9.9.5 Predictable improvements resulting from amorphous forms as compared to crystalline forms

Abstract

In T 672/21 the appellant (opponent 2) had provided submissions on obviousness based on the assumption that any improved property was absent, so that the objective technical problem was the mere provision of a further polymorph. It relied in this respect on decision T 777/08.

The board, however, defined the objective technical problem in a more ambitious way. For this reason alone, the board held the appellant's submission on obviousness had to fail. The objective technical problem as defined by the board was the provision of a crystalline form of selexipag with a balance of beneficial properties, namely an intermediate stability and at the same time improved industrial processability and improved purity in terms of reduced amounts of residual solvents and residual impurities.

The board noted that according to T 777/08 "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 cannot be regarded as involving an inventive step" (headnote 1) and "the arbitrary selection of a specific polymorph from a group of equally suitable candidates cannot be viewed as involving an inventive step" (headnote 2). However, in the present case 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, relied upon by the appellant for its further argument that the alleged stability of Form I was not a surprising technical effect because the skilled person always looked for the most thermodynamically stable polymorph in order to avoid the problem of interconversion within the dosage form. In T 41/17 it was concluded that the skilled person would have performed screening of the different polymorphs disclosed in the closest prior art, which could exist in order to isolate and identify the most thermodynamically stable form thereof. By doing so, the skilled person would have arrived at the claimed polymorph, which was the most thermodynamically stable form and which, for this reason, was expected not to convert to other forms under mechanical stress. However, unlike in T 41/17, in the present case the stability was not the only property, but rather part of a balance of beneficial properties. Hence, even if the stability of Form I (which is at an intermediate level) had been expected, the same would not apply to the balance of various beneficial properties.

The board also noted that the mere fact that the skilled person would have carried out routine screening for polymorphs as such did not render the claimed Form I obvious. As set out in T 1684/16, 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 or, as in the present case, balance of properties obvious.

Thus the subject-matter of claim 1 of the main request, and by the same token of claims 2 to 13, which included the subject-matter of claim 1, involved an inventive step in view of D10 as the closest prior art.

Abstract

In T 1994/22 the appeal lay from the opposition division's decision to reject the oppositions filed against the European patent. Claim 1 of the main request related to Form II of selexipag, an agonist of the prostaglandin receptor PGI2. The appellant (opponent) objected to the inventive step of the subject-matter of claim 1 of the main request in view of D10 as the closest prior art. The distinguishing feature of claim 1 of the main request in view of example 84 of D10 was the crystalline form, namely Form II of selexipag.

In view of the available experimental results, the board concluded that Form II exhibited the best stability but only intermediate industrial processability, intermediate residual solvent content and an intermediate amount of residual impurities. Contrary to the situation in T 672/21 there was no balance of beneficial properties for Form II according to the main request. The objective technical problem could therefore only be considered that of providing a crystalline form of selexipag which is the best for one property, but only intermediate for all other tested properties.

The respondent submitted that, in line with T 1684/16, there was no reasonable expectation based on the prior art that a suggested investigation in terms of polymorph screening would be successful in finding a form of selexipag having a balance of beneficial properties in terms of stability, industrial processability, solvent content and purity.

The board disagreed. Based on T 1684/16 and in line with T 777/08, an inventive step can be acknowledged if the claimed polymorph has an unexpected property meaning that its selection is non-arbitrary. 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.

Therefore, the selection of Form II is an arbitrary selection from the host of alternatives covered by the closest prior art. Such an arbitrary selection without any unexpected balance of properties being produced cannot contribute to inventive step. The subject-matter of claim 1 of the main request therefore does not involve an inventive step in view of D10 as the closest prior art.

Abstract

In T 2086/21 the board found that, as stated by the respondents (patent proprietors), the effects of improved hygroscopicity, high thermodynamic stability and high polymorphic stability represented a beneficial combination of properties possessed by Form B of apalutamide compared to the physical forms disclosed in D1 and D2. The objective technical problem underlying claim 1 starting from either of D1 or D2 was therefore the provision of a form of apalutamide with a beneficial combination of these mentioned properties.

On obviousness, the appellants (opponents) submitted that in view of the fact that apalutamide was the subject of an Investigational New Drug (IND) filing before the filing date of the patent, the skilled person would have been motivated to perform routine polymorphic analyses or screening, especially given apalutamide's development stage. They cited various documents to support the argument that polymorphic screening and stability testing were part of common general knowledge and that following such routine guidance the skilled person would have arrived at the claimed Form B in an obvious manner.

The board disagreed, emphasising that the appellants' submissions failed to take into account the formulation of the objective technical problem in accordance with the problem-solution approach. Specifically, 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 implication from the landmark decision T 777/08 was that when the advantages or effects of the claimed crystalline form were unexpected, i.e. they were not arbitrary and did not follow merely by virtue of being crystalline, then an inventive step was present. In the present case the board held there was no absence of unexpected properties, and that the selection of Form B was not arbitrary, since it possessed a beneficial combination of properties. Although the skilled person could have carried out a polymorphic screening, there was nothing in the prior art motivating the skilled person to have taken a particular path in the expectation of solving the aforementioned objective technical problem. The respondents further relied on T 325/16: "Only if the prior art either contains a clear pointer ...or at least creates a reasonable expectation that a suggested investigation would be successful, can an inventive step be denied", which supported the board's conclusion.

The board also addressed the appellants' argument that any unexpected effects associated with Form B, such as improved hygroscopicity, amounted to mere bonus effects. The board clarified that the objective technical problem solved by the claimed subject-matter was the provision of a beneficial combination of properties, not just a single property, and there was no reason for the skilled person to assume that the thermodynamically most stable form would at the same time be also polymorphically stable and in addition display improved hygroscopicity, and no such reason was provided by the appellants.

Distinguishing the case in hand from T 41/17, in which the solution was considered obvious because the skilled person would have performed a screening to identify the most thermodynamically stable form, the board highlighted that in the present case, in contrast, thermodynamic stability was only one property from a beneficial combination of properties displayed by the claimed Form B of apalutamide. Even if the effect of thermodynamic stability were to have been considered obvious, the same did not apply to the beneficial combination, since, for example, there was no teaching in the prior art that the effect of lower hygroscopicity could be obtained with the thermodynamically most stable form of apalutamide. 

The board also disagreed that the skilled person starting from the amorphous apalutamide of D1 would have been in a "try and see" situation, which is predicated on the existence of a pointer to the solution, the existence of such the board had ruled out.

In view of the above the board concluded that the subject-matter of claim 1 of the main request (and by extension dependent claims 2-6) involved an inventive step starting from each of the cited documents (D1 and D2). It thus ruled that the appellants' appeals were to be dismissed.