A clinical trial protocol as a pointer to the claimed crystalline form of a compound (T 1152/21)

In recent decision T 1152/21, the Board of Appeal finds that a phase I and phase II clinical trial protocol provided a pointer to the claimed crystalline form of a compound, despite the lack of any trial results.

Background

Claim 1 of the main request was directed to a crystalline polymorph Form A of the free base of palbociclib with particular characteristics, including a particular BET Nitrogen measured specific surface area and volume mean diameter characterized by a D[4,3] value.

“According to the patent (paragraph [0004]), using palbociclib as a potent and selective CDK4/CDK6 inhibitor is linked with challenges for pharmaceutical development. In the state of the art, the free base of palbociclib was provided by neutralisation of a salt. It formed small primary particles, which agglomerated into large, hard agglomerates that were difficult to disperse by sieving and were unsuitable for further development. The Patent is concerned with providing a crystalline free base of palbociclib having a larger particle size for improving the physicochemical and manufacturability properties” (section 2 of the Reasons).

The Appeal Board Decision

The closest prior art was a WO publication disclosing a method of making a free base of palbociclib, which is said to be in the form of a “slurry”. Neither the particular specific surface area nor the D[4,3] value was disclosed. “The patent proprietor submitted that a reduced specific surface area and a higher D[4,3] value implied a larger particle size. A larger particle size of the compound of claim 1 of the main request resulted in (i) improved filterability and (ii) a bioavailability suitable for commercial use.” (section 6 of the Reasons).

In relation to improved filterability, the Patentee relied on a declaration providing experimental data which demonstrates that particles of the free base of palbociclib having the particular specific surface area and the D[4,3] value in accordance with claim 1 of the main request have improved handling properties, namely improved friability compared with the free base of the prior art.

Regarding bioavailability compatible with commercial use, the Patentee relied on a later published assessment report by the European Medicines Agency CHMP for IBRANCE (trade name for palbociclib). The report discloses clinical studies using capsules of Form A of the free base of palbociclib, which were established to have a D[4,3] value and a specific surface area in accordance with claim 1 of the main request, based on characterisation filed by the Patentee in the form of a declaration. The assessment report states that “the active substance particle size does not impact finished product relative bioavailability, dissolution and stability within the proposed commercial active substance particle size specification”.

The Board considered the objective technical problem to be the provision of a crystalline form of palbociclib having improved filterability and a bioavailability compatible with commercial use.

The Board was satisfied that it is well known that larger particles are more easily filtered. In addition, the Board considered that the skilled person knew how to prepare larger particles, by reducing the number of nucleation sites and applying seeded crystallisation.

In addition, the Board found that the skilled person would have expected larger particles to have a bioavailability compatible with commercial use in view of the disclosure of a phase I clinical protocol directed to a “Relative Bioavailability Study” with four different palbociclib formulations. The protocol disclosed “a hard capsule including the free base of palbociclib with a ‘small’ particle size” and “a hard capsule including the free base of palbociclib with a ‘large’ particle size”. The Board considered that “[a]lthough the results of these trials were not available, this at least suggests that the bioavailability of the free base was acceptable for a clinical trial”.

The Patentee argued that the teaching of the closest prior art WO publication “encouraged the skilled person to seek new salt forms of palbociclib since the free base of palbociclib was disclosed as having poor water solubility and low bioavailability in animal studies”. However, the Board disagreed, noting that the closest prior art separately taught that “the free base of palbociclib, may be administered as crystalline or amorphous products”. Additionally, the Board noted that the clinical protocol “discloses that the bioavailability of the palbociclib free base in both ‘small’ and ‘large’ particle form was studied”. The Board held that “even if [the closest prior art] did teach that the free base of palbociclib has poor bioavailability, the skilled person would have considered free-base forms of palbociclib to be worthy of further investigation in view of the clinical trial [disclosure]” (section 7.2 of the Reasons).

Therefore, the Board found that the subject matter of claim 1 of the main request did not involve an inventive step and the Patent was revoked. 

Commentary

Interestingly, the Board put emphasis on the clinical trial disclosure, stating that it “explicitly teaches larger particles as an option to provide a bioavailability compatible with commercial use, and the skilled person would not have disregarded this option” (section 7.2 of the Reasons). The Board considered that the teaching in the closest prior art that “the free base of palbociclib was disclosed as having poor water solubility and low bioavailability in animal studies” was not sufficient to disregard the protocol. In other words, whilst in this case the clinical protocol was published after the closest prior art WO publication, it seems that a clinical protocol disclosure may be considered as more compelling evidence than other types of disclosures such as patent application publications.

Separately, whilst the Board took the effect of “bioavailability compatible with commercial use” into account for the assessment of inventive step based on the published assessment report by the European Medicines Agency CHMP for IBRANCE and the accompanying declaration, the Board commented that “[s]ince the overall decision is in the opponents' favour, there [was] no need to provide reasons for the admittance of [the post-filed declaration]” in view of G 2/21” (section 9 of the Reasons). Thus, the Board seemed reluctant to delve into G 2/21 when it was unnecessary. It is therefore not clear whether, upon review of the disclosure in the Patent, the technical effect relied on for inventive step would have been found to be “encompassed by the technical teaching and embodied by the same originally disclosed invention” as required by G 2/21.