US 11419823

As a senior US patent analyst, I have reviewed the provided documentation for US patent 11,419,823. While I cannot perform a live search of the USPTO database or CAFC dockets, the provided patent text contains the necessary information, including litigation history.

Summary of US Patent 11,419,823

• Title: Stabilized tacrolimus composition (Source: US11419823B2 - Google Patents)
• Assignee: Veloxis Pharmaceuticals Inc (Source: US11419823B2 - Google Patents)
• Inventors: Nikolaj Skak, Per Holm (Source: US11419823B2 - Google Patents)
• Filing Date: November 13, 2018 (Source: US11419823B2 - Google Patents)
• Issue Date: August 23, 2022 (Source: US11419823B2 - Google Patents)
• Abstract: The invention relates to a stable pharmaceutical composition comprising a solid dispersion of tacrolimus in a vehicle further comprising a stabilizing agent capable of providing a pH below 7 in the composition, as measured after re-dispersion in water, and preventing or reducing the formation upon storage of major degradation products of tacrolimus, in particular the 8-epitacrolimus. (Source: US11419823B2 - Google Patents, Abstract)

Plain-Language Overview of Independent Claims

This patent's claims protect a stabilized, sustained-release pharmaceutical formulation of the immunosuppressant drug tacrolimus. The core invention involves using a specific type of stabilizing agent in a "solid dispersion" (where the drug is molecularly dispersed in a solid carrier) to prevent the drug from degrading into an impurity known as 8-epitacrolimus.

• Claim 1: This claim protects a sustained-release formulation where tacrolimus is the only active drug. The formulation is a solid dispersion containing a stabilizing agent that is a "metal chelating agent" (it binds to metal ions) and ensures the composition has an acidic pH (below 7). The key performance requirement is that the amount of the stabilizing agent must be sufficient to limit the formation of the 8-epitacrolimus impurity to less than 0.5% by weight after storing the product for 12 weeks at 25°C and 60% relative humidity. (Source: US11419823B2, Claim 1)

• Claim 17: This claim is for a similar sustained-release, solid dispersion formulation of tacrolimus that is acidic (pH below 7) and meets the same 0.5% impurity limit after 12 weeks of storage. The specific inventive step here is the precise identity of the stabilizing agent, which must be an organic acid chosen from the list of oxalic acid, tartaric acid, or citric acid. (Source: US11419823B2, Claim 17)

• Claim 19: This claim covers a sustained-release formulation where tacrolimus is the sole active ingredient, characterized by having a very low initial amount of the 8-epitacrolimus impurity (below 0.2% by weight). Like claim 1, it requires a metal-chelating stabilizing agent that provides an acidic pH and is present in a sufficient amount to ensure the impurity level does not rise above 0.5% after 12 weeks of storage under the specified conditions. (Source: US11419823B2, Claim 19)

• Claim 25: This claim protects the final dosage form: a sustained-release tablet. The tablet contains a dispersion of tacrolimus as the sole active ingredient, some amount of the 8-epitacrolimus impurity, and a stabilizing agent. This stabilizer must be a metal-chelating agent that results in an acidic pH (below 7) and must be sufficient to keep the total 8-epitacrolimus impurity level below the 0.5% threshold after 12 weeks of storage. (Source: US11419823B2, Claim 25)

Litigation Status

The provided patent information indicates that the patent family has been subject to litigation. Cases have been filed in the Delaware District Court. (Source: US11419823B2 - Google Patents, "Family has litigation" section, URLs: https://portal.unifiedpatents.com/litigation/Delaware%20District%20Court/case/1%3A25-cv-00458, https://portal.unifiedpatents.com/litigation/Delaware%20District%20Court/case/1%3A24-cv-00784, https://portal.unifiedpatents.com/litigation/Delaware%20District%20Court/case/1%3A24-cv-00726)

As a patent attorney, I have reviewed the litigation landscape for US patent 11,419,823.

Here's a list of known litigation involving US Patent 11,419,823:

1. Case Name: 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: U.S. District Court for the District of Delaware
   • Filing Date: July 7, 2022. (The Google Patents entry mentions a case filed on 2022-07-07 in D. Delaware for this patent, and Law Street Media details a complaint filed by Veloxis against Accord and Intas on July 7, 2022, in the District of Delaware, citing US11419823 as one of the patents-in-suit.)
   • Outcome/Current Status: The case alleges patent infringement due to the defendants' submission of an Abbreviated New Drug Application (ANDA) to the FDA, seeking to market generic tacrolimus extended-release tablets before the expiration of Veloxis's patents, including US11419823. Veloxis is seeking favorable judgment, an order preventing the defendants from manufacturing their ANDA products, damages, and litigation fees.

2. Case Name: Veloxis Pharmaceuticals, Inc. v. Sun Pharmaceutical Industries Ltd.

   • Plaintiff(s): Veloxis Pharmaceuticals, Inc.
   • Defendant(s): Sun Pharmaceutical Industries Ltd.
   • Jurisdiction: District Court, D. Delaware
   • Filing Date: June 19, 2024.
   • Outcome/Current Status: The current status indicates "Start Trial".

3. Case Name: Veloxis Pharma Inc v. Alkem Laboratories Ltd.

   • Plaintiff(s): Veloxis Pharma Inc.
   • Defendant(s): Alkem Laboratories Ltd.
   • Jurisdiction: U.S. District Court for the District of Delaware
   • Case Number: 1:24-cv-00784
   • Filing Date: July 3, 2024.
   • Outcome/Current Status: The case is "Closed". It is categorized under "ANDA" (Abbreviated New Drug Application) nature of suit.

4. Case Name: Veloxis Pharmaceuticals, Inc. v. Glenmark Pharmaceuticals Inc., USA

   • Plaintiff(s): Veloxis Pharmaceuticals, Inc.
   • Defendant(s): Glenmark Pharmaceuticals Inc., USA
   • Jurisdiction: U.S. District Court for the District of Delaware
   • Case Number: 1:2025cv00458
   • Filing Date: A "Supplemental information for patent cases involving an Abbreviated New Drug Application (ANDA)" was filed on April 14, 2025, noting that the patentee received notice no earlier than March 4, 2025.
   • Outcome/Current Status: The case is ongoing, with filings such as proposed protective orders and scheduling orders occurring in August 2025.

The previous patent summary also indicated litigation filed in Delaware District Court with case numbers 1:25-cv-00458, 1:24-cv-00784, and 1:24-cv-00726. Case 1:25-cv-00458 aligns with Veloxis v. Glenmark. Case 1:24-cv-00784 aligns with Veloxis v. Alkem Laboratories. The details for case 1:24-cv-00726 were not readily available in the search results for specific identification of plaintiff, defendant, and status beyond its existence in the Delaware District Court as general litigation related to the patent.

Proceedings overview

There are no AIA trial proceedings on file for US Patent 11,419,823 as of the most recent ingest.

Strategic summary

Currently, all claims of US Patent 11,419,823 remain unchallenged and sustained. The absence of PTAB activity suggests that the patent has not yet been subjected to an inter partes review (IPR), post-grant review (PGR), or covered business method (CBM) review. This means there is no estoppel landscape established through AIA trials that would bar potential petitioners from raising any prior-art grounds.

Recommended next steps

Since there is no PTAB activity on file for US Patent 11,419,823, a potential defendant facing assertion of this patent has a full range of prior-art grounds available for an IPR or PGR petition, should they choose to pursue that avenue. The absence of PTAB challenges for a patent that has been in litigation in district court (as noted in the patent summary) could be a signal that potential challengers have not yet identified strong prior art grounds or chosen to litigate in that forum.

Inventors

• Nikolaj Skak: Veloxis Pharmaceuticals Inc.
• Per Holm: Veloxis Pharmaceuticals Inc.

Both inventors were employed by the original assignee, Veloxis Pharmaceuticals Inc., at the time of the patent's priority date (2008-05-30) and filing date (2018-11-13).

Original assignee

Veloxis Pharmaceuticals Inc. is the original assignee. Veloxis Pharmaceuticals is a pharmaceutical company focused on the development and commercialization of therapeutics for organ transplant patients, including products embodying tacrolimus, such as Envarsus XR (tacrolimus extended-release tablets). Veloxis Pharmaceuticals Inc. is currently operating.

Assignment timeline

The USPTO Assignment Center (https://assignmentcenter.uspto.gov/) shows the following assignments for US patent 11,419,823:

• 2021-03-17 (executed) / recorded 2021-03-17 — Reel 056461/0817

  • Conveyance: Assignment
  • Assignor: VELOXIS PHARMACEUTICALS A/S
  • Assignee: VELOXIS PHARMACEUTICALS INC.
  • Correspondent: Jeffrey M. Belson of GlaxoSmithKline, 1500 Rittenhouse Road, Collegeville, PA, 19426, US. This correspondent appears for GlaxoSmithKline related entities.
  • Context: Internal reorganization

• 2021-04-02 (executed) / recorded 2021-04-02 — Reel 056461/0818

  • Conveyance: Assignment
  • Assignor: VELOXIS PHARMACEUTICALS A/S
  • Assignee: VELOXIS PHARMACEUTICALS INC.
  • Correspondent: Jeffrey M. Belson of GlaxoSmithKline, 1500 Rittenhouse Road, Collegeville, PA, 19426, US. This correspondent appears for GlaxoSmithKline related entities.
  • Context: Internal reorganization

• 2024-06-07 (executed) / recorded 2024-06-07 — Reel 063073/0675

  • Conveyance: Change of Name
  • Assignor: VELOXIS PHARMACEUTICALS INC.
  • Assignee: VELOXIS PHARMACEUTICALS INC.
  • Correspondent: Jeffrey M. Belson of GlaxoSmithKline, 1500 Rittenhouse Road, Collegeville, PA, 19426, US. This correspondent appears for GlaxoSmithKline related entities.
  • Context: Change of address for the assignee

Timeline diagram

timeline
    title Ownership of US 11419823
    2008 : Priority claimed
    2018 : Application filed by Veloxis
    2021 : Assigned to Veloxis Pharm Inc
         : Assigned to Veloxis Pharm Inc
    2022 : Patent granted
    2024 : Change of Address for Veloxis

NPE / troll-pattern signals

1. Shell-entity transfer — not present. The assignments are between Veloxis Pharmaceuticals A/S and Veloxis Pharmaceuticals Inc., indicating an internal corporate restructuring rather than a transfer to a shell entity.
2. Known asserter in the chain — not present. Veloxis Pharmaceuticals Inc. is an operating company.
3. Repeat correspondent across the chain — present. Jeffrey M. Belson of GlaxoSmithKline is listed as the correspondent for all recorded assignments (Reel 056461/0817, Reel 056461/0818, Reel 063073/0675). This attorney is a repeat-player, handling recordings for GlaxoSmithKline-related entities.
4. Cascading transfers — not present. The two assignments in 2021 are very close in time, but appear to be part of a single internal reorganization from Veloxis Pharmaceuticals A/S to Veloxis Pharmaceuticals Inc., not a chain through multiple distinct shell LLCs.
5. Pre-litigation transfer — unclear. While there are litigation events noted for the patent family (starting in 2024 and 2025), the assignments occurred in 2021, well before the documented litigation dates. It's possible the litigation refers to an earlier stage or other patents in the family, but based solely on the provided information for this specific patent, the transfers are not immediately pre-litigation.
6. Bankruptcy fire-sale — not present. There is no indication of bankruptcy in the assignment records or patent metadata.
7. Privateering — not present. Veloxis Pharmaceuticals Inc. is the current assignee and an operating company.
8. Defensive aggregator (anti-NPE) — not present. The chain does not terminate at a defensive aggregator.

Verdict

Operating-company assertion. The patent remains with Veloxis Pharmaceuticals Inc., an operating company that markets products related to tacrolimus. The assignments recorded (Reel 056461/0817, Reel 056461/0818) appear to be part of an internal corporate reorganization, not a transfer to a non-practicing entity. The patent is currently involved in litigation, suggesting assertion by the operating company against competitors.

USPTO Assignment Center search page for US11419823: https://assignmentcenter.uspto.gov/detail-result-view/?id=91040854-3406-4448-b4b1-8b21c430e702

To identify the most relevant prior art for US patent 11419823, I will examine the patent citations listed within the patent itself. The provided patent text includes a section for "Patent Citations" and "Other references". I will focus on the listed patent citations first.

Patent Citations for US11419823:

The provided document lists 42 patent citations and 23 non-patent citations. I will list the patent citations here. Note that some of these citations are for related applications in the same patent family, which may not constitute prior art under 35 U.S.C. § 102 but are included for completeness as they are listed in the patent.

Here are some of the cited patents, with a brief description and potential anticipation:

• JPS59104326A

  • Full Citation: JPS59104326A (Patent document states "JPS59104326A * 1982-12-04 1984-06-16 Toyo Jozo Co Ltd Stable oral preparation of macrolide antibiotic substance")
  • Publication/Filing Date: Publication date 1984-06-16, Priority date 1982-12-04.
  • Brief Description: Describes a stable oral preparation of a macrolide antibiotic substance.
  • Potential Anticipation (35 U.S.C. § 102): This patent potentially anticipates aspects of the broader concept of stable macrolide antibiotic compositions, particularly oral preparations. Given its early date, it could be relevant to the general idea of stabilizing macrolides, including tacrolimus (which is a macrolide lactone). If the preparation discloses a solid dispersion or a stabilizing agent that provides a pH below 7 for a macrolide to prevent degradation, it could anticipate elements of claim 1.

• WO2005/020993

  • Full Citation: WO2005/020993
  • Publication/Filing Date: Cited in the description as disclosing tacrolimus formulations, but specific dates are not provided directly in the citation list. However, the text mentions "WO2005/020993... disclose tacrolimus-containing pharmaceutical compositions with improved bioavailability".
  • Brief Description: Discloses tacrolimus-containing pharmaceutical compositions with improved bioavailability and reduced peak-to-trough levels, specifically tacrolimus compositions comprising a solid dispersion of tacrolimus in polyethylene glycol (PEG).
  • Potential Anticipation (35 U.S.C. § 102): This reference is highly relevant as it describes tacrolimus compositions with improved bioavailability, specifically solid dispersions of tacrolimus in PEG. This directly addresses the vehicle aspect of claims 1, 17, 19, and 25. If WO2005/020993 describes a solid dispersion of tacrolimus in a vehicle and mentions any stabilizing agent that provides a pH below 7 and/or addresses the prevention of degradation products like 8-epitacrolimus, it could potentially anticipate several claims. The current patent even states that WO2005/020993 "may be useful in combination with the stabilizing agent(s) disclosed herein to yield a stabilized tacrolimus composition".

• WO2005/020994

  • Full Citation: WO2005/020994
  • Publication/Filing Date: Cited alongside WO2005/020993, specific dates are not directly provided in the citation list.
  • Brief Description: Also discloses tacrolimus-containing pharmaceutical compositions with improved bioavailability and reduced peak-to-trough levels, particularly tacrolimus compositions comprising a solid dispersion of tacrolimus in polyethylene glycol (PEG).
  • Potential Anticipation (35 U.S.C. § 102): Similar to WO2005/020993, this patent is highly relevant due to its focus on tacrolimus solid dispersions and improved bioavailability. It could anticipate claims 1, 17, 19, and 25 regarding the basic composition and vehicle.

• WO2008/0145143

  • Full Citation: WO2008/0145143
  • Publication/Filing Date: The priority date for US11419823 is listed as 2008-05-30, and it claims priority from PCT/DK2008/050130, filed May 30, 2008, which is WO2008145143A1. Therefore, this is likely an earlier publication in the same patent family.
  • Brief Description: Discloses tacrolimus-containing pharmaceutical compositions with improved bioavailability and reduced peak-to-trough levels, specifically tacrolimus compositions comprising a solid dispersion of tacrolimus in polyethylene glycol (PEG).
  • Potential Anticipation (35 U.S.C. § 102): As an earlier publication in the same patent family (PCT/DK2008/050130, which leads to WO2008/0145143), this document would generally not be considered prior art against the claims of US11419823 under 35 U.S.C. § 102, provided that US11419823 correctly claims priority back to this earlier application. It serves as foundational work for the current patent.

• WO2010/005980

  • Full Citation: WO2010/005980
  • Publication/Filing Date: Cited alongside other WO patents, specific dates are not directly provided in the citation list.
  • Brief Description: Discloses tacrolimus-containing pharmaceutical compositions with improved bioavailability and reduced peak-to-trough levels, specifically tacrolimus compositions comprising a solid dispersion of tacrolimus in polyethylene glycol (PEG).
  • Potential Anticipation (35 U.S.C. § 102): This reference, like the other WO publications, describes tacrolimus solid dispersions in PEG. Its relevance as prior art would depend on its effective filing or publication date relative to the priority date of US11419823 (May 30, 2008). If published before this date and disclosing the use of a stabilizing agent to control 8-epitacrolimus in a solid dispersion, it could anticipate claims 1, 17, 19, and 25.

• U.S. Pat. No. 4,894,366

  • Full Citation: U.S. Pat. No. 4,894,366
  • Publication/Filing Date: Issued January 16, 1990 (based on standard patent formatting, assuming 4,894,366 is the issue number, as stated in the full patent description).
  • Brief Description: This patent is mentioned in the background section regarding the IUPAC-style nomenclature for tacrolimus structure.
  • Potential Anticipation (35 U.S.C. § 102): Given that this patent is from 1990, it would be prior art for any claim in US11419823. However, based on the description, it appears to be cited for the chemical structure and nomenclature of tacrolimus itself, rather than for stabilized pharmaceutical compositions. Unless it discloses a stabilized tacrolimus composition meeting the specific pH and degradation product limitations, it is unlikely to anticipate the stabilization aspects of claims 1, 17, 19, and 25, but it does establish the existence and basic chemistry of tacrolimus as a known drug.

• US5601844A

  • Full Citation: US5601844A (Patent document states "5,601,844 A 12/1987 Morishita et al.")
  • Publication/Filing Date: The citation "12/1987" likely refers to its filing date or a related early date, with the issue date of February 11, 1997.
  • Brief Description: Cited as a general patent reference. Without further details from the provided text about its content, a specific description is not available.
  • Potential Anticipation (35 U.S.C. § 102): This patent predates US11419823. Its relevance would depend on whether it describes stabilized tacrolimus compositions, solid dispersions, metal chelating agents, or specific pH ranges to prevent 8-epitacrolimus formation.

This analysis focuses on the patent citations found directly within the provided text of US11419823B2. To provide an exhaustive list of all prior art, a complete search of the USPTO database and other relevant patent/non-patent literature would be necessary.

Obviousness Analysis of US Patent 11,419,823 under 35 U.S.C. § 103

This section analyzes the obviousness of US Patent 11,419,823 based on combinations of prior art references. An invention is obvious if the differences between the claimed invention and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art (POSA). This analysis will identify potential combinations of references and provide a rationale for a POSA's motivation to combine them.

The present invention, US 11,419,823, is directed to stabilized pharmaceutical compositions of tacrolimus, specifically addressing the degradation of tacrolimus into 8-epitacrolimus by incorporating a stabilizing agent, particularly a metal chelating agent or an organic acid, to maintain a pH below 7 in a solid dispersion formulation. The patent also emphasizes sustained-release and low levels of degradation products after storage.

Prior Art References:

The patent itself identifies several relevant prior art documents that disclose tacrolimus-containing pharmaceutical compositions with improved bioavailability and reduced peak-to-trough levels, particularly solid dispersions of tacrolimus in polyethylene glycol (PEG). These include:

• WO2005/020993 (WO '993): Discloses modified release compositions comprising tacrolimus, which may include a solid dispersion or solid solution of tacrolimus in a hydrophilic or water-miscible vehicle. It aims to increase bioavailability and reduce CYP3A4 metabolism.
• WO2005/020994 (WO '994): Discloses pharmaceutical compositions comprising tacrolimus dissolved and/or dispersed in a hydrophilic or water-miscible vehicle to form a solid dispersion or solid solution at ambient temperature, with improved bioavailability.
• WO2008/0145143 (WO '143): Discloses an extended release oral dosage form comprising tacrolimus, emphasizing improved pharmacokinetic parameters.
• WO2010/005980 (WO '980): Discloses tacrolimus-containing pharmaceutical compositions.
• WO2008/084698A1 (WO '698): Discloses a tacrolimus sustained-release pharmaceutical composition comprising a solid dispersion of tacrolimus or a pharmaceutically acceptable salt thereof and a carrier for sustained release.
• WO2007/091109A1 (WO '109): Discloses a pharmaceutical composition comprising tacrolimus in a stable amorphous morphological form, but specifically states it is not in a solid dispersion form.
• "Establishment of new preparation method for solid dispersion formulation of tacrolimus" by YAMASHITA et al. (2003) (Yamashita): Discloses a new method for preparing solid dispersion formulations of tacrolimus using HPMC as a carrier, without dichloromethane, and notes the stability of the formulation after storage at 40°C for 3 months.

Analysis of Obviousness Combinations:

A POSA in the field of pharmaceutical formulation development, around the priority date of US 11,419,823 (May 30, 2008 [cite: US11419823B2 - Google Patents]), would have been aware of the challenges associated with tacrolimus, specifically its poor solubility, low bioavailability, and the desirability of solid dispersion formulations for improved absorption. [cite: US11419823B2 - Google Patents] They would also have recognized the inherent instability of drugs in solid dispersions due to increased molecular exposure, leading to a higher risk of chemical degradation. [cite: US11419823B2 - Google Patents]

Combination 1: WO '993 / WO '994 / WO '143 / WO '980 (or WO '698) + General Knowledge of Pharmaceutical Stabilization

• References: WO2005/020993, WO2005/020994, WO2008/0145143, WO2010/005980 (or WO2008/084698A1).
• Elements Taught: These references collectively teach sustained-release tacrolimus compositions, often in the form of solid dispersions, using hydrophilic or water-miscible vehicles like polyethylene glycol (PEG) and poloxamers, to improve bioavailability and achieve desired pharmacokinetic profiles. [cite: 1, 2, 3, US11419823B2 - Google Patents] WO '143 explicitly describes an extended-release oral dosage form of tacrolimus. WO '698 also describes a sustained-release tacrolimus solid dispersion.
• Motivation to Combine/Modify: A POSA would understand that while solid dispersions offer improved bioavailability for poorly soluble drugs like tacrolimus, they also increase the risk of chemical degradation compared to crystalline forms. [cite: US11419823B2 - Google Patents] The need for preventing degradation products in pharmaceutical formulations is a well-known concern, and strict regulatory restrictions exist regarding impurities. [cite: US11419823B2 - Google Patents] Therefore, it would be obvious for a POSA to seek ways to stabilize these known solid dispersion formulations of tacrolimus.
  • The patent itself states that "For tacrolimus-containing formulations, in particular formulations containing ingredients which may, as starting materials in the manufacturing process, contain traces of metals or metal compounds, oxidants and other undesirable but unavoidable contaminants, there is a need for preventing the formation of degradation products from tacrolimus or, at least, to maintain an acceptable, low concentration of such degradation products throughout the shelf-life of the formulation". [cite: US11419823B2 - Google Patents] This highlights an existing need known to a POSA.
  • The use of stabilizing agents, including pH-regulating excipients and chelating agents, to prevent drug degradation is a common pharmaceutical formulation strategy. A POSA would routinely explore such agents to address stability issues. The patent describes that tacrolimus degradation, specifically the formation of 8-epitacrolimus, occurs under mild basic and potentially mild acidic conditions. [cite: US11419823B2 - Google Patents] This would motivate a POSA to investigate pH adjustment as a stabilization strategy.
  • The concept of maintaining a specific pH to enhance stability is a fundamental principle in pharmaceutical chemistry. The patent specifically explores pH ranges below 7, noting that "the stabilizing agent is capable of providing a pH below 7 in the composition, as measured after re-dispersing the composition in water, more preferably a pH in the range of 2.5 to 5 or 2.5 to 4 or 3 to 3.6 or 3 to 3.5". [cite: US11419823B2 - Google Patents] This suggests an optimization within a known stabilization approach.

Combination 2: WO '993 / WO '994 / WO '143 / WO '980 (or WO '698) + Yamashita

• References: WO2005/020993, WO2005/020994, WO2008/0145143, WO2010/005980 (or WO2008/084698A1) and Yamashita (2003).
• Elements Taught: As above, the WO patents disclose tacrolimus solid dispersions in various vehicles for improved bioavailability and sustained release. Yamashita specifically teaches the preparation of solid dispersion formulations of tacrolimus, noting their stability at 40°C for 3 months. Yamashita explicitly states that "the supersaturated dissolution profiles of tacrolimus were observed in all SDFs, and the highest level of supersaturation for tacrolimus was obtained and maintained for 24h from SDF with HPMC. On the other hand, the supersaturated level from SDF with PEG 6000 or PVP decreased rapidly". It also clarified that "HPMC is the most appropriate carrier for SDF of tacrolimus".
• Motivation to Combine: A POSA would combine the knowledge from the WO patents regarding desired release profiles and solid dispersion technology with Yamashita's findings on the stability of tacrolimus solid dispersions. Yamashita identifies HPMC as a suitable carrier for stable tacrolimus solid dispersions. While Yamashita focuses on HPMC, it also discusses PEG 6000 and PVP, noting the rapid decrease in supersaturation from PEG 6000. The present patent, US 11,419,823, also lists HPMC as a useful hydrophilic or water-miscible vehicle and describes in Example 1B a Tacrolimus Composition B which includes HPMC and PEG 6000 and poloxamer 188. [cite: US11419823B2 - Google Patents] The fact that Yamashita investigated stability (3 months at 40°C) would naturally lead a POSA to consider further improving or maintaining stability in tacrolimus solid dispersions, particularly when formulating for sustained release. This would include exploring additional stabilizing agents like those claimed in US 11,419,823, such as organic acids or chelating agents, to address specific degradation pathways (e.g., 8-epitacrolimus formation) that might not be fully mitigated by the vehicle alone.

Combination 3: WO '993 / WO '994 + WO '109 + General Knowledge of Tacrolimus Instability and Stabilization

• References: WO2005/020993, WO2005/020994 and WO2007/091109A1.
• Elements Taught: WO '993 and WO '994 disclose solid dispersions of tacrolimus for improved bioavailability. WO '109 discusses tacrolimus in a stable amorphous form, while explicitly stating it is not a solid dispersion. However, WO '109 also references the poor water solubility of tacrolimus and its relatively low bioavailability, and it cites Honbo, T. et al. (1987) which discusses the oral dosage form of FK-506 (tacrolimus). It also mentions a tacrolimus containing composition in the form of solid dispersion, disclosed in EP 024773, containing lactose, hydroxypropyl methylcellulose, croscarmellose sodium and magnesium stearate as excipients.
• Motivation to Combine: A POSA would recognize that despite WO '109 distinguishing itself from solid dispersions, it still highlights the known issues of tacrolimus solubility and bioavailability, which solid dispersions (from WO '993 and WO '994) are designed to address. The mention of tacrolimus solid dispersion in EP 024773 in WO '109 further confirms that solid dispersions of tacrolimus were well-known prior art. The general understanding of tacrolimus's instability, as acknowledged in US 11,419,823, would motivate a POSA to combine the solid dispersion approaches of WO '993/WO '994 with common stabilization techniques, such as the addition of pH-regulating agents or chelating agents, to address degradation products like 8-epitacrolimus, which the present patent identifies as a major degradation product formed under mild conditions. [cite: US11419823B2 - Google Patents]

Motivation to Use Specific Stabilizing Agents (Organic Acids/Chelating Agents) and pH Control:

The patent explicitly states that the "present invention is based on the finding that a very important, i.e. major, degradation product of tacrolimus is the hitherto undisclosed C8-epimer of tacrolimus, also denoted 8-epitacrolimus". [cite: US11419823B2 - Google Patents] However, the degradation of pharmaceutical compounds and the use of stabilizing agents to prevent it are well-established practices.

• Metal Chelating Agents: The patent notes that "It has been found that formation of the major degradation product 8-epitacrolimus is decreased in the presence in the composition of a metal chelating agent." [cite: US11419823B2 - Google Patents] It explicitly identifies tartaric acid as having a chelating effect. [cite: US11419823B2 - Google Patents] The use of chelating agents to mitigate metal-catalyzed degradation is a common strategy in pharmaceutical formulation. A POSA, facing a degradation issue, would consider chelating agents if metal ion contamination was suspected or known to be a factor, especially given that "traces of e.g. metal ions will inevitably occur in the vehicle due to the use of equipment and excipients containing metal ions". [cite: US11419823B2 - Google Patents]
• Organic Acids (Citric, Tartaric, Oxalic): The patent highlights citric acid, tartaric acid, and oxalic acid as preferred stabilizing agents. [cite: US11419823B2 - Google Patents] These are commonly used pharmaceutical excipients known for their acidic and/or chelating properties.
  • Citric acid is a well-known acidulant and chelating agent in pharmaceutical and food industries.
  • Tartaric acid is also a known acidulant and chelating agent. The patent specifically demonstrates that tartaric acid and oxalic acid had an improved stabilizing effect compared to citric acid at 0.5% w/w. [cite: US11419823B2 - Google Patents]
  • Oxalic acid is also an acid and a chelating agent, though the patent notes it is "conventionally less useful in pharmaceutical compositions for regulatory reasons." [cite: US11419823B2 - Google Patents]
• pH Control: The patent emphasizes maintaining a pH below 7, preferably in the range of 2.5-5.0, more preferably 2.5-4.0, and even more preferably 3.0-3.6. [cite: US11419823B2 - Google Patents] Adjusting the pH of a formulation to optimize drug stability is a routine practice. The specific range would be determined through routine experimentation by a POSA to find the optimal balance for tacrolimus stability in the chosen vehicle system. The experiments in Example 7 of the patent, which demonstrate that "pH matters" and that "even a small pH increase has a significant effect on the stability of tacrolimus", would represent routine optimization for a POSA once the general strategy of pH control was identified. [cite: US11419823B2 - Google Patents]

Conclusion on Obviousness:

While US Patent 11,419,823 identifies 8-epitacrolimus as a "hitherto undisclosed" major degradation product and presents experimental data demonstrating the effectiveness of specific stabilizing agents and pH ranges, the core elements of the invention appear to be variations and optimizations of known pharmaceutical formulation principles. A POSA would have been motivated to combine existing knowledge of tacrolimus solid dispersions (from WO '993, WO '994, WO '143, WO '980, WO '698, and Yamashita) with general pharmaceutical stabilization strategies, including the use of pH-regulating agents and chelating agents, to address the known instability challenges of tacrolimus in solid dispersion systems. The selection of specific organic acids like citric, tartaric, or oxalic acid, and the optimization of their concentration and the resulting pH, would be considered routine experimentation within the skill of a POSA.

Therefore, the claims of US 11,419,823, particularly those related to the use of metal chelating agents or specific organic acids to achieve a stabilizing pH in a sustained-release tacrolimus solid dispersion, would likely be considered obvious to a person having ordinary skill in the art in light of the cited prior art and common pharmaceutical formulation knowledge.

Patent Term Adjustments (PTA)

Patent Term Adjustment (PTA) extends the term of a U.S. patent to compensate for certain administrative delays by the USPTO during the patent prosecution process. These delays are categorized into specific timeframes, such as issuing an office action within 14 months of filing, responding to a reply within four months, and issuing a patent within 36 months from the filing date. The total PTA is added to the standard 20-year lifespan of the patent.

The provided information for US patent 11,419,823 does not explicitly state the calculated patent term adjustment. To determine the exact PTA, one would typically need to review the "Patent Term Adjustment" section in the patent's file wrapper on the USPTO Patent Center.

Patent Term Extensions (PTE)

Patent Term Extension (PTE) is distinct from PTA and is granted to compensate for delays in obtaining regulatory approval for products, most commonly drugs. For pharmaceutical patents, PTE aims to restore some of the patent term lost during the FDA approval process.

The provided patent text and search results do not explicitly mention whether US patent 11,419,823 has been granted a Patent Term Extension. This information would typically be found in the regulatory approval records associated with tacrolimus products covered by this patent.

Continuation and Divisional Applications

The provided patent description explicitly states that US patent 11,419,823 is part of a family of related applications:

• "The present application is a continuation of U.S. patent application Ser. No. 15/405,879, filed Jan. 13, 2017".
• "which is a continuation of U.S. patent application Ser. No. 13/029,304, filed Feb. 17, 2011".
• "which (i) claims the benefit of Danish Patent Application No. PA 2010-00137 filed Feb. 17, 2010, and U.S. Provisional Application No. 61/305,941, filed Feb. 18, 2010, and (ii) is a continuation-in-part of U.S. patent application Ser. No. 12/499,034, filed Jul. 7, 2009".
• "which (a) is a continuation-in-part of International Application No. PCT/DK2008/050130, filed May 30, 2008".

Therefore, US patent 11,419,823 is a continuation application of U.S. patent application Ser. No. 15/405,879, which itself is a continuation of Ser. No. 13/029,304. This chain of applications also includes a continuation-in-part relationship with Ser. No. 12/499,034, and ultimately traces back to PCT/DK2008/050130, filed May 30, 2008, and related provisional and Danish applications.

The provided information does not explicitly list any divisional applications directly stemming from US patent 11,419,823 itself.

Related Family Members

Based on the continuation chain described above, the following are related family members:

• U.S. patent application Ser. No. 15/405,879, filed Jan. 13, 2017
• U.S. patent application Ser. No. 13/029,304, filed Feb. 17, 2011
• U.S. patent application Ser. No. 12/499,034, filed Jul. 7, 2009
• International Application No. PCT/DK2008/050130, filed May 30, 2008
• Danish Patent Application No. PA 2010-00137, filed Feb. 17, 2010
• U.S. Provisional Application No. 61/305,941, filed Feb. 18, 2010

Additionally, US20190282504A1 is a publication related to the patent.

Projected Expiration Date

The Google Patents entry for US patent 11,419,823 states the "Anticipated expiration" date as 2028-05-30.

For applications filed on or after June 8, 1995, the patent term is generally 20 years from the date of the earliest related application, or the filing date if there are no earlier applications. Given that the earliest priority date for US 11,419,823 is May 30, 2008 (from PCT/DK2008/050130), a 20-year term from this date would indeed lead to an expiration date around May 30, 2028. This anticipated expiration date would include any Patent Term Adjustments that may have been granted.