T 0500/16 - Plausibility attack not admitted

Key points

•  Claim 1 is directed to the crystalline malate salt of the known pharmaceutical compound cabozantinib.
• As to novelty: “D29 [" EMEA; Committee for Orphan Medicinal Products; December 2008, Plenary Meeting Monthly Report"] (page 1) discloses cabozantinib (L)-malate for treatment of medullary thyroid carcinoma (a thyroid cancer). D29 only refers to the malate salt without stating whether it is crystalline. While D29 implicitly discloses that the salt is in a solid form, it cannot be deduced from D29 that the salt is crystalline. The subject-matter of claim 1 of the main request, referring to the crystalline form of a cabozantinib malate salt, is therefore not directly and unambiguously derivable from D29.”
• For inventive step: “The objective technical problem ... is the provision of a cabozantinib malate salt which, as a pharmaceutical formulation, has an improved dissolution profile under physiological conditions.”
• As to obviousness: “The above documents only show that crystalline forms of pharmaceutical solids are preferred. However, none of the above documents includes any teaching on how to improve the dissolution profile under physiological conditions of the cabozantinib malate salt. This is not disputed by the appellants. In the absence of such a teaching, the solution provided by claim 1 of the main request is thus not obvious.”
• This reasoning may be an illustrative example of the problem-solution approach being effect-centred. 
• “In the current case, it has been shown in annex 1 that the unexpected property of the claimed compound is an improved dissolution profile under physiological conditions. Thus, the case at hand does not correspond to the situation in case T 777/08 where no unexpected property was recognised.”
• The opponents argue that the found effect is a bonus effect (which hence does not provide for inventive step): “[The opponents] argued that the improved dissolution profile under physiological conditions of the crystalline form of cabozantinib (L)-malate was a mere bonus effect since the skilled person would have had ample motivation in view of the teachings of D3, D5, D7, D13, D14, D25, D26, A005 and A006 to select the crystalline form of cabozantinib (L)-malate, the compound disclosed in D29.”
• “The board does not agree. A "bonus effect" arises when the state of the art forces the skilled person to adopt a certain solution, the lack of alternatives leading to a "one-way street" situation. In such a situation, any additional effect does not necessarily contribute to inventive step (see e.g. T 405/17, reasons, 4.3.3). However, this situation does not apply in this case for the following reasons. [follows a detailed review of cited prior art] In view of the above disclosures and teachings, there is no indication in the prior art that in searching for an adequate solid form of the compound disclosed in the closest prior-art document D29, the skilled person would have been forced specifically to choose only the crystalline form of cabozantinib (L)-malate as required by claim 1 of the main request. Thus, the improved dissolution profile under physiological conditions of the crystalline form of cabozantinib (L)-malate, as shown in annex 1, cannot be considered a mere bonus effect.”
• The Board also rejects that the case at hand was an obvious-to-try situation.
  
  
• Then,  to plausibility: “With the statement of grounds of appeal, [opponent] submitted that it was not made plausible on the basis of the content of the application as filed that the claimed compounds achieved the effect shown in annex 1, namely the improved dissolution profile. Therefore, the post-published data of annex 1 were not to be taken into consideration in the formulation of the objective technical problem. This objection is referred to below as the "plausibility objection".”
• The patentee requested that this objection be not admitted. The opponents in turn “requested that the respondent's request for non-admittance of appellant 2's submissions on a lack of plausibility not be admitted into the proceedings.”
• “The board decided to admit the respondent's request [i.e. admissibility objection] into the proceedings [under Art. 13 RPBA 2007] for the following reasons [follows a consideration of factors such as procedural economy].
• The “plausibility objection” is not admitted under Art. 12(4) RPBA 2007. “In the proceedings before the opposition division, the parties had discussed the data presented in annex 1 as to their merits, i.e. the parties had proceeded on the basis that the data could be taken into account and the decision under appeal is based thereupon. ”
• The Board: “Admitting the objection into the proceedings would have given appellant 2 a new chance, after opposition proceedings which had been instituted by it and having been terminated, to object to inventive step based on an entirely new submission. The admittance of the plausibility objection would have led to an entirely fresh case regarding inventive step. More specifically, had the plausibility objection been admitted and found convincing, the post-published data in annex 1 would have had to be disregarded, and the effect relied upon by the respondent could not have been taken into account. The objective technical problem would thus have changed, and the obviousness as regards a different objective technical problem would have had to be considered for the first time during the appeal proceedings.”
• “[The opponent] argued that the submissions on plausibility did not constitute an allegation of fact but rather an argument and that the board did not have any discretion not to admit an argument.”
• “The board does not agree. The appellant's allegation was that the application as filed did not make it plausible that the claimed subject-matter resulted in an improved dissolution profile. Whether, on the basis of the application as filed, it can be concluded that a certain effect, here an improved dissolution profile, is plausible or not is based on a factual consideration rather than a mere argument. More specifically, numerous facts play a role in making this consideration, such as what is actually disclosed in the application as filed as regards the effect and what the technical relationship between the claimed compound and the effect is. Therefore, appellant 2's submissions on plausibility included an allegation of fact (see also T 1875/15, reasons, 2.3 to 2.4), and the board had under Article 114(2) EPC the discretion not to admit appellant 2's late-filed submissions.”
• The opponent further argues that plausibility was a new issue in the case law. The Board seem to accept that new case law can be a valid reason for admitting a submission, but finds that the issue of plausibility was in fact not new in 2013-2015 (proceedings before the OD) in view of T 415/11 (reasons, 50, 12 January 2012), T 1329/04 (reasons, 12, 28 June 2005). 

EPO - T 0500/16 

Link to the decision after the jump, as well as an extract of the decision text.

https://www.epo.org/law-practice/case-law-appeals/recent/t160500eu1.html

5.4 Obviousness

The appellants relied on D3, D5, D7, D13, D14, D25, D26, A005 and A006 for assessing the obviousness of the solution proposed by claim 1 of the main request.

D3 (pages 208-209) and D5 (page 351, salt forms of enalapril) refer to the advantages of crystalline forms of drugs over the amorphous forms in terms of chemical and thermodynamic stability.

D7 (figure 1, page 1047), D13 (figure 1, page 29) and D25 (figure 1, page 946; page 952) give instructions for salt and crystal screening.

D14 (page 712, left column, section "Salt Selection Decision Making", fifth- and fourth-from-last lines of the first paragraph) states that "As a practical consideration, it is essential that the NCEs [i.e. new chemical entities] have high purity, and that salts be crystallized" (text in squared brackets added by the board).

D26 (page 527, left-hand column, third paragraph; page 528, left-hand column, first paragraph) discloses that "Polymorphs have crystal lattices which differ in the ways in which the same molecule is bound in the unit cell. The differences may reflect different ways of packing molecules in the cell, or conformational changes, which can be large. Hydrogen-bonding will be involved for most molecules of interest to the pharmaceutical industry." and "In giving each development candidate the best chance of progressing, it seems better to search for polymorphs rather than to leave their appearance to time and chance with the consequent disruption."

A005 (page 799, left-hand column) refers to the disadvantages of amorphous pharmaceutical solids ("It is the apparent chemical and physical instability of most amorphous pharmaceutical solids which is the major factor precluding their more widespread use in solid dosage forms.").

A006 (page 947, left column, first full paragraph) discloses that "..., in general the commonly held view is that amorphous materials are undesirable forms".

The above documents only show that crystalline forms of pharmaceutical solids are preferred. However, none of the above documents includes any teaching on how to improve the dissolution profile under physiological conditions of the cabozantinib malate salt. This is not disputed by the appellants. In the absence of such a teaching, the solution provided by claim 1 of the main request is thus not obvious.

This conclusion is not in contradiction with decision T 777/08. According to this decision (headnotes), "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". In the current case, it has been shown in annex 1 that the unexpected property of the claimed compound is an improved dissolution profile under physiological conditions. Thus, the case at hand does not correspond to the situation in case T 777/08 where no unexpected property was recognised.

5.5 Appellants 1 and 2 argued that the improved dissolution profile under physiological conditions of the crystalline form of cabozantinib (L)-malate was a mere bonus effect since the skilled person would have had ample motivation in view of the teachings of D3, D5, D7, D13, D14, D25, D26, A005 and A006 to select the crystalline form of cabozantinib (L)-malate, the compound disclosed in D29.

The board does not agree.

A "bonus effect" arises when the state of the art forces the skilled person to adopt a certain solution, the lack of alternatives leading to a "one-way street" situation. In such a situation, any additional effect does not necessarily contribute to inventive step (see e.g. T 405/17, reasons, 4.3.3). However, this situation does not apply in this case for the following reasons.

Even if, as set out above, the passages of the documents relied on by the appellants disclose that a crystalline form is preferred, this is not the only teaching available in these documents and the art, as submitted by the respondent. D3 (page 208, left column, last paragraph) teaches that "amorphous solids are occasionally preferred because they undergo dissolution at a faster rate". The same teaching is found in D25, which discloses that the amorphous forms may be of interest (page 946, left column, last paragraph; page 952, left column "Amorphous forms") since these forms "usually are much more soluble than their crystalline counterparts". D13 (page 50) does not exclude the amorphous calcium salt of L-649,923 in the process of salt screening and selection to improve stability. A005 (introduction on page 799) refers to the "use of amorphous form of drugs to improve solubility, increase dissolution and promote therapeutic activity". A006 (abstract on page 946) teaches that amorphous solids and crystalline salts are both of interest as a means of improving the dissolution characteristics and apparent solubility of poorly water-soluble active pharmaceutical ingredients which have low bioavailability in humans. D35 (page 216, first paragraph of "Discussion") discloses that "Usually the dissolution rate of a compound increases when converted into its amorphous state".

In view of the above disclosures and teachings, there is no indication in the prior art that in searching for an adequate solid form of the compound disclosed in the closest prior-art document D29, the skilled person would have been forced specifically to choose only the crystalline form of cabozantinib (L)-malate as required by claim 1 of the main request. Thus, the improved dissolution profile under physiological conditions of the crystalline form of cabozantinib (L)-malate, as shown in annex 1, cannot be considered a mere bonus effect.

5.6 Appellant 1 further submitted that the case at hand was an obvious-to-try situation since the claimed subject-matter was the result of a selection of one component, i.e. the crystalline form, from a list of two alternatives, namely the crystalline and amorphous forms. The prior art taught to select the crystalline form.

The board does not agree. In the problem-solution approach, the question to be answered is whether the skilled person, having regard to the closest prior art and being faced with the objective technical problem, would have been motivated by the prior art to arrive at the claimed solution or would have had at least a reasonable expectation that a suggested investigation would be successful. In such a case, inventive step can be denied (T 1684/16, reasons, 4.3.4). However, in the case at hand, the skilled person would not have arrived at the subject-matter of claim 1 of the main request because no such motivation or suggestion is available in the documents relied on by the appellants (see 5.4 above) that a crystalline form of a cabozantinib malate salt has an improved dissolution profile under physiological conditions in a pharmaceutical formulation.

6. Admittance of the submissions based on plausibility

6.1 With the statement of grounds of appeal, appellant 2 submitted that it was not made plausible on the basis of the content of the application as filed that the claimed compounds achieved the effect shown in annex 1, namely the improved dissolution profile. Therefore, the post-published data of annex 1 were not to be taken into consideration in the formulation of the objective technical problem. This objection is referred to below as the "plausibility objection".

The respondent requested with the letter of 20 October 2020 that this objection not be admitted.

During the oral proceedings, appellants 2 and 3 requested that the respondent's request for non-admittance of appellant 2's submissions on a lack of plausibility not be admitted into the proceedings.

6.2 Admittance of respondent's request for non-admittance of appellant 2's plausibility objection

As set out above, the respondent's request for non-admittance of appellant 2's plausibility objection was submitted with the letter of 20 October 2020, i.e. after the first summons to oral proceedings. Since the first summons to attend oral proceedings was notified before the date of the entry into force of the revised version of the RPBA on 1 January 2020, Article 13(2) RPBA 2020 does not apply and Article 13 RPBA 2007 continues to apply (T 1083/16, reasons, 2.1 to 2.2).

In exercising its discretion under Article 13(1) and (3) RPBA 2007, the board considers, inter alia, the state of the proceedings, the complexity of the new subject-matter submitted, and the need for procedural economy (Article 13(1) RPBA 2007). Furthermore, amendments of a party's case made after oral proceedings have been arranged are not admitted if they raise issues which the board or the other party cannot reasonably be expected to deal with without adjournment of the oral proceedings (Article 13(3) RPBA 2007).

The board decided to admit the respondent's request into the proceedings for the following reasons.

The respondent's request focuses on procedural issues, namely whether appellant 2's plausibility objection should be admitted into the appeal proceedings. The main point to be examined as regards the respondent's objection is whether appellant 2's plausibility objection could and should have been filed in the opposition proceedings (see below). This did not raise any complex new issue, and the admittance of the respondent's request did not lead to a fresh case to be considered at an extremely late stage of the appeal proceedings. This was not disputed by the appellants. The admittance of the respondent's request was also not detrimental to procedural economy (Article 13(1) RPBA 2007) and it could be dealt with without adjournment of the oral proceedings (Article 13(3) RPBA 2007).

6.3 Admittance of appellant 2's plausibility objection

As set out above, appellant 2's plausibility objection was raised in the statement of grounds of appeal. Consequently, the admittance of the objection is governed by Article 12(4) RPBA 2007 (see the transitional provisions pursuant to Article 25(2) RPBA 2020, the statement of grounds of appeal having been filed before 1 January 2020).

In the proceedings before the opposition division, the parties had discussed the data presented in annex 1 as to their merits, i.e. the parties had proceeded on the basis that the data could be taken into account and the decision under appeal is based thereupon. Hence, as not disputed by the parties, the objection of lack of plausibility and whether the post-published data in annex 1 were to be taken into account had not been discussed in the proceedings before the opposition division.

Furthermore, appellant 2 did not argue that the objection was submitted in response to facts, objections, arguments or evidence presented at a late stage of proceedings before the opposition division, and on which the decision under appeal was based, and the board saw no reason that justified the submission of the objection only at the appeal stage.

It is the primary object of the appeal proceedings to review the decision under appeal in a judicial manner, as now explicitly confirmed in Article 12(2) RPBA 2020. Admitting the objection into the proceedings would have given appellant 2 a new chance, after opposition proceedings which had been instituted by it and having been terminated, to object to inventive step based on an entirely new submission. The admittance of the plausibility objection would have led to an entirely fresh case regarding inventive step. More specifically, had the plausibility objection been admitted and found convincing, the post-published data in annex 1 would have had to be disregarded, and the effect relied upon by the respondent could not have been taken into account. The objective technical problem would thus have changed, and the obviousness as regards a different objective technical problem would have had to be considered for the first time during the appeal proceedings.

In light of the above, the objection not only could but also should have been presented during the proceedings before the opposition division. Accordingly, the board decided not to admit the plausibility objection in accordance with Article 12(4) RPBA 2007 and Article 12(2) RPBA 2020.

6.4 Appellant 2 argued that the submissions on plausibility did not constitute an allegation of fact but rather an argument and that the board did not have any discretion not to admit an argument.

The board does not agree. The appellant's allegation was that the application as filed did not make it plausible that the claimed subject-matter resulted in an improved dissolution profile. Whether, on the basis of the application as filed, it can be concluded that a certain effect, here an improved dissolution profile, is plausible or not is based on a factual consideration rather than a mere argument. More specifically, numerous facts play a role in making this consideration, such as what is actually disclosed in the application as filed as regards the effect and what the technical relationship between the claimed compound and the effect is. Therefore, appellant 2's submissions on plausibility included an allegation of fact (see also T 1875/15, reasons, 2.3 to 2.4), and the board had under Article 114(2) EPC the discretion not to admit appellant 2's late-filed submissions.

6.5 Appellant 2 also argued that the plausibility objection could only be raised with the statement of grounds of appeal since the case law on plausibility cases involving "small" molecules, such as the one defined in claim 1, was only developed after the proceedings before the opposition division. Reference was made to decisions T 415/11 (reasons, 50, 12 January 2012), T 1329/04 (reasons, 12, 28 June 2005), T 488/16 (reasons, 4.2, 1 February 2017) and T 184/16 (reasons, 2.1 to 2.8, 7.2 and 11, 12 December 2019).

The board does not agree. Appellant 2's notice of opposition was filed on 5 December 2013. Oral proceedings before the opposition division took place on 14 December 2015. The board acknowledges that T 1329/04 (reasons, 12) relates to the plausibility issue in a case concerning polynucleotides, which might be considered what appellant 2 terms "large" molecules. While it can be accepted that other decisions such as T 488/16 (of 1 February 2017) or T 184/16 (of 12 December 2019) on the plausibility of "small" molecules were issued after the proceedings before the opposition division, the board observes that other decisions such as T 710/05 (glutathione, a C10 molecule; of 22 February 2007) relate to the plausibility of "small" molecules and thus the concept of plausibility of "small" molecules was known in the case law on the date when the opposition was filed. Furthermore, the board does not see, and appellant 2 has not brought forward any argument, why the case law on "large" molecules should be different from that on "small" molecules and thus why appellant 2 should not have taken into account the case law on "large" molecules, such as T 1329/04, which was available before the opposition was filed. Thus, appellant 2's submission is not convincing.