Obviousness

Obviousness Analysis of US Patent 11,839,689 under 35 U.S.C. § 103

This analysis evaluates the obviousness of US Patent 11,839,689, which claims formulations of enzalutamide, under 35 U.S.C. § 103. The claims generally focus on solid amorphous dispersions of enzalutamide with hydroxypropylmethylcellulose acetate succinate (HPMCAS) and a specific disintegrant concentration for treating prostate cancer.

Person Having Ordinary Skill in the Art (PHOSITA)

A PHOSITA in this field would be a pharmaceutical scientist or formulator with experience in developing oral dosage forms for poorly water-soluble drugs, particularly anticancer agents. They would possess knowledge of different formulation techniques, excipients, and methods to improve drug solubility, dissolution, and bioavailability.

Claim 1: Solid Pharmaceutical Composition

Claim 1 describes a solid pharmaceutical composition comprising about 160 mg of enzalutamide, wherein at least 60% of the enzalutamide is amorphous, dispersed in HPMCAS, and further comprising 6-10% by weight of a disintegrant.

Combination of References: US 2014/0100256 A1 (Lorenz et al.) in view of general knowledge regarding solid dispersions, enzalutamide dosage, and common pharmaceutical excipients.

Rationale for Obviousness:

1. Amorphous Enzalutamide and HPMCAS in Solid Dispersions: US 2014/0100256 A1, which shares inventors and a priority date with US 11,839,689, explicitly discloses solid formulations comprising amorphous enzalutamide and pharmaceutical compositions comprising a solid dispersion containing enzalutamide and at least one polymer. It specifically identifies HPMCAS as a concentration-enhancing polymer suitable for use in enzalutamide dispersions. The patent also states that enzalutamide dispersions with HPMCAS can be made by spray-drying. The disclosure notes that "at least a major portion" (at least 60%) of the enzalutamide in the composition should be amorphous to improve solubility and absorption. The use of amorphous solid dispersions (ASDs) to enhance the solubility and bioavailability of poorly water-soluble drugs like enzalutamide was a well-known technique in the pharmaceutical industry prior to the priority date of US 11,839,689. HPMCAS was a recognized and effective polymer for ASD formulations due to its ability to solubilize poorly soluble drugs, promote rapid dissolution, and prevent precipitation.

2. Enzalutamide Dosage (160 mg): Enzalutamide was approved for treating castration-resistant prostate cancer, and a recommended dose of 160 mg orally once daily was known in the prior art, often administered as four 40 mg capsules. A PHOSITA would recognize the advantage of formulating this 160 mg dose into a single, compact tablet for patient convenience, especially given the existing "pill burden" from multiple soft gel capsules.

3. Disintegrants (6-10% by weight): US 2014/0100256 A1 also broadly discloses that the solid dispersion of enzalutamide and polymer can be mixed with one or more pharmaceutically acceptable additives, including disintegrants. Examples of disintegrants listed in the patent include croscarmellose sodium and sodium starch glycolate, which are commonly used in pharmaceutical formulations. The general knowledge in pharmaceutical formulation would include the use of disintegrants to aid in tablet disintegration and drug release, with typical ranges for disintegrant concentrations being well-established. For example, a tablet formulation in the patent itself explicitly states that tablets comprising 60% A:HPMCAS-M dispersion can comprise 6 to 10 wt % disintegrant, and provides examples of tablets with 8 wt% croscarmellose sodium. This indicates that the specific range of 6-10% by weight would be a routine optimization for a PHOSITA to achieve desired dissolution profiles.

Therefore, combining these elements would have been obvious to a PHOSITA who would understand the need to improve enzalutamide's bioavailability, formulate a convenient 160 mg dosage, and apply routine pharmaceutical formulation techniques, including using a well-known concentration-enhancing polymer like HPMCAS and a conventional amount of disintegrant.

Claim 8: Method of Treating Prostate Cancer

Claim 8 describes a method of treating prostate cancer by administering the pharmaceutical composition of Claim 1.

Combination of References: US 2014/0100256 A1 (Lorenz et al.) in view of the known therapeutic use of enzalutamide.

Rationale for Obviousness:

1. Enzalutamide for Prostate Cancer: The use of enzalutamide to treat prostate cancer, including castration-resistant prostate cancer, was well-established in the prior art. U.S. Pat. No. 7,709,517 (cited in US 11,839,689 and US 2014/0100256 A1) already disclosed enzalutamide and its method of use for treating prostate cancer.

2. Administration of Improved Formulations: Given that US 2014/0100256 A1 already teaches amorphous enzalutamide with HPMCAS to improve solubility and absorption (as discussed for Claim 1), it would have been obvious to a PHOSITA to administer this improved formulation for the known treatment of prostate cancer. The goal of such formulations is precisely to enhance the therapeutic effect by increasing bioavailability.

Therefore, using an improved formulation of a known drug for its known therapeutic indication would be a straightforward and obvious application for a PHOSITA.

Claim 15: Solid Amorphous Dispersion

Claim 15 describes a solid amorphous dispersion comprising enzalutamide and HPMCAS, where the enzalutamide constitutes 55% to 65% by weight of the dispersion.

Combination of References: US 2014/0100256 A1 (Lorenz et al.) in view of general knowledge regarding optimizing solid dispersion drug loading.

Rationale for Obviousness:

1. Solid Amorphous Dispersion of Enzalutamide and HPMCAS: As established with Claim 1, US 2014/0100256 A1 explicitly teaches solid amorphous dispersions of enzalutamide and HPMCAS to enhance solubility and absorption.

2. Drug Loading (55-65% by weight): US 2014/0100256 A1 broadly discloses compositions containing from about 1 to about 80 wt% enzalutamide in the dispersion, and more specifically states that "dispersions comprise greater than 50 wt % and less than 70 wt % enzalutamide." The range of 55-65% by weight falls directly within this disclosed range of 50-70 wt%. A PHOSITA would recognize that optimizing the drug loading in an amorphous solid dispersion is a routine experimental parameter, balancing desired drug concentration, physical stability, and processing feasibility. Various prior art references discuss the impact of drug loading on the performance of ASDs and the need for optimization. Given the explicit disclosure of ranges encompassing 55-65% enzalutamide, selecting this specific sub-range would be a matter of routine optimization, not inventive ingenuity. The patent itself mentions that optimum results are best determined by in vitro dissolution and/or in vivo bioavailability tests.

Therefore, the solid amorphous dispersion of enzalutamide and HPMCAS with a drug loading of 55-65% by weight would have been obvious to a PHOSITA in light of US 2014/0100256 A1 and routine optimization practices for solid dispersions.