Many drug compounds can exist in more than one crystalline form, or ‘polymorph’. Different polymorphs can have different properties and identification of the optimal polymorph can be a key factor in the success of a drug.
Polymorphs may therefore have a high commercial value, but obtaining patents for polymorphs at the European Patent Office (EPO) can be challenging. Here are some considerations to assess your chances and some tips for improving them.
Can you show that a polymorph is new?
A claimed polymorph must be shown to differ from any previously known forms of the compound.
Characterising data from established techniques for identifying polymorphs (e.g. X-ray diffraction data) should be used. Not all analytical techniques are suitable. For example, in T 885/92 a difference in IR peak listings was not sufficient to show that two forms prepared by similar methods were different.
Data may be required, even if an earlier disclosure is simply of an uncharacterised solid compound. Repetition of the earlier compound synthesis and characterisation may be needed to show it differs from the claimed polymorph.
Tip: Include extensive characterisation of the polymorph in your application. Be aware that, if comparison with a previously known form isn’t in your application, you may need to provide this during prosecution or in post-grant proceedings.
Are there any unpredictable properties?
The EPO views polymorph screening as a routine part of drug development. An unexpected technical effect generally needs to be demonstrated for a polymorph to be considered inventive.
EPO Examining Divisions may accept a broad range of technical effects. However, the Boards of Appeal take a stricter approach and this is filtering down to the Examining Divisions.
Arguments based on typical polymorph properties are likely to be rejected, especially where the prior art is an amorphous form. For example, in T 777/08 inventive step was denied for a polymorph with improved filterability and drying over an amorphous form, as amorphous forms are generally more soluble than crystalline forms and crystalline forms are generally easier to isolate, purify and dry than amorphous forms.
Perhaps, counterintuitively demonstrating inventive step is generally easier when the closest prior art is another polymorph.
Effects that have been successful include:
Tip: Bear in mind that evidence of an unexpected technical effect is likely to be needed to show inventive step. Wherever possible, include evidence demonstrating beneficial effects of the polymorph in your application.
Was the polymorph particularly difficult to obtain? Were non-standard techniques required?
If so, this can be used to argue the polymorph is inventive, because it would not have been found through routine screening methods.
Tip: In this situation, consider claiming the process as well as the polymorph itself.
Is a complete method for obtaining the polymorph provided?
A polymorph application can fail due to insufficiency if it doesn’t disclose a complete and reproducible method for obtaining the polymorph.
Tip: Ensure that the application describes a complete method of preparing the polymorph. If the method involves seeding, include the method used for preparing seed crystals.
Is the claimed polymorph characterised by clearly defined parameters?
The EPO considers claims in the form “Crystalline Form X of compound Y” to lack clarity. Instead, a polymorph should be defined by characterising data obtained using analytic techniques, for example, XRPD, single crystal X-ray diffraction or thermal methods such as thermogravimetric analysis (TGA), differential thermal analysis (DTA), differential scanning calorimetry (DSC) or melting point. In our experience, most polymorph applications granted by the EPO have the polymorph defined at least by characteristic XRPD peaks.
Key characterising information, such as 2Theta values for characteristic XPRD peaks or onset/peak endotherm temperatures from a DSC thermogram, should be disclosed in the original application. Without this, options for claim amendments may be limited. For example, a full listing of 2Theta values and relative intensities for XRPD peaks might not be considered to provide basis (support) for claiming just the 2Theta values of selected characteristic peaks (T 764/06).
Tip: Define your polymorph using characterising data and provide experimental details of the analytical techniques used in the application. Include complete analytical data (e.g. a full XRPD peak listing or DSC thermogram), but also include claims and embodiments in the description specifying key characterising information for the polymorph (e.g. a listing of characteristic XRPD peaks, onset/peak DSC endotherm temperatures).
For more information, please contact Claire Weston, Jenny Harris, Kathryn Eldridge, or your usual Kilburn & Strode advisor.