T 0325/16 - (II) New crystalline form inventive

 Key points

•  Patents direct to salt forms, solvate forms, and polymorphs are commercially rather important in the pharma field. T 777/08 held that "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." This decision is generally seen as raising the bar for this kind of "follow up" pharma patents.
• “pharmaceutical polymorphs provide an excellent way for a company to further protect a small molecule drug in order to recoup the billions of dollars that go into research and development, thereby enabling further research and development” (link, emphasis added) 
• In the present case, the Board finds the claimed crystalline forms to be inventive.
• " The [opponent] respondent also relied on T 777/08 in its inventive-step analysis. In this decision, the board held that the skilled person, starting from the amorphous form of an API as the closest prior art, would have gained a clear expectation from the common general knowledge that a crystalline form of it would have provided a solution to the problem of providing a product having improved filterability and drying characteristics. This expectation was considered reasonable because, although it could not be assumed that every single crystalline form would solve the problem, it could be assumed that many of these crystalline forms would. In view of this, the board considered the provision of a specific polymorph from the group of equally suitable candidates to be arbitrary and not involving an inventive step (T 777/08, point 5.2 of the Reasons)." 
• The Board: “The current case differs not only in that the closest prior art discloses a crystalline rather than an amorphous API, but also in that the skilled person would not have gleaned from it a reasonable expectation of success in solving the problem of providing crystal forms of CNDAC-HCl that are more stable than others. This is because the mere suggestion to look for more stable forms cannot be considered a reasonable expectation to find a specific solution, let alone a pointer.”
• “ the board essentially accepts the appellant's submission based on decision T 1684/16” thereby finding that “Only if the prior art either contains a clear pointer that the claimed subject-matter solves the objective technical problem or at least creates a reasonable expectation that a suggested investigation would be successful, can an inventive step be denied. ”
• “ It is true that it is in the common general knowledge of the skilled person to screen for polymorphs of an API to find one having improved properties such as an improved stability. However, this alone is not sufficient to deny inventive step to a solution by which this improvement is achieved.”
• “In the case at hand, there is no disclosure in the cited prior art creating any expectation, let alone containing any pointer, that the type I or type II crystals of CNDAC-HCl defined in claims 1 and 2 of the main request could be more stable than other crystalline forms of CNDAC-HCl. There is no suggestion that the crystal types I and II of CNDAC-HCl are more stable than others. While D3 mentions the solvent system EtOH-Et2O to be used for crystallisation, it gives no details on the stability of the crystal form obtained. The mere mention of the solvent system in D3, therefore, would not have given a reasonable expectation to the skilled person, let alone a pointer, that its use would have led to crystalline forms of CNDAC-HCl which are more stable than others.”
• The present decision seems to suggest that any polymorph with good or improved properties is inventive, since it can not be predicted in advance which crystalline form in particular will have good properties.

T 0325/16 -

https://www.epo.org/law-practice/case-law-appeals/recent/t160325eu1.html

16.4 Based on the previous point, the objective technical problem can be seen in the provision of an anti-tumour agent containing a crystalline form of CNDAC-HCl with a higher stability.

16.5 Faced with this objective technical problem, the skilled person would not have arrived at the claimed solution in an obvious manner.

16.5.1 The respondent's position was essentially that the skilled person would have screened for different polymorphic forms as a matter of routine. The common general knowledge even suggested searching for the most stable form (D15: page 948, left column, penultimate line to right column, line 3; T 777/08, point 5.2 of the Reasons). In carrying out this screening, the skilled person would inevitably have found crystal types I and II of CNDAC-HCl. Since the combination of the known anti-tumour agent CNDAC-HCl with a pharmaceutically acceptable carrier would have been routine for the skilled person, the skilled person would have found a solution to the above-mentioned objective technical problem without inventive efforts. This argument gained even more weight given that D3 proposed the solvent system EtOH-Et2O for crystallisation, i.e. incidentally the solvents used in the patent for the manufacture of type I and type II crystals.

16.5.2 The board does not agree. It is true that it is in the common general knowledge of the skilled person to screen for polymorphs of an API to find one having improved properties such as an improved stability. However, this alone is not sufficient to deny inventive step to a solution by which this improvement is achieved. Only if the prior art either contains a clear pointer that the claimed subject-matter solves the objective technical problem or at least creates a reasonable expectation that a suggested investigation would be successful, can an inventive step be denied. With this view, the board essentially accepts the appellant's submission based on decision T 1684/16 (point 4.3.4 of the Reasons; catchword) in which essentially the same view is expressed.

In the case at hand, there is no disclosure in the cited prior art creating any expectation, let alone containing any pointer, that the type I or type II crystals of CNDAC-HCl defined in claims 1 and 2 of the main request could be more stable than other crystalline forms of CNDAC-HCl.

There is no suggestion that the crystal types I and II of CNDAC-HCl are more stable than others. While D3 mentions the solvent system EtOH-Et2O to be used for crystallisation, it gives no details on the stability of the crystal form obtained. The mere mention of the solvent system in D3, therefore, would not have given a reasonable expectation to the skilled person, let alone a pointer, that its use would have led to crystalline forms of CNDAC-HCl which are more stable than others.

16.6 The respondent also relied on T 777/08 in its inventive-step analysis. In this decision, the board held that the skilled person, starting from the amorphous form of an API as the closest prior art, would have gained a clear expectation from the common general knowledge that a crystalline form of it would have provided a solution to the problem of providing a product having improved filterability and drying characteristics. This expectation was considered reasonable because, although it could not be assumed that every single crystalline form would solve the problem, it could be assumed that many of these crystalline forms would. In view of this, the board considered the provision of a specific polymorph from the group of equally suitable candidates to be arbitrary and not involving an inventive step (T 777/08, point 5.2 of the Reasons).

The current case differs not only in that the closest prior art discloses a crystalline rather than an amorphous API, but also in that the skilled person would not have gleaned from it a reasonable expectation of success in solving the problem of providing crystal forms of CNDAC-HCl that are more stable than others. This is because the mere suggestion to look for more stable forms cannot be considered a reasonable expectation to find a specific solution, let alone a pointer.