

The other references (EP-A-0 184 162, EP-A-0 444 659, U.S. Pat. No. 6,387,918, WO 2005/020993, WO 2005/020994, WO 03/004001, WO 00/50007) provide background on tacrolimus, its analogues, formulation components, or general manufacturing methods, but do not appear to disclose the full scope of the specific extended release dosage form, its in vivo characteristics, or the particular conversion methods claimed in US8664239.

Obviousness Analysis under 35 U.S.C. § 103 for US Patent 8,664,239

This analysis assesses whether the claimed invention of US Patent 8,664,239 would have been obvious to a person having ordinary skill in the art (PHOSITA) at the time of the invention (priority date 2007-05-30), considering combinations of the identified prior art. A PHOSITA in this field would be a pharmaceutical formulator or pharmacologist with experience in developing controlled-release drug delivery systems, particularly for immunosuppressants or drugs with narrow therapeutic windows and complex absorption profiles.

1. Obviousness of Claim 1 (Dissolution Profile)

Claim 1: A method for immunosuppressive treatment of a patient in need thereof comprising administering a once daily extended release oral dosage form comprising tacrolimus or a pharmaceutically active analogue thereof, wherein the dosage form releases the active substance over an extended period of time defined by a release of at the most 63.5% of the content of the active substance at the 12 hours time point defined by in vitro dissolution and when tested according to the USP II dissolution test (paddle) or USP I dissolution test (basket) form in a medium at pH 4.5 and comprising 0.005% hydroxypropylcellulose, and a rotation of 50 rpm.

Combination of Prior Art: WO99/49863 (Fujisawa Pharmaceutical Co.) in view of general knowledge in pharmaceutical formulation for once-daily dosing.

• WO99/49863's Disclosure: WO99/49863 explicitly describes sustained-release tacrolimus formulations characterized by a T63.2% value (time for dissolving 63.2% of tacrolimus) between 0.7 and 15 hours. While it notes that the most preferred embodiment has a T63.6 value of 2-5 hours, and examples range from 1.9 to 8.2 hours, the broad range of 0.7 to 15 hours for 63.2% release demonstrates that sustained release over a longer period was already contemplated.
• Motivation for Combination/Modification: A PHOSITA would be motivated to develop once-daily tacrolimus formulations to enhance patient compliance and convenience, thereby mitigating issues related to missed doses and variable drug concentrations. [cite: "An increased bioavailability in combination with an extended release formulation may allow a reduction in the dosage units taken by a patient, e.g. down to a single dose daily without risk of lack of clinical effect due to low doses in the last past of the dosing interval.", "a further advantage of an extended-release-dosage-form invention is the possibility of obtaining an effective therapeutic response with a decreased dosage compared to traditional oral treatment."] Given that WO99/49863 already teaches sustained-release tacrolimus, and its disclosed T63.2% range extends up to 15 hours, a PHOSITA would find it obvious to modify the release rate of these formulations to achieve an even more prolonged effect suitable for 24-hour dosing. Techniques for extending drug release, such as adjusting the concentration of rate-controlling excipients (e.g., polymers like hydroxypropylcellulose, which is explicitly mentioned in the patent classification A61K9/1652 and A61K9/2054, and the dissolution method of Claim 1), or modifying the matrix composition, are well-known and routinely applied in pharmaceutical formulation. [cite: "the desired release profile of the pharmaceutical composition may be provided by combining one or more of the following possibilities.", "the release may also be pH independent, e.g., by providing the composition with a controlled release coating such as, e.g. a cellulose based coating like e.g. ethylcellulose or by providing the composition in the form of a matrix composition such as, e.g., a hydrophilic cellulose polymer matrix type e.g. based on HPMC."] Achieving a dissolution profile of "at most 63.5% at the 12 hours time point" would be a predictable outcome of such routine optimization aimed at once-daily administration. The specific in vitro dissolution conditions described in Claim 1 are standard testing methodologies and do not introduce non-obviousness.

2. Obviousness of Claim 11 (Pharmacokinetic Profile)

Claim 11: A method for immunosuppressive treatment of a patient in need thereof comprising administering a once daily extended release oral dosage form comprising tacrolimus or a pharmaceutically active analogue thereof, wherein upon oral administration of a single 5 mg dose of the oral dosage form in fasted state to at least 6 healthy subjects, the mean maximal concentration (C max ) of tacrolimus in blood is at the most 15 ng/mL and the mean AUC(0-96 h) of tacrolimus in blood is at least 45 ng·h/L.

Combination of Prior Art: WO99/49863 (sustained release tacrolimus, improved bioavailability, suppressed variability) + WO 2005/020993 (improved bioavailability of tacrolimus formulations) + WO 2005/020994 (solid dispersions of tacrolimus) + general pharmacokinetic principles for controlled release drugs.

• Prior Art Disclosures:
  • WO99/49863: Teaches sustained-release tacrolimus formulations designed to achieve "improved bioavailability" and "suppressed variation of its absorbability."
  • WO 2005/020993 and WO 2005/020994: These references, by the same inventors, underscore the importance of improved bioavailability for tacrolimus. WO 2005/020994 specifically discusses solid dispersions as a means to enhance bioavailability, and the present patent acknowledges that solid dispersions "will contribute to a predictable and constant in vivo release of tacrolimus." [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 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.", "a smaller particle size in micro and nano scale and preferable a molecular solution will contribute to a predictable and constant in vivo release of tacrolimus."]
  • General Pharmacokinetic Principles: For drugs like tacrolimus, which exhibit a narrow therapeutic window and significant Cmax-related toxicities (e.g., nephro- and neuro-toxicity, GI side effects), achieving a lower Cmax while maintaining adequate overall exposure (AUC) for a once-daily regimen is a recognized and highly desirable objective in controlled-release drug design. [cite: "Tacrolimus is known to induce significant side effects, of nephro- or neuro-toxic origin, as well as GI side-effects and others.", "the plasma concentration versus time profile show an extended period of time in which the plasma concentration is maintained within the therapeutic window (i.e., the plasma concentration leads to a therapeutic effect) without leading to serious unwanted side effects. Thus, a reduction in peak concentration is also observed.", "the compositions provide a significant reduction in side effects, especially side effect related to a high peak concentration (such as, e.g., nephro- and neuro-toxicity, diarrhea, constipation, abdominal pain, nausea etc) and provide for an extended release of tacrolimus leading to a better therapy."]
• Motivation for Combination/Modification: A PHOSITA would be motivated to combine sustained-release approaches (WO99/49863) with bioavailability-enhancing techniques (WO 2005/020993, WO 2005/020994) to develop a tacrolimus formulation optimized for once-daily administration. The expectation of "improved bioavailability" and "suppressed variation" from WO99/49863, combined with the goal of reducing peak concentrations to minimize side effects, would lead a PHOSITA to anticipate a pharmacokinetic profile characterized by a lower Cmax and a stable or improved AUC. [cite: 4, "the plasma concentration versus time profile show an extended period of time in which the plasma concentration is maintained within the therapeutic window (i.e., the plasma concentration leads to a therapeutic effect) without leading to serious unwanted side effects. Thus, a reduction in peak concentration is also observed."] The specific numerical values for Cmax (≤15 ng/mL) and AUC(0-96 h) (≥45 ng·h/L) in Claim 11, while quantitative, represent the successful optimization of expected benefits when applying these known principles to tacrolimus for once-daily extended release, rather than an unexpected result. The patent itself highlights that such "reduced peak concentration is also observed" and that "enhanced bioavailability may also result in a more reproducible (i.e., less variable compared to that of Prograf®) release profile." [cite: "the plasma concentration versus time profile show an extended period of time in which the plasma concentration is maintained within the therapeutic window (i.e., the plasma concentration leads to a therapeutic effect) without leading to serious unwanted side effects. Thus, a reduction in peak concentration is also observed.", "enhanced bioavailability may also result in a more reproducible (i.e., less variable compared to that of Prograf®) release profile."]

3. Obviousness of Claim 18 (Conversion Method)

Claim 18: A method for converting a patient undergoing immunosuppressive treatment from a twice daily immediate release oral tacrolimus regimen to a once daily extended release oral tacrolimus regimen, wherein the total daily dose of tacrolimus administered in the once daily extended release oral tacrolimus regimen is reduced by from 20% to 34% compared to the total daily dose of tacrolimus administered in the twice daily immediate release tacrolimus regimen.

Combination of Prior Art: Knowledge of Prograf® (conventional immediate-release tacrolimus) + WO99/49863 (sustained release tacrolimus with improved bioavailability) / WO 2005/020993 (improved bioavailability tacrolimus formulations) + general clinical and pharmacokinetic principles of dose adjustment.

• Prior Art Disclosures:
  • Prograf®: Represents the widely used immediate-release tacrolimus, administered twice daily with known absorption variability, for which blood levels are routinely monitored. [cite: "Tacrolimus (Prograf®) was approved by the FDA in April of 1994 under NDA No.", "Prograf® is indicated for the prophylaxis of organ rejection in patients receiving allogeneic liver or kidney transplants.", "Tacrolimus administered as Prograf® capsules, exhibits a large inter- and intra-individual variability of its absorption and metabolism. Because of this variability, standard dosing is not an accurate predictor of concentration. In clinical use, tacrolimus dose-adjustments are frequently required based on monitoring of tacrolimus trough blood concentrations."]
  • WO99/49863 and WO 2005/020993: These references teach the development of sustained-release tacrolimus formulations that provide improved bioavailability compared to conventional forms. The present patent itself asserts that its extended-release formulation offers "an increased bioavailability." [cite: 4, "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®.", "An increased bioavailability in combination with an extended release formulation may allow a reduction in the dosage units taken by a patient, e.g. down to a single dose daily without risk of lack of clinical effect due to low doses in the last past of the dosing interval."]
  • General Clinical/Pharmacokinetic Principles: It is a fundamental and routine clinical practice for a PHOSITA (e.g., a physician or clinical pharmacologist) to adjust the dose of a drug when converting a patient from one formulation to another, especially if the new formulation exhibits altered bioavailability. The objective is to maintain equivalent therapeutic exposure (AUC) to ensure consistent efficacy and minimize potential toxicity. Given that tacrolimus requires careful blood level monitoring, dose adjustments are a standard part of patient management. [cite: "In clinical use, tacrolimus dose-adjustments are frequently required based on monitoring of tacrolimus trough blood concentrations.", "two compositions are regarded as bioequivalent if the value of the parameter used is within 80-125% of that of Prograf® or a similar commercially available tacrolimus-containing product used in the test."]
• Motivation for Combination/Modification: A PHOSITA would be highly motivated to transition patients from a twice-daily immediate-release tacrolimus regimen (e.g., Prograf®) to a more convenient once-daily extended-release regimen to improve patient adherence. [cite: "An increased bioavailability in combination with an extended release formulation may allow a reduction in the dosage units taken by a patient, e.g. down to a single dose daily without risk of lack of clinical effect due to low doses in the last past of the dosing interval.", "the pharmaceutical compositions according to the invention provide significant higher bioavailability of tacrolimus, which may reduce the number of daily administered dosage units, and reduce or abolish the need for administration in connection with food intake, which provide for a higher degree of freedom for the recipient of the pharmaceutical compositions, and consequently the patients acceptance and/or compliance may be significantly improved."] Since the extended-release formulations are designed to offer "increased bioavailability," it would be a straightforward and obvious pharmacokinetic calculation to reduce the daily dose of the more bioavailable extended-release formulation to achieve systemic exposure comparable to the previous regimen. The specific dose reduction range of 20% to 34% (equivalent to administering 66% to 80% of the original dose) is an empirical adjustment that would directly stem from observed bioavailability differences in clinical trials. The patent itself explicitly supports this, stating that "a similar bioavailability and an improved profile after administration in a dose that is at the about most about 85% w/w such as, e.g., at the most about 80% w/w, at the most about 75%, at the most about 70% w/w, at the most about 65% w/w, at the most about 60% w/w, at the most about 55% w/w or at the most about 50% w/w of the dose of tacrolimus administered in the form of Prograf®." [cite: "a similar bioavailability and an improved profile after administration in a dose is that is at the about most about 85% w/w such as, e.g., at the most about 80% w/w, at the most about 75%, at the most about 70% w/w, at the most about 65% w/w, at the most about 60% w/w, at the most about 55% w/w or at the most about 50% w/w of the dose of tacrolimus administered in the form of Prograf® or a similar commercially available tacrolimus-containing product or as a commercial available extended release product including Advagraf®."] It further notes, "One method for such conversion from inter alia Prograf® to once daily regimen is decreasing the daily dosage of the tacrolimus immediate release regimen with between 25% to 50%, such as with between 30% to 40%, preferable with approximately 33%." [cite: "One method for such conversion from inter alia Prograf® to once daily regimen is decreasing the daily dosage of the tacrolimus immediate release regimen with between 25% to 50%, such as with between 30% to 40%, preferable with approximately 33%."] This explicit description within the patent demonstrates that such a dose reduction for conversion was an expected and logical consequence of the improved formulation's characteristics, thus making the claimed method obvious to a PHOSITA.