T 2320/16 - (II) Inventive step chemical compound

 Key points

• This is a post from stock; the decision was issued 24.03.2021, well before referral G 2/21 was made. 
• In this decision, the Board also deals with inventive step. Claim 1 is a 'pure' chemical compound claim (directed to a Marush group of chemical compounds as such).
• “According to the respondent [patentee], the objective technical problem was the provision of further kinase inhibitors for the treatment of inter alia cancer.”
• “It is undisputed that the patent comprises examples falling within the scope of claim 1 ...  It is also undisputed that the patent ... lacks any biological activity data for compounds falling within the scope of contested claim 1.” The patent contains other biological activity data.
• "It was not disputed by the [opponent] that the compounds tested in [the declarations D7 and D23 filed by the patentee in the course of the proceedings] exhibited biological activity as kinase inhibitors."
• "The respondent [patentee] submitted that the biological data disclosed in D7 and D23 showed that a reasonable and representative structural selection of the claimed compounds displayed a kinase inhibitory effect. Claim 1 encompassed a relatively precise structural definition of a specific pharmacophore to which the stated biological activity could be attributed, and was a reasonable extrapolation of these examples and biological data, based on structure-activity relationship (SAR) analysis for the pharmacophore identified. In the absence of any evidence to the contrary, the board can only agree".
• " It follows from the foregoing that the objective technical problem is as formulated by the respondent [patentee], namely the provision of further kinase inhibitors for the treatment of inter alia cancer."
• The claims are held to be inventive.
  
  
• As a comment, this decision illustrates that the problem-solution approach, at least in the field of chemistry, is focused on the effect. Even though the claim at issue is directed to the (class of) molecules as such and hence is not limited to any particular use, the Board's conclusion that the subject matter is inventive is based entirely on the biological activity observed when the compound is used in a particular way (the treatment of cancer, or more precisely used as a kinase inhibitor).
• Fully in line with established case law, the Board analyses the credibility of the technical effect over the whole scope of the claim in terms of chemical composition (under the Markush formula), but not over the whole scope of the protection in terms of possible uses of the molecule. In other words, a technical effect in the context of one use of the compound is sufficient for acknowledging inventive step of a product claim which covers every use of the molecule. 
• The basis of this approach to inventive step of claims directed to a chemical compound (or a class of chemical compounds) appears to be the " Kongorot" judgment of the German Reichsgericht of 20.03.1889, as confirmed by BGH 27.02.1969 X ZB 11/68 Disiloxan; see also Bruchhausen in GRUR 1989, 153. 
• As a question to readers, are there any decisions of the Boards expressly addressing this matter?

T 2320/16

https://www.epo.org/law-practice/case-law-appeals/recent/t162320eu1.html

According to the respondent [patentee], the objective technical problem was the provision of further kinase inhibitors for the treatment of inter alia cancer. It was a matter of dispute between the parties whether this problem was solved over the entire scope of claim 1.

5.3 It must therefore be determined whether the data addressed below render it sufficiently credible that biological activity as tyrosine kinase inhibitors is exhibited across the scope of claim 1.

5.4 It is undisputed that the patent comprises examples falling within the scope of claim 1, and specifically describes further named compounds also falling within its scope (paragraph [0212]). It is also undisputed that the patent, although providing biological activity data on the inhibition of specific kinases and specific tumour growth for some exemplified compounds (tables 1-5), lacks any biological activity data for compounds falling within the scope of contested claim 1.

5.5 D6, D7 and D23 are declarations comprising data, filed by the respondent during opposition proceedings and relied upon in appeal.

D6 provides a list of examples and named compounds disclosed in the patent and falling within the scope of claim 1 at issue (Annex 1). Annex 2 of D6 lists additional compounds A-Z and AA-NN, prepared by the respondent, which although encompassed within the scope of claim 1 at issue, were not prepared, exemplified, nor mentioned in the patent. Annex 3 details the characterisation of the structure of the compounds of Annex 2.

D7 describes inter alia in Annex 1 biological activity data (IC50; TNIK kinase assay) for the compounds of Annex 1 of D6, namely for those compounds exemplified or mentioned in the patent falling within the scope of claim 1. In Annexes 2, 3 and 3A further IC50 data is provided for the further compounds listed in Annex 2 of D6, falling within the scope of claim 1 but neither exemplified nor mentioned in the patent.

D23 discloses further Abl1 and Src kinase inhibitory data for compounds falling within the scope of claim 1.

5.6 It was not disputed by the appellant that the compounds tested in D7 and D23 exhibited biological activity as kinase inhibitors.

5.7 The appellant argued that it was not credible that substantially all of the claimed compounds displayed the alleged activity and that the burden of proof in this regard lay with the respondent.

This argument was based on a comparison of the variation in specific substituents displayed by the compounds of D7 for which biological data was provided, with the breadth of claim 1 in terms of the definition of those substituents, in particular (but not exclusively) X, G1 and R6 (for details see XI, above) as well as the arguments that:

(a) it was generally known that minor changes in structure were expected to disrupt biological activity (Case Law of the Boards of Appeal, 9th Edition, I.D.9.8.2, and in particular decisions T 643/96 and T 488/16); and

(b) D13 and D15 (page 1600, scheme 3 and right hand column, first ten lines) provided evidence that a minor structural change led to significant reduction in activity: for example a large difference in kinase inhibitory activity was observed for structurally similar compounds 2 and 24 in table 1 of D15. Since claim 1 covered much greater substituent variation, the skilled person would expect a complete loss of kinase inhibition activity if the changes in structure were greater than those displayed in D15.

With regard to both (a) and (b), the board notes that the data in D7, D23 and D15 all confirm that minor structural changes affect the kinase inhibitory activity of compounds falling within the scope of claim 1. Indeed, this would appear to be part of the common general knowledge for the skilled person in the field of drug discovery. However, it was not contested by the appellant that all of said compounds exhibited some level of kinase inhibitory activity. Hence, D15 merely demonstrates that one specific minor structural change (table 1, compound 2 versus compound 24) leads to changes in the level of inhibition of the enzyme tested from a nanomolar to a micromolar level. However, the argument that more substantial structural changes will have an even greater effect to the extent that no kinase inhibitory activity will be displayed can only be seen as unsubstantiated speculation, without any evidence to support it.

In this regard D13, also cited by the appellant in support of its argument, is less relevant than D15 since the compounds disclosed therein and relied upon by the appellant in its arguments (page 3967, right hand column, first full paragraph; scheme 1) do not fall within the scope of claim 1. In this respect, the appellant did not rely on D13 in its oral arguments.

5.8 The appellant, citing T 415/11 (Case Law of the Boards of Appeal, 9th edition 2019, I.D.10.9), furthermore submitted that the burden of proof lay with the respondent (patent proprietor) to demonstrate that said activity was achieved across the entire scope of the claim.

The board disagrees. The relevant passage of T 415/11 (reasons, 46.1) reads as follows:

"When the credibility that a technical effect is achieved by substantially all claimed compounds is at issue and in a situation where, it is prima facie unlikely that this is credible, it is ... not the opponent..., but the patentee... who has the burden of proof that the effect is achieved".

However, in T 415/11, no evidence had been presented by the patent proprietor supporting the alleged effect (reasons, 45.1 and 46). A similar situation was addressed earlier in that decision in which the problem to be solved included improved stability (reasons, 9 and 10). There, it was concluded that the comparative examples in the patent were not directed to compositions of the closest prior art, and thus there was also no evidence of the alleged improvement. Thus the facts underlying that case stand in contrast to those of the present case in which biological data has been provided (supra) for a significant number of compounds falling within the claimed scope.

5.9 Furthermore, it is established jurisprudence of the Boards of Appeal, as noted by the respondent, that each party bears the burden of proof for the facts it alleges. Hence, in opposition proceedings, if an opponent argues a lack of inventive step under Article 100(a) EPC, it is for the opponent to prove it. Therefore, the burden of proof normally lies with the opponent (here: appellant) and does not automatically shift to the patent proprietor (here: respondent) on appeal. It is not sufficient in opposition proceedings for the opponent to impugn a granted patent with an assertion which has not been substantiated (Case Law of the Boards of Appeal, 9th edition 2019, III.G.5.1.1, sixth paragraph; III.G.5.2.1, fourth paragraph).

5.10 In the present case no evidence has been submitted by the appellant casting doubt on whether the compounds falling within the scope of claim 1 possess kinase inhibitory activity.

5.11 The respondent [patentee] submitted that the biological data disclosed in D7 and D23 showed that a reasonable and representative structural selection of the claimed compounds displayed a kinase inhibitory effect. Claim 1 encompassed a relatively precise structural definition of a specific pharmacophore to which the stated biological activity could be attributed, and was a reasonable extrapolation of these examples and biological data, based on structure-activity relationship (SAR) analysis for the pharmacophore identified.

5.12 In the absence of any evidence to the contrary, the board can only agree (see for example the tables in annexes 1, 2 ,3 and 3A of D7). In T 939/92 and T 668/94, cited by the appellant [opponent] to argue that the problem was to be seen as the mere provision of compounds, the situation was different to the present one, as addressed in the following.

5.12.1 In T 939/92 ("AgrEvo"), claim 1 was directed to triazole compounds which could be optionally substituted - by anything. The board concluded that the test results presented for some compounds did not constitute sufficient evidence that substantially all claimed compounds possessed the alleged herbicidal activity, the reason being that there was no proven common general knowledge showing that the type of substituent would be irrelevant to said activity (reasons, 2.6.2). On the other hand, it was also stated that "the Board finds that reasonable predictions of relations between chemical structure and biological activity are in principle possible, but that there is a limit beyond which no such prediction can be validly made" (reasons, 2.6.2), and

"In the Board's judgement, this limit has to be established on the basis of the available facts and the evidence submitted for this purpose in each particular case" (reasons, 2.6.3).

Furthermore, the board stated that

" ... if it is evident that the number of compounds claimed is such that it is inherently unlikely that all of them, or at least substantially all of them, will possess the promised activity, then the burden of proof of that fact ... can indeed rest only upon the shoulder of the person alleging it." (reasons, 2.6.1, emphasis added by the deciding board).

This final statement is similar to that cited in decision T 415/11, cited by the appellant (supra) to argue that the burden of proof lay with the respondent.

In contrast to the situation in T 939/92, contested claim 1 does not comprise open-ended definitions and as stated above, represents a reasonable generalisation of the compounds for which biological data was provided. Hence, the respondent has discharged its burden of proof in this regard.

5.12.2 T 668/94 related to compounds useful as fungicides and plant growth regulators (reasons, 8.1). It had been explicitly stated in the specification that only some of the claimed compounds possessed the latter activity, which was thus disregarded in the formulation of the technical problem (reasons, 8.3, second paragraph). The use as a fungicide was recognised as being solved despite an objection to the presence of "optionally substituted" open-ended definitions in the claim. This issue was however not addressed since the solution was in any case seen as obvious (reasons, 8.3, first paragraph). Hence, also this decision does not support the appellant's position.

5.13 It follows from the foregoing that the objective technical problem is as formulated by the respondent, namely the provision of further kinase inhibitors for the treatment of inter alia cancer.

6. Obviousness

6.1 The appellant argued that D3, although not explicitly disclosing the possibility of substitution at the 3-position when the ring system is quinoline (X = CH), must be read taking into account the intention of the patent drafter at the time, whose aim was not just to draft the application in terms of the invention, but also having other purposes in mind, such as the need to avoid overlap with the state of the art. Thus, it could not be concluded from the explicit lack of substitution at the 3-position in D3 that compounds substituted at that position would be inactive.

6.2 The board disagrees. It is established jurisprudence that the prior art should be interpreted solely as it would be understood by the person skilled in the art. As noted by the respondent, when the ring system in formula (I) of D3 (claim 1) is quinoline, the 3-position is the only position on the ring at which substitution is not permitted. Thus, the skilled person is taught away from the introduction of any substituent at this position, and a fortiori from substitution by a strongly electron withdrawing moiety such as a cyano group, which would be expected to have unpredictable electrostatic effects at the enzyme binding site.

6.3 There is therefore no motivation in D3 for the skilled person to substitute hydrogen in the 3-position with a cyano group in order to solve the above-mentioned problem.

6.4 The appellant furthermore submitted that there was an inconsistency in the reasoning of the contested decision. On the one hand, the opposition division concluded that the technical problem (including the biological effect) was solved over the entire scope of claim 1. On the other hand, the opposition division recognised inventive step on the basis that the skilled person would have had no motivation to replace the hydrogen in the 3-position of the compound of formula (I) of D3 (i.e. when X = CH) with a specific cyano group, and expect the same biological activity (contested decision, 2.5.5.1). This approach was inconsistent since the difference between X being CH or CN was far less than the structural extrapolations required to conclude that the technical problem was solved across the entire scope of the claim 1 at issue. It was not sufficient for the respondent to allege a particular structure-activity relationship (SAR) based on the core structure of claim 1 - the presence of such a relationship needed to be proven.

6.4.1 The board disagrees, and sees no such contradiction. First of all, the data on file demonstrating biological activity for a range of compounds falling within the scope of claim 1 itself constitutes sufficient evidence of a SAR based on the pharmacophore of claim 1 corresponding to the non-variable part of the compound of Formula 1. The presence of the SAR lends credibility to the retention of biological activity within a genus of compounds representing a reasonable extrapolation of those for which data is available (D7 and D23). On the other hand, the question of non-obviousness is a subsequent step in the problem-solution approach which can only be addressed once the objective technical problem has been identified, and involves a different question, namely whether the solution to the said problem would have been obvious to the skilled person in view of the disclosure of the closest prior art.

Therefore the question of whether the effect of kinase inhibition is credible over the entire scope of claim 1 is different from the question of obviousness, including e.g. the question of whether D3 teaches away from the subject-matter of claim 1.

6.5 Since no further inventive step objections were raised by the appellant, it must be concluded that the subject-matter of claim 1, and by analogy, claims 2-7, involves an inventive step.

The ground for opposition under Article 100(a) EPC in combination with Article 56 EPC therefore does not prejudice the maintenance of the patent as granted.

6.6 The board noted the alleged violation of the appellant's right to be heard, put forward in the context of the discussion on inventive step (statement of grounds of appeal, page 11, point 45). However, the appellant neither requested remittal to the opposition division pursuant to Article 11 RPBA 2020 nor reimbursement of the appeal fee pursuant to Rule 103(1)(a) EPC. Consequently, there was no need for the board to consider the allegation further.

7. The main request is consequently allowable.

Order

For these reasons it is decided that:

The appeal is dismissed.