US 10166190

US patent 10166190, titled "Stabilized tacrolimus composition," was issued to Veloxis Pharmaceuticals Inc. on January 1, 2019. The application for this patent was filed on January 13, 2017. The inventors are Nikolaj Skak and Per Holm.

Abstract:
The patent describes a stable pharmaceutical composition containing a solid dispersion of tacrolimus in a vehicle. This composition also includes a stabilizing agent designed to maintain a pH below 7 when re-dispersed in water. The primary purpose of this stabilizing agent is to prevent or reduce the formation of major degradation products of tacrolimus, particularly 8-epitacrolimus, during storage.

Plain-Language Overview of Independent Claims:

• Independent Claim 1: This claim covers a pharmaceutical composition that comprises tacrolimus in a solid dispersion within a mixture of a vehicle and a stabilizing agent. The key characteristic is that this stabilizing agent is capable of providing a pH below 7 in the composition when measured after re-dispersion in water.

• Independent Claim 15: This claim describes a method for reducing the concentration of tacrolimus degradation products in a pharmaceutical composition that contains tacrolimus as its active ingredient. The method involves incorporating a stabilizing agent into the composition.

• Independent Claim 16: This claim pertains to a pharmaceutical composition consisting of a dispersion of tacrolimus in a vehicle, where the vehicle specifically includes tartaric acid.

• Independent Claim 19: This claim details a pharmaceutical composition comprising a solid dispersion of tacrolimus in a mixture of a vehicle and a stabilizing agent. The stabilizing agent must be capable of providing a pH below 7 in the composition. A critical feature is that the pharmaceutical composition contains 8-epitacrolimus at a concentration below 0.2% by weight.

• Independent Claim 21: This claim describes a pharmaceutical composition with a dispersion of tacrolimus, characterized by having less than 0.5% of 8-epitacrolimus after 12 weeks of storage at 25°C and 60% relative humidity.

• Independent Claim 22: This claim is similar to Claim 21 but specifies a longer storage period: less than 0.5% of 8-epitacrolimus after 10 months of storage at 25°C and 60% relative humidity.

• Independent Claim 23: This claim describes a pharmaceutical composition with a dispersion of tacrolimus, characterized by having less than 0.5% of 8-epitacrolimus after 3 weeks of storage at 40°C and 75% relative humidity.

• Independent Claim 24: This claim is similar to Claim 23 but specifies a longer storage period: less than 0.5% of 8-epitacrolimus after 19 weeks of storage at 40°C and 75% relative humidity.

• Independent Claim 25: This claim covers a pharmaceutical composition comprising a solid dispersion of tacrolimus in a mixture of a vehicle and a stabilizing agent. The composition meets specific stability criteria regarding 8-epitacrolimus levels: either no more than 0.5% more 8-epitacrolimus after 5 weeks at 40°C/75% RH compared to prior to storage, or no more than 0.2% more 8-epitacrolimus after 5 weeks at 25°C/60% RH compared to prior to storage.

• Independent Claim 26: This claim describes a stabilized pharmaceutical composition comprising a solid dispersion of tacrolimus. It specifies limits for multiple degradation products after 5 weeks of storage at 25°C and 60% relative humidity: no more than 0.5% of 8-epitacrolimus, diene of tacrolimus, C4-epimer diene of tacrolimus, and/or Regioisomer A of tacrolimus.

• Independent Claim 27: Similar to Claim 26, this claim specifies the same limits for the same degradation products, but after 5 weeks of storage at 40°C and 75% relative humidity.

• Independent Claim 28: This claim covers a pharmaceutical composition comprising tacrolimus and between about 0.05% and about 0.6% by weight of tartaric acid.

• Independent Claim 29: This claim describes a pharmaceutical composition comprising tacrolimus and tartaric acid at a specific weight ratio of about 19:0.5 to about 20:6.

CAFC 2026 Dockets:
A targeted search for "CAFC 2026 dockets US10166190" did not yield specific dockets directly linked to this patent number within the provided search results. CAFC dockets are typically searched by case number or party name, and the available results for 2026 scheduling do not list cases by patent number. Therefore, authoritative information on potential litigation for patent US10166190B2 in CAFC 2026 dockets is not available through this search.

Known litigation involving US patent 10166190 is listed below, based on the provided patent text. Due to limitations in accessing external links and obtaining detailed real-time litigation data, specific information regarding plaintiffs, defendants, filing dates, and current status for each case is not available from the provided authoritative source or accessible via the search function.

Known Litigation for US Patent 10166190:

1. Jurisdiction: Delaware District Court

   • Case Number: 1:26-cv-00467
   • Plaintiff(s): Not available
   • Defendant(s): Not available
   • Filing Date: Not available
   • Outcome or Current Status: Not available

2. Jurisdiction: Delaware District Court

   • Case Number: 1:25-cv-00458
   • Plaintiff(s): Not available
   • Defendant(s): Not available
   • Filing Date: Not available
   • Outcome or Current Status: Not available

3. Jurisdiction: Delaware District Court

   • Case Number: 1:24-cv-00784
   • Plaintiff(s): Not available
   • Defendant(s): Not available
   • Filing Date: Not available
   • Outcome or Current Status: Not available

4. Jurisdiction: Delaware District Court

   • Case Number: 1:24-cv-00726
   • Plaintiff(s): Not available
   • Defendant(s): Not available
   • Filing Date: Not available
   • Outcome or Current Status: Not available

5. Jurisdiction: Delaware District Court

   • Case Number: 1:22-cv-00909
   • Plaintiff(s): Not available
   • Defendant(s): Not available
   • Filing Date: Not available
   • Outcome or Current Status: Not available

Proceedings overview

There are no AIA trial proceedings on file for US patent 10166190 as of the most recent ingest of USPTO Open Data Portal information, and web search did not surface any additional proceedings. This means the patent's claims remain untested by an AIA trial at the PTAB, offering a defendant maximum flexibility in challenging the patent.

Strategic summary

As of today, US patent 10166190 has no PTAB activity on file. All claims of the patent are currently UNTESTED in an AIA trial setting. This means that a potential defendant facing assertion of this patent would have the full range of prior-art grounds available under §§ 102 and 103 for an Inter Partes Review (IPR), or broader grounds for a Post-Grant Review (PGR) if applicable, without facing any estoppel bars under § 315(e)(2). The absence of PTAB challenges for a patent of this age (published January 1, 2019, with priority to 2008-05-30) could indicate a lack of assertion or that prior challenges were resolved privately.

Recommended next steps

Since no PTAB activity exists for US10166190, a defendant facing assertion would have a clear path to file an IPR petition without concern for estoppel from previous PTAB trials. The absence of previous challenges means the patent has not been "hardened" by surviving IPRs, and all available prior art and statutory grounds are open for challenge.

Inventors

• Nikolaj Skak
• Per Holm

No unusual patterns observed regarding inventor departures.

Original assignee

Veloxis Pharmaceuticals AS.
Veloxis Pharmaceuticals is a pharmaceutical company that develops and commercializes immunosuppressive therapeutics for organ transplant recipients. Their primary product, Envarsus XR (tacrolimus extended-release tablets), embodies the claims of US10166190B2. Veloxis Pharmaceuticals AS was acquired by Asahi Kasei in February 2021. As of today, Veloxis Pharmaceuticals Inc. (the current assignee) appears to be an operating subsidiary of Asahi Kasei Pharma.

Assignment timeline

• 2018-02-15 (executed) / recorded 2018-02-23 — Reel 044030/0858

  • Conveyance: Security Interest
  • Assignor: VELOXIS PHARMACEUTICALS A/S
  • Assignee: ATHYRIUM OPPORTUNITIES III ACQUISITION LP
  • Correspondent: Ropes & Gray LLP, 1211 Avenue of the Americas, New York, NY 10036.
  • Context: Securitization (granting a security interest in patents as collateral for a loan)

• 2020-01-23 (executed) / recorded 2020-02-04 — Reel 048705/0137

  • Conveyance: Release by Secured Party
  • Assignor: ATHYRIUM OPPORTUNITIES III ACQUISITION LP
  • Assignee: VELOXIS PHARMACEUTICALS A/S
  • Correspondent: Ropes & Gray LLP, 1211 Avenue of the Americas, New York, NY 10036. This correspondent also appears on reel 044030/0858.
  • Context: Release of security interest

• 2021-03-17 (executed) / recorded 2021-03-24 — Reel 051939/0751

  • Conveyance: Assignment of Assignors Interest
  • Assignor: VELOXIS PHARMACEUTICALS A/S
  • Assignee: VELOXIS PHARMACEUTICALS INC.
  • Correspondent: Potter Minton, P.C., P.O. BOX 359, TYLER, TX 75710.
  • Context: Internal reorganization / transfer between related entities

• 2021-04-02 (executed) / recorded 2021-04-05 — Reel 051994/0270

  • Conveyance: Assignment of Assignors Interest
  • Assignor: VELOXIS PHARMACEUTICALS A/S
  • Assignee: VELOXIS PHARMACEUTICALS INC.
  • Correspondent: Potter Minton, P.C., P.O. BOX 359, TYLER, TX 75710. This correspondent also appears on reel 051939/0751.
  • Context: Internal reorganization / transfer between related entities (likely a confirmatory assignment or correction)

• 2024-06-07 (executed) / recorded 2024-06-13 — Reel 063678/0784

  • Conveyance: Change of Address
  • Assignor: VELOXIS PHARMACEUTICALS INC.
  • Assignee: VELOXIS PHARMACEUTICALS INC.
  • Correspondent: Cantor Colburn LLP, 20 Church St 22nd Floor, Hartford, CT 06103.
  • Context: Change of address only

Timeline diagram

timeline
    title Ownership of US 10166190
    2017 : Filed
    2018 : Security interest to Athyrium
    2019 : Issued
    2020 : Security interest released
    2021 : Assigned to Veloxis Inc
         : Confirmatory assignment
    2024 : Change of address

NPE / troll-pattern signals

1. Shell-entity transfer — not present. All recorded assignees (Veloxis Pharmaceuticals A/S, Athyrium Opportunities III Acquisition LP, and Veloxis Pharmaceuticals Inc.) appear to be legitimate operating companies or financial entities, not shell corporations. Veloxis Pharmaceuticals is a commercial entity. Athyrium is a healthcare-focused investment firm.
2. Known asserter in the chain — not present. None of the listed assignees or assignors (Veloxis Pharmaceuticals A/S, Athyrium Opportunities III Acquisition LP, Veloxis Pharmaceuticals Inc.) are identified as known NPEs or patent asserters.
3. Repeat correspondent across the chain — present. Ropes & Gray LLP appears on reel 044030/0858 and reel 048705/0137. Potter Minton, P.C. appears on reel 051939/0751 and reel 051994/0270. While these are repeat correspondents, the transfers appear to be related to financing and internal corporate restructuring, which are common for operating companies.
4. Cascading transfers — not present. The assignments are spread out over several years, and the transfers between Veloxis A/S and Veloxis Inc. appear to be internal corporate restructuring, not rapid transfers through multiple shell entities.
5. Pre-litigation transfer — unclear. While there are ongoing litigations for this patent, the assignment records do not show a clear transfer within 6 months before the first litigation filing. The earliest litigation noted on Google Patents is for 2022-07-05, while the transfers to Veloxis Pharmaceuticals Inc. happened in March and April 2021.
6. Bankruptcy fire-sale — not present. There is no indication that Veloxis Pharmaceuticals A/S or Veloxis Pharmaceuticals Inc. have undergone bankruptcy proceedings leading to a patent sale.
7. Privateering — not present. No evidence suggests that Veloxis Pharmaceuticals has transferred the patent to an NPE to assert on their behalf.
8. Defensive aggregator (anti-NPE) — not present. The chain does not terminate at any known defensive aggregator.

Verdict

Operating-company assertion
The current assignee, Veloxis Pharmaceuticals Inc., is an operating pharmaceutical company that sells products embodying the claims of the patent. The assignment history reflects internal corporate restructuring and a security interest, typical for operating businesses, rather than NPE-driven transfers. There are ongoing litigations related to this patent, suggesting an operating company asserting its intellectual property.

USPTO Assignment Center search for US10166190: https://assignmentcenter.uspto.gov/

To identify the most relevant prior art for US Patent 10166190, I will analyze the citations listed within the patent itself. The patent document provides a list of "Prior art documents" and also mentions several publications in the "Background of the Invention" and "Detailed Description of the Invention" sections that could be considered prior art.

Here's an analysis of the prior art cited directly within US10166190B2:

I. Patent Documents Cited:

• WO2005/020993 A2

  • Full Citation: WO2005/020993 A2 (Veloxis Pharmaceuticals A/S) March 10, 2005.
  • Publication/Filing Date: Publication: March 10, 2005.
  • Brief Description: This patent application discloses tacrolimus formulations with improved bioavailability and reduced peak-to-trough levels, particularly those comprising a solid dispersion of tacrolimus in polyethylene glycol (PEG). It also includes methods of preparation and related pharmaceutical compositions and dosage forms.
  • Potential Anticipation (35 U.S.C. § 102):
    • Claims 1, 10, 11, 12, 16, 17, 18: This reference teaches tacrolimus in a solid dispersion with a vehicle (like PEG), which forms the basis of many claims in US10166190. While US10166190 adds a stabilizing agent and specific pH/degradation limits, the fundamental concept of a solid dispersion of tacrolimus in a vehicle is anticipated. Specifically, the patent states, "WO2005/020993... disclose tacrolimus-containing pharmaceutical compositions with improved bioavailability... in particular tacrolimus compositions comprising a solid dispersion of tacrolimus in polyethylene glycol (PEG)."
    • Claims 15, 19-27: While WO2005/020993 doesn't explicitly teach the stabilizing agent or the specific degradation limits of US10166190, it lays the groundwork for tacrolimus formulations, which the current patent seeks to stabilize. The current patent explicitly states, "WO 2005/020993 discloses tacrolimus formulations which may be useful in combination with the stabilizing agent(s) disclosed herein to yield a stabilized tacrolimus composition." Therefore, if the stabilizing agent or degradation limits were deemed inherent in certain formulations disclosed in WO2005/020993, it could potentially anticipate these claims.

• WO2005/020994 A2

  • Full Citation: WO2005/020994 A2 (Veloxis Pharmaceuticals A/S) March 10, 2005.
  • Publication/Filing Date: Publication: March 10, 2005.
  • Brief Description: Similar to WO2005/020993, this patent application also describes tacrolimus formulations with improved bioavailability and reduced peak-to-trough levels, focusing on solid dispersions in polyethylene glycol.
  • Potential Anticipation (35 U.S.C. § 102):
    • Claims 1, 10, 11, 12, 16, 17, 18: This reference, like WO2005/020993, broadly teaches tacrolimus in a solid dispersion within a vehicle, anticipating the basic composition described in these claims. The US10166190 patent itself lists "Tacrolimus composition A (tacrolimus tablets) (disclosed in Example 2 of WO2005/020993 and WO 2005/020994)" as a prior art composition for comparison.

• WO2008/0145143 A1

  • Full Citation: WO2008/0145143 A1 (Veloxis Pharmaceuticals A/S) December 4, 2008.
  • Publication/Filing Date: Publication: December 4, 2008.
  • Brief Description: This patent application further details tacrolimus-containing pharmaceutical compositions with improved bioavailability and reduced peak-to-trough levels, specifically mentioning solid dispersions of tacrolimus in polyethylene glycol.
  • Potential Anticipation (35 U.S.C. § 102):
    • Claims 1, 10, 11, 12, 16, 17, 18: This document, like the other WO references, describes tacrolimus solid dispersions, which could anticipate the foundational elements of these claims. The patent states that WO2008/0145143 "disclose tacrolimus-containing pharmaceutical compositions with improved bioavailability and a reduced peak-to-trough level as compared to the commercially available tacrolimus products, in particular tacrolimus compositions comprising a solid dispersion of tacrolimus in polyethylene glycol (PEG)."

• WO2010/005980 A1

  • Full Citation: WO2010/005980 A1 (Veloxis Pharmaceuticals A/S) January 21, 2010.
  • Publication/Filing Date: Publication: January 21, 2010.
  • Brief Description: This patent application, similar to the others, covers tacrolimus-containing pharmaceutical compositions with improved bioavailability and reduced peak-to-trough levels, specifically including solid dispersions of tacrolimus in polyethylene glycol.
  • Potential Anticipation (35 U.S.C. § 102):
    • Claims 1, 10, 11, 12, 16, 17, 18: This patent, like the others, contributes to the general knowledge of tacrolimus solid dispersions in PEG, potentially anticipating the basic composition aspects of these claims. The patent mentions WO2010/005980 as disclosing "tacrolimus compositions comprising a solid dispersion of tacrolimus in polyethylene glycol (PEG)."

• U.S. Pat. No. 4,894,366

  • Full Citation: U.S. Pat. No. 4,894,366 (Fujisawa Pharmaceutical Co., Ltd.) January 16, 1990.
  • Publication/Filing Date: Publication: January 16, 1990.
  • Brief Description: This patent relates to tacrolimus and its derivatives, including their preparation and use. It provides a structural basis and early understanding of tacrolimus.
  • Potential Anticipation (35 U.S.C. § 102):
    • Claims 1, 15, 16, 19, 21, 22, 23, 24, 25, 26, 27, 28, 29: This patent, being an early disclosure of tacrolimus itself, is foundational. It provides the active ingredient ("tacrolimus") for all the claims. While it doesn't disclose the specific formulations or stabilizing agents of US10166190, it establishes the prior art for the core compound. The current patent refers to the "IUPAC-style nomenclature used in U.S. Pat. No. 4,894,366 for the tacrolimus structure".

II. Non-Patent Literature (NPL) Cited:

• Hone et al., Transplantation Proceedings, Vol XIX, No 5, Suppl 6 (October), 1987: pp 17-22

  • Full Citation: Hone et al., Transplantation Proceedings, Vol XIX, No 5, Suppl 6 (October), 1987: pp 17-22.
  • Publication/Filing Date: October 1987.
  • Brief Description: This article discusses solid dispersions with different formulations of tacrolimus, providing early insights into addressing its poor solubility and low bioavailability.
  • Potential Anticipation (35 U.S.C. § 102):
    • Claims 1, 10, 11, 12, 16, 17, 18: This publication describes attempts to prepare solid solutions, "preferably in the form of solid dispersions," for tacrolimus. This directly anticipates the concept of a "solid dispersion of tacrolimus in a vehicle" as claimed in US10166190.

• YAMASHITA Kazunari et al., International Journal of Pharmaceutics 2003, vol. 267, no1-2, pp. 79-91

  • Full Citation: YAMASHITA Kazunari et al., "Establishment of new preparation method for solid dispersion formulation of tacrolimus", International Journal of Pharmaceutics 2003, vol. 267, no1-2, pp. 79-91.
  • Publication/Filing Date: 2003.
  • Brief Description: This article discloses an improved solvent method for preparing solid dispersion formulations of tacrolimus, aiming to avoid the use of dichloromethane.
  • Potential Anticipation (35 U.S.C. § 102):
    • Claims 1, 10, 11, 12, 16, 17, 18: Similar to Hone et al., this reference describes methods for preparing solid dispersions of tacrolimus, broadly anticipating the underlying composition claims.

• Skytte, D. M. et al.: Synthesis and characterization of an epimer of tacrolimus, an immunosuppresive drug in J. Nat. Prod., 2010 Apr. 23; 73(4):776-9

  • Full Citation: Skytte, D. M. et al.: "Synthesis and characterization of an epimer of tacrolimus, an immunosuppresive drug" in J. Nat. Prod., 2010 Apr. 23; 73(4):776-9.
  • Publication/Filing Date: April 23, 2010.
  • Brief Description: This publication details the synthesis and characterization of the 8-epitacrolimus, the major degradation product of tacrolimus. This is significant because US10166190 explicitly addresses preventing or reducing this specific degradation product.
  • Potential Anticipation (35 U.S.C. § 102):
    • Claims 19, 21, 22, 23, 24, 25, 26, 27: This article directly discloses the degradation product (8-epitacrolimus) that US10166190 seeks to control. While it doesn't disclose the method of stabilization, it establishes the prior knowledge of the problem that US10166190 aims to solve. The current patent explicitly cites this work for the structure determination of 8-epitacrolimus.

• Sierra-Paredes et al., CNS Neurosci. Ther. 2008, vol. 14, p. 36-46

  • Full Citation: Sierra-Paredes et al., "Pharmacological aspects of ascomycin (FK520): a tacrolimus analogue", CNS Neurosci. Ther. 2008, vol. 14, p. 36-46.
  • Publication/Filing Date: 2008.
  • Brief Description: This article discusses ascomycin, an analogue of tacrolimus, and its pharmacological profile, highlighting that minor structural modifications can significantly alter activity.
  • Potential Anticipation (35 U.S.C. § 102):
    • Claims 1, 15: This reference contributes to the general knowledge of tacrolimus analogues and the sensitivity of their pharmacological profiles to structural changes. While not directly anticipating the stabilized composition, it informs the background of the patent regarding the importance of degradation product control.

General Note on Anticipation (35 U.S.C. § 102):
For a prior art reference to anticipate a claim under 35 U.S.C. § 102, it must describe, either expressly or inherently, each and every limitation of the claim. In the context of US10166190, the earlier WO applications and NPL describe the basic tacrolimus compositions and solid dispersions. However, the inventive step of US10166190 lies in the stabilizing agent and its ability to achieve specific pH ranges and degradation product limits. Therefore, the cited prior art generally anticipates the broad concept of tacrolimus formulations and solid dispersions, but the specific combination of a stabilizing agent to achieve the recited stability characteristics is likely the distinguishing feature of US10166190.

It is important to note that the priority date of US10166190 is May 30, 2008. Any publications or patents with a publication date before this priority date would be considered prior art, subject to specific exceptions like those for an inventor's own prior disclosure within a grace period (35 U.S.C. § 102(b)(1)(A)). The family history of US10166190 shows a priority claimed from PCT/DK2008/050130 filed May 30, 2008, which aligns with the prior art dates.

Obviousness Analysis of US Patent 10166190 under 35 U.S.C. § 103

This analysis identifies combinations of prior art references that would render the claims of US patent 10166190 obvious to a person having ordinary skill in the art (POSA). The primary prior art references establishing the basic tacrolimus compositions are WO2005/020993 and WO2005/020994, which the patent itself acknowledges as disclosing "tacrolimus-containing pharmaceutical compositions... in particular tacrolimus compositions comprising a solid dispersion of tacrolimus in polyethylene glycol (PEG)" [Description].

The common problem addressed by the patent is the known instability of tacrolimus, particularly in solid dispersions, leading to the formation of degradation products, and the need to maintain low concentrations of these impurities throughout the product's shelf-life to meet regulatory standards [Description]. A POSA in the field of pharmaceutical formulation would possess knowledge of drug stability, excipient selection, and common methods for preventing chemical degradation, including pH control and metal chelation.

Obviousness of Independent Claim 1 (and related compositional claims 16, 19, 28, 29)

Independent Claim 1: A pharmaceutical composition comprising a solid dispersion of tacrolimus in a mixture of a vehicle and a stabilizing agent capable of providing a pH below 7 in the composition.

Combination of Prior Art:

1. WO2005/020993 (or WO2005/020994): These references teach a pharmaceutical composition comprising a solid dispersion of tacrolimus in a vehicle, specifically polyethylene glycol (PEG) [Description]. This establishes the core composition of tacrolimus dispersed in a vehicle.
2. General Pharmaceutical Knowledge: It is a well-established principle in pharmaceutical formulation that active pharmaceutical ingredients (APIs) can degrade, and that various excipients, including pH-adjusting agents and chelating agents, are used to enhance stability. The patent itself highlights the "need for preventing the formation of degradation products from tacrolimus" and that "stabilizing compounds preventing degradation of the active substance... are desired" [Description]. The patent also notes that the major degradation product, 8-epitacrolimus, "may be formed... under mild basic conditions" [Description]. Furthermore, "traces of e.g. metal ions will inevitably occur in the vehicle due to the use of equipment and excipients containing metal ions" [Description, Example 3], motivating the use of chelating agents.

Motivation to Combine:
A POSA would be motivated to combine the known tacrolimus solid dispersion (from WO2005/020993) with a stabilizing agent to address the recognized problem of tacrolimus degradation. Knowing that 8-epitacrolimus forms under "mild basic conditions" [Description], a POSA would naturally be motivated to introduce a pH-regulating agent to maintain a pH below 7 to counteract this degradation. Given the inevitable presence of metal ions in formulations, and the fact that such ions can catalyze degradation, a POSA would also be motivated to include a chelating agent to mitigate this effect. Tartaric acid, specifically mentioned in the patent as a preferred stabilizing agent and a chelating agent [Description], is a common pharmaceutical excipient with both acidic and chelating properties. Its selection and incorporation into the tacrolimus solid dispersion to achieve a stable composition would therefore be obvious. The subsequent optimization of the concentration of tartaric acid (as claimed in claims 28 and 29) to achieve a desired stability profile would be considered routine experimentation for a POSA.

Obviousness of Independent Claim 15 (method claim)

Independent Claim 15: A method for reducing the concentration of tacrolimus degradation products in a pharmaceutical composition comprising tacrolimus as the active ingredient, wherein a stabilizing agent is incorporated into the composition.

Combination of Prior Art:

1. Tacrolimus as an active ingredient with known instability: The patent's background section clearly establishes that tacrolimus is an active ingredient and that "the presence of degradation products in a pharmaceutical formulation... is highly undesirable" [Description]. This highlights the long-standing problem of tacrolimus degradation.
2. General Pharmaceutical Practice: It is a fundamental and well-known practice in pharmaceutical development to incorporate stabilizing agents into drug compositions to reduce or prevent the formation of degradation products. The patent itself states that "stabilizing compounds preventing degradation of the active substance... are desired" [Description].

Motivation to Combine:
A POSA, confronted with the acknowledged instability of tacrolimus and the need to reduce degradation products, would be readily motivated to employ the well-established pharmaceutical strategy of incorporating a stabilizing agent into the composition. This is a direct and conventional approach to address drug instability and is a standard part of formulation development.

Obviousness of Independent Claims 21, 22, 23, 24, 25, 26, and 27 (stability criteria claims)

Independent Claims 21-27: These claims define pharmaceutical compositions comprising tacrolimus that meet specific stability criteria regarding the levels of 8-epitacrolimus and other degradation products after storage under various conditions.

Combination of Prior Art:

1. Underlying Tacrolimus Composition and Stabilizing Agent: The foundation of these claims rests on a tacrolimus solid dispersion containing a stabilizing agent, as rendered obvious by the arguments for Claim 1.
2. Regulatory Requirements and Industry Standards: The International Conference of Harmonization (ICH) guidelines (e.g., ICH Topic 3 Q B (R2)) set limits for degradation products in pharmaceutical formulations [Description]. The patent notes that the ICH limit is typically 0.5% for a single degradation product for certain daily dosages [Description]. Pharmaceutical manufacturers are routinely required to demonstrate that their products meet these stability specifications under various storage conditions (e.g., 25°C/60% RH, 40°C/75% RH) for specified durations.

Motivation to Combine:
Once a POSA is motivated to stabilize tacrolimus formulations using a stabilizing agent, the subsequent motivation is to ensure the product meets acceptable stability profiles for regulatory approval and commercial viability. Achieving specific thresholds for degradation products (e.g., less than 0.5% or less than 0.2% of 8-epitacrolimus, or specific increases in these levels) after various standard storage conditions and durations is a routine objective in pharmaceutical development. The selection and optimization of known stabilizing agents (such as tartaric acid, which the patent's examples demonstrate can achieve these stability profiles [Description, Example 3]) to meet these predefined stability specifications would be a matter of routine experimentation for a POSA striving to develop a marketable and compliant pharmaceutical product. The patent itself recognizes that "prevention of degradation does not always follow a simple linear effect, but windows of optimal effect may exist" [Description], implying that optimization is expected. While the specific identification of other degradation products (Diene, C4-epimer diene, Regioisomer A) might be novel, the motivation to control all relevant degradation products to within acceptable limits using known stabilization techniques remains obvious.