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Case law 19 Apr 2022

Inventiveness of alternative crystalline polymorphs

A patent (EP2431376) claiming new crystalline polymorphs of a known anti-leukemia drug radgocitabine, was revoked in an opposition for lacking inventive step. The Patentee (P) appealed the decision of the Opposition Division (OD), highlighting that the new polymorphs showed improved stability over already known crystalline forms of the drug, and referring back to a decision T 1684/16 wherein a more stable form of a different known drug (bosutinib) was evaluated as inventive. The Board agreed that the new polymorphs of the revoked patent were solving a problem of providing more stable crystal forms of a known drug. Interestingly, they also suggested that because it was impossible to predict if a newly-discovered polymorph would exhibit such an improved feature, any new polymorph actually showing an improvement would likely be inventive.
  • A patent claiming new and relatively more stable polymorphs of a known drug was revoked by Opposition Division (OD) for lacking inventive step.
  • The patentee (P) appealed referring to decision T 1684/16, wherein it was decided that “the fact that the skilled person is taught in the prior art to investigate polymorphs in order to isolate the crystalline form having the most desirable properties is in itself not necessarily sufficient to consider a specific polymorphic form having a certain desired property obvious “”
  • The opponent (O) responded that the skilled person would have screened for most stable forms as a matter of routine and cited the decision T 777/08.
  • The Board acknowledged that, although it indeed considered the common general knowledge for the skilled person to screen for polymorphs with improved properties, this “alone was not sufficient to deny inventive step to a solution by which this improvement is achieved.”
  • The Board concluded that “a mere suggestion to look for more stable forms” could not be “considered a reasonable expectation to find a specific solution”, i.e. the specific more stable polymorphs as claimed in the revoked patent.

Background

Polymorphs are different crystal structures of the same chemical compound. When a non-crystalline form of such chemical compound exists, it is called an amorphous form. Usually, the amorphous forms exhibit different physicochemical properties than the one or more crystalline forms, and this is generally accepted. For example, in decision T 777/08, improved filterability and drying properties of a new crystalline over a known amorphous solid of the same compound, was not considered unexpected.

However, different crystalline forms frequently also differ from each other in physicochemical properties such as thermal stability, melting point, dissolution rate, solubility, and/or bioavailability in a particular organism. There however appears to exists no logical pattern or trend allowing to link or predict such properties as exhibited by a new crystalline vis-à-vis an already known one. The present decision appears to acknowledge this unpredictability and consequently suggests that any new specific crystalline polymorphs exhibiting an improved property over previously known and different crystalline polymorphs, will likely be inventive.

The Appeal

In response to the Appeal by P, the respondent O referred to the decision T 777/08 and submitted that screening for polymorphs with improved properties belonged to routine and common general practice. Consequently, O expressed the opinion that the crystals of improved stability as claimed in the revoked patent “would have been the inevitable consequence of this screening”. In a nutshell, O argued that: “In carrying out the screening, the skilled person would inevitably have found (the) crystal types” as specified in the claims.

The Board noted that in the decision T 777/08 relied upon by O, the inventive-step analysis was made “starting from the amorphous form …  as the closest prior art”. Based on this, the Board concluded that the skilled person starting an amorphous form, “would have gained a clear expectation from the common general knowledge that a crystalline form [of the same active pharmaceutical ingredient (API)] would have provided … improved characteristics.” The Board then explained that, in such circumstances,“(t)his 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 provision of a specific polymorph from the group of equally suitable candidates [was considered] to be arbitrary and not involving an inventive step (T 777/08, point 5.2 of the Reasons).

In view of the above, firstly, the Board acknowledged that the prior art did suggest screening for the most stable polymorph. Then, the Board also acknowledged that the closest prior art disclosed crystalline form preparation conditions identical to those taught in the contested patent.

However, in contrast to the reasoning of O, the Board also noted that in view of the situation under question, the initial inventive step submissions of the P’s based on decision T 1684/16 (point 4.3.4), were much more applicable. The decision T 1684/16 concerned a very similar case wherein a new crystalline polymorph of another known drug (bosutinib) showed enhanced stability relative to the closest prior art API also being a crystalline polymorph of the same drug.

The Board thus acknowledged that, unlike in T 777/08, T 1684/16 and the present case were not about the selection of just any crystalline forms, but about the selection of specific and well-defined crystalline forms. Furthermore, the Board acknowledged that said selection of specific forms as claimed could not be arbitrary because these crystals had unexpected properties, i.e. improved stability, when compared with the other crystals of the same drug as known from the cited prior art.

Decision of the Board

Based on the above considerations, the Board concluded that it was not obvious to the skilled person to isolate the specific crystal types as claimed in the main request under Appeal, because none of the identified prior art documents created any expectation or contained any pointer that the claimed crystal-types could be more stable than the already known crystals of the same API.

The Board notably stated:
“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 [the] crystal forms .. 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.(emphasis added)

Consequently, the crystals as claimed in the main request were considered inventive, resulting in the request being allowable. Consequently, the case was remitted to the OD with the order to grant the initially revoked patent.

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