T 2370/19 (DARUNAVIR / POLYMORPHS) 10-01-2023
Download and more information:
Pseudopolymorphic forms of a HIV protease inhibitor
I. The appeal lodged by the opponent ("appellant") lies from the decision of the opposition division to reject the opposition against European patent No. 2 767 539 ("the patent").
II. The patent as granted contains 17 claims, with independent claims 1 and 10 reading as follows:
"1. An ethanolate pseudopolymorph of (3R,3aS,6aR)-hexahydrofuro [2,3-b] furan-3-yl (1S,2R)-3-[[(4-aminophenyl) sulfonyl] (isobutyl) amino]-1-benzyl-2-hydroxypropylcarbamate, for use as a medicine."
"10. A hydrate pseudopolymorph of (3R,3aS,6aR)-hexahydrofuro [2,3-b] furan-3-yl (1S,2R)-3-[[(4-aminophenyl) sulfonyl] (isobutyl) amino]-1-benzyl-2-hydroxypropylcarbamate, for use as a medicine."
Claims 2 to 9 and 11 to 17 concern specific embodiments of the subject-matter of claim 1 and claim 10, respectively.
III. The opposition had been filed under Article 100(a) (invoking lack of inventive step) and (b) (invoking lack of sufficiency of disclosure) EPC. The opposition division concluded that none of the grounds for opposition invoked by the opponent prejudiced the maintenance of the patent as granted.
IV. In its statement of grounds of appeal and a subsequent letter, the appellant raised objections for lack of sufficiency of disclosure and lack of inventive step. It also objected to the admittance of auxiliary requests 1 to 9 filed by the patent proprietor (see below).
V. In its reply to the appeal, the patent proprietor ("respondent") rebutted the appellant's arguments. It also filed sets of claims according to auxiliary requests 1 to 9.
VI. The parties were summoned to oral proceedings as per their requests. In preparation for oral proceedings, the board issued a communication under Article 15(1) RPBA 2020, in which it expressed, inter alia, the preliminary opinion that the grounds for opposition invoked by the appellant did not prejudice the maintenance of the patent as granted.
VII. By its letter dated 5 January 2023, the appellant replied to the board's communication and maintained that the claimed invention was not sufficiently disclosed in the patent.
VIII. Oral proceedings before the board were held on 10 January 2023 by videoconference. During oral proceedings, the appellant withdrew its request that auxiliary requests 1 to 9 not be admitted into the proceedings. Furthermore, it withdrew its opposition and appeal to the extent that it related to the ground for opposition according to Article 100(a) together with Article 56 EPC.
IX. Final requests relevant to the decision
The appellant requested that the decision under appeal be set aside and that the patent be revoked in its entirety.
The respondent requested that the appeal be dismissed, meaning that the patent be maintained as granted (main request). Alternatively, it requested that the patent be maintained on the basis of the claims of one of auxiliary requests 1 to 9 as filed with the reply to the appeal. The respondent also requested not to admit into the proceedings the allegation made by the appellant in its letter dated 5 January 2023 that the conditions in example 1 of the patent were unspecific and general in nature and not sufficient to obtain the intermediate isopropanol solvate of darunavir.
X. The appellant's submissions relevant to the present decision are summarised as follows. For further details, reference is made to the reasons for the decision below.
- Example 1 of the patent defined the process for producing crystals of isopropanol solvate of darunavir only in general terms. The conditions specified were entirely standard.
- Declaration D19 provided the necessary evidence that the claimed solid forms of darunavir could not be obtained when following example 1 of the patent.
- It had to be concluded that the claimed invention was not sufficiently disclosed in the patent.
XI. The respondent's submissions relevant to the present decision are summarised as follows.
- Example 1 of the patent disclosed all the information that the skilled person needed to produce the claimed ethanolate form of darunavir.
- Specific conditions in terms of the required solvent, temperature and pressure were indicated. These were not standard crystallisation conditions.
- Example 7 disclosed how to obtain the claimed hydrate form of darunavir from the ethanolate form.
- There was no inconsistency between the teaching of the patent and declaration D19 by the respondent. This declaration related to the history of the underlying research before the invention was made - and before the invention was disclosed. Thus, the scientists involved at the time were entirely in the dark as to whether any solid form of darunavir would exist and, if so, which form.
- Therefore, the skilled person reading the detailed teaching in the patent was in an entirely different position from that reflected in D19, i.e. of the skilled person not having any knowledge of the invention.
- Contrary to the appellant's view, point 12 of D19 did not convey the message that crystalline isopropanol solvate of darunavir could not be produced without having a first crystal. Rather, point 12 simply added that not only could a first crystal be obtained, but also that the experiment could be scaled up.
- The appellant did not provide any evidence that the claimed solid forms of darunavir might not be obtained by following the instructions given in examples 1 and 7 of the patent.
- It had to be concluded that the claimed invention was sufficiently disclosed in the patent.
Allegation by the appellant in its letter dated 5 January 2023 - admittance into the proceedings
1. In its letter dated 5 January 2023, the appellant replied to the board's communication under Article 15(1) RPBA 2020 and made further submissions regarding the issue of sufficiency of disclosure.
1.1 At the oral proceedings the respondent requested not to admit into the proceedings the allegation made by the appellant in this letter that the conditions in example 1 of the patent were unspecific and general in nature and insufficient to obtain the intermediate isopropanol solvate of darunavir.
1.2 The board concluded that this request by the respondent had to be rejected. However, since the final decision is in the respondent's favour (see below), no reasoning by the board concerning this rejection is needed.
Main request - the patent as granted - ground for opposition under Article 100(b) EPC - sufficiency of disclosure
2. Independent claims 1 and 10 as granted (point II above) are directed to two pseudopolymorphic forms of the same compound referred to in the following as darunavir as the parties have done in their submissions: the ethanolate pseudopolymorph (claim 1) and the hydrate pseudopolymorph (claim 10), for use as a medicine.
3. The appellant argued that the patent disclosed the preparation of the ethanolate form in example 1 (paragraph [0086], page 15). The ethanolate form was prepared via an intermediate crystalline isopropanol solvate of darunavir. The preparation of the hydrate form was disclosed in example 7 (paragraph [0100], page 18) of the patent and involved treating the ethanolate form. Therefore, the patent only described how to make the claimed compounds via an intermediate crystalline isopropanol solvate of darunavir.
3.1 Declaration D19 by the respondent explained that the preparation of solid (i.e. crystalline) forms of darunavir had proven difficult and had only been possible after a chance formation of an isopropanol solvate crystal after many hundreds of experiments and hundreds of hours of scratching. The appellant referred to points 4, 6, 7, 9 to 12 and 14 to 16 of D19. Point 12 of D19 in particular made it clear that the production of crystalline isopropanol solvate of darunavir could be repeated and scaled up only after a first crystal had been obtained, i.e. only once the laboratory had been exposed to this crystal.
3.2 It was not disputed that the conditions mentioned in example 1 of the patent made it possible to achieve crystallisation of isopropanol solvate of darunavir. According to the appellant, however, it was only possible in the presence of a first sample of these crystals. Point 12 of D19 confirmed that the claimed isopropanol form could be prepared and scaled up only after - not before - the laboratory ChemShop had had access to a sample of this isopropanol solvate crystal. Until the skilled person had got access to a sample of the isopropanol solvate crystal, that form could not be prepared using the method of example 1 of the patent. However, isopropanol solvate crystals were needed to prepare the claimed ethanolate and hydrate forms.
3.3 The appellant argued further that the respondent's allegation that example 1 disclosed all the necessary conditions to achieve the crystallisation of isopropanol solvate of darunavir was inconsistent with the above disclosure in D19. The process described in example 1 was, namely, not a highly specific, optimised process developed to overcome the difficulties in obtaining the crystalline isopropanol solvate stated in D19. On the contrary, example 1 defined the process only in general terms, thus conveying the information that preparing the crystalline isopropanol solvate was straightforward. The skilled person merely had to dissolve darunavir in isopropanol and then concentrate the solution by heating to just below isopropanol's boiling point under reduced pressure; the isopropanol solvate was then formed by crystallisation. According to this process, the precise conditions in terms of temperature and amounts of darunavir and solvent, and therefore the concentrations, were not important. However, had these simple conditions provided the isopropanol solvate crystals without prior access to that form, the external company ChemShop would not have failed to prepare it despite undertaking hundreds of experiments, as disclosed in D19.
3.4 According to the appellant, it was clear from D19 that the breakthrough for obtaining crystals of isopropanol solvate of darunavir was not the discovery of the - entirely standard - conditions described in example 1 of the patent. The breakthrough came when the isopropanol solvate crystal was prepared by chance. After this chance event, any company would be able to prepare this solid form but only after having been provided with a sample of it. While the preparation appeared to be easy in a laboratory where seeds of the solid form were present, the skilled person at the priority date of the patent was not in that position. They did not have access to the solid form or work in a laboratory in which seeds of that form were present.
3.5 The appellant acknowledged that it had the burden of proving that the claimed invention was insufficiently disclosed. However, the required proof did not necessarily have to be in the form of experimental data since the proceedings before the EPO were conducted in accordance with the principle of the free evaluation of evidence (see the Case Law of the Boards of Appeal, Tenth Edition, 2022, III.G.4.1). The respondent's own declaration D19, which had not been contested, provided the necessary evidence that the invention as defined in the claims could not be put into practice without undue burden. Therefore, the claimed subject-matter was insufficiently disclosed.
3.6 The board finds the appellant's arguments unconvincing for the following reasons.
3.6.1 Sufficiency of disclosure has to be assessed on the basis of the teaching contained in the patent in consideration of the common general knowledge. Example 1 of the patent (paragraph [0086]) discloses the specific experimental conditions needed for preparing the ethanolate form of darunavir as defined in claim 1 as granted. In particular, a solution of darunavir and isopropanol is formed at the beginning. The solution is then concentrated by vacuum distillation at 70°C and 200-500 mbar pressure and cooled from a T > 35°C to a temperature between 15°C and 20°C over about 10 hours. Under these conditions, crystals of isopropanol solvate of darunavir are formed. Isopropanol is then exchanged with ethanol to obtain the claimed ethanolate form of darunavir.
3.6.2 Therefore, example 1 of the patent discloses specific conditions in terms of the solvent to be used, temperature, pressure and cooling time to allow crystals of isopropanol solvate of darunavir to form. The appellant's allegation that these conditions were entirely standard has not been corroborated by any evidence and thus has to be regarded as mere speculation.
3.6.3 Moreover, the board concurs with the respondent that there is no inconsistency or contradiction between example 1 of the patent and declaration D19. Document D19 merely discloses the development that led to the claimed invention in general terms, i.e. the general procedure followed by the patent proprietor to determine the conditions necessary to prepare a solid form of darunavir. Even if this development proved to be challenging (D19, points 5 to 7 and 10), D19 does not state that crystals of isopropanol solvate of darunavir were obtained by chance, contrary to the appellant's view. Rather, these crystals were obtained by using isopropanol as the solvent and by employing scratching, a technique recognised by both parties at the oral proceedings as part of the common general knowledge.
3.6.4 Contrary to the appellant's view, D19 (point 12) does not state that isopropanol solvate of darunavir could only be produced in the presence of a first crystal; it merely states that once this crystal was obtained the experiment could also be scaled up. The respondent did not dispute that further crystallisation was achieved with less effort once first crystals were obtained. However, this does not imply that no initial crystals can be obtained with the process run under the specific conditions disclosed in example 1 of the patent (see above).
3.6.5 In fact, there is no indication in D19 that the specific conditions disclosed in example 1 of the patent were used at all in the experiments mentioned in that document, let alone in experiments that failed to produce solid forms of darunavir.
3.6.6 Therefore, D19 may well demonstrate the difficulties experienced before the knowledge of the patent when preparing crystals of the isopropanol solvate of darunavir. Yet this does not imply that these difficulties would still have been encountered when carrying out the teaching of example 1 of the patent.
3.6.7 The board concurs with the appellant that experimental proof that a claimed invention cannot be reproduced on the basis of the information contained in a patent is not necessarily needed for an objection of sufficiency of disclosure to be successful. Any kind of evidence can be used, as declaration D19 in the current case.
3.6.8 However, for the above reasons, declaration D19 is not sufficient to cast reasonable doubts on the fact that the claimed solid forms of darunavir cannot be obtained on the basis of the teaching contained in the patent - in particular example 1. In other words, it does not raise a doubt that the skilled person, using common general knowledge and following the instructions given in this example, would have encountered an undue burden in obtaining the ethanolate form of darunavir as defined in claim 1 as granted (point II above).
3.6.9 According to example 7 of the patent (paragraphs [0100] to [0103]), the ethanolate form of darunavir was transferred into its hydrate form by means of an adsorption-desorption procedure. The appellant did not challenge that the hydrate form as defined in claim 10 (point II above) could be readily prepared by following this procedure.
3.7 For the reasons set out above, the board concludes that the claimed subject-matter is sufficiently disclosed in the patent. The ground for opposition under Article 100(b) EPC does not prejudice the maintenance of the patent as granted.
4. Since the appellant restricted its opposition and appeal only to the ground for opposition under Article 100(b) EPC, the board concludes that the patent can be maintained as granted. Therefore, the respondent's main request is allowable.
For these reasons it is decided that:
The appeal is dismissed.