Prior art — US Patent 9549918

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:

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.

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.

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.

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.

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.