The European Patent Office's Board of Appeal recently revoked a patent concerning a crystalline polymorph (Form A) of palbociclib, a CDK4/CDK6 inhibitor, citing a lack of inventive step. The decision, documented in case T 1152/21, turned on the implications of a Phase I and Phase II clinical trial protocol, which suggested acceptable bioavailability of the palbociclib free base, even though the trial results were not available.
The patent in question claimed a crystalline Form A of palbociclib's free base, characterized by specific surface area and volume mean diameter (D[4,3]) values. The patent aimed to address challenges in pharmaceutical development related to the free base of palbociclib, which, when produced via neutralization of a salt, formed agglomerates unsuitable for further processing. The claimed invention purported to offer improved physicochemical and manufacturability properties through a larger particle size.
The appeal centered on whether the claimed crystalline form involved an inventive step over prior art. A key piece of prior art disclosed a method for making the free base of palbociclib in a slurry form, without specifying surface area or D[4,3] values. The patent holder argued that the claimed form's reduced specific surface area and higher D[4,3] value implied a larger particle size, leading to improved filterability and bioavailability suitable for commercial use.
To support the claim of improved filterability, the patentee provided experimental data demonstrating enhanced handling properties compared to the prior art's free base. For bioavailability, they referenced a European Medicines Agency (EMA) assessment report for IBRANCE (palbociclib's trade name), which included clinical studies using capsules of Form A. The assessment indicated that particle size did not impact bioavailability, dissolution, or stability within the proposed commercial specifications.
The Board defined the objective technical problem as providing a crystalline form of palbociclib with improved filterability and commercially viable bioavailability. While the Board acknowledged the known benefits of larger particles for filterability and the feasibility of producing such particles through established methods, the pivotal point was bioavailability.
The Board highlighted a clinical protocol for Phase I and Phase II trials that included formulations of palbociclib free base with both 'small' and 'large' particle sizes. Even without available trial results, the Board inferred that "this at least suggests that the bioavailability of the free base was acceptable for a clinical trial."
The patentee argued that prior art discouraged investigation of the free base due to its poor water solubility and low bioavailability in animal studies. However, the Board countered that the prior art also mentioned the free base could be administered in crystalline or amorphous forms. Furthermore, the clinical protocol indicated that the bioavailability of the free base was being studied in both small and large particle forms. The Board concluded that even if the prior art suggested poor bioavailability, the clinical trial disclosure made free-base forms worthy of further investigation.
Ultimately, the Board found that the subject matter of the patent claim lacked an inventive step, leading to the patent's revocation. The decision underscores the significance of clinical trial disclosures, even in the absence of concrete results, as indicators of potential bioavailability and commercial viability. This ruling suggests that such disclosures can be considered compelling evidence when assessing the inventive step in pharmaceutical patent cases.
