T 2730/16 - Losing inventive step attack

 Key points

• This case provides a stern warning in my view regarding the admissibility of inventive step attacks in opposition appeal, and in particular the risk of losing inventive step attacks in the course of the first instance opposition proceedings in cases wherein the opposition division aims for first selecting one (and only one) closest prior art document and then discussing inventive step.
• “During the written opposition proceedings, the appellant [opponent] initially argued on the basis of D1, D2 or D3 as the closest prior art. [The] opposition division took the preliminary view that D2 could not constitute the closest prior art. In its subsequent letter in response to the summons, the [opponent] put forward inventive-step objections based on D1 and D3 only. Then, at the oral proceedings before the opposition division, the appellant agreed to D1 being the closest prior art - see minutes page 2 - and apparently did not put forward inventive-step objections based on D2 or D3. Consequently, the decision under appeal [] only discusses the objection based on D1, but not those based on D2 or D3.”
• “The course of the proceedings described above shows that the appellant did not actively maintain its objection based on D2 as the closest prior art during the oral proceedings before the opposition division and that it did indeed abandon it, thereby preventing it from being discussed in the decision under appeal. However, in its statement of grounds of appeal, the appellant again put forward an objection based on D2 as the closest prior art.”
• The inventive step attack based on D2 is not admitted under Art.12(4) RPBA 2007. 
• I doubt if Art.12(4) RPBA 2007 provides legal basis for doing so but Art. 12(4) RPBA 2020 seems to support such an approach.
• In appeal, the opponent/appellant argued " that it had not actively withdrawn or abandoned the inventive-step attack starting from D2 as the closest prior art in the opposition proceedings".
• The  Board: “ It may be that the appellant had not withdrawn its inventive-step objection based on D2 verbatim during the opposition proceedings; however, as explained above, the course of the opposition proceedings and the decision under appeal show that such a withdrawal had occurred (at least) implicitly. In this connection, it is also noted that the appellant did not at any time request a correction of the minutes, nor did it claim that the decision under appeal was erroneous in that it did not deal with the appellant's objection based on D2.”
• I note that the Chair was M. O. Müller.

Crystalline forms

• “The subject-matter of claim 1, i.e. the SC-3 form, differs from amorphous dapagliflozin [of D1] in that it is a crystalline form further comprising (S)-PG and water.”
• “it has to be concluded that the SC-3 form has a higher stability, i.e. a lower hygroscopicity, than amorphous dapagliflozin.”
• The Board finds the crystalline form to be inventive. In particular D4 would not make the solution obvious. “ 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 solvate properties (see above), the skilled person would not have had a reasonable expectation of obtaining a less hygroscopic form of dapagliflozin.”

T 2730/16

https://www.epo.org/law-practice/case-law-appeals/recent/t162730eu1.html

4. Closest prior art

4.1 The appellant considered both D1 and D2 to be suitable as the closest prior art.

4.2 D2 as the closest prior art

During the written opposition proceedings, the appellant initially argued on the basis of D1, D2 or D3 as the closest prior art. In the annex to the summons to oral proceedings (page 11, penultimate paragraph), the opposition division took the preliminary view that D2 could not constitute the closest prior art. In its subsequent letter in response to the summons, the appellant put forward inventive-step objections based on D1 and D3 only. Then, at the oral proceedings before the opposition division, the appellant agreed to D1 being the closest prior art - see minutes page 2 - and apparently did not put forward inventive-step objections based on D2 or D3. Consequently, the decision under appeal (page 11 f., point 4) only discusses the objection based on D1, but not those based on D2 or D3.

The course of the proceedings described above shows that the appellant did not actively maintain its objection based on D2 as the closest prior art during the oral proceedings before the opposition division and that it did indeed abandon it, thereby preventing it from being discussed in the decision under appeal. However, in its statement of grounds of appeal, the appellant again put forward an objection based on D2 as the closest prior art.

In its communication pursuant to Article 15(1) RPBA 2020 the board expressed its preliminary view that this objection should not be admitted into the appeal proceedings pursuant to Article 25(2) RPBA 2020 in conjunction with Article 12(4) RPBA 2007 because, inter alia, the appeal proceedings were judicial in nature, meaning that the decision of a board of appeal should in principle be based on the substance of the dispute before the department of first instance; see T 724/08 (point 3 of the Reasons) and Article 25(1) RPBA 2020 in conjunction with Article 12(2) RPBA 2020.

At the oral proceedings before the board the appellant did not argue in substance in this matter. Instead, it referred to its written submissions. In its letter of 6 October 2020, the appellant had contested the board's preliminary view and argued that it had not actively withdrawn or abandoned the inventive-step attack starting from D2 as the closest prior art in the opposition proceedings, and also that the decisions to which the board referred were not applicable to the present case. The conclusion drawn by the board in its communication was therefore incorrect.

This reasoning cannot be accepted. It may be that the appellant had not withdrawn its inventive-step objection based on D2 verbatim during the opposition proceedings; however, as explained above, the course of the opposition proceedings and the decision under appeal show that such a withdrawal had occurred (at least) implicitly. In this connection, it is also noted that the appellant did not at any time request a correction of the minutes, nor did it claim that the decision under appeal was erroneous in that it did not deal with the appellant's objection based on D2.

The two decisions cited by the board in its communication (T 1067/08 (points 6 and 7 of the Reasons) and T 933/04 (point 2 of the Reasons)) concern cases in which a patent proprietor was responsible for the fact that the opposition division had not made a decision on requests filed by the patent proprietor on appeal. In the board's view, these cases were indeed applicable, mutatis mutandis, to the present case, in which the appellant must be held responsible for having abandoned its objection based on D2 before the department of first instance. Thus, during the oral proceedings, the board decided not to admit the appellant's objection based on D2 as the closest prior art into the proceedings.

4.3 Based on the two previous points, this decision will assess only the appellant's objections based on D1 as the closest prior art.

D1 as the closest prior art

4.4 Claim 1 essentially relates to a crystalline solvate ("SC-3 form") of dapagliflozin with water and (S)-propylene glycol ("(S)-PG") (for the exact wording of claim 1, see point IV above).

4.5 D1 (page 1, lines 5 to 13 and page 35, lines 13 to 20) is directed to a process of producing 1-C-(substituted diphenylmethane-3-yl)-beta-D-glucopyranose compounds, such as dapagliflozin in particular. It also relates to crystalline complexes of these C-aryl glucoside compounds formed with an amino acid complex forming agent such as L-phenylalanine.

D1 describes the stepwise synthesis of dapagliflozin. In the last step of the synthesis, dapagliflozin is obtained "as a glassy off white solid" (Example 20). It was common ground between the parties that this should be understood as a reference to amorphous dapagliflozin.

Furthermore, according to the appellant, D1 disclosed the preparation of a crystalline complex of dapagliflozin with L-phenylalanine (Example 13). Both parties disagreed on whether or not this disclosure was enabling. In the following, it is accepted in the appellant's favour that the approach taken in Example 13 of D1 is enabling and that it does in fact disclose a crystalline complex of dapagliflozin with L-phenylalanine.

The appellant put forward inventive-step objections starting from both forms of dapagliflozin disclosed in D1, i.e. amorphous dapagliflozin and the crystalline complex of dapagliflozin with L-phenylalanine.

Both of the appellant's objections are assessed in the following.

5. Amorphous dapagliflozin as the starting point

5.1 The subject-matter of claim 1, i.e. the SC-3 form, differs from amorphous dapagliflozin in that it is a crystalline form further comprising (S)-PG and water.

5.2 D12 is a declaration submitted by the respondent. It is a summary of the respondent's efforts made in the course of developing a pharmaceutically acceptable form of dapagliflozin. Points 4 and 12 of this declaration relate to amorphous dapagliflozin and to the SC-3 form of claim 1, respectively. These points read as follows (emphases added):

"4. [...] After complete solvent removal, an amorphous glassy foam was formed inside the reactor vessel. This amorphous glassy material was physically unstable. It transformed to a gel on exposure to relative humidities >33% at room temperature within a day, thereby posing significant handling issues."

"12. [...] the mixed solvate SC-3 (dapagliflozin + 1 (S)-propylene glycol + 1 H2O) was found to be physically stable under ambient temperature and humidity. Results from moisture sorption-desorption studies indicated that SC-3 was non-hygroscopic at 25 °C (Fig. 2)."

The above two statements are clear and nothing was apparent that could have cast doubt on their accuracy. Contrary to the view expressed in the decision under appeal, they allow a direct comparison to be made between the SC-3 form and amorphous dapagliflozin and it has to be concluded that the SC-3 form has a higher stability, i.e. a lower hygroscopicity, than amorphous dapagliflozin.

5.3 The appellant contested the conclusion drawn from D12, namely that the SC-3 form was more stable, i.e. less hygroscopic, than amorphous dapagliflozin. It put forward the following arguments.

5.3.1 The appellant reported on experimental tests in which tablets containing amorphous dapagliflozin were stored with and without desiccant under different conditions of temperature, relative humidity and duration. Before and after the tests, the tablets were analysed for the presence of amorphous and/or crystalline forms of dapagliflozin and for the presence of impurities. In these tests, the tablets containing the amorphous form of dapagliflozin were found to be stable regardless of the presence of a desiccant. These tests proved that the SC-3 form did not offer any advantages over the amorphous form in terms of stability.

This is not convincing for several reasons. Firstly, these tests only examined the stability of amorphous dapagliflozin against decomposition (determined by the content of impurities) and against transformation into a crystalline form. From D12 it was concluded that the SC-3 form and amorphous dapagliflozin differ from each other in terms of their hygroscopicity. However, the hygroscopicity of a compound, i.e. its propensity to bind water from the environment, is different from its stability against decomposition and its stability against conversion into a crystalline form. Secondly, the appellant's tests examined the stability of the amorphous form contained in a tablet. In a tablet, however, the API is not only diluted, but the API is also shielded from the environment, at least to some extent. A result obtained for a tablet containing dapagliflozin therefore cannot be compared with a result obtained for dapagliflozin in substance, as was the case in the respondent's studies as summarised in point 4 of D12.

5.3.2 The appellant also referred to D14 (page 14, paragraphs 1 and 5 from the bottom). It disclosed that the SC-3 form was susceptible to oxidative degradation and that the SC-3 form transformed into the amorphous anhydrous form upon long exposure to high temperature. This again showed the lack of stability of the SC-3 form and even proved that amorphous dapagliflozin was thermodynamically more stable than the SC-3 form.

As noted in the previous point, the stability of a compound to decomposition, e.g. oxidative degradation, is different from its propensity to bind water from the environment, i.e. its hygroscopicity. Similarly, stating that the hydrous SC-3 form was converted to anhydrous amorphous dapagliflozin upon long exposure to high temperature is equivalent to saying that the SC-3 form decomposed to an anhydrous form (dehydration induced by high temperature). These observations do not allow any conclusion to be drawn about the hygroscopic properties of the compounds in question.

5.3.3 The appellant also argued that both D1 and D12 referred to amorphous dapagliflozin; however, detailed instructions for its preparation were only disclosed in D1. Therefore, it was possible that the two amorphous forms did not correspond to each other or that the modification was not the same in both cases. In this context, it was quite conceivable that dapagliflozin showed polyamorphism, i.e. that there were several amorphous modifications. It was also not demonstrated in D12 that the amorphous form described therein was completely amorphous and that it did not contain residual solvent(s).

This is not convincing. According to point 4 of D12, amorphous dapagliflozin is obtained "[a]fter complete solvent removal" (emphasis added). Without any apparent reason to doubt this statement, it cannot simply be asserted that amorphous dapagliflozin, as referred to in D12, contains residual solvent(s). Further, amorphous dapagliflozin is obtained in D1 and D12 in essentially the same way, namely by removing the solvent from a solution of dapagliflozin. Although the solvent used is not specified in D12, this alone, at least in the absence of evidence to the contrary, does not support the allegation that the two amorphous forms of D1 and D12 could be different in any way. This conclusion is also supported by the fact that, as pointed out by the respondent, the appellant itself did not indicate how it had obtained the amorphous dapagliflozin used in its tablet studies (see point 5.3.1 above).

5.4 Thus, in line with the respondent, the objective technical problem can be considered that of providing a crystalline form of dapagliflozin which is more stable, i.e. less hygroscopic.

5.4.1 The appellant argued that the effect inferred from D12 could not be derived from the application as filed (e.g. from paragraph [0062]) and that it therefore should not have been taken into account for formulating the objective technical problem.

This is not persuasive. The application as filed (paragraphs [0005] ff.) relates to solid forms of dapagliflozin such as, inter alia, the SC-3 form from claim 1. It not only discusses the stability of polymorphic forms in general (paragraph [0062]), but also indicates that stable forms of dapagliflozin can be crystallised as solvates (paragraph [00115] in conjunction with paragraph [0005]). Undoubtedly, hygroscopicity is an important stability aspect in the pharmaceutical field. This is evidenced not only by D4 (page 3, paragraph 2 and the more extensive discussion below) but also, for example, by D11 (page 327, third paragraph under point 3.3) and some of the decisions cited by the respondent in this appeal (T 1684/16 (point 4.3.4 of the Reasons), T 94/11 (point 3.2 of the Reasons) and T 643/12 (point 5.3 of the Reasons)). Therefore, the formulation of the objective technical problem as that of providing a crystalline form of dapagliflozin which is more stable, i.e. less hygroscopic, falls within the framework of the invention as disclosed in the application as filed (T 1422/12, point 2.3.3 of the Reasons; T 440/91, points 4.1 to 4.3 of the Reasons) and the effect inferred from D12 can be taken into account.

5.4.2 The appellant also argued that the application as filed did not plausibly demonstrate that the effect(s)/problem(s) relied on by the respondent at the time, such as an alleged superior stability, in particular, had actually been solved on the effective date (letter of 20 December 2017, point 3). The post-published evidence D12 should therefore have been disregarded altogether for the assessment of inventive step and the formulation of the objective technical problem based on e.g. T 488/16 (point 4.2 of the Reasons).

Nonetheless, in this respect the appellant only referred to the thermal stability of the dapagliflozin forms in the application as filed, but not to stability in the sense of reduced hygroscopicity (see letter of 20 December 2017, point 3.1.1). In addition, at the oral proceedings, the appellant expressly emphasised that it was not discussing plausibility when comparing the stability of the different forms of dapagliflozin. Therefore the plausibility of the effect of increased stability in the sense of reduced hygroscopicity in the application as filed was no longer contested at the oral proceedings and as a consequence, there is no reason not to take D12 into account.

5.5 As regards obviousness, the appellant pointed to D4.

5.5.1 D4 relates to PG solvates of APIs. In particular, D4 (page 4, paragraph 4; page 3, paragraphs 2 and 3) states quite generally

(i) that the formation of PG solvates makes it possible to obtain crystalline compounds from APIs which are difficult to crystallise

(ii) that the API PG solvates are more stable and less hygroscopic than the APIs themselves.

5.5.2 The appellant argued that the skilled person would have consulted D4 and would have taken its teaching into account. This was because D4 offered solutions to the problem of providing a crystalline form of an API as well as to the problem of providing a form that is less hygroscopic. Furthermore, it was clear from Example 7 of D4, describing the manufacture of a mixed PG/water solvate of the API celecoxib, that not only PG solvates as such but also mixed PG/water solvates were in accordance with the invention in D4. The SC-3 form from claim 1 with a 1:1:1 molar ratio of dapagliflozin, PG and water would inevitably have been obtained when trying to crystallise dapagliflozin according to D4. Consequently, the subject-matter of claim 1 did not involve an inventive step over a combination of D1 and D4.

5.5.3 Even if it were assumed in the appellant's favour that an attempt to crystallise dapagliflozin according to D4 would inevitably have resulted in the SC-3 form, the argument that the skilled person would have consulted D4 when trying to solve the objective technical problem is not sufficient. For this argument to be correct, the skilled person, in order to take the teaching of D4 into account, would also have had to have a reasonable expectation of success, i.e. a reasonable expectation that this teaching would actually have solved the objective technical problem. Whether or not this is the case will be assessed in the following.

5.5.4 On pages 45 to 296, D4 gives a very long list of APIs whose PG solvates are said to be covered by the invention in D4. Among these compounds is also T-1095 (page 267, entry 4), i.e. a compound which is structurally similar to dapagliflozin. In view of points 5.5.1 (i) and (ii) above, this list amounts to D4 pretending to have found an almost universal solution to the problem of providing a crystalline form of an API and in particular to the problem of providing a form of an API which is less hygroscopic. This alone would not have given the skilled person a reasonable expectation of success, i.e. a reasonable expectation of obtaining a crystalline form of dapagliflozin which is less hygroscopic than amorphous dapagliflozin. The reason is that, as put forward by the respondent in its letter dated 11 September 2020 (point 7.11) and during the oral proceedings, the formation of solvates, let alone their properties such as crystallinity and hygroscopicity, is highly unpredictable. This is evident, for example, from D10 (page 945, paragraph bridging both columns; page 946, left column, second paragraph; figure 6), which suggests searching for solvates at an early stage of drug development because they display a wide and largely unpredictable variety of properties and therefore their sudden appearance at a later stage usually slows down the drug-approval process and makes planning difficult. In this context, the board acknowledges that D4 demonstrates that four structurally very different and unrelated APIs can be transformed into crystalline PG solvates. As regards hygroscopicity, however, D4 lacks experimental data showing that an API PG solvate is less hygroscopic than the API itself. D4 (page 44, last paragraph) only sets out the following (emphases added):

"Dynamic moisture sorption studies of several embodiments of the present invention have been discussed in PCT/US03/XXXXX filed on December 24, 2003, entitled "Pharmaceutical Compositions With Improved Dissolution" (Attorney Docket No. TPI-1700CXC2 PCT) by Tawa et al, which is hereby incorporated by reference, in its entirety. Dynamic moisture sorption studies can be used to illustrate important characteristics of the solvates of the present invention, such as decreased hygroscopicity or increased form stability."

According to the appellant, moisture sorption studies were commonly used to examine the hygroscopicity of a compound. After all, the respondent had used the same method in D12. It could therefore be inferred from the above paragraph that the API PG solvates from D4 also had to exhibit a lower hygroscopicity than the corresponding APIs themselves.

This argument cannot be accepted. The above paragraph refers to "several embodiments of the present invention" and not, for example, to all embodiments. It also indicates that sorption studies may be used to illustrate properties other than hygroscopicity. Therefore, it cannot be inferred from this paragraph alone that a lower hygroscopicity is achieved with such a high number of structurally very different and unrelated APIs that this would have given the skilled person a reasonable expectation of success.

Furthermore, the examples in D4 cast legitimate doubt on whether the effect of a lower hygroscopicity is actually achieved as universally as suggested. In Example 1, celecoxib sodium PG solvate is prepared. Then in Example 7, this PG solvate is allowed to bind water from the environment, eventually resulting in celecoxib sodium PG trihydrate (i.e. a mixed PG/water solvate of celecoxib sodium). This shows that celecoxib sodium PG solvate, i.e. a PG solvate according to the teaching of D4, is still hygroscopic.

According to the appellant, this did not allow the conclusion to be drawn that a lower hygroscopicity would not have been achieved. In order to draw such a conclusion celecoxib sodium PG solvate would have had to be compared with its reference compound celecoxib sodium (D4: page 14, last paragraph). This argument fails to convince because D4 does in fact allow an indirect comparison between celecoxib sodium PG solvate and celecoxib sodium in terms of their hygroscopicity. D4 provides a classification scheme for the degree of hygroscopicity ranging from class 1 (non-hygroscopic) to class 4 (very hygroscopic). According to this classification scheme compounds are very hygroscopic if they absorb moisture at relative humidities as low as 40 to 50% (D4: page 14, paragraph 2). Based on this scheme, celecoxib sodium PG solvate is very hygroscopic because it begins to absorb moisture even at relative humidities between 31 and 40% (D4: page 43, lines 6 to 7 below "Example 7"). With celecoxib sodium PG solvate belonging to the worst hygroscopicity class, its hygroscopicity cannot be lower than that of its reference compound, celecoxib sodium, at least when judged according to D4's own classification scheme.

Based on the above, 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 solvate properties (see above), the skilled person would not have had a reasonable expectation of obtaining a less hygroscopic form of dapagliflozin.

5.5.5 In view of the foregoing, the present case is also clearly different from the case underlying decision T 777/08, on which the appellant relied. In that decision, as in the present case, the starting point for the assessment of inventive step was the amorphous form of an API. The objective technical problem was considered that of providing a form having improved filterability and drying characteristics. The board concluded (page 12, paragraph 3; emphases added):

"Thus, in view of his general knowledge, as reflected in this excerpt from document (28), the skilled person, starting from the amorphous form of a pharmaceutically active compound as closest prior art, would have a clear expectation that a crystalline form thereof would provide a solution to the problem as defined under point 5.1 above. Although this might not be true of every crystalline form obtained (cf. document (28), page 527, left-hand column, second and third sentences), it was nevertheless obvious to try this avenue with a reasonable expectation of success without involving any inventive ingenuity."

Hence, in this case, the skilled person would have had a reasonable expectation that providing a crystalline form of the API would have solved the objective technical problem. The present case is different in that, although a solution to the objective technical problem may have been suggested by D4, the skilled person would not have had a reasonable expectation that the solution offered by D4 would have actually solved this problem.

5.5.6 In summary, the subject-matter of claim 1 involves an inventive step over amorphous dapagliflozin as disclosed in D1 in combination with D4 because the skilled person, considering the teaching of D4, would not have had a reasonable expectation of obtaining a form of dapagliflozin which is less hygroscopic than amorphous dapagliflozin.