9.9.5 Predictable improvements resulting from to crystalline forms

It has been held in numerous decisions that an inventive step could be acknowledged if the claimed polymorph had an unexpected property meaning that its selection was non-arbitrary (T 1994/22, see also e.g. T 777/08, T 1684/16, T 2086/21). However, the mere presence of a further polymorph does not involve an inventive step, since screening for polymorphs is a routine activity in the context of pharmaceutical development (see e.g. T 2157/21).

In T 777/08 (OJ 2011, 633) the claims in question related to a particular polymorph (form IV) of crystalline atorvastatin hydrate. The board found that the skilled person in the field of pharmaceutical drug development would have been aware of the fact that instances of polymorphism were commonplace in molecules of interest to the pharmaceutical industry, and would have known it to be advisable to screen for polymorphs early on in the drug development process. Moreover, the skilled person would be familiar with routine methods of screening. 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 could not be regarded as involving an inventive step (see also T 41/17, T 1831/18). Further, when starting from the amorphous form of a pharmaceutically active compound as closest prior art, the skilled person would have a clear expectation that a crystalline form thereof 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.

In T 478/17 the board distinguished the case in hand from T 777/08 and T 41/07. The case in hand was not about the selection of any crystalline form but about the selection of one specific salt, namely eliglustat hemitartrate, in which at least 70% by weight of the salt was crystalline. The selection of this specific salt was not arbitrary. Rather, this salt had unexpected properties, namely an improved (reduced) hygroscopicity and an improved chemical stability. The board could not see any "one-way street situation" in view of D1, as claimed by the appellant. The skilled person starting from D1 would have had various choices in terms of stoichiometry and degree of crystallinity. It concluded that, having regard to the cited prior art, it would not have been obvious to the skilled person to isolate eliglustat hemitartrate in which at least 70% by weight of the salt was crystalline and arrive at the compound as defined in claim 19 of the main request.

In T 1684/16 the board distinguished the case in hand from T 777/08, in the light of which the appellant submitted that the solution in the case in hand was obvious since screening of polymorphs was a routine task as demonstrated in the prior art. Unlike T 777/08 the case in hand was not about the selection of any crystalline form but about the selection of one specific crystalline form (Form I of bosutinib monohydrate). The board found that the selection of this specific crystalline form was not arbitrary, but rather this form had unexpected properties, namely an improved stability when compared with the other crystalline forms in D1, D2 and D3. The fact that the skilled person was taught in the prior art to investigate polymorphs in order to isolate the crystalline form having the most desirable properties was in itself not necessarily sufficient to consider a specific polymorphic form having a certain desired property obvious (see also T 1326/18).

In T 1079/18 the board found that the skilled person, faced with the problem of providing a crystalline form of febuxostat that has a higher solubility than form A, would clearly be inclined to check whether form A underwent an endothermic phase transition into a new higher-melting form at higher temperatures. Such a form existed or it did not. It found that the skilled person would have been in a "try and see" situation. By performing a DSC analysis of form A, the skilled person aiming at higher solubility would have identified form I as being the desired form. The fact that form I merely retained the non-hygroscopicity of form A could be considered merely as a bonus effect that the skilled person inevitably achieved because they were primarily looking for a crystalline form of febuxostat with higher solubility.

In T 215/20 the board distinguished the case in hand from T 777/08. First, the effect relied on for inventive step was different (filterability and drying characteristics in T 777/08 vs hygroscopicity in the case at hand) and, second, although a solution to the objective technical problem of providing a pharmaceutical composition comprising a crystalline form of dapagliflozin which is more stable (i.e. less hygroscopic) may have been suggested by D4, the skilled person would not have had a reasonable expectation that the solution offered by D4 would have solved this problem. The skilled person would have considered the effect suggested by D4, namely the universal decrease in hygroscopicity, to be a mere allegation. Given the generally recognised high unpredictability of properties of crystalline forms, the skilled person would not have had a reasonable expectation of obtaining a less hygroscopic form of dapagliflozin.

In T 672/21 the objective technical problem as defined by the board was the provision of a crystalline form of selexipag with a balance of beneficial properties. There was no absence of unexpected properties and the selection was not arbitrary, since the selected Form I had a balance of beneficial properties in terms of stability, industrial processability and purity in comparison with Form II and Form III. There was nothing in the prior art which pointed to the fact that the claimed Form I would have this balance of beneficial properties and they were thus not expected. The present case thus differed from the situation at issue in decision T 777/08.  The board also distinguished T 41/17 in which it was concluded that the skilled person would have performed screening of the different polymorphs disclosed in the closest prior art, to identify the most stable form. In the present case, stability was not the only property, but rather part of a balance of beneficial properties. Hence, even if the stability of Form I had been expected, the same would not have applied to the balance of various beneficial properties (see also T 2086/21).

The board in T 1994/22 distinguished the case in hand from T 672/21, finding that there was no balance of beneficial properties. In the present case, the board saw nothing unexpected in finding a polymorph that was optimum for one property but only intermediate for several other properties. If this were unexpected and thus gave rise to an inventive step being acknowledged, an applicant or proprietor having identified a new polymorph would simply need to carry out tests for long enough to find one single property for which the identified polymorph performed best. This might result in a situation in which almost any polymorph in the world becomes inventive, which would render Art. 56 EPC meaningless.

In T 2086/21 the board confirmed the objective technical problem underlying claim 1 was the provision of a form of apalutamide with a beneficial combination of properties: improved hygroscopicity, high thermodynamic stability and high polymorphic stability. The appellants (opponents) submitted that apalutamide was the subject of an Investigational New Drug filing before the filing date of the patent and argued the skilled person would thus have been motivated to perform routine screening, polymorphic screening and stability testing being part of common general knowledge. The board found these submissions failed to take into account the formulation of the objective technical problem in accordance with the problem-solution approach, that Form B displayed a beneficial combination of properties which could not have been expected by the mere provision of a crystalline form per se. The board held there was no absence of unexpected properties. The board distinguished T 41/17; in the present case even if the effect of thermodynamic stability were to have been considered obvious, the same did not apply to the beneficial combination.

For more on "Try and see situation" see this chapter I.D.7.4. For more on "Unexpected bonus effect" see chapter I.D.10.8.