Obviousness

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

A patent claim is obvious under 35 U.S.C. § 103 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 considers the scope and content of the prior art, the differences between the prior art and the claims, the level of ordinary skill in the art, and any secondary considerations of non-obviousness.

For US patent 11110081, the core inventive concept revolves around an extended-release oral dosage form of tacrolimus that provides improved pharmacokinetic profiles and treatment outcomes, particularly for once-daily administration and in de novo transplant patients.

Level of Ordinary Skill in the Art (POSA)

A POSA in the field of immunosuppressive drug formulations, specifically tacrolimus, would likely possess a strong background in pharmaceutical sciences, including pharmacokinetics, pharmacodynamics, drug delivery systems (e.g., controlled release, solid dispersions), and clinical experience with transplant patient management. They would be familiar with the challenges associated with tacrolimus, such as its low and variable bioavailability, extensive CYP3A4 metabolism, and significant side effects related to high peak concentrations. They would also be aware of conventional tacrolimus formulations like Prograf® (immediate release) and Advagraf® (extended release), their dosing regimens, and their pharmacokinetic characteristics.

Combinations of Prior Art References and Motivation to Combine

Several prior art references, individually or in combination, could render various claims of US 11110081 obvious.

1. General Concept of Extended-Release Tacrolimus for Improved Bioavailability and PK Profile (Claims 1, 13)

Prior Art:

• WO 2005/020993 (by the same inventors): This application explicitly discusses increasing tacrolimus bioavailability through modified or controlled release compositions that reduce or avoid CYP3A4 metabolism. It notes that both fast and slow-release tablets can improve bioavailability compared to Prograf®. It also highlights the problem of high peak concentrations of tacrolimus leading to side effects and the desire for more reproducible release profiles. The inventors in WO 2005/020993 tested different formulations demonstrating improved bioavailability and suppressed variation in absorbability with sustained-release formulations.
• WO 2005/020994 (by the same inventors): This document specifically relates to solid dispersions comprising tacrolimus, where tacrolimus is dissolved or dispersed in a hydrophilic or water-miscible vehicle to form a solid dispersion or solid solution at ambient temperature, leading to improved bioavailability. It suggests that improved bioavailability could be linked to having tacrolimus in a dissolved state in the dosage form.
• Advagraf® (MR4): This commercially available extended-release tacrolimus formulation was approved in 2007 (before the priority date of US11110081) and was known to offer once-daily dosing with comparable absorption to Prograf®. The EPAR for Advagraf® details its properties and is incorporated by reference in US11110081.

Motivation to Combine:
A POSA would be highly motivated to develop an extended-release tacrolimus formulation that overcomes the limitations of existing products like Prograf® (twice-daily dosing, high variability, significant side effects from peak concentrations) and Advagraf® (while extended release, the present invention claims to improve upon it). The inventors of US11110081 themselves were exploring improved bioavailability and modified release of tacrolimus in WO 2005/020993 and WO 2005/020994. The explicit mention in WO 2005/020993 that "enhanced bioavailability may also result in a more reproducible (i.e. less variable compared to that of Prograf®) release profile" and that "the bioavailability of tacrolimus is significantly increased when tacrolimus is administered to a mammal in a modified or controlled release composition providing a rate and a timing of release of active ingredient, i.e. an in vivo release profile, effectively reducing or even avoiding the effects of CYP3A4 metabolism" directly points towards the objectives of US11110081.

The challenge with extended-release forms of tacrolimus, as recognized in the prior art, was achieving sufficient absorption in the lower gastrointestinal tract due to factors like reduced fluids, increased solids, and a smaller absorption surface in the colon. However, the prior art already suggested that controlled release could lead to better absorption by reducing CYP3A4 metabolism.

Given the existence of Advagraf® as an extended-release, once-daily tacrolimus product, a POSA would be motivated to further optimize such formulations to achieve superior pharmacokinetic profiles (e.g., lower Cmax, increased AUC, improved consistency, better safety profile) as outlined in Claim 13, as these are well-known desirable outcomes in drug development.

2. Specific Dissolution Profile (Claim 1)

Prior Art:

• WO 2005/020993: Discusses sustained-release formulations with T63.6% values ranging from 1.9 to 8.2 hours, indicating that these formulations achieved improved bioavailability. It also mentions T63.6% values of 3.0, 3.3, 2.0, and 2.5 hours for specific formulations.
• Prograf® FDA label and dissolution methods: The FDA provides dissolution methods for drug products like Prograf®. A POSA would be aware of and utilize such standard in vitro dissolution tests (like USP I or II) to characterize drug release.
• WO 99/49863: Describes sustained-release tacrolimus formulations where 63.2% of tacrolimus is released between 0.7 and 15 hours.

Motivation to Combine:
The specific dissolution profile claimed in Claim 1 (at most 63.5% release at 12 hours, at least 8% at 4 hours and/or at least 15% at 8 hours using specified USP methods and media) represents a refinement of known extended-release characteristics. Given the information in WO 2005/020993 and WO 99/49863 regarding various release rates that lead to improved bioavailability, a POSA would be motivated to experiment with different dissolution profiles to optimize the balance between extended release, continuous release throughout the dosing interval, and absorption, especially in the lower GI tract where CYP3A4 metabolism is lower. The cited ranges for T63.6% in WO 2005/020993 (1.9 to 8.2 hours) and WO 99/49863 (0.7 to 15 hours for T63.2%) overlap with and suggest the feasibility of achieving the specific 12-hour release criteria of Claim 1. The use of standard USP dissolution tests with appropriate media (e.g., pH 4.5 with hydroxypropylcellulose) is routine in pharmaceutical development for characterizing and comparing formulations.

3. Conversion Regimens (Claims 14, 15)

Prior Art:

• Prograf® and Advagraf®: Both were commercially available tacrolimus formulations with established dosing regimens. Prograf® was a twice-daily immediate-release product, and Advagraf® was a once-daily extended-release product. The need for dose adjustments and therapeutic drug monitoring for tacrolimus was well-known due to its narrow therapeutic index and variable absorption.
• EMA Scientific Discussion for Advagraf®: This report, published in 2007, compared Advagraf® and Prograf®, noting comparable absorption in the body and providing information on their use. It also mentioned that for de novo kidney and liver transplant patients, AUC(0-24) of Advagraf® on Day 1 was 30% and 50% lower, respectively, compared to immediate-release Prograf® at equivalent doses.

Motivation to Combine:
The development of conversion regimens (Claims 14 and 15) when introducing a new extended-release formulation would be a routine practice for a POSA. Given the narrow therapeutic window of tacrolimus and the criticality of maintaining appropriate blood levels to prevent organ rejection or toxicity, any new formulation would necessitate carefully designed conversion strategies from existing treatments. The ratios specified in the claims (e.g., 1:0.66-0.80 for Prograf® conversion, 1:0.30-0.75 for Advagraf® conversion) would be derived from pharmacokinetic studies comparing the new formulation with existing ones, aiming to achieve comparable or improved systemic exposure and therapeutic effects while minimizing side effects. The knowledge that Advagraf® initially showed lower exposure compared to Prograf® in de novo patients would further motivate a POSA to carefully define conversion protocols for a new extended-release product, especially one aiming for enhanced bioavailability.

4. Treatment of De Novo Transplant Patients with Specific Day 1 Exposure (Claims 16, 17)

Prior Art:

• Prograf® Dosing for Transplant Patients: Prograf® had established initial dosing guidelines for liver and kidney transplant patients, with dosages adjusted based on trough blood concentrations.
• Advagraf® in De Novo Patients: The EMA Scientific Discussion for Advagraf® highlighted that in de novo kidney and liver transplant patients, Advagraf® showed lower systemic exposure on Day 1 compared to immediate-release Prograf®. Specifically, AUC(0-24) was 30% lower for kidney transplant patients and 50% lower for liver transplant patients.
• WO 2005/020993: Acknowledges the variability in tacrolimus absorption and metabolism, emphasizing the need for improved formulations that reduce side effects and provide more reproducible release profiles. It also discusses the impact of CYP3A4 metabolism in the gut wall and liver on tacrolimus bioavailability.

Motivation to Combine:
A significant challenge in tacrolimus therapy, especially for de novo transplant patients, is managing the initial high variability in absorption and metabolism, alongside the risk of rejection or toxicity. The observation from the Advagraf® EPAR that its Day 1 exposure was significantly lower than Prograf® in de novo patients would strongly motivate a POSA to develop a new extended-release formulation that could achieve at least comparable (or superior) Day 1 exposure to immediate-release Prograf®, or even to other extended-release forms, to ensure adequate immunosuppression from the outset. The claimed systemic exposure on Day 1 (at least 50% for liver, at least 70% for kidney, relative to immediate release Prograf®; and at least 100% compared to an extended release form releasing >30% in 5 hours) directly addresses the known limitations of existing extended-release products in the critical immediate post-transplant period. A POSA would seek to design a formulation and dosing strategy that ensures efficacy early on while minimizing the risks associated with inadequate drug levels, thus leading to the development of methods like those in Claims 16 and 17. The dissolution criteria specified (less than 50% released after 10 hours by the FDA Prograf® method) are a means to achieve the desired extended release characteristics that contribute to this improved early exposure.

Conclusion on Obviousness

Considering the cited prior art, a POSA would have been motivated to combine known elements and principles to arrive at the claimed invention. The desire for improved tacrolimus formulations with better bioavailability, reduced variability, once-daily dosing, and optimized pharmacokinetic profiles was clearly articulated in the prior art, including by the same inventors. While US 11110081 describes specific dissolution profiles and conversion regimens, these appear to be optimizations achievable through routine experimentation and well-understood pharmaceutical development principles, particularly given the detailed disclosures in WO 2005/020993 and WO 2005/020994 regarding enhancing bioavailability and controlling release. The specific pharmacokinetic parameters claimed in Claim 13 are desirable outcomes that a POSA would aim for when developing an improved tacrolimus formulation. Similarly, the conversion methods and de novo patient treatment methods (Claims 14-17) address known clinical challenges and represent logical applications of an improved extended-release formulation within the therapeutic context of tacrolimus.