US 9549918

An analysis of U.S. Patent 9,549,918 reveals a focus on improving the stability of the immunosuppressant drug tacrolimus in pharmaceutical formulations. As of the current date, there is no indication of active litigation involving this patent before the Court of Appeals for the Federal Circuit (CAFC) in 2026.

Summary of U.S. Patent 9,549,918

• Title: Stabilized tacrolimus composition
• Assignee: Veloxis Pharmaceuticals Inc.
• Inventors: Nikolaj Skak, Per Holm
• Filing Date: February 17, 2011
• Issue Date: January 24, 2017
• Abstract: The patent describes a stable pharmaceutical composition of the drug tacrolimus. The invention involves a solid dispersion of tacrolimus within a "vehicle" (an inactive carrier). A key feature is the inclusion of a stabilizing agent that maintains a pH below 7, which helps to prevent or reduce the formation of degradation products, particularly 8-epitacrolimus, during storage.

Plain-Language Overview of Independent Claims

The independent claims of a patent define the core of the invention. For US 9,549,918, these claims broadly cover a stabilized, solid, sustained-release oral dosage form of tacrolimus.

• Claim 1: This claim protects a solid, sustained-release oral dosage form of tacrolimus. The tacrolimus is in a "solid dispersion" mixed with tartaric acid and a carrier vehicle made of polyethylene glycol and poloxamer.

• Claim 8: This claim covers a tablet containing a solid dispersion of tacrolimus with tartaric acid in a vehicle of polyethylene glycol and poloxamer. The defining characteristic of this tablet is that it contains less than 0.2% by weight of the degradation product 8-epitacrolimus.

• Claim 10: This claim is for a tablet with a dispersion of tacrolimus, tartaric acid, and a vehicle of polyethylene glycol and poloxamer. Its novelty lies in its stability over time; it must contain less than 0.5% by weight of the degradation product 8-epitacrolimus after being stored for 12 weeks at 25°C and 60% relative humidity.

• Claim 11: Similar to claim 10, this claim defines a tablet with tacrolimus, tartaric acid, and a vehicle of polyethylene glycol and poloxamer, but with a longer-term stability requirement. It must have less than 0.5% by weight of 8-epitacrolimus after 10 months of storage under the same conditions.

• Claim 12: This claim is for a tablet with a solid dispersion of tacrolimus, tartaric acid, and a vehicle of polyethylene glycol and poloxamer that demonstrates stability under accelerated conditions. The amount of 8-epitacrolimus must not increase by more than 0.5% after 5 weeks at 40°C and 75% relative humidity, or by more than 0.2% after 5 weeks at 25°C and 60% relative humidity.

• Claim 13: This claim describes a stabilized tablet containing a solid dispersion of tacrolimus, tartaric acid, and a vehicle of polyethylene glycol and poloxamer. It is defined by having low levels (no more than 0.5% by weight of each) of several specified degradation products after 5 weeks of storage at 25°C and 60% relative humidity.

• Claim 14: This claim specifies a tablet containing tacrolimus with a vehicle (polyethylene glycol and poloxamer) and a particular concentration of tartaric acid—between approximately 0.05% and 0.6% by weight of the total mixture of tacrolimus, vehicle, and tartaric acid.

• Claim 15: This claim defines a tablet with tacrolimus and a vehicle of polyethylene glycol and poloxamer where the weight ratio of tacrolimus to the stabilizing tartaric acid is within the range of about 19:0.5 to 20:6.

It should be noted that while a search of CAFC dockets for 2026 did not reveal any specific litigation for this patent, records indicate past litigation in the Delaware District Court.

Known Litigation Involving US Patent 9,549,918

As of April 26, 2026, US patent 9,549,918, assigned to Veloxis Pharmaceuticals Inc., is involved in ongoing and past litigation, primarily related to generic drug applications. These cases fall under the Hatch-Waxman Act, where a generic drug manufacturer challenges the patents of a branded drug, in this case, Envarsus XR® (tacrolimus extended-release tablets).

Here is a list of known litigation involving this patent:

Recently Filed Litigation (2026):

• Plaintiff: Veloxis Pharmaceuticals, Inc.
• Defendants: Zydus Pharmaceuticals (USA) Inc. and Zydus Lifesciences Ltd.
• Jurisdiction: U.S. District Court for the District of Delaware
• Case Number: 1:26-cv-00467
• Filing Date: April 23, 2026
• Status: This case was recently filed and is in its early stages. The complaint alleges patent infringement based on the defendants' Abbreviated New Drug Application (ANDA) to market a generic version of Envarsus XR®.

Ongoing and Recently Settled Litigation (2025):

• Plaintiff: Veloxis Pharmaceuticals, Inc.

• Defendant: Glenmark Pharmaceuticals Inc.

• Jurisdiction: U.S. District Court for the District of Delaware

• Case Number: 1:25-cv-00458

• Filing Date: April 14, 2025

• Status: This case is listed as ongoing.

• Plaintiff: Veloxis Pharmaceuticals Inc.

• Defendant: Sun Pharmaceutical Industries Ltd.

• Jurisdiction: U.S. District Court for the District of Delaware

• Filing Date: Not specified, but active in 2026.

• Status: Settled. Veloxis and Sun reached an agreement in April 2026, preventing a generic version of Envarsus XR from Sun until May 2028. A bench trial that was scheduled for the week of the settlement was averted.

Past Litigation (2022):

• Plaintiff: Veloxis Pharmaceuticals, Inc.
• Defendants: Accord Healthcare, Inc. and Intas Pharmaceuticals LTD
• Jurisdiction: U.S. District Court for the District of Delaware
• Case Number: 1:22-cv-00909
• Filing Date: July 7, 2022
• Status: The complaint alleged that the defendants' ANDA for generic tacrolimus extended-release tablets infringed on six Veloxis patents, including the '918 patent. Veloxis sought to prevent the manufacturing and marketing of the generic product before the patents expired. The specific outcome of this case is not detailed in the provided search results, but it is part of the broader enforcement strategy for the Envarsus XR® patent portfolio.

Proceedings overview

The USPTO Open Data Portal (ODP) API currently indicates no AIA trial proceedings on file for US Patent 9,549,918 as of its most recent ingest. A comprehensive web search for Inter Partes Review (IPR), Post-Grant Review (PGR), or Covered Business Method (CBM) proceedings related to US9549918 also did not surface any active or concluded cases. This means the patent has not been subjected to validity challenges before the Patent Trial and Appeal Board (PTAB).

Strategic summary

As of the current date, no claims of US Patent 9,549,918 have been challenged, canceled, or sustained through any PTAB trial proceedings. Consequently, all claims (claims 1-15) of the patent remain untested in this forum.

The absence of PTAB activity indicates that, from a defensive posture, a defendant currently being asserted against by Veloxis Pharmaceuticals Inc. would face the patent in its original granted form. There is no existing estoppel landscape from PTAB proceedings that would bar a defendant (or their privies) from raising any prior art grounds in a new IPR or other validity challenge. The lack of PTAB challenges for a patent that has been involved in district court litigation (as noted in the "Litigation summary" section) is an interesting signal; often, patents asserted in district court, particularly under the Hatch-Waxman Act, become targets for IPR petitions.

Recommended next steps

Since no PTAB activity currently exists for US Patent 9,549,918, a potential defendant has several options:

• Validity Analysis: Conduct a thorough prior art search and validity analysis to identify potential grounds for an IPR petition. This would involve scrutinizing claims 1-15 against existing prior art, especially those references cited in the patent's prosecution history (e.g., WO 2005/020993 A1, US 6,372,760 B1, US 4,716,153 A).
• Monitor PTAB Filings: Regularly monitor the USPTO PTAB search portals (e.g., P-TACTS) for any new petitions filed against US9549918, especially given the ongoing district court litigation involving generic drug manufacturers.
• Consider Filing an IPR: If strong prior art grounds are identified, filing an IPR petition could be a strategic move to challenge the validity of the patent's claims. This would initiate a trial before the PTAB, which has a statutory 1-year deadline from institution to issue a Final Written Decision.

Inventors

• Nikolaj Skak: Employer not explicitly stated in the patent, but was an assignor to LIFECYCLE PHARMA A/S and then VELOXIS PHARMACEUTICALS A/S.
• Per Holm: Employer not explicitly stated in the patent, but was an assignor to VELOXIS PHARMACEUTICALS A/S.

Unusual patterns: Not present. Nikolaj Skak and Per Holm were assignors to Lifecycle Pharma A/S and Veloxis Pharmaceuticals A/S, which aligns with the original assignee and its name change.

Original assignee

The entity named on the issued patent is Veloxis Pharmaceuticals AS (initially Lifecycle Pharma A/S, which changed its name to Veloxis Pharmaceuticals A/S).

Veloxis Pharmaceuticals Inc. is a specialty pharmaceutical company focused on the development and commercialization of drugs for organ transplant recipients. They market Envarsus XR® (tacrolimus extended-release tablets), which embodies the claims of this patent.

Current status: Operating. Veloxis Pharmaceuticals Inc. is an active, operating company.

Assignment timeline

• 2011-03-10 (executed) / recorded 2011-03-25 — Reel 026024/0570

  • Conveyance: ASSIGNMENT
  • Assignor: SKAK, NIKOLAJ and HANSEN, LISELOTTE
  • Assignee: LIFECYCLE PHARMA A/S, DENMARK
  • Correspondent: KENNETH F REICK, REICK AND CHAPPELL, P.C., P.O. BOX 1007, BOULDER, CO 80306
  • Context: Transfer of inventors' interests to the original assignee.

• 2011-07-14 (executed) / recorded 2011-07-15 — Reel 026598/0929

  • Conveyance: CHANGE OF NAME
  • Assignor: LIFECYCLE PHARMA A/S
  • Assignee: VELOXIS PHARMACEUTICALS A/S, DENMARK
  • Correspondent: KENNETH F REICK, REICK AND CHAPPELL, P.C., P.O. BOX 1007, BOULDER, CO 80306 (This correspondent recurs in this chain.)
  • Context: Internal reorg, change of company name.

• 2013-05-15 (executed) / recorded 2013-10-02 — Reel 031327/0467

  • Conveyance: ASSIGNMENT
  • Assignor: HOLM, PER
  • Assignee: VELOXIS PHARMACEUTICALS A/S, DENMARK
  • Correspondent: KENNETH F REICK, REICK AND CHAPPELL, P.C., P.O. BOX 1007, BOULDER, CO 80306 (This correspondent recurs in this chain.)
  • Context: Transfer of inventor's interest to the assignee.

• 2018-02-14 (executed) / recorded 2018-02-15 — Reel 044942/0597

  • Conveyance: SECURITY INTEREST
  • Assignor: VELOXIS PHARMACEUTICALS A/S
  • Assignee: ATHYRIUM OPPORTUNITIES III ACQUISITION LP, NEW YORK
  • Correspondent: MORRISON & FOERSTER LLP, 250 WEST 55TH STREET, NEW YORK, NEW YORK 10019
  • Context: Securitization (loan collateral).

• 2020-01-23 (executed) / recorded 2020-01-23 — Reel 051602/0704

  • Conveyance: RELEASE BY SECURED PARTY
  • Assignor: ATHYRIUM OPPORTUNITIES III ACQUISITION LP
  • Assignee: VELOXIS PHARMACEUTICALS A/S, DENMARK
  • Correspondent: MORRISON & FOERSTER LLP, 250 WEST 55TH STREET, NEW YORK, NEW YORK 10019 (This correspondent recurs in this chain.)
  • Context: Release of security interest.

• 2020-12-30 (executed) / recorded 2021-03-17 — Reel 055613/0695

  • Conveyance: ASSIGNMENT
  • Assignor: VELOXIS PHARMACEUTICALS A/S
  • Assignee: VELOXIS PHARMACEUTICALS INC., NORTH CAROLINA
  • Correspondent: JENSEN AND HIATT, PLLC, 8180 SOUTH 700 EAST, SUITE 350, SANDY, UTAH 84070
  • Context: Internal reorg, likely a change of corporate structure or domicile.

• 2020-12-30 (executed) / recorded 2021-04-02 — Reel 055815/0597

  • Conveyance: ASSIGNMENT
  • Assignor: VELOXIS PHARMACEUTICALS A/S
  • Assignee: VELOXIS PHARMACEUTICALS INC., NORTH CAROLINA
  • Correspondent: JENSEN AND HIATT, PLLC, 8180 SOUTH 700 EAST, SUITE 350, SANDY, UTAH 84070 (This correspondent recurs in this chain.)
  • Context: Internal reorg, likely a duplicate or clarification of the previous assignment due to the same execution date.

• 2024-06-07 (executed) / recorded 2024-06-07 — Reel 067666/0352

  • Conveyance: CHANGE OF ADDRESS
  • Assignor: VELOXIS PHARMACEUTICALS INC.
  • Assignee: VELOXIS PHARMACEUTICALS INC., NORTH CAROLINA
  • Correspondent: JENSEN AND HIATT, PLLC, 8180 SOUTH 700 EAST, SUITE 350, SANDY, UTAH 84070 (This correspondent recurs in this chain.)
  • Context: Change of address for the current assignee.

Timeline diagram

timeline
    title Ownership of US 9549918
    2011 : Inventors to Lifecycle Pharma A/S
         : Lifecycle Pharma A/S becomes Veloxis A/S
    2013 : Inventor Holm to Veloxis A/S
    2018 : Security interest to Athyrium
    2020 : Security interest released
    2021 : Veloxis A/S to Veloxis Inc
    2024 : Veloxis Inc address change

NPE / troll-pattern signals

1. Shell-entity transfer — not present. The transfers involve Lifecycle Pharma A/S (which became Veloxis Pharmaceuticals A/S) and then Veloxis Pharmaceuticals Inc., both operating companies. Athyrium Opportunities III Acquisition LP appears to be a legitimate investment fund providing financing (security interest), not a shell entity for assertion.
2. Known asserter in the chain — not present. None of the assignees (Lifecycle Pharma A/S, Veloxis Pharmaceuticals A/S, Athyrium Opportunities III Acquisition LP, Veloxis Pharmaceuticals Inc.) match known NPE lists.
3. Repeat correspondent across the chain — present.
   • KENNETH F REICK, REICK AND CHAPPELL, P.C. appears on Reels 026024/0570, 026598/0929, and 031327/0467.
   • MORRISON & FOERSTER LLP appears on Reels 044942/0597 and 051602/0704.
   • JENSEN AND HIATT, PLLC appears on Reels 055613/0695, 055815/0597, and 067666/0352.
     While the presence of repeat correspondents is a signal, in this case, it appears to be indicative of consistent legal counsel for the operating companies (Lifecycle/Veloxis) and their financing partners (Morrison & Foerster for Athyrium), rather than a sign of NPE activity.
4. Cascading transfers — not present. The transfers are spaced out over years, reflecting corporate actions rather than rapid patent aggregation for assertion.
5. Pre-litigation transfer — unclear. The case 1:22-cv-00909 was filed on July 7, 2022. The last assignment to Veloxis Pharmaceuticals Inc. was recorded on March 17, 2021, and April 2, 2021, which is more than 6 months prior to the litigation. However, the litigation summary also states "Filing Date: Not specified, but active in 2026." for the Sun Pharma case and April 14, 2025, for the Glenmark case. The earliest recorded litigation for this patent is July 7, 2022 (case 1:22-cv-00909). The assignments in 2021 (Reel 055613/0695 and 055815/0597) occurred more than 6 months before this earliest recorded litigation.
6. Bankruptcy fire-sale — not present. There is no indication of bankruptcy proceedings for Lifecycle Pharma A/S or Veloxis Pharmaceuticals.
7. Privateering — not present. All identified litigation is initiated by Veloxis Pharmaceuticals Inc., an operating company, against generic drug manufacturers, which is a standard operating-company assertion model.
8. Defensive aggregator (anti-NPE) — not present. The patent is currently held by an operating company that is asserting it.

Verdict

Operating-company assertion. The patent has been consistently held by Veloxis Pharmaceuticals (or its predecessor Lifecycle Pharma), which manufactures and sells a product embodying the claims (Envarsus XR®). The litigation is against generic drug manufacturers, which is typical of operating companies defending their market. The repeated correspondents are consistent with the ongoing legal representation of an operating entity through corporate changes and financial transactions.

USPTO Assignment Center search page for US9549918

Analysis of Prior Art for U.S. Patent 9,549,918

The core invention of U.S. Patent 9,549,918 is a stabilized solid oral dosage form of tacrolimus. The key features claimed are the use of a solid dispersion of tacrolimus within a specific vehicle composed of polyethylene glycol (PEG) and poloxamer, stabilized by tartaric acid to maintain a low pH and limit the formation of degradation products, especially 8-epitacrolimus. The claims further specify sustained-release properties and define acceptable levels of degradation products over time.

An analysis of the prior art cited by the patent examiner reveals several key references that, while relevant to tacrolimus formulations, do not appear to fully anticipate the specific combination and stability requirements claimed in the '918 patent. The novelty of the '918 patent seems to lie in the identification of 8-epitacrolimus as a major degradation product and the use of tartaric acid in a specific polymeric matrix to control its formation.

Here are the most relevant prior art references and their potential relation to the claims of US 9,549,918:

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1. WO 2005/020993 A1

• Full Citation: Holm, P., & Skak, N. (2005). Modified release compositions comprising tacrolimus. WO 2005/020993 A1.
• Publication Date: March 10, 2005 (Filing Date: August 29, 2003).
• Brief Description: This international patent application, from the same inventors and original assignee as the '918 patent, discloses modified-release compositions of tacrolimus. It describes creating a solid dispersion of tacrolimus in a hydrophilic or water-miscible vehicle to improve its bioavailability. Example 2 of this reference specifically mentions a formulation containing tacrolimus, PEG 6000, and poloxamer 188. This formulation is identical to the base composition described in Example 1A of the '918 patent, which was shown to be unstable without a stabilizing agent.
• Potential Anticipation Analysis: This reference is highly relevant as it discloses the core components of the vehicle (PEG and poloxamer) used in a solid dispersion with tacrolimus. However, WO 2005/020993 A1 does not teach or suggest the use of a stabilizing agent, specifically tartaric acid, to prevent the formation of the 8-epitacrolimus degradation product. The '918 patent builds upon this earlier work by identifying the stability problem and providing a specific solution. Therefore, while it discloses the vehicle, it does not anticipate the claims of the '918 patent which require the presence of tartaric acid and the resulting stability against specific degradation pathways. It provides a clear motivation for the invention of the '918 patent.

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2. US 4,716,153 A

• Full Citation: Morishita, M., et al. (1987). Stable oral preparation of macrolide antibiotics and method for stabilizing the same. US Patent 4,716,153 A.
• Publication Date: December 29, 1987 (Filing Date: December 4, 1982).
• Brief Description: This patent addresses the issue of stabilizing macrolide antibiotics (like erythromycin) in solid dosage forms. It teaches that the stability of these antibiotics, which are unstable under acidic conditions, can be improved by including a basic substance, such as an alkaline metal salt of a weak acid (e.g., sodium citrate). The goal is to create a micro-environment with a pH of 7 or higher around the antibiotic particles.
• Potential Anticipation Analysis: This patent teaches the general concept of using pH-modifying agents to stabilize macrolide antibiotics. However, it teaches the opposite approach to that claimed in the '918 patent. The '153 patent uses a basic substance to achieve a pH above 7, whereas the '918 patent uses an acidic substance (tartaric acid) to achieve a pH below 7. This fundamental difference in the stabilization strategy means that US 4,716,153 A does not anticipate any of the claims of the '918 patent. In fact, it teaches away from the claimed invention.

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3. US 6,372,760 B1

• Full Citation: Kato, K., et al. (2002). Stabilized composition comprising antidementia medicament. US Patent 6,372,760 B1.
• Publication Date: April 16, 2002 (Filing Date: March 31, 1999).
• Brief Description: This patent describes stabilizing a specific antidementia drug (donepezil) by adding an organic acid to the formulation. The purpose is to prevent the drug from discoloring over time when it interacts with certain excipients like lactose. The patent mentions a wide range of organic acids, including tartaric acid.
• Potential Anticipation Analysis: This reference discloses the use of organic acids, including tartaric acid, as stabilizing agents in pharmaceutical compositions. However, it addresses a different technical problem (discoloration of donepezil) in a different drug class. It does not mention tacrolimus, solid dispersions, the specific vehicle of PEG and poloxamer, or the prevention of specific degradation products like 8-epitacrolimus. Therefore, it does not anticipate the specific combination of elements required by the claims of the '918 patent.

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4. US 2008/0153866 A1

• Full Citation: Shin, H-J., et al. (2008). Amorphous Tacrolimus Solid Dispersion Having an Enhanced Solubility and Pharmaceutical Composition Comprising Same. US Patent Application Publication 2008/0153866 A1.
• Publication Date: June 26, 2008 (Filing Date: February 4, 2005).
• Brief Description: This patent application describes amorphous solid dispersions of tacrolimus with a carrier to enhance solubility. The carriers mentioned are typically polymers like polyvinylpyrrolidone (PVP) or hydroxypropyl methylcellulose (HPMC). The focus is on improving the dissolution rate of tacrolimus.
• Potential Anticipation Analysis: This application teaches the concept of using solid dispersions to improve the properties of tacrolimus. However, it does not disclose the specific vehicle combination of polyethylene glycol and poloxamer, nor does it address the chemical stability of tacrolimus by using tartaric acid to prevent the formation of 8-epitacrolimus. The carriers and the technical problem being solved are different from those in the '918 patent.

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5. US 2009/0011018 A1

• Full Citation: Abe, T., et al. (2009). Sustained release formulation for tacrolimus. US Patent Application Publication 2009/0011018 A1.
• Publication Date: January 8, 2009 (Filing Date: December 28, 2006).
• Brief Description: This application from Astellas Pharma, the originator of Prograf® (a commercial tacrolimus product), describes a sustained-release formulation of tacrolimus. The formulation uses a matrix of a water-soluble polymer and a water-insoluble polymer to control the release of the drug.
• Potential Anticipation Analysis: This reference is relevant in that it deals with sustained-release tacrolimus formulations. However, the mechanism for achieving sustained release and the composition of the formulation are different from what is claimed in the '918 patent. It does not teach a solid dispersion in a PEG/poloxamer vehicle, nor the use of tartaric acid for stabilization against specific degradation products.

In summary, while the prior art establishes the use of solid dispersions for tacrolimus and the general use of pH modifiers for drug stability, no single reference appears to disclose the specific combination of a tacrolimus solid dispersion in a polyethylene glycol/poloxamer vehicle stabilized with tartaric acid to control the formation of 8-epitacrolimus, as claimed in US 9,549,918.

Based on the provided prior art analysis, here is an assessment of the obviousness of US patent 9,549,918 under 35 U.S.C. § 103.

Obviousness Analysis Under 35 U.S.C. § 103

Under United States patent law, an invention is considered obvious if the differences between the invention and the prior art are such that the invention as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art (PHOSITA). This analysis considers the scope of the prior art, the differences between the prior art and the claims, and the level of ordinary skill in the relevant art.

Person Having Ordinary Skill in the Art (PHOSITA)

At the time of this invention (priority date 2008-05-30), a PHOSITA would be a pharmaceutical scientist or formulation chemist with a graduate degree in a relevant field (e.g., pharmaceutics, chemistry) and several years of experience in developing oral dosage forms, particularly for poorly soluble and chemically sensitive compounds. This individual would be familiar with solid dispersion technology, common pharmaceutical excipients including polymers (like PEGs and poloxamers) and pH-modifying agents, and standard methods for drug stability analysis.

Potential Obviousness Combination

A compelling argument for the obviousness of the claims of US 9,549,918 can be constructed by combining the teachings of WO 2005/020993 A1 (Holm) and US 6,372,760 B1 (Kato).

1. Base Reference: WO 2005/020993 A1 (Holm)
   This application, by the same inventors, provides the foundational formulation. It explicitly discloses a solid dispersion of tacrolimus in a vehicle comprising polyethylene glycol (PEG 6000) and poloxamer 188. This is the exact, unstabilized formulation that the '918 patent aims to improve. A PHOSITA would select this reference as a starting point for developing a sustained-release tacrolimus product.

2. Motivation to Modify the Holm Formulation
   A PHOSITA, following standard pharmaceutical development protocols, would conduct stability testing on the formulation described in Holm. As demonstrated in Example 2 of the '918 patent, this base formulation is unstable and leads to significant degradation of tacrolimus into its C8-epimer (8-epitacrolimus). The discovery of this instability would present a clear and well-recognized problem that the PHOSITA would be motivated to solve to create a commercially viable product with an acceptable shelf life.

3. Secondary Reference: US 6,372,760 B1 (Kato)
   Faced with a chemical stability problem, the PHOSITA would search the prior art for known methods of stabilizing drug formulations. Kato expressly teaches the use of an organic acid, specifically mentioning tartaric acid, as a stabilizing agent to prevent the degradation (discoloration) of a different drug, donepezil. Kato provides the clear suggestion that adding an organic acid is a known technique for improving the chemical stability of a pharmaceutical composition.

4. Reason to Combine and Expectation of Success
   The motivation to combine Holm and Kato is straightforward: to solve the stability problem identified in the Holm formulation by applying the known stabilization strategy taught in Kato. A PHOSITA would have a reasonable expectation of success in this endeavor. Using acidic excipients to control pH is a fundamental and common tool in formulation science to enhance drug stability. While Kato addresses a different drug and degradation pathway, it establishes the principle of using tartaric acid as a pharmaceutical stabilizer. A PHOSITA would find it routine to test a small number of well-known, pharmaceutically acceptable organic acids, such as citric acid and tartaric acid, to see if they could resolve the instability of the tacrolimus formulation. The optimization of the acid concentration (as claimed in claim 14) and the confirmation of stability over time (as in claims 10-13) would be the result of routine experimentation, not an inventive leap.

Arguments Against Obviousness

Despite the strong prima facie case for obviousness, the patentee has significant counterarguments:

• Teaching Away: The most powerful counterargument comes from US 4,716,153 A (Morishita). This patent addresses the stability of macrolide antibiotics, the same chemical class as tacrolimus. Morishita teaches that these compounds are unstable in acidic conditions and must be stabilized by adding a basic substance to create a microenvironment with a pH above 7. This directly contradicts the invention of the '918 patent, which requires adding an acidic substance to lower the pH to below 7. A PHOSITA, knowing that macrolides are generally unstable in acid, might be deterred from trying an acidic stabilizer and would instead be guided by Morishita's teaching to use a basic one. This "teaching away" suggests the solution in the '918 patent was non-obvious.

• Unpredictability of the Art: The patentee would argue that drug stabilization is highly unpredictable. There was no reason for a PHOSITA to believe that a method for preventing the discoloration of donepezil (Kato) would be effective at preventing the specific C8-epimerization of tacrolimus in a melted PEG/poloxamer matrix. The '918 patent identifies a novel degradation product (8-epitacrolimus) and provides a specific, unexpectedly effective solution. As shown in the '918 patent's own examples (Example 5), not all acids work; tartaric acid and other chelating organic acids showed superior performance compared to inorganic acids, indicating that the solution was more complex than simple pH adjustment.

Conclusion

A strong case for obviousness can be made by combining the Holm reference, which provides the base formulation, with the Kato reference, which suggests using tartaric acid as a general-purpose stabilizer. A PHOSITA would have been motivated to combine these teachings to solve the inherent instability of the Holm formulation.

However, the "teaching away" nature of the Morishita patent provides a substantial argument for non-obviousness. It suggests that a person skilled in the art would have been discouraged from exploring the very path that led to the invention. The unpredictability of the specific chemical reaction and the superior, non-linear performance of tartaric acid further support the argument that the solution was not a product of mere routine experimentation. Therefore, while a rejection under § 103 is plausible, the patentee possesses strong rebuttal arguments that could overcome such a rejection.

US Patent 9,549,918: Term, Continuations, and Family

Projected Expiration Date

The projected expiration date for US patent 9,549,918 is May 30, 2028. This date is calculated 20 years from the earliest effective non-provisional filing date, which is May 30, 2008. This date stems from the patent's claim to priority from International Application No. PCT/DK08/050130, which was filed on that day.

Patent Term Adjustments (PTA) and Extensions (PTE)

• Patent Term Adjustment (PTA): The front page of the issued patent explicitly states that the term of the patent is extended or adjusted under 35 U.S.C. 154(b) by 0 days. PTA is granted to compensate for certain administrative delays by the U.S. Patent and Trademark Office (USPTO) during prosecution. In this case, no such adjustment was awarded.

• Patent Term Extension (PTE): There is no evidence that a Patent Term Extension under 35 U.S.C. § 156 was sought or granted for this patent. PTE is used to restore patent life lost during a product's regulatory review period by agencies like the FDA.

Continuation and Divisional Applications

The patent is part of a larger family of applications that includes several continuations, which are applications that claim the benefit of the filing date of an earlier application.

• Parent Application: US patent 9,549,918 issued from application US13/029,304, which is a continuation-in-part of application US12/499,034 (filed July 7, 2009, and now issued as US Patent 8,685,998).

• Continuation (Child) Applications: Several applications have been filed that claim continuation status from the '918 patent or its parent, extending the patent family:

  • US15/405,879: Filed January 13, 2017, and issued as US 10,166,190 B2.
  • US16/188,805: Filed November 13, 2018, and issued as US 11,419,823 B2.
  • US17/857,442: Filed July 5, 2022, and issued as US 12,403,095 B2.

• Divisional Applications: Based on the provided documentation, there are no applications identified as divisional applications related to US 9,549,918.

Patent Family Members

US patent 9,549,918 is part of an extensive international patent family. Key family members include:

• United States:

  • US 8,685,998 B2 (Parent)
  • US 10,166,190 B2 (Continuation)
  • US 11,419,823 B2 (Continuation)
  • US 12,403,095 B2 (Continuation)

• International:

  • WO 2011/100975 A2: The international application filed under the Patent Cooperation Treaty (PCT).
  • EP 2575769 B1: The patent granted by the European Patent Office.
  • Counterpart patents and applications have also been filed in Argentina (AR), Taiwan (TW), and several other jurisdictions, including under the Eurasian Patent Organization (EA).

Defensive Disclosure: Derivatives and Novel Applications of Stabilized Macrolide Solid Dispersions

Publication Date: May 1, 2026
Reference Patent: US 9549918 B2

This document discloses novel and non-obvious extensions, variations, and applications derived from the core teachings of US patent 9,549,918. The purpose of this disclosure is to place these concepts into the public domain, thereby establishing them as prior art for any future patent applications. The following descriptions are enabling for a person having ordinary skill in the art (PHOSITA) of pharmaceutical formulation.

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Axis 1: Material & Component Substitution

1.1. Stabilizer Substitution: Non-Acidic Metal Ion Chelator System

• Enabling Description: A solid dispersion of tacrolimus is prepared using a hot-melt extrusion process with a vehicle of polyethylene glycol 8000 (PEG 8000) and Poloxamer 407 (70:30 w/w ratio). Instead of an organic acid, stability against C8-epimerization is achieved by incorporating 0.2% w/w of ethylenediaminetetraacetic acid (EDTA) and 1.5% w/w of a beta-cyclodextrin derivative, such as hydroxypropyl-β-cyclodextrin (HP-β-CD). The EDTA actively chelates divalent metal ions (e.g., Mg²⁺, Ca²⁺) that catalyze the epimerization reaction, while the HP-β-CD encapsulates a portion of the tacrolimus molecule, sterically hindering the degradation pathway without altering bulk pH.
• Mermaid Diagram:

  graph TD
      A[Tacrolimus] --> C{Melt Extruder @ 90°C};
      B[PEG 8000 / Poloxamer 407] --> C;
      D[EDTA + HP-β-CD] --> C;
      C --> E[Extruded Filament];
      E --> F[Pelletization];
      F --> G[Compression into Tablet];
      subgraph "Stabilization Mechanism"
          D1(EDTA) -- Chelates --> M(Metal Ions);
          D2(HP-β-CD) -- Encapsulates --> A;
      end
  

1.2. Stabilizer Substitution: Mixed Organic Acid System

• Enabling Description: A stable, sustained-release tacrolimus tablet is formulated using a solid dispersion wherein the stabilizing agent is a synergistic combination of two organic acids. The formulation contains 0.15% w/w L-tartaric acid and 0.25% w/w succinic acid within a PEG 6000/Poloxamer 188 vehicle. The tartaric acid provides strong chelation and initial pH reduction, while the succinic acid acts as a secondary buffer, maintaining the acidic microenvironment more effectively over a prolonged period as the tablet matrix hydrates and dissolves in the gastrointestinal tract. This dual-acid system provides superior long-term stability (>12 months) compared to tartaric acid alone.
• Mermaid Diagram:

  stateDiagram-v2
      [*] --> Unstabilized: Formulation Prepared
      Unstabilized --> Stabilized: Add Tartaric + Succinic Acid
      state Stabilized {
          direction LR
          [*] --> pH_Lowered: Tartaric Acid acts
          pH_Lowered --> pH_Maintained: Succinic Acid buffers
          pH_Maintained --> [*]
      }
  

1.3. Vehicle Substitution: Biodegradable Polymer Matrix

• Enabling Description: The PEG/poloxamer vehicle is replaced with a biodegradable matrix of poly(lactic-co-glycolic acid) (PLGA 75:25) and a plasticizer, triethyl citrate. Tacrolimus and 0.5% w/w tartaric acid are dissolved in a solvent system (acetone/dichloromethane) with the PLGA. This solution is then used to create microspheres via an oil-in-water emulsion-solvent evaporation technique. The resulting tartaric acid-infused microspheres provide sustained release of tacrolimus over 72 hours and are fully biodegradable. This formulation is intended for targeted delivery or implantable depots.
• Mermaid Diagram:

  flowchart LR
      subgraph "Aqueous Phase"
          B[Polyvinyl Alcohol Solution]
      end
      subgraph "Organic Phase"
          A[Tacrolimus + Tartaric Acid + PLGA in Acetone/DCM]
      end
      A -- Emulsification --> C{Homogenizer};
      B --> C;
      C -- Solvent Evaporation --> D[PLGA Microspheres];
      D -- Lyophilization --> E[Dry Powder for Injection/Implant];
  

1.4. Active Ingredient Substitution: Sirolimus (Rapamycin) Formulation

• Enabling Description: The principles of the '918 patent are applied to stabilize sirolimus, another macrolide lactone known for its instability. A solid solution of sirolimus is prepared in a vehicle of Gelucire 50/13, a polyglycolized glyceride, via a melt-granulation process. The formulation is stabilized by the inclusion of 0.3% w/w citric acid, which prevents oxidative degradation and hydrolysis by maintaining an acidic microenvironment (pH 3.5-4.0). The resulting granules can be filled into hard capsules for oral administration.
• Mermaid Diagram:

  classDiagram
      class SirolimusFormulation {
          +active_ingredient: Sirolimus
          +vehicle: Gelucire_50_13
          +stabilizer: Citric_Acid
          +dosage_form: Hard_Capsule
          +stabilization_pH: 3.5
      }
      Sirolimus --|> MacrolideLactone
      Tacrolimus --|> MacrolideLactone
      SirolimusFormulation ..> Sirolimus : contains
  

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Axis 2: Operational Parameter Expansion

2.1. Manufacturing Parameter: Cryogenic Spray-Congealing

• Enabling Description: A molten mixture of tacrolimus, PEG 10000, Poloxamer 338, and 0.2% w/w tartaric acid at 100°C is atomized through a heated nozzle into a cryogenic chamber filled with liquid nitrogen vapor at -120°C. The rapid solidification (congealing) traps the tacrolimus and tartaric acid in a highly uniform, amorphous solid dispersion. This process minimizes thermal exposure time, reducing the formation of initial degradation products to below 0.01% w/w at t=0 and yielding microparticles suitable for direct compression or filling into sachets for pediatric use.
• Mermaid Diagram:

  sequenceDiagram
      participant MoltenSlurry as "Molten Slurry (100°C)"
      participant Atomizer
      participant CryoChamber as "Cryo Chamber (-120°C)"
      participant Collector
      MoltenSlurry->>Atomizer: Feed molten mixture
      Atomizer->>CryoChamber: Spray fine droplets
      CryoChamber->>Collector: Rapidly congeal droplets into microparticles
      Collector-->>MoltenSlurry: Particles < 0.01% degradants
  

2.2. Environmental Parameter: High-Altitude/Aerospace Formulation

• Enabling Description: For use by astronauts in low-gravity and high-radiation environments, the stabilized tacrolimus tablet is further enhanced. The solid dispersion is prepared as claimed but is then coated with a dual-layer system. The inner layer is hydroxypropyl methylcellulose (HPMC) containing 1% w/w butylated hydroxytoluene (BHT) as an antioxidant to mitigate degradation from ionizing radiation. The outer layer is a UV-blocking enteric coating (e.g., Eudragit L100-55 with embedded titanium dioxide) to protect against light-induced degradation and ensure release in the small intestine.
• Mermaid Diagram:

  graph TD
      A(Core Tablet: Tacrolimus + Tartaric Acid in PEG/Poloxamer) --> B{Inner Coating};
      B -- Contains --> B1(HPMC + BHT for Radiation Shielding);
      B --> C{Outer Coating};
      C -- Contains --> C1(Eudragit + TiO2 for UV Shielding);
      C --> D[Final Aerospace-Ready Tablet];
  

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Axis 3: Cross-Domain Application

3.1. AgTech Application: Controlled-Release Fungicide

• Enabling Description: A solid dispersion of the pH-sensitive fungicide Azoxystrobin is prepared in a biodegradable vehicle of polylactic acid (PLA) and a surfactant. The formulation is stabilized against hydrolysis in alkaline soils by incorporating 2% w/w of oxalic acid. The mixture is extruded into pellets, which are coated with a water-permeable membrane. When applied to soil, moisture slowly penetrates the pellet, dissolving the oxalic acid and creating an acidic micro-environment that stabilizes the Azoxystrobin as it is slowly released over a 90-day period.
• Mermaid Diagram:

  stateDiagram-v2
      [*] --> InPellet: Fungicide Stable (Acidic)
      InPellet --> Releasing: Soil moisture ingress
      Releasing --> InSoil: Active fungicide released
      InSoil --> Degraded: Hydrolysis in alkaline soil
      note right of InPellet
          Oxalic acid maintains low pH
          inside the pellet, protecting
          the active ingredient.
      end note
  

3.2. Food Science Application: Stabilized Probiotic Delivery

• Enabling Description: Live probiotic bacteria (e.g., Lactobacillus rhamnosus) are lyophilized with a cryoprotectant mixture containing lactose and 0.5% w/w malic acid. This powder is then incorporated into a solid dispersion vehicle of PEG 4000 and Poloxamer 188 using a low-temperature melt granulation process (<45°C). The malic acid creates an acidic micro-environment that keeps the bacteria in a state of suspended animation and protects them from premature activation by ambient humidity. The final granules are enteric-coated to bypass stomach acid and release the viable probiotics in the intestine.
• Mermaid Diagram:

  flowchart TD
      A[Probiotics + Cryoprotectant + Malic Acid] --> B(Lyophilization);
      B --> C[Stabilized Powder];
      D[Melted PEG 4000/Poloxamer < 45°C] --> E{Low-Shear Granulator};
      C --> E;
      E --> F[Granules with Dormant Probiotics];
      F --> G(Enteric Coating);
      G --> H[Final Oral Capsule];
  

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Axis 4: Integration with Emerging Tech

4.1. AI-Driven Process Analytical Technology (PAT)

• Enabling Description: During the hot-melt extrusion of the tacrolimus/tartaric acid/PEG/poloxamer formulation, a near-infrared (NIR) and a Raman spectroscopy probe are fitted to the extruder die. These sensors provide real-time data on the crystallinity, uniformity of dispersion, and concentration of both tacrolimus and 8-epitacrolimus. A trained machine learning model interprets the spectral data and dynamically adjusts process parameters (screw speed, temperature profile, feed rate) to maintain the concentration of 8-epitacrolimus in the final extrudate below a target threshold of 0.1% w/w, ensuring batch-to-batch consistency.
• Mermaid Diagram:

  sequenceDiagram
      participant Extruder
      participant Sensors as "NIR/Raman Probes"
      participant AI_Model as "AI Control Model"
      loop Real-time Process Control
          Extruder->>Sensors: Provides material for analysis
          Sensors->>AI_Model: Sends spectral data
          AI_Model->>Extruder: Adjusts parameters (temp, speed)
      end
      Note right of AI_Model: Goal: Minimize 8-epitacrolimus < 0.1%
  

4.2. IoT-Enabled Adherence and Stability Monitoring

• Enabling Description: The stabilized tacrolimus formulation is packaged in a "smart" blister pack equipped with NFC (Near-Field Communication) technology and a small temperature/humidity logger. Each time a patient pushes a tablet through the foil, a circuit is broken, and the event is logged. The patient can scan the pack with their smartphone to upload adherence data. The logger continuously monitors storage conditions. If the pack is exposed to temperatures exceeding 30°C for a cumulative period of 72 hours, an alert is sent to the patient and pharmacist, warning of potential accelerated degradation and compromised stability.
• Mermaid Diagram:

  graph TD
      subgraph SmartBlisterPack
          A[Tablet Cavity] -- Push-through --> B(Conductive Trace Break);
          C[Temp/Humidity Logger] -- Logs --> D(Storage Data);
          E[NFC Chip] -- Stores --> B & D;
      end
      F(Patient Smartphone) -- Scans --> E;
      E -- Transmits Data --> F;
      F --> G{Cloud Platform};
      G -- Adherence Log --> H(Provider Portal);
      G -- Stability Alert? --> F;
  

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Axis 5: The "Inverse" or Failure Mode

5.1. Intentional Inactivation for Safe Disposal

• Enabling Description: A tacrolimus solid dispersion is formulated with tartaric acid as in the primary invention. However, it also incorporates 5% w/w of sodium bicarbonate, physically separated from the acidic solid dispersion by a pH-sensitive coating of Eudragit E 100. The coating is stable in the acidic core but dissolves rapidly at pH > 5. For disposal, the user dissolves the tablet in a provided "Disposal Solution" containing a mild phosphate buffer at pH 8. The Eudragit E 100 dissolves, allowing the sodium bicarbonate to react with the tartaric acid, raising the internal pH of the dissolving matrix to > 8, which rapidly accelerates the degradation of tacrolimus into inactive epimers and hydrolysis products.
• Mermaid Diagram:

  flowchart TD
      A[Core: Tacrolimus + Tartaric Acid] --> B{Coating: Eudragit E 100};
      B --> C{Outer Layer: Sodium Bicarbonate};
      C --> D[Final Tablet];
      subgraph "Disposal Process"
          D -- Add to --> E[Disposal Solution pH 8];
          E -- Dissolves --> B;
          A -- Reacts with --> C;
          F{pH shifts to > 8};
          F --> G[Tacrolimus Rapidly Degrades];
      end
  

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Combination Prior Art Scenarios

1. Combination with Open-Source 3D-Printed Polypill: The stabilized tacrolimus/tartaric acid/PEG/poloxamer granules, produced via melt-granulation, are used as a feedstock material for a Fused Deposition Modeling (FDM) 3D printer. The printer uses an open-source design file (e.g., from the Open-Source Pharma initiative) to print a "polypill" containing metformin, lisinopril, and the tacrolimus formulation in separate, defined compartments. This allows for a single, personalized, once-daily tablet for diabetic transplant patients, with the tacrolimus component protected from chemical interaction with the other APIs.

2. Combination with OMOP Common Data Model: Data from an IoT-enabled "smart pill" containing the stabilized tacrolimus formulation is collected. This data includes in-vivo pH measurements, transit time, and patient-reported outcomes. The data is then structured and mapped according to the open-source Observational Medical Outcomes Partnership (OMOP) Common Data Model. This allows for large-scale, federated analysis by researchers to correlate the formulation's in-vivo behavior (i.e., maintenance of the acidic micro-environment) with clinical outcomes like rejection rates and trough level variability across diverse patient populations.

3. Combination with OpenMTA for Research Tools: The exact formulation and manufacturing protocol for a non-commercial, research-grade version of the stabilized tacrolimus composition is made available to academic researchers under the OpenMTA (Open Material Transfer Agreement) framework. This allows academic labs to easily obtain, replicate, and improve upon the formulation for non-commercial research into macrolide stability, GI tract absorption models, or new analytical methods for detecting degradation products, without the legal friction of traditional MTAs.