Patenting Polymorphs in Europe: Key Considerations at the EPO

Polymorphs are different crystalline forms of the same chemical compound. In the pharmaceutical sector, different polymorphs can exhibit different properties, such as stability, hygroscopicity, dissolution behaviour, bioavailability and processability. As a result, polymorph patents are frequently used as part of pharmaceutical lifecycle management strategies, in order to extend patent protection for a pharmaceutical compound beyond the term of the base patent.

 

Although the European Patent Office (EPO) recognises that a novel crystalline form of a known compound can constitute patentable subject matter, Applicants can face challenges in establishing inventive step. Over the last fifteen years, the Boards of Appeal have developed a body of case law defining the circumstances in which polymorph inventions are, and are not, likely to be considered patentable. Unfortunately, the situation is not always clear and apparently conflicting judgments are often issued.

 

What makes a pharmaceutical polymorph novel?

A polymorph can be novel even if the underlying chemical compound is already known. The key issue is whether the specific crystalline form was previously made available to the public. Applicants should therefore characterise the polymorph thoroughly, typically using XRPD data together with other analytical techniques such as DSC, TGA, IR and/or Raman spectroscopy so as to provide demonstrable novelty over a previous disclosure of the same chemical compound in a different form (e.g. amorphous).

 

In this regard, the novelty of a claimed new polymorphic form can sometimes be challenged by demonstrating that the process used to produce a particular compound in the prior art (often the Applicant’s own prior art disclosure) actually and inevitably results in measurable levels of the newly claimed polymorph.

 

Why is inventive step often the biggest hurdle?

Inventive step is usually the main hurdle for polymorph patents at the EPO. A widely referenced decision is T 777/08, in which the Board held that polymorph screening is a routine part of pharmaceutical development. Consequently, the mere discovery of a new crystalline form of a known compound is not normally inventive. In other words, in the absence of a technical prejudice or an unexpected property, a polymorph is likely to be regarded as an arbitrary selection from a number of equally suitable alternatives. However, real-world situations are typically far more nuanced than this general statement assumes.

 

The most effective way to establish inventive step is therefore to demonstrate an unexpected technical advantage. Examples that have been accepted by the Boards of Appeal include improved stability, reduced hygroscopicity, improved processability and other advantageous properties that could not have been predicted from routine screening.

 

Recent decisions also show that inventive step may be based on a balance of beneficial properties rather than a single superior characteristic.

 

However, the application of EPO case law to different situations and the ultimate decisions that result are highly situation dependent and apparently conflicting judgments have been issued. For example, acknowledgement of an inventive step is typically influenced by the definition of the ‘closest prior art’ to the claimed invention, and whether the closest prior art is considered to be an amorphous form of the compound or a different polymorphic form is often arguable. To optimise the chances of obtaining useful patent protection for a polymorphic form, therefore, Applicants or their attorneys should be aware of the relevant EPO case law in this complex field.

 

What must the application disclose?

In addition to novelty and inventive step, Applicants must ensure that a patent application discloses the polymorph in a manner sufficiently clear and complete for it to be reproduced by the skilled person.

 

In practice, this means providing adequate characterisation data and a reproducible method for obtaining the claimed form. Particular care should be taken where the polymorph can only be prepared using specific crystallisation conditions, solvents or seeding procedures. Failure to provide enough information to reliably reproduce the claimed form may result in an insufficiency objection under Article 83 EPC, which may be impossible to overcome after the application has been filed.

 

How can comparative data support patentability?

Experimental data is critical to obtaining patents for polymorph inventions. Applicants should include comparative evidence showing that the claimed polymorph exhibits one or more unexpected advantages over known forms of the compound, including the amorphous form and other polymorphs that are already known.

 

However, following G 2/21, Applicants cannot assume that newly discovered advantages can be introduced after filing. Any technical effect relied upon for inventive step should therefore be reflected in the application as originally filed, even if additional supporting data is generated subsequently.

 

Practical Recommendations

For a polymorph patent to have a realistic prospect of success before the EPO, the application should:

• Clearly define the polymorph using robust analytical data;
• Include a reproducible method for preparation of the claimed polymorph;
• Provide comparative data against prior known forms (e.g. different polymorphic forms and/or the amorphous compound); and
• Identify unexpected technical advantages from the outset.

 

Conclusion

The EPO does not treat polymorphs as unpatentable subject matter. However, as polymorph screening is generally considered routine, a new crystal form of a known compound will usually only be patentable if the Applicant can demonstrate an unexpected technical effect that provides a concrete benefit over the prior art. In practice, successful EPO polymorph patents are typically built around strong experimental evidence showing that the claimed form provides one or more advantages that would not have been predicted from routine pharmaceutical development and knowledge of the prior art.