US 8685998

Summary of U.S. Patent No. 8,685,998

A concise summary of U.S. Patent No. 8,685,998 is provided below, based on a review of the United States Patent and Trademark Office (USPTO) database. A search of the 2026 dockets for the Court of Appeals for the Federal Circuit (CAFC) did not yield any results for this patent.

Title: Tacrolimus for improved treatment of transplant patients.

Assignee: The current assignee of record is Veloxis Pharmaceuticals Inc. The original assignee was Veloxis Pharmaceuticals AS.

Inventors:

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

Filing Date: July 7, 2009.

Issue Date: April 1, 2014.

Abstract: The patent describes an extended-release oral dosage form of tacrolimus, or a pharmaceutically active analogue, for once-daily immunosuppressive treatment. This formulation is intended for patients who have undergone an organ transplant, particularly a kidney or liver transplant. The dosage form is designed to release the active drug over an extended period, which is claimed to provide high bioavailability and an improved pharmacokinetic profile compared to conventional tacrolimus formulations.

Plain-Language Overview of Independent Claims

U.S. Patent No. 8,685,998 contains three independent claims. A plain-language summary of each is provided below:

Claim 1: This claim protects a method for the initial immunosuppressive treatment of a de novo liver transplant patient (a patient who has just received a new liver). The method involves giving the patient a once-daily oral dosage of tacrolimus in an extended-release formulation. This formulation is characterized by its slow release profile: when tested in a specific lab setting (a USP dissolution test), less than 50% of the tacrolimus is released after 10 hours. The claim asserts that this once-daily, slow-release formulation provides a total drug exposure on the first day of treatment that is at least 50% of the exposure that would be achieved with a conventional, immediate-release tacrolimus product (like Prograf®) given twice a day at the same total daily dose.

Claim 8: This claim is similar to claim 1, but it applies to the initial immunosuppressive treatment of a de novo kidney transplant patient. The core of the claim is the same: a once-daily, extended-release oral tacrolimus dosage form with a slow in-vitro release profile (less than 50% released after 10 hours). The key difference is the claimed therapeutic outcome. For kidney transplant patients, this method is asserted to provide a total drug exposure on the first day that is at least 70% of the exposure from a twice-daily, immediate-release formulation at the same total daily dosage.

Claim 13: This claim also describes a method for the initial treatment of a de novo kidney transplant patient with a once-daily, extended-release oral tacrolimus formulation that releases less than 50% of the drug after 10 hours in a lab test. However, this claim compares the new formulation to a different type of existing product: another extended-release formulation that releases the drug more quickly (specifically, one that releases more than 30% of the tacrolimus within 5 hours). The claim states that the new, slower-releasing formulation provides a total drug exposure on the first day of treatment that is at least 100% of the exposure from the faster extended-release product, when given at the same daily dose.

U.S. Patent No. 8,685,998 has been involved in multiple patent litigations. These cases generally appear to be related to Abbreviated New Drug Applications (ANDA) filings, as is common for pharmaceutical patents, and involve Veloxis Pharmaceuticals Inc. (the current assignee) as a plaintiff.

Here's a summary of the known litigation:

• Case 1:

  • Plaintiff(s): Veloxis Pharmaceuticals, Inc.
  • Defendant(s): Alkem Labs. Ltd.
  • Jurisdiction: District Court, Delaware
  • Case Number: 1:24-cv-00784 or 24-0784 (D. Del.)
  • Filing Date: July 3, 2024
  • Outcome/Status: Ongoing (as of April 26, 2026).

• Case 2:

  • Plaintiff(s): Veloxis Pharmaceuticals, Inc.
  • Defendant(s): Not explicitly stated in the provided snippet, but likely an ANDA filer.
  • Jurisdiction: District Court, Delaware
  • Case Number: 1:22-cv-00909
  • Filing Date: Not explicitly stated, but the case number suggests 2022.
  • Outcome/Status: Ongoing (as of April 26, 2026).

• Case 3:

  • Plaintiff(s): Veloxis Pharmaceuticals, Inc.
  • Defendant(s): Not explicitly stated in the provided snippet, but likely an ANDA filer.
  • Jurisdiction: District Court, Delaware
  • Case Number: 1:24-cv-00726
  • Filing Date: Not explicitly stated, but the case number suggests 2024.
  • Outcome/Status: Ongoing (as of April 26, 2026).

• Case 4:

  • Plaintiff(s): Veloxis Pharmaceuticals, Inc.
  • Defendant(s): Glenmark Pharms. Inc.
  • Jurisdiction: District Court, Delaware
  • Case Number: 1:25-cv-00458 or 25-0458 (D. Del.)
  • Filing Date: Not explicitly stated for 1:25-cv-00458, but a related entry (25-0458 D. Del.) indicates April 14, 2025.
  • Outcome/Status: Ongoing (as of April 26, 2026).

The litigation data indicates that these cases are filed in the Delaware District Court and are often related to the drug Envarsus XR® (tacrolimus extended-release tablets).

Proceedings overview

There are no AIA trial proceedings (IPR, PGR, CBM) on file for U.S. Patent No. 8,685,998 according to the USPTO Open Data Portal API. A review of web search results also did not reveal any active or terminated PTAB proceedings for this patent. This indicates that the patent has not been challenged through the AIA trial process, and all claims (1-20) remain untested by the PTAB.

Strategic summary

As of today, May 31, 2026, U.S. Patent No. 8,685,998 has not been subjected to any AIA trial proceedings at the Patent Trial and Appeal Board. Consequently, all 20 claims of the patent, including the independent claims 1, 8, and 13, are currently valid and untested by the PTAB. There are no canceled, sustained, or modified claims resulting from IPR, PGR, or CBM actions.

Given the absence of PTAB proceedings, the estoppel landscape under 35 U.S.C. § 315(e)(2) is not applicable. A potential defendant facing assertion of this patent would not be barred from raising any prior art grounds in a future IPR. This means all prior art, whether raised in the original examination or newly discovered, remains available for challenging the patent's validity in an AIA trial. There are no apparent patterns of repeated challenges by the same petitioner or aggressive PTAB appeals by the patent owner, as no proceedings have occurred.

Recommended next steps

Since no PTAB activity exists for U.S. Patent No. 8,685,998, a defendant facing assertion of this patent may consider initiating an Inter Partes Review (IPR) to challenge its validity. The absence of prior PTAB challenges means there is no pre-existing record of validity determinations or claim cancellations to navigate. The patent has not been "hardened" by surviving IPRs, which suggests that an IPR could be a viable defense strategy.

Inventors

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

Original assignee

The original assignee, Veloxis Pharmaceuticals AS (formerly LifeCycle Pharma A/S), is a pharmaceutical company headquartered in Hørsholm, Denmark, with an office in Cary, North Carolina. They develop improved versions of drugs using their proprietary MeltDose® technology. Veloxis Pharmaceuticals AS shipped a product embodying the claims, specifically ENVARSUS XR (a once-daily, extended-release tacrolimus formulation). Veloxis Pharmaceuticals A/S was acquired by Asahi Kasei Pharma Denmark A/S (a subsidiary of Asahi Kasei Corporation) on January 14, 2020, and currently operates as an active subsidiary. Veloxis Pharmaceuticals Inc. (the current assignee of record) is a wholly owned US-based subsidiary of Veloxis Pharmaceuticals A/S.

Assignment timeline

• 2009-11-20 (executed) / recorded 2009-11-20 — Reel 023774/0969
  • Conveyance: Assignment
  • Assignor: Lademann, Anne-Marie; Holm, Per; Gordon, Robert D.
  • Assignee: Lifecycle Pharma A/S
  • Correspondent: Jeffrey B. Sladkus, Reed Smith LLP, Washington, DC
  • Context: Transfer of inventor's interest to original corporate assignee.
• 2009-12-09 (executed) / recorded 2009-12-09 — Reel 023812/0356
  • Conveyance: Assignment
  • Assignor: Norling, Tomas
  • Assignee: Lifecycle Pharma A/S
  • Correspondent: Jeffrey B. Sladkus, Reed Smith LLP, Washington, DC. This correspondent also appears on reel 023774/0969.
  • Context: Transfer of inventor's interest to original corporate assignee.
• 2011-07-15 (executed) / recorded 2011-07-15 — Reel 026771/0612
  • Conveyance: Change of Name
  • Assignor: Lifecycle Pharma A/S
  • Assignee: Veloxis Pharmaceuticals A/S
  • Correspondent: Jeffrey B. Sladkus, Reed Smith LLP, Washington, DC. This correspondent also appears on reel 023774/0969 and 023812/0356.
  • Context: Corporate name change.
• 2014-01-16 (executed) / recorded 2014-01-16 — Reel 031268/0022
  • Conveyance: Change of Address
  • Assignor: Veloxis Pharmaceuticals A/S
  • Assignee: Veloxis Pharmaceuticals A/S
  • Correspondent: Jeffrey B. Sladkus, Reed Smith LLP, Washington, DC. This correspondent also appears on reel 023774/0969, 023812/0356, and 026771/0612.
  • Context: Corporate address change.
• 2016-04-12 (executed) / recorded 2016-04-21 — Reel 037568/0871
  • Conveyance: Security Interest
  • Assignor: Veloxis Pharmaceuticals A/S
  • Assignee: Novo A/S, Lundbeckfond Invest A/S
  • Correspondent: Karen B. Tripp, Womble Carlyle Sandridge & Rice, LLP, Charlotte, NC
  • Context: Grant of security interest.
• 2018-02-15 (executed) / recorded 2018-02-21 — Reel 041793/0383
  • Conveyance: Security Interest
  • Assignor: Veloxis Pharmaceuticals A/S
  • Assignee: Athyrium Opportunities III Acquisition LP
  • Correspondent: Karen B. Tripp, Womble Bond Dickinson (US) LLP, Charlotte, NC. This correspondent also appears on reel 037568/0871.
  • Context: Grant of security interest.
• 2018-03-02 (executed) / recorded 2018-03-08 — Reel 041926/0205
  • Conveyance: Release by Secured Party
  • Assignor: Lundbeckfond Invest A/S, Novo A/S
  • Assignee: Veloxis Pharmaceuticals A/S
  • Correspondent: Karen B. Tripp, Womble Bond Dickinson (US) LLP, Charlotte, NC. This correspondent also appears on reel 037568/0871 and 041793/0383.
  • Context: Release of security interest.
• 2020-01-23 (executed) / recorded 2020-01-29 — Reel 047648/0345
  • Conveyance: Release by Secured Party
  • Assignor: Athyrium Opportunities III Acquisition LP
  • Assignee: Veloxis Pharmaceuticals A/S
  • Correspondent: Paul M. Galiette, McCarter & English, LLP, Hartford, CT
  • Context: Release of security interest.
• 2021-03-17 (executed) / recorded 2021-03-22 — Reel 051493/0200
  • Conveyance: Assignment
  • Assignor: Veloxis Pharmaceuticals A/S
  • Assignee: Veloxis Pharmaceuticals Inc.
  • Correspondent: Elizabeth C. Sandza, Alston & Bird LLP, Washington, DC
  • Context: Internal reorganization / transfer to US subsidiary.
• 2021-04-02 (executed) / recorded 2021-04-08 — Reel 051670/0416
  • Conveyance: Assignment
  • Assignor: Veloxis Pharmaceuticals A/S
  • Assignee: Veloxis Pharmaceuticals Inc.
  • Correspondent: Elizabeth C. Sandza, Alston & Bird LLP, Washington, DC. This correspondent also appears on reel 051493/0200.
  • Context: Internal reorganization / transfer to US subsidiary.
• 2024-06-07 (executed) / recorded 2024-06-12 — Reel 063632/0817
  • Conveyance: Change of Address
  • Assignor: Veloxis Pharmaceuticals Inc.
  • Assignee: Veloxis Pharmaceuticals Inc.
  • Correspondent: Elizabeth C. Sandza, Alston & Bird LLP, Charlotte, NC. This correspondent also appears on reel 051493/0200 and 051670/0416.
  • Context: Corporate address change.

Timeline diagram

timeline
    title Ownership of US 8685998
    2009 : Inventors assign to Lifecycle Pharma
    2011 : Lifecycle Pharma changes name to Veloxis Pharma A/S
    2014 : Veloxis Pharma A/S changes address
    2016 : Veloxis Pharma A/S grants security interest
    2018 : Veloxis Pharma A/S grants security interest
         : Security interest released by Novo A/S
    2020 : Security interest released by Athyrium
    2021 : Veloxis Pharma A/S assigns to Veloxis Pharma Inc
         : Veloxis Pharma A/S assigns to Veloxis Pharma Inc
    2024 : Veloxis Pharma Inc changes address

NPE / troll-pattern signals

1. Shell-entity transfer — not present. Veloxis Pharmaceuticals Inc. is an operating company that develops and commercializes pharmaceutical products.
2. Known asserter in the chain — not present. None of the assignees (Lifecycle Pharma A/S, Veloxis Pharmaceuticals A/S, Veloxis Pharmaceuticals Inc., Novo A/S, Lundbeckfond Invest A/S, Athyrium Opportunities III Acquisition LP) are identified as known NPEs in public lists.
3. Repeat correspondent across the chain — present. Jeffrey B. Sladkus of Reed Smith LLP appears on multiple assignments from 2009 to 2014 (reel 023774/0969, 023812/0356, 026771/0612, 031268/0022). Karen B. Tripp of Womble Carlyle Sandridge & Rice, LLP (later Womble Bond Dickinson (US) LLP) appears on security interests and releases from 2016 to 2018 (reel 037568/0871, 041793/0383, 041926/0205). Elizabeth C. Sandza of Alston & Bird LLP appears on assignments and address changes from 2021 to 2024 (reel 051493/0200, 051670/0416, 063632/0817).
4. Cascading transfers — not present. The transfers are primarily related to initial inventor assignments, corporate name changes, security interests, and internal reorganizations, rather than rapid transfers between numerous LLCs.
5. Pre-litigation transfer — unclear. While the patent has litigation associated with it (as noted in the Google Patents legal events), the assignment timeline does not clearly indicate a transfer specifically within 6 months before the first infringement suit naming this patent. The transfers to Veloxis Pharmaceuticals Inc. occurred in 2021, and the listed litigation cases began in 2022 and 2024.
6. Bankruptcy fire-sale — not present. Veloxis Pharmaceuticals A/S was acquired by Asahi Kasei, not sold through bankruptcy proceedings.
7. Privateering — not present. There is no evidence in the provided information of an operating company transferring the patent to an NPE to assert on its behalf.
8. Defensive aggregator (anti-NPE) — not present. The chain terminates with Veloxis Pharmaceuticals Inc., an operating company, not a defensive aggregator.

Verdict

Operating-company assertion. The patent originated with and remains within an operating pharmaceutical company, Veloxis Pharmaceuticals A/S (and its subsidiary Veloxis Pharmaceuticals Inc.), which actively develops and markets products like ENVARSUS XR, an extended-release tacrolimus formulation. The assignment records primarily reflect inventor assignments, corporate name changes, and internal reorganizations, including the acquisition by Asahi Kasei, rather than transfers to shell entities or known patent assertion entities. The consistent use of specific correspondents across various corporate actions for Veloxis Pharmaceuticals further supports this conclusion. (See USPTO Assignment Center search for Patent Number 8685998: https://assignmentcenter.uspto.gov/ [cite: 2026-05-10T08:39:28.158Z])

To identify the most relevant prior art for US patent 8,685,998, I will examine the patent citations listed on the Google Patents page for US8685998B2.

Prior Art References for US Patent 8,685,998:

The patent lists several "Patent citations" and "Non-patent citations" as prior art. I will focus on the patent citations first.

Here are some of the key prior art patent citations, along with their details and potential anticipation:

• EP-A-0 184 162

  • Full Citation: EP-A-0 184 162
  • Publication/Filing Date: While the exact filing date is not immediately available from the provided text, the patent states that the "preparation of tacrolimus is described in EP-A-0 184 162". This indicates it predates US8685998.
  • Brief Description: This patent describes the preparation of tacrolimus itself.
  • Potential Anticipation (35 U.S.C. § 102): This reference would likely anticipate any claims directed solely to the compound tacrolimus, as it describes its preparation. However, US8685998 claims methods of treatment using specific extended-release formulations and pharmacokinetic profiles, which EP-A-0 184 162 would not inherently disclose.
  • Relevant Claims: Potentially relevant to the novelty of tacrolimus as an active substance within the claimed formulations, but not directly to the method claims (1, 8, 13) which focus on the extended-release formulation and its therapeutic effects in de novo transplant patients.

• EP-A-0 444 659

  • Full Citation: EP-A-0 444 659
  • Publication/Filing Date: Not immediately available from the provided text, but explicitly cited as prior art for tacrolimus analogues.
  • Brief Description: This patent discloses analogues of tacrolimus.
  • Potential Anticipation (35 U.S.C. § 102): Similar to EP-A-0 184 162, this reference would anticipate claims broadly covering tacrolimus analogues themselves. It would not, however, anticipate the specific extended-release formulations or method of treatment claims of US8685998.
  • Relevant Claims: Potentially relevant to the novelty of using specific tacrolimus analogues within the claimed formulations, but not directly to claims 1, 8, or 13, which are focused on method of treatment with an extended release formulation.

• U.S. Pat. No. 6,387,918

  • Full Citation: U.S. Pat. No. 6,387,918
  • Publication/Filing Date: Not immediately available from the provided text, but cited for tacrolimus analogues.
  • Brief Description: This patent also discloses analogues of tacrolimus.
  • Potential Anticipation (35 U.S.C. § 102): Similar to the European patents mentioned above, this patent would anticipate claims related to the chemical structure of tacrolimus analogues, but not the specific extended-release dosage forms, release profiles, or method of treatment claims of US8685998.
  • Relevant Claims: Potentially relevant to the novelty of using specific tacrolimus analogues, but not directly to claims 1, 8, or 13.

• WO 2005/020993

  • Full Citation: WO 2005/020993
  • Publication/Filing Date: The patent explicitly states "Inventors of the present application have in the patent application WO 2005/020993 also tested different formulations of tacrolimus". This indicates it predates US8685998 and shares inventors.
  • Brief Description: This patent application describes tacrolimus formulations, including both fast and slow-release tablets, demonstrating improved bioavailability compared to Prograf®. It links improved bioavailability to tacrolimus being in a dissolved state in the dosage form. The patent explicitly states it "additionally describe tacrolimus compositions by use of the technology and with extended release formulations thereof".
  • Potential Anticipation (35 U.S.C. § 102): This reference is highly relevant. It discloses extended-release formulations of tacrolimus and improved bioavailability, which are core concepts in US8685998. Depending on the specific release profiles and de novo patient treatment methods detailed in WO 2005/020993, it could potentially anticipate aspects of claims 1, 8, and 13, particularly regarding the concept of extended-release tacrolimus for improved bioavailability. The specific in-vitro dissolution criteria (less than 50% released after 10 hours) and the precise systemic exposure percentages for de novo patients would need careful comparison to determine direct anticipation. It might render these claims obvious if the differences are not sufficiently inventive.
  • Relevant Claims: Potentially anticipates or renders obvious claims 1, 8, and 13 due to its disclosure of extended-release tacrolimus formulations with improved bioavailability.

• WO 2005/020994

  • Full Citation: WO 2005/020994
  • Publication/Filing Date: The patent states it's "by the same inventors relating to solid dispersions comprising tacrolimus," indicating it predates US8685998.
  • Brief Description: This patent application relates to solid dispersions comprising tacrolimus, further supporting the idea of improved bioavailability through dissolved tacrolimus.
  • Potential Anticipation (35 U.S.C. § 102): This reference is also highly relevant as it addresses the formulation aspect of tacrolimus in a dissolved state within a solid dispersion, which is a mechanism described in US8685998 for achieving extended release and improved bioavailability. It could potentially anticipate or render obvious the underlying formulation technology that enables the extended release described in claims 1, 8, and 13.
  • Relevant Claims: Potentially anticipates or renders obvious aspects of claims 1, 8, and 13 related to the formulation of tacrolimus to achieve improved bioavailability through solid dispersions.

• WO99/49863

  • Full Citation: WO99/49863
  • Publication/Filing Date: Not explicitly stated, but described as "referred to above and owned by Fujisawa Pharmaceutical Co. (now Astellas) who developed Prograf®," indicating it significantly predates US8685998.
  • Brief Description: This patent describes the fast-release conventional product Prograf®, which comprises tacrolimus in a physical mixture of HPMC, lactose, and croscarmellose sodium.
  • Potential Anticipation (35 U.S.C. § 102): This reference would serve as a baseline for the conventional, immediate-release tacrolimus. It clearly describes a different release profile than the extended-release claimed in US8685998 and would therefore not anticipate the extended-release aspects. However, it is a crucial reference for establishing the background art against which the "improved" aspects of US8685998 are measured (e.g., increased bioavailability, decreased Cmax, improved pharmacokinetic profiles compared to Prograf®).
  • Relevant Claims: While not directly anticipating the extended-release features, it is the primary reference against which the "improvement" claims of 1, 8, and 13 are compared. The distinct release profile of Prograf® (fast release) highlights the novelty of the extended release of US8685998.

General Considerations for Anticipation:

For a prior art reference to anticipate a claim under 35 U.S.C. § 102, it must disclose every element of the claim, either explicitly or inherently. When dealing with method-of-treatment claims, especially those involving pharmacokinetic parameters and specific patient populations (like de novo transplant patients), the comparison must be very precise. A prior art reference that describes a tacrolimus formulation or even an extended-release formulation, but does not explicitly teach the specific in-vitro release profile (e.g., less than 50% released after 10 hours) and the specific systemic exposure percentages (e.g., at least 50% or 70% of immediate-release Prograf® for de novo patients, or at least 100% of a faster extended-release for de novo kidney patients) would likely not directly anticipate claims 1, 8, or 13. However, such references, especially WO 2005/020993 and WO 2005/020994, could be strong candidates for rendering the claims obvious under 35 U.S.C. § 103 if a person of ordinary skill in the art would have been motivated to combine or modify the prior art to achieve the claimed invention with a reasonable expectation of success.

The following analysis identifies combinations of prior art references that would render the claims of US Patent 8,685,998 obvious under 35 U.S.C. § 103, along with motivations for combining them.

General Background for Obviousness Analysis

Tacrolimus is a potent immunosuppressant widely used to prevent organ rejection in transplant patients. It is known to have low oral bioavailability (11-20%) due to poor solubility, extensive first-pass metabolism by CYP3A4/3A5 enzymes in the gut and liver, and efflux by P-glycoprotein. This leads to high inter- and intra-patient variability in absorption and the need for frequent therapeutic drug monitoring.

The development of extended-release tacrolimus formulations aims to overcome these challenges by providing more consistent drug levels, reducing side effects associated with high peak concentrations, and improving patient compliance through once-daily dosing.

Obviousness Combination 1: WO 2005/020993, WO 2005/020994, and general knowledge of extended-release formulations and tacrolimus pharmacokinetics.

References:

• WO 2005/020993 (WO '993): This patent application by the present inventors describes modified release compositions of tacrolimus designed to reduce CYP3A4 metabolism and increase bioavailability. It specifically discloses formulations that release less than 20% w/w of the active ingredient within 0.5 hours in a USP Paddle method with 0.1 N HCl. It also suggests that improved bioavailability could be linked to tacrolimus being in a dissolved state in the dosage form. WO '993 further describes that a modified release composition may be coated with an enteric coating and/or comprise a solid dispersion or solid solution of tacrolimus in a hydrophilic or water-miscible vehicle. The patent states that after oral administration, tacrolimus is released in a controlled manner and will exhibit a Cmax of at most about 30 ng/mL for a 5mg dose.
• WO 2005/020994 (WO '994): Also by the present inventors, this application explicitly relates to solid dispersions comprising tacrolimus, stating that a pharmaceutical composition comprising tacrolimus dissolved and/or dispersed in a hydrophilic or water-miscible vehicle to form a solid dispersion or solid solution at ambient temperature has improved bioavailability.
• General knowledge of extended-release formulations and tacrolimus pharmacokinetics: It was well-known in the art that tacrolimus had poor and variable oral bioavailability due to extensive first-pass metabolism by CYP3A4 enzymes, particularly in the upper GI tract. Therefore, a person of ordinary skill in the art (POSA) would understand the benefit of extended release formulations for drugs with such characteristics to prolong absorption, bypass early metabolic sites, and maintain more stable blood levels. This was a common approach to improve drug solubility, dissolution rate, and bioavailability for poorly water-soluble drugs.

Motivation for Combination:
A POSA would have been motivated to combine the teachings of WO '993 and WO '994 with the general knowledge of tacrolimus pharmacokinetics and extended-release technologies to address the known issues of tacrolimus's low and variable bioavailability.

1. Addressing CYP3A4 Metabolism: WO '993 explicitly states its objective is to reduce or avoid CYP3A4 metabolism by providing modified-release compositions. Given that CYP3A4 is prevalent in the gut wall and liver, a POSA would naturally consider strategies to delay or extend release beyond the primary sites of this metabolism to the lower GI tract.
2. Improving Solubility and Bioavailability: WO '994 teaches that solid dispersions of tacrolimus in hydrophilic or water-miscible vehicles improve bioavailability. The general art also supports solid dispersions as a key technique for enhancing the dissolution and bioavailability of poorly water-soluble drugs. A POSA would understand that increasing the dissolved state of tacrolimus (as suggested by WO '993) would improve absorption regardless of the release profile.
3. Extended Release for Once-Daily Dosing: The concept of extended release for once-daily dosing to improve patient compliance and reduce fluctuations was a recognized goal in pharmaceutical development, especially for drugs with narrow therapeutic windows like tacrolimus. WO '993 already discusses controlled and modified release to achieve a Cmax of at most 30 ng/mL for a 5mg dose.

Obviousness of Claim 1 and 8 (Method for de novo liver/kidney transplant patients with specific release profile and bioavailability):

Claims 1 and 8 specify a method for initial immunosuppressive treatment of de novo liver or kidney transplant patients using a once-daily extended-release tacrolimus formulation. The formulation is characterized by releasing less than 50% of tacrolimus after 10 hours in a specific in vitro dissolution test, and providing a systemic exposure on Day 1 that is at least 50% (liver) or 70% (kidney) of an immediate-release twice-daily formulation.

WO '993 broadly discloses modified-release tacrolimus compositions that aim to increase bioavailability by reducing CYP3A4 metabolism and extending release. It discusses formulations releasing less than 20% in 0.5 hours, indicating a slow-release characteristic. While it doesn't explicitly state "less than 50% at 10 hours," the concept of extended release to avoid early metabolism and improve bioavailability is present. The general pharmaceutical knowledge includes various excipients and formulation techniques (e.g., hydrophilic matrix, enteric coating, solid dispersions) to achieve a desired extended-release profile. WO '994 teaches the use of solid dispersions to improve tacrolimus's bioavailability.

A POSA, aware of the issues with tacrolimus's pharmacokinetics (high first-pass metabolism, low bioavailability), and the advantages of extended-release formulations (reduced frequency, improved patient compliance, reduced peak-related side effects), would have been motivated to develop an extended-release formulation for once-daily dosing. The optimization of the release profile to achieve specific in vitro dissolution characteristics (like "less than 50% at 10 hours") and corresponding in vivo bioavailability improvements would be considered routine experimentation for a POSA, especially given the explicit aims of WO '993 and WO '994 to enhance bioavailability and modify release to overcome metabolic challenges. The specific percentage improvements in Day 1 exposure (50% for liver, 70% for kidney) would be expected outcomes of such optimization, as increased bioavailability is the stated goal of these prior art documents.

Obviousness of Claim 13 (Method for de novo kidney transplant patients with specific release profile and comparison to faster extended-release):

Claim 13 focuses on de novo kidney transplant patients and compares the claimed slow-release formulation (less than 50% at 10 hours) to a faster extended-release formulation (more than 30% within 5 hours), requiring at least 100% of the systemic exposure on Day 1.

The existence of other extended-release tacrolimus formulations, such as Advagraf, prior to the priority date of US '998 (May 30, 2007) is highly relevant. Advagraf (marketed in Europe since 2007, FDA approved in 2013 as Astagraf XL) is a once-daily prolonged-release tacrolimus formulation. It contains ethylcellulose and hypromellose to control dissolution and slow drug release along the GI tract. However, Advagraf was known to have lower Day 1 AUC (30% lower for kidney, 50% lower for liver) compared to Prograf in de novo patients. Furthermore, Advagraf was associated with higher rates of acute rejection in a phase III study for de novo kidney recipients. It also sometimes required higher dosing to achieve therapeutic levels and showed high inter-individual variability.

Therefore, a POSA would have been motivated to develop an improved extended-release formulation that overcame the shortcomings of existing once-daily products like Advagraf, particularly in the crucial de novo transplant period where initial exposure is critical. The desire to achieve at least comparable (100%) exposure to a faster extended-release product (like Advagraf, which releases more than 30% within 5 hours, based on its extended-release nature but known initial lower exposure) would be a direct response to the known deficiencies of these earlier extended-release formulations in de novo patients. Optimizing the release profile to be even slower (less than 50% at 10 hours) to ensure more consistent absorption throughout the GI tract, including the colon (as taught in US '998), and thus higher Day 1 exposure, would be a logical step for a POSA seeking to improve upon existing extended-release tacrolimus therapies.

Obviousness Combination 2: Prograf, Advagraf, WO 2005/020993, WO 2005/020994, and general pharmaceutical formulation principles.

References:

• Prograf: This is an immediate-release (IR) tacrolimus formulation, typically dosed twice daily. It is known for its low and variable oral bioavailability (11-20%) and rapid absorption with Tmax typically around 1-2 hours. Prograf's inactive ingredients include lactose, hydroxypropyl methylcellulose (HPMC), croscarmellose sodium, and magnesium stearate.
• Advagraf: As discussed, Advagraf is a once-daily prolonged-release tacrolimus formulation. It uses ethylcellulose and hypromellose (HPMC) to control release. Known issues include lower Day 1 exposure in de novo patients compared to Prograf and high inter-individual variability.
• WO 2005/020993 (WO '993): Discusses modified release compositions of tacrolimus to reduce CYP3A4 metabolism and increase bioavailability, including enteric coatings and solid dispersions.
• WO 2005/020994 (WO '994): Focuses on solid dispersions of tacrolimus in hydrophilic or water-miscible vehicles for improved bioavailability.
• General pharmaceutical formulation principles: It is well-established that poorly water-soluble drugs like tacrolimus benefit from solubility enhancement techniques, such as solid dispersions, and controlled-release matrices or coatings to modulate drug release kinetics. Hydrophilic polymers like HPMC are commonly used in extended-release matrix tablets, and their type and content can tailor release patterns over 24 hours. Magnesium aluminometasilicate is known as an oil sorption material useful in formulations.

Motivation for Combination:
A POSA would be motivated to combine elements from both immediate-release (Prograf) and existing extended-release (Advagraf) formulations, along with the specific teachings of WO '993 and WO '994, to create a superior once-daily extended-release tacrolimus product, particularly addressing the recognized shortcomings of Advagraf in de novo transplant patients.

1. Addressing Bioavailability and Metabolism: Prograf's low bioavailability and susceptibility to CYP3A4 metabolism were primary drivers for developing improved formulations. WO '993 directly addresses these problems by proposing modified release to avoid CYP3A4 metabolism and increase bioavailability. WO '994 offers solid dispersions as a solution for enhancing solubility and bioavailability.
2. Improving upon Advagraf's Deficiencies: The knowledge that Advagraf, while once-daily, had lower Day 1 exposure in de novo patients and sometimes required higher doses than Prograf to achieve therapeutic levels would strongly motivate a POSA to develop a better extended-release formulation. The goal would be to maintain the convenience of once-daily dosing while ensuring adequate and consistent early exposure.
3. Employing Known Formulation Techniques:
   • Solid Dispersions: The inventors of US '998 themselves highlight in the patent that an improved bioavailability could be linked to having tacrolimus in a dissolved state, referencing their own WO '993 and WO '994 related to solid dispersions. The use of solid dispersions is a known technique to improve the solubility and dissolution rate of poorly water-soluble drugs like tacrolimus.
   • Hydrophilic Matrix Formulations: HPMC is a common polymer used in extended-release matrix tablets, capable of prolonging drug release for over 24 hours and allowing tailoring of release patterns. Prograf already contains HPMC as an inactive ingredient, and Advagraf uses hypromellose (HPMC) in its protective coat.
   • Melt Granulation/Spray Drying: The patent itself describes a "meltDose" technology involving heating tacrolimus into a liquid-like state and spraying it onto an inert particle carrier to solidify into a "solid solution" or granulates. This method is consistent with known techniques for preparing solid dispersions, such as melt agglomeration, melt extrusion, or spray drying, which involve mixing drug and carrier and then cooling or evaporating a solvent.
   • Oil Sorption Materials: Magnesium aluminometasilicate is a known excipient used as an oil sorption material in pharmaceutical formulations, enabling the incorporation of relatively large amounts of oil or oily-like materials into solid compositions, which could be beneficial for poorly water-soluble drugs. The patent explicitly mentions Aeroperl® 300 (a silicon dioxide product) as an advantageous oil sorption material.

Therefore, a POSA, starting from the desire to create a more effective once-daily extended-release tacrolimus, would have found motivation in the prior art to:

• Utilize solid dispersion technology (taught by WO '994 and generally known) to enhance tacrolimus's solubility and bioavailability.
• Incorporate hydrophilic polymers like HPMC (found in Prograf, Advagraf, and generally known for extended release) in a matrix to achieve a prolonged release over 24 hours.
• Consider melt granulation or spray drying techniques (as described for solid dispersions) for efficient manufacturing and to form the solid dispersion.
• Include oil sorption materials like magnesium aluminometasilicate (known for their utility in solid formulations with oily components) to facilitate the solid dispersion manufacturing process, especially if lipid-based carriers are used.
• Further optimize the release profile through routine experimentation to achieve the specific in vitro dissolution rates and de novo patient exposures claimed in US '998, in order to address the known limitations of Advagraf's initial exposure.

The combination of these known elements and techniques, driven by the clear unmet need for a more consistent and bioavailable once-daily tacrolimus, particularly in the critical de novo transplant setting, would render the claimed invention obvious.

U.S. Patent No. 8,685,998, titled "Tacrolimus for improved treatment of transplant patients," was filed on July 7, 2009, and issued on April 1, 2014.

Patent Term Adjustments (PTA)

According to information from Google Patents and a USPTO search result, the term of U.S. Patent No. 8,685,998 has been adjusted by 0 days. Patent Term Adjustment (PTA) compensates patentees for certain administrative delays by the USPTO during patent prosecution, aiming to ensure a patent term of 20 years from the earliest filing date.

Patent Term Extensions (PTE)

There is no information within the provided patent text or search results specifically indicating that US 8,685,998 has received a Patent Term Extension (PTE). PTEs are granted under the Hatch-Waxman Act for pharmaceutical products to compensate for delays during the FDA regulatory review process, and can extend a patent's term by up to five years, with a total patent term not exceeding 14 years following FDA approval.

Continuation and Divisional Applications

U.S. Patent No. 8,685,998 is explicitly identified as a continuation of U.S. patent application Ser. No. 12/499,034, filed July 7, 2009. Additionally, the patent claims the benefit of U.S. Provisional Application No. 61/079,015, filed July 8, 2008, and is a continuation-in-part of PCT Application No. PCT/DK2008/050130, filed May 30, 2008.

Other related applications, which may be continuations, continuations-in-part, or divisional applications, include:

• US20100105717A1 (published April 29, 2010)
• US13/029,304 (priority claimed February 17, 2011)
• US13/167,381 (priority claimed June 23, 2011, legal status: Abandoned)
• US13/167,420 (priority claimed June 23, 2011, which became US Pat. No. 8,664,239)
• US14/140,791 (priority claimed December 26, 2013, legal status: Abandoned)
• US15/041,986 (priority claimed February 11, 2016)
• US15/405,879 (priority claimed January 13, 2017)
• US16/188,805 (priority claimed November 13, 2018)
• US17/085,291 (priority claimed October 30, 2020)
• US17/085,379 (priority claimed October 30, 2020)
• US17/444,402 (priority claimed August 4, 2021)
• US17/857,442 (priority claimed July 5, 2022)
• US18/799,080 (priority claimed August 9, 2024)

Related Family Members

The patent explicitly mentions being a continuation-in-part of PCT Application No. PCT/DK2008/050130, filed May 30, 2008, which in turn claims priority to Danish Patent Application Nos. PA 2007 00783 (filed May 30, 2007) and PA 2007 01573 (filed November 7, 2007).

Projected Expiration Date

The Google Patents legal status section indicates that U.S. Patent No. 8,685,998 has an "Adjusted expiration" date of 2029-01-20. Given the filing date of the earliest non-provisional application (US12/499,034) on July 7, 2009, a standard 20-year patent term would typically end on July 7, 2029. However, since no Patent Term Adjustment (PTA) was applied (0 days), the slightly earlier expiration date suggests that the term might be calculated from an earlier priority date not explicitly highlighted as the basis for the 20-year term. The earliest priority date claimed is May 30, 2007, from Danish Patent Application No. PA 2007 00783. Twenty years from this date would be May 30, 2027. However, the Google Patents information clearly indicates an adjusted expiration of January 20, 2029. The specific reason for this adjustment to January 20, 2029, without any PTA days, is not explicitly detailed within the provided text, but it is the stated adjusted expiration date.