Patents and Polymorphs

Patents directed to a specific compound polymorph can be a great way to obtain second- or third-line protection for lead candidates, and they usually will outlast earlier composition of matter filings by a few years.The EPO does grant patents relating to polymorphs, but not all applications are ultimately successful. Josh Price provides a review to help patent attorneys and agents understand what the polymorph patentability standards at the EPO actually are.

Key learning points:

  • A crystalline polymorph made in a routine manner and not having any kind of out-of-the-ordinary characteristic is unlikely to be inventive.
  • Data is crucial – without it a polymorph patent application will almost certainly fail.
  • Detail relating to the preparation and characterisation of the polymorph is vital.

When can polymorphs not be patented?

The gold standard for inventiveness of a polymorph is in T777/08.

“It is well known to screen compounds for polymorphism in drug development. Consequently, in the absence of any technical prejudice and in the absence of any unexpected property, the mere provision of a crystalline form of a known pharmaceutically active compound is obvious.”

“When starting from the amorphous form of a pharmaceutically active compound, a chemist would have a clear expectation that a crystalline form would provide a solution to the problem of providing a product having improved filterability and drying characteristics. The arbitrary selection of a specific polymorph from a group of equally suitable candidates cannot be viewed as involving an inventive step” (emphasis added).

Apart from improved filterability and drying characteristics, the general knowledge on polymorphs appears to include the following properties of the crystalline form:

  • Increased chemical stability
  • Decreased solubility rate
  • Decreased hygroscopicity
  • Decreased wettability
  • Increased hardness
  • Increased physical stability

This is also broadly in line with the approach taken by the UK courts. Ivax Pharmaceuticals UK Ltd v Akzo Nobel NV [2006] EWHC 1089 (Ch) (22 May 2006) and Leo Pharma (a/s Leo Laboratories Ltd) v Sandoz Ltd [2009] EWHC 996 (Pat) (15 May 2009) contain helpful discussions on the common general knowledge surrounding polymorphs.

Consequently, polymorphs will normally need something above and beyond these characteristics to be patentable.

When could polymorphs be patented?

There are a number of cases in which polymorphs were found to be patentable.

Polymorphic stability (the tendency to interconvert between polymorphs, as distinguished from normal physical stability) is one property that can support an inventive step. As seen in T2114/13 sometimes several crystalline forms might already be known that are capable of interconversion. A new, polymorphically stable polymorph that did not convert into other forms was found to be inventive. Similarly, in T1555/12, the claimed polymorph was patentable because it could be obtained in a high purity and did not suffer from the interconversion seen for other polymorphs.

In T0517/14 a polymorph already existed which had good polymorphic stability. You might expect that it would be tricky to rely on polymorphic stability for further polymorphs. However, in the Board’s view, it was not to be expected that a further crystalline form with similar polymorphic stability could be obtained. A patent was granted because the applicant had provided an additional solution to a problem.

When considering bioavailability, it pays to think about where in the body the compound is to be absorbed. In T1723/10 there was a question of whether an amorphous polymorph was patentable because of its improved bioavailability. Although it was generally known that amorphous forms are usually more water soluble (and thus potentially more bioavailable), in this case, the polymorph was still found to be inventive. The reason was that it was not obvious that it would have good solubility in the specific (acidic) conditions of the stomach. This case was also a good example of an amorphous form being patentable – it is not only crystals that can be protected!

It is not always easy to crystallise a compound. If routine methods were not able to produce a crystalline form from an amorphous form, then the development of a process to produce a crystalline form should allow the polymorph and the associated method for production to be patented.

Non-standard preparation methods may also lead to patentable claims. In T0699/05 a method using a laser to induce nucleation of a polymorph was found inventive. In T1210/05 an unusual work-up (involving the suspension of a solvate hydrate in water in order to, surprisingly, ultimately cause the removal of the water from the solvate) was enough to support a patentable claim.

Experimental data is crucial for polymorph applications. In T0256/13 a claim to a polymorph was lost because there was no evidence to support its claimed properties – the EPO’s increasingly tough stance on “plausibility” came into play here. On a related note, in T2007/11 a claim was found to be too broad because the evidence did not support the properties of the polymorph. The take home message is that it is better to wait and file an application with evidence for the polymorph’s characteristics than risk filing too early.

It is true that general knowledge dictates that crystalline forms usually have certain properties over the amorphous form. However, the properties of specific salt forms are less predictable. In T0643/12 it was confirmed that the selection of the salt form that exhibits the desired combination of properties remains a difficult semi-empirical choice. Having identified a suitable salt form, the skilled person then has a further freedom in selecting the polymorph. So a specific salt form of a specific polymorph is more likely to be inventive, as long as it is associated with a technical benefit.

The above-mentioned points should be borne in mind when drafting polymorph applications for Europe. The success of the case may ultimately depend upon how the advantage of the polymorph is portrayed in the application.

If you have any questions on the patentability of polymorphs, contact Josh at Josh.Price@gje.com.

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