Obviousness

The following analysis identifies combinations of prior art references that would render the claims of US Patent 8,685,998 obvious under 35 U.S.C. § 103, along with motivations for combining them.

General Background for Obviousness Analysis

Tacrolimus is a potent immunosuppressant widely used to prevent organ rejection in transplant patients. It is known to have low oral bioavailability (11-20%) due to poor solubility, extensive first-pass metabolism by CYP3A4/3A5 enzymes in the gut and liver, and efflux by P-glycoprotein. This leads to high inter- and intra-patient variability in absorption and the need for frequent therapeutic drug monitoring.

The development of extended-release tacrolimus formulations aims to overcome these challenges by providing more consistent drug levels, reducing side effects associated with high peak concentrations, and improving patient compliance through once-daily dosing.

Obviousness Combination 1: WO 2005/020993, WO 2005/020994, and general knowledge of extended-release formulations and tacrolimus pharmacokinetics.

References:

• WO 2005/020993 (WO '993): This patent application by the present inventors describes modified release compositions of tacrolimus designed to reduce CYP3A4 metabolism and increase bioavailability. It specifically discloses formulations that release less than 20% w/w of the active ingredient within 0.5 hours in a USP Paddle method with 0.1 N HCl. It also suggests that improved bioavailability could be linked to tacrolimus being in a dissolved state in the dosage form. WO '993 further describes that a modified release composition may be coated with an enteric coating and/or comprise a solid dispersion or solid solution of tacrolimus in a hydrophilic or water-miscible vehicle. The patent states that after oral administration, tacrolimus is released in a controlled manner and will exhibit a Cmax of at most about 30 ng/mL for a 5mg dose.
• WO 2005/020994 (WO '994): Also by the present inventors, this application explicitly relates to solid dispersions comprising tacrolimus, stating that a pharmaceutical composition comprising tacrolimus dissolved and/or dispersed in a hydrophilic or water-miscible vehicle to form a solid dispersion or solid solution at ambient temperature has improved bioavailability.
• General knowledge of extended-release formulations and tacrolimus pharmacokinetics: It was well-known in the art that tacrolimus had poor and variable oral bioavailability due to extensive first-pass metabolism by CYP3A4 enzymes, particularly in the upper GI tract. Therefore, a person of ordinary skill in the art (POSA) would understand the benefit of extended release formulations for drugs with such characteristics to prolong absorption, bypass early metabolic sites, and maintain more stable blood levels. This was a common approach to improve drug solubility, dissolution rate, and bioavailability for poorly water-soluble drugs.

Motivation for Combination:
A POSA would have been motivated to combine the teachings of WO '993 and WO '994 with the general knowledge of tacrolimus pharmacokinetics and extended-release technologies to address the known issues of tacrolimus's low and variable bioavailability.

1. Addressing CYP3A4 Metabolism: WO '993 explicitly states its objective is to reduce or avoid CYP3A4 metabolism by providing modified-release compositions. Given that CYP3A4 is prevalent in the gut wall and liver, a POSA would naturally consider strategies to delay or extend release beyond the primary sites of this metabolism to the lower GI tract.
2. Improving Solubility and Bioavailability: WO '994 teaches that solid dispersions of tacrolimus in hydrophilic or water-miscible vehicles improve bioavailability. The general art also supports solid dispersions as a key technique for enhancing the dissolution and bioavailability of poorly water-soluble drugs. A POSA would understand that increasing the dissolved state of tacrolimus (as suggested by WO '993) would improve absorption regardless of the release profile.
3. Extended Release for Once-Daily Dosing: The concept of extended release for once-daily dosing to improve patient compliance and reduce fluctuations was a recognized goal in pharmaceutical development, especially for drugs with narrow therapeutic windows like tacrolimus. WO '993 already discusses controlled and modified release to achieve a Cmax of at most 30 ng/mL for a 5mg dose.

Obviousness of Claim 1 and 8 (Method for de novo liver/kidney transplant patients with specific release profile and bioavailability):

Claims 1 and 8 specify a method for initial immunosuppressive treatment of de novo liver or kidney transplant patients using a once-daily extended-release tacrolimus formulation. The formulation is characterized by releasing less than 50% of tacrolimus after 10 hours in a specific in vitro dissolution test, and providing a systemic exposure on Day 1 that is at least 50% (liver) or 70% (kidney) of an immediate-release twice-daily formulation.

WO '993 broadly discloses modified-release tacrolimus compositions that aim to increase bioavailability by reducing CYP3A4 metabolism and extending release. It discusses formulations releasing less than 20% in 0.5 hours, indicating a slow-release characteristic. While it doesn't explicitly state "less than 50% at 10 hours," the concept of extended release to avoid early metabolism and improve bioavailability is present. The general pharmaceutical knowledge includes various excipients and formulation techniques (e.g., hydrophilic matrix, enteric coating, solid dispersions) to achieve a desired extended-release profile. WO '994 teaches the use of solid dispersions to improve tacrolimus's bioavailability.

A POSA, aware of the issues with tacrolimus's pharmacokinetics (high first-pass metabolism, low bioavailability), and the advantages of extended-release formulations (reduced frequency, improved patient compliance, reduced peak-related side effects), would have been motivated to develop an extended-release formulation for once-daily dosing. The optimization of the release profile to achieve specific in vitro dissolution characteristics (like "less than 50% at 10 hours") and corresponding in vivo bioavailability improvements would be considered routine experimentation for a POSA, especially given the explicit aims of WO '993 and WO '994 to enhance bioavailability and modify release to overcome metabolic challenges. The specific percentage improvements in Day 1 exposure (50% for liver, 70% for kidney) would be expected outcomes of such optimization, as increased bioavailability is the stated goal of these prior art documents.

Obviousness of Claim 13 (Method for de novo kidney transplant patients with specific release profile and comparison to faster extended-release):

Claim 13 focuses on de novo kidney transplant patients and compares the claimed slow-release formulation (less than 50% at 10 hours) to a faster extended-release formulation (more than 30% within 5 hours), requiring at least 100% of the systemic exposure on Day 1.

The existence of other extended-release tacrolimus formulations, such as Advagraf, prior to the priority date of US '998 (May 30, 2007) is highly relevant. Advagraf (marketed in Europe since 2007, FDA approved in 2013 as Astagraf XL) is a once-daily prolonged-release tacrolimus formulation. It contains ethylcellulose and hypromellose to control dissolution and slow drug release along the GI tract. However, Advagraf was known to have lower Day 1 AUC (30% lower for kidney, 50% lower for liver) compared to Prograf in de novo patients. Furthermore, Advagraf was associated with higher rates of acute rejection in a phase III study for de novo kidney recipients. It also sometimes required higher dosing to achieve therapeutic levels and showed high inter-individual variability.

Therefore, a POSA would have been motivated to develop an improved extended-release formulation that overcame the shortcomings of existing once-daily products like Advagraf, particularly in the crucial de novo transplant period where initial exposure is critical. The desire to achieve at least comparable (100%) exposure to a faster extended-release product (like Advagraf, which releases more than 30% within 5 hours, based on its extended-release nature but known initial lower exposure) would be a direct response to the known deficiencies of these earlier extended-release formulations in de novo patients. Optimizing the release profile to be even slower (less than 50% at 10 hours) to ensure more consistent absorption throughout the GI tract, including the colon (as taught in US '998), and thus higher Day 1 exposure, would be a logical step for a POSA seeking to improve upon existing extended-release tacrolimus therapies.

Obviousness Combination 2: Prograf, Advagraf, WO 2005/020993, WO 2005/020994, and general pharmaceutical formulation principles.

References:

• Prograf: This is an immediate-release (IR) tacrolimus formulation, typically dosed twice daily. It is known for its low and variable oral bioavailability (11-20%) and rapid absorption with Tmax typically around 1-2 hours. Prograf's inactive ingredients include lactose, hydroxypropyl methylcellulose (HPMC), croscarmellose sodium, and magnesium stearate.
• Advagraf: As discussed, Advagraf is a once-daily prolonged-release tacrolimus formulation. It uses ethylcellulose and hypromellose (HPMC) to control release. Known issues include lower Day 1 exposure in de novo patients compared to Prograf and high inter-individual variability.
• WO 2005/020993 (WO '993): Discusses modified release compositions of tacrolimus to reduce CYP3A4 metabolism and increase bioavailability, including enteric coatings and solid dispersions.
• WO 2005/020994 (WO '994): Focuses on solid dispersions of tacrolimus in hydrophilic or water-miscible vehicles for improved bioavailability.
• General pharmaceutical formulation principles: It is well-established that poorly water-soluble drugs like tacrolimus benefit from solubility enhancement techniques, such as solid dispersions, and controlled-release matrices or coatings to modulate drug release kinetics. Hydrophilic polymers like HPMC are commonly used in extended-release matrix tablets, and their type and content can tailor release patterns over 24 hours. Magnesium aluminometasilicate is known as an oil sorption material useful in formulations.

Motivation for Combination:
A POSA would be motivated to combine elements from both immediate-release (Prograf) and existing extended-release (Advagraf) formulations, along with the specific teachings of WO '993 and WO '994, to create a superior once-daily extended-release tacrolimus product, particularly addressing the recognized shortcomings of Advagraf in de novo transplant patients.

1. Addressing Bioavailability and Metabolism: Prograf's low bioavailability and susceptibility to CYP3A4 metabolism were primary drivers for developing improved formulations. WO '993 directly addresses these problems by proposing modified release to avoid CYP3A4 metabolism and increase bioavailability. WO '994 offers solid dispersions as a solution for enhancing solubility and bioavailability.
2. Improving upon Advagraf's Deficiencies: The knowledge that Advagraf, while once-daily, had lower Day 1 exposure in de novo patients and sometimes required higher doses than Prograf to achieve therapeutic levels would strongly motivate a POSA to develop a better extended-release formulation. The goal would be to maintain the convenience of once-daily dosing while ensuring adequate and consistent early exposure.
3. Employing Known Formulation Techniques:
   • Solid Dispersions: The inventors of US '998 themselves highlight in the patent that an improved bioavailability could be linked to having tacrolimus in a dissolved state, referencing their own WO '993 and WO '994 related to solid dispersions. The use of solid dispersions is a known technique to improve the solubility and dissolution rate of poorly water-soluble drugs like tacrolimus.
   • Hydrophilic Matrix Formulations: HPMC is a common polymer used in extended-release matrix tablets, capable of prolonging drug release for over 24 hours and allowing tailoring of release patterns. Prograf already contains HPMC as an inactive ingredient, and Advagraf uses hypromellose (HPMC) in its protective coat.
   • Melt Granulation/Spray Drying: The patent itself describes a "meltDose" technology involving heating tacrolimus into a liquid-like state and spraying it onto an inert particle carrier to solidify into a "solid solution" or granulates. This method is consistent with known techniques for preparing solid dispersions, such as melt agglomeration, melt extrusion, or spray drying, which involve mixing drug and carrier and then cooling or evaporating a solvent.
   • Oil Sorption Materials: Magnesium aluminometasilicate is a known excipient used as an oil sorption material in pharmaceutical formulations, enabling the incorporation of relatively large amounts of oil or oily-like materials into solid compositions, which could be beneficial for poorly water-soluble drugs. The patent explicitly mentions Aeroperl® 300 (a silicon dioxide product) as an advantageous oil sorption material.

Therefore, a POSA, starting from the desire to create a more effective once-daily extended-release tacrolimus, would have found motivation in the prior art to:

• Utilize solid dispersion technology (taught by WO '994 and generally known) to enhance tacrolimus's solubility and bioavailability.
• Incorporate hydrophilic polymers like HPMC (found in Prograf, Advagraf, and generally known for extended release) in a matrix to achieve a prolonged release over 24 hours.
• Consider melt granulation or spray drying techniques (as described for solid dispersions) for efficient manufacturing and to form the solid dispersion.
• Include oil sorption materials like magnesium aluminometasilicate (known for their utility in solid formulations with oily components) to facilitate the solid dispersion manufacturing process, especially if lipid-based carriers are used.
• Further optimize the release profile through routine experimentation to achieve the specific in vitro dissolution rates and de novo patient exposures claimed in US '998, in order to address the known limitations of Advagraf's initial exposure.

The combination of these known elements and techniques, driven by the clear unmet need for a more consistent and bioavailable once-daily tacrolimus, particularly in the critical de novo transplant setting, would render the claimed invention obvious.