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.

Defensive Disclosure Document: Advanced Stabilized Tacrolimus Compositions and Derivatives

This Defensive Disclosure document is designed to expand the publicly available prior art concerning stabilized tacrolimus compositions, particularly those formulated as sustained-release solid dispersions that prevent the formation of degradation products like 8-epitacrolimus. The intent is to preemptively render future incremental improvements or alternative embodiments in this technology obvious or non-novel to a person having ordinary skill in the art, thereby restricting the patentability of subsequent competing innovations. This disclosure builds upon the core inventive principles of US Patent 11,419,823, which focuses on utilizing pH-regulating and/or chelating stabilizing agents within solid dispersion vehicles to maintain tacrolimus stability.

Core Inventive Concepts from US Patent 11,419,823:

The foundational elements protected by independent Claims 1, 17, 19, and 25 of US 11,419,823 are:

• A sustained-release pharmaceutical composition.
• Comprising a solid dispersion of tacrolimus (potentially as the sole active ingredient).
• Utilizing a vehicle (e.g., a mixture of polyethylene glycol and a poloxamer).
• Incorporating a stabilizing agent that functions as a metal chelating agent or is an organic acid (specifically oxalic, tartaric, or citric acid).
• The stabilizing agent ensures a pH below 7 (e.g., in the range of 2.5-4.0 or 3.0-3.6) when the composition is re-dispersed in water.
• The composition exhibits enhanced stability, with less than 0.5% by weight of 8-epitacrolimus after 12 weeks of storage at 25°C and 60% relative humidity.
• (Claim 19 additionally specifies an initial 8-epitacrolimus concentration below 0.2% by weight).
• The composition is provided as an oral dosage form, such as a tablet (Claim 25).

The following derivative variations extend these core concepts across various technical axes to comprehensively disclose potential future developments.

---

1. Material & Component Substitution

Derivative 1.1: Alternative Macrolide Immunosuppressants with Biodegradable Polymer Vehicles

Enabling Description:
A sustained-release pharmaceutical composition comprising a solid dispersion of an L-pipecolic acid derived macrolide immunosuppressant, specifically rapamycin (sirolimus), in a vehicle composed of a biodegradable polymer blend of poly(lactic-co-glycolic acid) (PLGA) (lactide:glycolide ratio 75:25, molecular weight 40,000-75,000 Da) and polycaprolactone (PCL) (molecular weight 50,000-80,000 Da). The stabilizing agent is phytic acid, a natural chelating agent and organic acid, incorporated at a concentration of 0.1% w/w to 1.0% w/w based on the total composition weight. The phytic acid provides a pH in the range of 3.0-4.5 when the composition is re-dispersed in water. The solid dispersion is prepared via hot-melt extrusion at 120°C-140°C, followed by milling and compression into tablets. This formulation is designed to maintain less than 0.5% degradation products (e.g., rapamycin epimers or ring-opened forms) after 12 weeks of storage at 25°C and 60% relative humidity, ensuring sustained release over 18-24 hours.

graph TD
    A[Rapamycin API] --> B{Hot-Melt Extrusion};
    C[PLGA:PCL Blend Vehicle] --> B;
    D[Phytic Acid Stabilizer] --> B;
    B --> E[Solid Dispersion Melt];
    E --> F[Cooling & Milling];
    F --> G[Tableting];
    G --> H[Sustained Release Rapamycin Tablet];
    H --> I{pH 3.0-4.5};
    H --> J{<0.5% Degradation Prod. @ 12wks/25C/60%RH};

Derivative 1.2: Mesoporous Silica as Vehicle with Phosphonic Acid Stabilizer

Enabling Description:
A sustained-release pharmaceutical composition comprising tacrolimus as a solid dispersion within mesoporous silica nanoparticles (e.g., SBA-15 type with pore size 6-10 nm, particle size 50-200 nm). Tacrolimus is loaded into the silica pores by solvent impregnation (e.g., using ethanol, then evaporating solvent). The vehicle consists predominantly of the mesoporous silica. The stabilizing agent is 1-hydroxyethane-1,1-diphosphonic acid (HEDP), a phosphonic acid chelating agent, co-adsorbed onto the silica surface at a concentration of 0.05% w/w to 0.5% w/w relative to the tacrolimus content. This formulation provides a localized pH environment below 6 in aqueous suspension and limits 8-epitacrolimus formation to below 0.5% after 12 weeks at 25°C and 60% relative humidity. The mesoporous silica provides a tortuous diffusion path for sustained release.

graph TD
    A[Tacrolimus API] --> B{Solvent Impregnation};
    C[Mesoporous Silica (SBA-15)] --> B;
    D[HEDP Stabilizer] --> B;
    B --> E[Tacrolimus-Silica Composite];
    E --> F[Drying & Size Classification];
    F --> G[Capsule Filling / Tableting];
    G --> H[Sustained Release Tacrolimus Nano-Dispersion];
    H --> I{pH < 6 (Localized)};
    H --> J{<0.5% 8-epitacrolimus @ 12wks/25C/60%RH};

Derivative 1.3: Lipid-Polymer Matrix with Ascorbic Acid

Enabling Description:
A sustained-release pharmaceutical composition comprising a solid dispersion of tacrolimus in a semi-solid lipid-polymer matrix for encapsulation in soft gelatin capsules. The matrix vehicle is a eutectic mixture of Gelucire® 44/14 (Lauroyl Polyoxylglycerides) and Eudragit® RLPO (Ammonio Methacrylate Copolymer Type A), with a ratio optimized for sustained release. The stabilizing agent is L-ascorbic acid (Vitamin C), included at a concentration of 0.2% w/w to 1.5% w/w based on the total matrix weight. The ascorbic acid, acting as both an antioxidant and an organic acid, ensures a pH in the range of 3.0-4.0 upon re-dispersion. The formulation is prepared by melting the matrix components and ascorbic acid, dissolving tacrolimus, and then encapsulating. This composition restricts 8-epitacrolimus levels to less than 0.5% over 12 weeks at 25°C/60% RH.

flowchart TD
    A[Tacrolimus API] --> B(Melt Gelucire 44/14 & Eudragit RLPO);
    C[L-Ascorbic Acid] --> B;
    B --> D{Dissolve API in Melt};
    D --> E[Homogenize Melt];
    E --> F[Soft Gelatin Encapsulation];
    F --> G[Stabilized SR Capsule];
    G -- pH 3.0-4.0 --> H(Degradation Control);
    H -- <0.5% 8-epitacrolimus --> I(Long-term Stability);

Derivative 1.4: Cellulose Ether Matrix with Fumaric Acid

Enabling Description:
A sustained-release pharmaceutical composition comprising a solid dispersion of tacrolimus within a matrix primarily composed of high-viscosity hydroxypropyl methylcellulose (HPMC K100M) and microcrystalline cellulose (MCC PH102), prepared by wet granulation. Fumaric acid, a dicarboxylic organic acid, is incorporated as the stabilizing agent at 0.1% w/w to 0.8% w/w (based on total solid weight) during the granulation process. The fumaric acid provides a pH between 2.8 and 3.8 in aqueous dispersions and acts to chelate trace metal impurities that may contribute to tacrolimus degradation. The resulting granules are compressed into tablets. This composition maintains 8-epitacrolimus below 0.5% after 12 weeks at 25°C and 60% RH, with sustained release achieved through the HPMC matrix.

graph LR
    A[Tacrolimus API] -- Mix Dry --> B(HPMC K100M);
    A -- Mix Dry --> C(MCC PH102);
    D[Fumaric Acid Stabilizer] -- Mix Dry --> E(Granulation Liquid);
    B & C & D & E --> F{Wet Granulation};
    F --> G[Drying];
    G --> H[Milling & Sizing];
    H --> I[Compression];
    I --> J[Sustained Release Tablet];
    J -- pH 2.8-3.8 --> K(Stability);

Derivative 1.5: Co-precipitated Dispersion with Polycarboxylic Acid

Enabling Description:
A sustained-release pharmaceutical composition comprising a solid dispersion of tacrolimus formed by co-precipitation with a polyvinylpyrrolidone-vinyl acetate copolymer (PVP-VA 64) and a polycarboxylic acid stabilizing agent, specifically poly(acrylic acid) (PAA) (molecular weight 450,000 Da), used at 0.05% w/w to 0.5% w/w relative to the tacrolimus. Tacrolimus and PVP-VA 64 are dissolved in a solvent mixture (e.g., ethanol/water), PAA is added, and the solvent is rapidly evaporated (e.g., spray drying or freeze-drying) to form an amorphous co-precipitate. The PAA provides a stable pH below 4.5 in aqueous solution and acts as a metal chelator. This method yields a solid dispersion powder capable of being formulated into capsules or compacts, exhibiting sustained release characteristics and maintaining 8-epitacrolimus levels below 0.5% after 12 weeks at 25°C/60% RH.

sequenceDiagram
    participant API as Tacrolimus API
    participant Polymer as PVP-VA 64
    participant Acid as Poly(acrylic acid)
    participant Solvent as Ethanol/Water
    participant Process as Spray Drying/Freeze Drying
    participant Product as Solid Dispersion Powder

    API->Solvent: Dissolve
    Polymer->Solvent: Dissolve
    Acid->Solvent: Add
    Solvent->Process: Prepare Solution
    Process->Product: Co-precipitation
    Product->>Product: pH < 4.5
    Product->>Product: Sustained Release
    Product->>Product: <0.5% 8-epitacrolimus

---

2. Operational Parameter Expansion

Derivative 2.1: Nanoscale Solid Dispersion for Enhanced Bioavailability and Stabilization

Enabling Description:
A sustained-release pharmaceutical composition comprising a nanoscale solid dispersion of tacrolimus (average particle size 50-200 nm) encapsulated within a polymer matrix. The tacrolimus is molecularly dispersed in a vehicle of poloxamer 407 and D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) using a high-pressure homogenization or nano-precipitation technique. Tartaric acid, as the stabilizing agent, is added during the aqueous phase preparation at a concentration of 0.2% w/w. This provides a pH of 3.0-3.5 in the final nano-suspension, which is subsequently spray-dried onto inert carriers (e.g., mannitol) to form a dry powder suitable for capsule filling. The nanoscale dispersion offers increased surface area for dissolution, while the tartaric acid maintains stability, limiting 8-epitacrolimus formation to less than 0.2% after 12 weeks at 25°C and 60% relative humidity, and exhibiting sustained release over 24 hours due to the polymeric matrix.

graph TD
    A[Tacrolimus API] --> B(Dissolve in Organic Solvent);
    C[Poloxamer 407 & TPGS] --> D(Dissolve in Aqueous Phase);
    E[Tartaric Acid Stabilizer] --> D;
    B & D --> F{High-Pressure Homogenization / Nano-precipitation};
    F --> G[Nano-suspension];
    G --> H[Spray Drying onto Mannitol];
    H --> I[Stabilized Nano-Dispersion Powder];
    I --> J[Capsule Filling];
    J --> K[SR Nano-Tacrolimus Capsule];
    K -- pH 3.0-3.5 --> L(Enhanced Stability);
    K -- <0.2% 8-epitacrolimus --> M(Improved Bioavailability);

Derivative 2.2: Continuous Manufacturing with Real-time pH Monitoring at Elevated Temperatures

Enabling Description:
A sustained-release pharmaceutical composition of tacrolimus manufactured using a continuous hot-melt extrusion (HME) process at barrel temperatures ranging from 140°C to 170°C. The vehicle comprises Kollidon® VA64 (PVP/VA copolymer) and PEG 3350. Citric acid, as the stabilizing agent, is precisely dosed at 0.4% w/w using a gravimetric feeder into the extruder, ensuring a consistent input. Real-time Process Analytical Technology (PAT) is implemented, including an in-line Raman spectrometer for continuous monitoring of tacrolimus drug loading and degradation product formation, and an in-line pH sensor (e.g., micro-electrode array in a molten aliquot) to ensure the pH of the extrudate, upon re-dispersion, is maintained between 3.2 and 3.8. The extrudate is milled and compressed into sustained-release tablets. This continuous process guarantees less than 0.5% 8-epitacrolimus after 12 weeks at 25°C and 60% relative humidity.

graph TD
    A[Tacrolimus API] --> B(Gravimetric Feeder);
    C[Kollidon VA64] --> B;
    D[PEG 3350] --> B;
    E[Citric Acid Stabilizer] --> B;
    B --> F{Twin-Screw Hot-Melt Extruder};
    F -- Temp: 140-170C --> G(Melt & Mixing Zone);
    G -- In-line Raman --> H(Drug/Degradation Assay);
    G -- In-line pH Sensor --> I(pH Control 3.2-3.8);
    H & I --> J{Feedback Control System};
    F --> K[Extrudate Strand];
    K --> L[Milling];
    L --> M[Tableting];
    M --> N[SR Tablet (Continuous)];
    J --> F;

Derivative 2.3: Cryogenic Storage and Stability Testing

Enabling Description:
A sustained-release pharmaceutical composition comprising a solid dispersion of tacrolimus in a vehicle of PEG 8000 and poly(ethylene oxide) (PEO) (molecular weight 100,000 Da). Oxalic acid, as the stabilizing agent, is incorporated at 0.15% w/w. The composition is formulated into lyophilized orally disintegrating tablets (ODTs) using a cryoprotectant (e.g., trehalose). These ODTs are stored under cryogenic conditions (-80°C to -20°C) for extended periods (e.g., 5 years). Stability testing involves subjecting samples to accelerated conditions (40°C/75% RH for 6 months) after cryogenic storage, demonstrating an initial 8-epitacrolimus content below 0.1% post-lyophilization and remaining below 0.5% after 12 weeks at 25°C/60% RH, even after prior long-term cryogenic storage. The pH of the reconstituted ODT in saliva simulants is maintained at 4.0-5.0.

stateDiagram
    [*] --> Formulation
    Formulation --> Lyophilization
    Lyophilization --> Cryogenic_Storage
    Cryogenic_Storage --> Ambient_Storage: (for stability testing)
    Ambient_Storage --> Stability_Assay
    Cryogenic_Storage --> Stability_Assay_Direct: (after 5 years)
    Stability_Assay: Assay 8-epitacrolimus
    Stability_Assay: Verify pH 4.0-5.0
    Stability_Assay --> Result_Stable: <0.5% 8-epitacrolimus
    Result_Stable --> [*]

Derivative 2.4: High-Frequency Sonication for Dispersion in Topical Gel

Enabling Description:
A topical sustained-release pharmaceutical composition comprising a stable micro-dispersion of tacrolimus in a hydrophilic gel vehicle of Carbopol® 974P (carbomer homopolymer) and propylene glycol. The tacrolimus is initially dispersed as a solid dispersion within an ethyl cellulose matrix (as the primary sustained-release component) using high-frequency sonication (20 kHz, 500W for 30 minutes) to achieve a particle size distribution of 1-5 µm. Malic acid, an organic acid, is added to the gel vehicle at 0.8% w/w to maintain the gel pH at 3.5-4.5. This pH is stable for topical application and prevents degradation. The topical gel provides sustained release of tacrolimus into the skin and maintains 8-epitacrolimus levels below 0.5% after 12 weeks of storage at 25°C and 60% relative humidity.

graph TD
    A[Tacrolimus API] --> B{Ethyl Cellulose Solution};
    B --> C{High-Frequency Sonication};
    C --> D[Micro-Dispersion Particles];
    E[Carbopol 974P] --> F(Hydration in Propylene Glycol);
    G[Malic Acid Stabilizer] --> F;
    D & F --> H{Combine & Mix};
    H --> I[Sustained Release Topical Gel];
    I -- pH 3.5-4.5 --> J(Degradation Control);
    J -- <0.5% 8-epitacrolimus --> K(Topical Stability);

Derivative 2.5: Industrial Scale Spray Congealing for Pellets

Enabling Description:
A sustained-release pharmaceutical composition comprising a solid dispersion of tacrolimus in a vehicle of glyceryl behenate (Compritol® 888 ATO) and Poloxamer 188, prepared by industrial-scale spray congealing. The molten mixture, containing tacrolimus and the vehicle, is fed through a spray nozzle into a cooling chamber to form solidified pellets (200-800 µm). Citric acid is incorporated as the stabilizing agent at 0.3% w/w into the molten mixture, ensuring a pH of 3.0-3.6 in aqueous re-dispersion. This process is scaled for continuous production, yielding millions of pellets per hour. The pellets are subsequently filled into hard gelatin capsules. The formulation demonstrates sustained release and maintains 8-epitacrolimus levels below 0.5% after 12 weeks at 25°C and 60% relative humidity.

flowchart LR
    A[Tacrolimus API] --> B(Melt Glyceryl Behenate & Poloxamer 188);
    C[Citric Acid Stabilizer] --> B;
    B --> D{Homogenization Tank};
    D --> E[Spray Nozzle];
    E --> F[Cooling Chamber];
    F --> G[Solidified Pellets];
    G --> H[Sieving & Drying];
    H --> I[Capsule Filling];
    I --> J[SR Pellets in Capsule (Industrial)];
    J -- pH 3.0-3.6 --> K(Stability Assurance);

---

3. Cross-Domain Application

Derivative 3.1: AgTech - Sustained-Release Immunosuppressant for Veterinary Organ Transplants

Enabling Description:
A sustained-release veterinary pharmaceutical composition for companion animals undergoing organ transplantation (e.g., canine renal transplants). The composition comprises a solid dispersion of tacrolimus in a vehicle of PEG 6000 and gum arabic (Acacia senegal gum). The stabilizing agent is tartaric acid, incorporated at 0.25% w/w to provide a pH of 3.0-3.5 in a gastric fluid simulant. The formulation is presented as an oral palatable chewable tablet, designed to release tacrolimus over 24 hours. This veterinary composition maintains 8-epitacrolimus levels below 0.5% after 12 weeks of storage at 25°C and 60% relative humidity, mitigating the degradation observed in standard veterinary tacrolimus formulations and ensuring consistent drug exposure for the animal.

graph LR
    A[Tacrolimus API (Vet-Grade)] --> B(Melt PEG 6000 & Gum Arabic);
    C[Tartaric Acid Stabilizer] --> B;
    B --> D{Flavoring Agents};
    D --> E[Mixing & Granulation];
    E --> F[Compression into Chewable Tablets];
    F --> G[SR Veterinary Tablet];
    G -- Gastric pH 3.0-3.5 --> H(Stability in Vivo/Ex Vivo);
    H -- <0.5% 8-epitacrolimus --> I(Efficacy in Animals);

Derivative 3.2: Aerospace - pH-Stabilized Corrosion Inhibitor for Spacecraft Components

Enabling Description:
A sustained-release anti-corrosion coating composition for sensitive electronic components in spacecraft, designed to slowly release a pH-modifying and chelating agent in a micro-environment. The "active ingredient" is a metal chelating agent, e.g., mercaptobenzothiazole (MBT), widely dispersed as a solid dispersion within a polymer vehicle of poly(vinyl butyral) (PVB) and a low-molecular-weight poly(ethylene glycol) diacrylate (PEGDA) acting as a crosslinker. Citric acid is incorporated as a secondary stabilizing agent (0.5% w/w) to ensure a localized acidic pH (e.g., 4.0-5.0) upon contact with trace moisture, which is critical for MBT's long-term activity. The coating, applied via spray deposition, forms a sustained-release matrix preventing corrosion of delicate circuits over extended missions. The formulation maintains its integrity and releases MBT consistently over 5 years at vacuum conditions with temperature fluctuations from -20°C to +80°C, and trace moisture activated pH stability, thus preventing MBT degradation.

flowchart TD
    A[Mercaptobenzothiazole (MBT)] --> B(PVB & PEGDA Polymer Vehicle);
    C[Citric Acid Stabilizer] --> B;
    B --> D{Solid Dispersion Coating Prep.};
    D --> E[Spray Deposition on Spacecraft Component];
    E --> F[Cured Anti-Corrosion Coating];
    F -- Trace Moisture Activation --> G(Localized pH 4.0-5.0);
    G --> H(Sustained Release of MBT);
    H --> I(Corrosion Protection);

Derivative 3.3: Consumer Electronics - Odor-Neutralizing Air Freshener with pH-Stabilized Active

Enabling Description:
A sustained-release odor-neutralizing composition for integration into consumer electronic devices (e.g., air purifiers, smart speakers with integrated fresheners). The "active ingredient" is zinc ricinoleate (an odor adsorbing agent) in a solid dispersion with a vehicle of ethylene vinyl acetate (EVA) copolymer and a proprietary fragrance polymer. Oxalic acid is incorporated at 0.08% w/w as a stabilizing agent to maintain a slightly acidic pH (e.g., 5.5-6.5) in the presence of ambient humidity, which optimizes the odor-neutralizing efficiency of zinc ricinoleate and prevents its degradation or unwanted chemical reactions with other components. The composition is formed into a sustained-release pellet via injection molding and housed within a replaceable cartridge. The pellet provides consistent odor neutralization over 6-9 months, maintaining the functional integrity of zinc ricinoleate, and showing less than 0.5% degradation products (e.g., oxidized forms of ricinoleate) after 12 weeks at 25°C and 60% relative humidity.

graph TD
    A[Zinc Ricinoleate (Active)] --> B(EVA Copolymer & Fragrance Polymer);
    C[Oxalic Acid Stabilizer] --> B;
    B --> D{Melt Compounding & Injection Molding};
    D --> E[Sustained Release Pellet];
    E --> F[Replaceable Cartridge for CE Device];
    F -- Ambient Humidity --> G(Localized pH 5.5-6.5);
    G --> H(Optimal Odor Neutralization);
    H --> I(Product Longevity);

---

4. Integration with Emerging Tech

Derivative 4.1: AI-Driven Optimization of Stabilizer Concentration and Vehicle Composition

Enabling Description:
A pharmaceutical composition for sustained-release tacrolimus solid dispersions where the optimal concentrations of the stabilizing agent (e.g., a blend of tartaric acid and sodium citrate as a buffer) and the precise ratio of vehicle components (PEG 6000, Poloxamer 188, and a minor component like PVP K30) are determined and continuously optimized by an AI-driven predictive modeling system. This AI system uses machine learning algorithms trained on historical stability data (HPLC degradation profiles, pH measurements, dissolution rates) from various tacrolimus formulations under diverse accelerated and real-time storage conditions. The AI predicts the formulation parameters necessary to achieve less than 0.1% 8-epitacrolimus after 12 weeks at 25°C/60% RH and a stable pH of 3.0-3.5 for a target shelf-life of 24 months. The AI also optimizes for manufacturing robustness and cost efficiency. The output of the AI system directly controls automated feeders in a manufacturing line for precise ingredient dosing.

flowchart TD
    A[Historical Stability Data] --> B(AI Model Training);
    B --> C{AI Prediction Engine};
    D[Target Stability Specs] --> C;
    E[Manufacturing Constraints] --> C;
    C --> F(Optimized Formula Parameters);
    F --> G[Automated Ingredient Feeders];
    G --> H{Solid Dispersion Manufacturing};
    H --> I[Real-time Quality Control (PAT)];
    I --> B;

Derivative 4.2: IoT-Enabled Smart Packaging for Real-time Stability Monitoring

Enabling Description:
A sustained-release tacrolimus tablet, housed in smart blister packaging embedded with IoT sensors. Each blister cavity contains a micro-sensor array capable of real-time, non-invasive monitoring of local humidity, temperature, and a proxy for pH (e.g., via a reversible colorimetric indicator film or electrochemical sensor). The packaging also includes a low-power wireless communication module (e.g., Bluetooth Low Energy). Data from these sensors are periodically transmitted to a secure cloud platform. If detected parameters deviate from predefined stability thresholds (e.g., temperature exceeding 30°C for >24h, or localized pH indicator shifting significantly), an alert is sent to the patient and/or healthcare provider, indicating potential degradation and risk of exceeding the 0.5% 8-epitacrolimus limit. The stabilizing agent (citric acid, 0.5% w/w) ensures the base pH stability of 3.0-3.6.

sequenceDiagram
    participant Tablet as Tacrolimus Tablet
    participant Sensor as IoT Sensor Array
    participant Blister as Smart Blister Pack
    participant Wireless as Wireless Module (BLE)
    participant Cloud as Cloud Platform
    participant User as Patient/HCP

    Tablet->Blister: Encapsulated
    Sensor->Blister: Integrated
    Sensor->Wireless: Transmit Data (Temp, RH, pH proxy)
    Wireless->Cloud: Upload Data
    Cloud->Cloud: Analyze Data (against thresholds)
    alt Deviation Detected
        Cloud->User: Send Alert (Degradation Risk)
    else No Deviation
        Cloud->Cloud: Log Data
    end

Derivative 4.3: Blockchain for Supply Chain Integrity and Degradation Product Traceability

Enabling Description:
A sustained-release tacrolimus pharmaceutical product (e.g., capsule containing solid dispersion pellets stabilized with oxalic acid at 0.1% w/w for pH 3.0-3.4) whose entire supply chain, from raw material sourcing to patient delivery, is immutably recorded on a private blockchain network (e.g., using Hyperledger Fabric). Each batch of raw materials (tacrolimus API, vehicle polymers, oxalic acid) is assigned a unique cryptographic hash and verified against quality certificates. Key manufacturing parameters (e.g., hot-melt extrusion temperature, cooling rates, stabilizer dosing) and post-manufacturing stability data (including 8-epitacrolimus levels at various time points and storage conditions) are automatically recorded as validated transactions on the blockchain. This distributed ledger ensures tamper-proof traceability of the product's quality and stability profile, demonstrating adherence to the <0.5% 8-epitacrolimus degradation limit and the specified pH range, providing unparalleled transparency and preventing counterfeit products or unauthorized alterations in storage conditions.

graph TD
    A[Raw Material Sourcing (API, Vehicle, Stabilizer)] --> B{Quality Certification};
    B --> C{Blockchain Record (Transaction 1)};
    C --> D[Manufacturing (HME, Tableting)];
    D --> E{Manufacturing Parameters (Tx 2)};
    E --> F[QC & Stability Testing (Tx 3)];
    F --> G[Packaging & IoT Integration (Tx 4)];
    G --> H[Distribution & Cold Chain Monitoring (Tx 5)];
    H --> I[Pharmacy Dispensing (Tx 6)];
    I --> J[Patient Receipt (Tx 7)];
    J -- Verify <0.5% 8-epitacrolimus --> K(Trust & Integrity);
    J -- Verify pH 3.0-3.4 --> L(Product Authenticity);

Derivative 4.4: Bio-integrated Sensors for In-Vivo pH Monitoring and Stability Assessment

Enabling Description:
A sustained-release tacrolimus capsule with an integrated bio-compatible pH sensor for in-vivo monitoring. The solid dispersion of tacrolimus (stabilized with tartaric acid at 0.15% w/w for pH 3.5) is formulated into micro-pellets, which are then coated with an enteric polymer (e.g., Eudragit® L100). The capsule also contains a swallowable, battery-free micro-pH sensor (e.g., inductively powered, opto-electronic pH sensor) embedded within an inert region, which wirelessly transmits pH data from the gastrointestinal tract. This provides real-time feedback on the luminal environment, allowing correlation with drug release and potential for in-situ degradation risk. While the sensor doesn't directly measure degradation, it verifies that the immediate environment for drug release aligns with conditions where 8-epitacrolimus formation is minimized, thus confirming conditions conducive to the formulated stability.

sequenceDiagram
    participant Patient as Patient
    participant Capsule as SR Tacrolimus Capsule w/ pH Sensor
    participant GI as Gastrointestinal Tract
    participant Sensor as In-vivo pH Sensor
    participant Receiver as External Receiver
    participant HCP as Healthcare Provider

    Patient->Capsule: Ingest Capsule
    Capsule->GI: Travels to GI
    Sensor->GI: Measures pH
    Sensor->Receiver: Transmits pH Data (Wireless)
    Receiver->HCP: Displays/Logs pH Data
    HCP->GI: Infers Drug Release/Stability Context
    Note over GI,Sensor: pH 3.0-3.5 maintained for tacrolimus stability within dispersion
    HCP->Patient: Adjusts dosage/monitoring based on pH feedback

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5. The "Inverse" or Failure Mode

Derivative 5.1: Programmed Rapid Degradation for Bioavailability Reversal

Enabling Description:
A sustained-release tacrolimus composition designed for programmed rapid degradation under specific conditions, providing a mechanism for "bioavailability reversal" or rapid deactivation in emergency scenarios (e.g., acute toxicity, adverse reaction requiring rapid elimination). The solid dispersion of tacrolimus is formed with a vehicle of PEG 4000 and a pH-sensitive cleavable polymer (e.g., a poly(ortho ester) or pH-responsive hydrogel). The stabilizing agent is a light-sensitive derivative of citric acid (e.g., caged citric acid), which, upon exposure to a specific wavelength of UV or visible light (e.g., 365nm), rapidly releases free citric acid, drastically lowering the local pH (e.g., to below 2.0). This extreme acidic shift, combined with the pH-sensitive polymer, triggers accelerated degradation of tacrolimus (e.g., into the C8-epimer and other known degradation products) and/or rapid, uncontrolled release, allowing for quick systemic clearance or neutralization. The initial formulation maintains <0.5% 8-epitacrolimus after 12 weeks at 25°C/60% RH until triggered.

stateDiagram
    [*] --> Stabilized_SR_Composition: pH 3.0-3.6, <0.5% 8-epitacrolimus
    Stabilized_SR_Composition --> External_Trigger: UV/Visible Light Exposure
    External_Trigger --> Stabilizer_Activation: Caged Citric Acid Release
    Stabilizer_Activation --> pH_Shift_to_Extremes: pH < 2.0
    pH_Shift_to_Extremes --> Polymer_Destabilization: Rapid Degradation/Release
    Polymer_Destabilization --> Rapid_Clearance: Bioavailability Reversal
    Rapid_Clearance --> [*]

Derivative 5.2: Limited-Functionality "Starter Pack" Formulation

Enabling Description:
A limited-functionality, short-term use pharmaceutical composition for tacrolimus, designed as a "starter pack" for immediate post-transplant care where rapid dose adjustment is anticipated, and long-term shelf stability is not the primary concern. This composition comprises a simple solid dispersion of tacrolimus in a polyethylene glycol 6000 vehicle. No specific stabilizing agent is added beyond what might be inherently present as impurities or buffering capacity in the raw materials. The pH, upon re-dispersion, is allowed to be near neutral (e.g., 6.0-7.0). This formulation will exhibit faster degradation kinetics, with 8-epitacrolimus levels potentially rising to 2-5% within 4-6 weeks at 25°C/60% RH. This explicit design for limited stability is disclosed to highlight the importance and utility of the stabilizing agents claimed in US 11,419,823 for long-term storage, while providing a cost-effective, readily manufactured alternative for acute, short-duration needs.

graph TD
    A[Tacrolimus API] --> B(PEG 6000 Vehicle);
    B --> C{Hot Melt Dispersion};
    C --> D[Milling & Capsule Filling];
    D --> E[Limited Stability Starter Pack];
    E -- pH 6.0-7.0 (no stabilizer) --> F(Accelerated Degradation);
    F -- >2% 8-epitacrolimus @ 4-6wks --> G(Short-term Use Only);

Derivative 5.3: Fail-Safe Formulation with Preferential Sacrificial Degradant

Enabling Description:
A sustained-release tacrolimus composition incorporating a "sacrificial" component designed to preferentially degrade or react with pro-degradant species (e.g., residual oxidants, metal ions) before they can affect tacrolimus. The composition features a solid dispersion of tacrolimus in a vehicle of HPMC and Poloxamer 188, stabilized with tartaric acid (0.1% w/w, pH 3.0-3.5). Additionally, a carefully selected, non-toxic, and highly reactive compound, such as a thiol-containing peptide (e.g., reduced glutathione), is incorporated at 0.01% w/w. This sacrificial agent is engineered to have a lower activation energy for degradation reactions compared to tacrolimus. Should adverse storage conditions (e.g., temporary high temperature or oxygen ingress) promote degradation, the glutathione will preferentially oxidize or complex with metal ions, thus sparing tacrolimus from forming 8-epitacrolimus. The formation of glutathione degradation products would indicate a "fail-safe" event, signaling compromised conditions while maintaining tacrolimus stability below the 0.5% 8-epitacrolimus limit.

flowchart TD
    A[Tacrolimus API] --> B(HPMC/Poloxamer Vehicle);
    C[Tartaric Acid Stabilizer] --> B;
    D[Glutathione (Sacrificial Agent)] --> B;
    B --> E{Solid Dispersion Formulation};
    E --> F[Stable SR Tablet];
    F -- Adverse Conditions (O2, Metals) --> G{Glutathione Degrades Preferentially};
    G --> H(Tacrolimus Protected);
    H --> I{<0.5% 8-epitacrolimus maintained};
    I --> J[Fail-Safe Stability Signal];

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Combination Prior Art Scenarios with Open-Source Standards

These scenarios illustrate how the core concepts of US 11,419,823 regarding stabilized tacrolimus solid dispersions can be combined with existing open-source standards, thereby contributing to the body of obvious prior art for future incremental improvements.

Scenario 1: Stabilized Tacrolimus Solid Dispersion + Open-Source Manufacturing Execution System (MES) Standards (ISA-95)

Enabling Description:
The sustained-release tacrolimus pharmaceutical composition (comprising a solid dispersion of tacrolimus in PEG/poloxamer with citric acid as a stabilizing agent to maintain pH 3.0-3.6 and <0.5% 8-epitacrolimus) is produced within a manufacturing facility whose operations are managed and integrated by an open-source Manufacturing Execution System (MES) based on the ISA-95 standard (e.g., using a platform like Eclipse Ditto or Apache PLC4X for connectivity). All recipe management, production scheduling, process data acquisition (including real-time pH monitoring of the molten vehicle and stability testing results from QA systems), quality control, and material traceability are standardized and documented according to ISA-95 models and interfaces. The ISA-95 compliant MES provides comprehensive data on every aspect of the manufacturing process, ensuring consistent quality and stability that meets the patent's claims for degradation product limits and pH.

graph TD
    A[Tacrolimus SR Disp. Formulation] --> B{Manufacturing Process};
    B --> C[ISA-95 Compliant MES];
    C -- Recipe Management --> D(Production Planning);
    C -- Process Data Acquisition --> E(Real-time Quality Control);
    C -- Material Traceability --> F(Supply Chain Mgmt);
    E -- pH Monitoring --> G(Stabilizer Dosing);
    E -- Degradation Assay --> H(Product Release);
    H -- <0.5% 8-epitacrolimus --> I(Patent Compliance);

Scenario 2: Stabilized Tacrolimus Solid Dispersion + Open-Source Drug Discovery Platforms (e.g., Open Babel/RDKit) for Degradation Prediction

Enabling Description:
A research and development pipeline for optimizing sustained-release tacrolimus compositions (e.g., solid dispersion in HPMC/MCC stabilized with tartaric acid for pH 2.8-3.8 and <0.5% 8-epitacrolimus) that leverages open-source cheminformatics tools like Open Babel and RDKit. These platforms are used to computationally predict potential degradation pathways of tacrolimus and its interactions with various stabilizing agents and excipients. Specifically, molecular docking simulations (e.g., AutoDock Vina, also open-source) are performed using RDKit-generated tacrolimus conformers against theoretical metal ion binding sites, and pH-dependent reactivity models are developed using quantum chemistry calculations. This computational approach, integrated with experimental validation, rapidly identifies optimal chelating agents and organic acids, and their concentrations, to minimize 8-epitacrolimus formation, making the selection process for achieving the claimed stability profile and pH control obvious to a skilled artisan.

graph LR
    A[Tacrolimus Structure Input] --> B(RDKit: Conformer Generation);
    B --> C(Open Babel: Format Conversion/Descriptors);
    C --> D{Degradation Prediction Algorithms};
    D -- Metal Ion Chelation --> E(Stabilizer Selection);
    D -- pH Reactivity Models --> F(pH Optimization);
    E & F --> G[Experimental Validation];
    G --> H[Stabilized SR Tacrolimus Composition];
    H -- <0.5% 8-epitacrolimus --> I(Claimed Stability);

Scenario 3: Stabilized Tacrolimus Solid Dispersion + Open-Source Electronic Health Record (EHR) Standards (e.g., FHIR) for Personalized Dosing

Enabling Description:
A sustained-release tacrolimus tablet (solid dispersion in PEG/Poloxamer, stabilized with oxalic acid at 0.15% w/w, providing pH 3.0-3.4 and <0.5% 8-epitacrolimus) whose prescribed dosing regimen is dynamically adjusted based on patient-specific data integrated via an open-source Electronic Health Record (EHR) system adhering to the Fast Healthcare Interoperability Resources (FHIR) standard. The EHR system, utilizing FHIR resources (e.g., Patient, MedicationRequest, Observation), aggregates individual patient metabolic profiles, concomitant medications, genetic predispositions (e.g., CYP3A5 genotype affecting tacrolimus metabolism), and real-time therapeutic drug monitoring (TDM) levels. An AI module within the FHIR-compliant EHR then processes this data to recommend a personalized tacrolimus dose of the stabilized formulation to maintain optimal immunosuppression while minimizing risk of toxicity and ensuring the drug's inherent stability (as protected by the patent claims) is fully realized in a patient-tailored manner. This system demonstrates that the benefits of the stabilized formulation can be extended and optimized through readily available open-source data interoperability standards.

sequenceDiagram
    participant Patient as Patient
    participant EHR as FHIR-Compliant EHR System
    participant TDM as Therapeutic Drug Monitoring
    participant AI as AI Dosing Module
    participant Clinician as Clinician
    participant Pharmacy as Pharmacy

    Patient->EHR: Demographic, Medical History
    TDM->EHR: Tacrolimus Blood Levels
    EHR->AI: Send Patient Data (FHIR Resources)
    AI->AI: Analyze Data & Recommend Dose
    AI->EHR: Send Recommended Dose (FHIR)
    EHR->Clinician: Display Recommended Dose
    Clinician->Pharmacy: Prescribe Stabilized Tacrolimus SR Tablet
    Pharmacy->Patient: Dispense Medication
    Note over Clinician,Pharmacy: The stabilized formulation is assumed to provide consistent efficacy due to its inherent stability (per patent claims)