T 1019/22 (Bispecific nanobodies/ABLYNX) 20-02-2024

1. The appellant did not attend the oral proceedings but maintained its written submissions. It had notified the board in writing of its non-attendance. The appellant was treated as relying on its written case, in line with Rule 115(2) EPC and Article 15(3) RPBA.

Admittance of objections under Article 100(a) EPC in the context of novelty and under Article 100(b) and (c) EPC

2. In the statement of grounds of appeal the appellant referred to the notice of opposition (which was attached to the statement of grounds of appeal) with respect to its objections under Article 100(a) EPC in the context of novelty as well as under Article 100(b) and (c) EPC.

In view of the primary object of the appeal proceedings being to review the decision under appeal in a judicial manner, general references to submissions from opposition proceedings, even if copies of the relevant submissions are annexed to a letter in appeal proceedings, cannot replace a dedicated argument tailored to the grounds for the decision, as required by Article 12(2) RPBA. They are also critical in view of the substantiation requirements set out in Article 12(3) RPBA, according to which parties must submit their complete case in the statement of grounds of appeal or in the reply to it, to allow the board and the other parties to understand why the contested decision should be reversed without having to make any further investigations of their own (see Case Law of the Board of Appeal of the European Patent Office, 10th edition, 2022, V.A.3.2.1 and 3.2.2). All the letters from the opposition proceedings are accessible from the file anyway; therefore, attaching letters from the opposition proceedings and making general references to them does not fulfil this requirement.

3. No further substantiation has been provided that specifically addresses the opposition division's reasoning in the decision under appeal on these issues. Therefore, the appellant's submissions with regard to these objections cannot be considered to satisfy the requirements of Article 12(3) RPBA. Therefore, pursuant to Article 12(5) RPBA, the board decided not to admit the objections of lack of novelty, lack of sufficiency and added subject-matter in respect of the set of claims in the main request.

Claim construction

4. Claim 1 of the main request is a product claim directed to an at least bispecific polypeptide comprising an ISV targeting a first antigen with a dissociation constant (KD) of 10 to 200 nM and another ISV targeting a second target with a KD of 10 nM to 0.1 pM. The two targets are not the same but need to be expressed on the surface of the same cell. Binding of the higher-affinity second ISV to the second target enhances the binding to the lower-affinity first ISV to its first target. Upon binding, the first ISV inhibits a function of the first target.

Lists of specific target molecules for the first and second ISVs are defined.

According to the claim language the affinities of the two ISVs for the two different targets may be identical (i.e. 10 nM) or differ by a factor of up to 2x10**(6) (i.e. 200 nM vs. 0.1 pM); however, there is also the functional requirement that the second (targeting) ISV enhances the binding of the first (effector) ISV, which excludes the situation in which two ISVs are used that do not result in the binding of the first ISV being enhanced.

5. In this context it is important to note that a "lower affinity" corresponds to a higher dissociation constant (KD) value, while a "higher affinity" corresponds to a lower KD value, because KD inversely reflects the strength of binding between two molecules.

6. The term "immunoglobulin single variable domain" (ISV) encompasses any (single) domain antibody (dAb) with an immunoglobulin-like structure, including "VHHs"/"nanobodies".

Inventive step - Articles 100(a) and 56 EPC

Closest prior art

7. Documents D1, D15 and D11 were indicated as suitable starting points for assessing inventive step.

8. Document D15 is a divisional application of document D1 in the United States national phase. The teaching of the two documents is virtually identical. Some of the contradictions in document D1 (see below) have been resolved in document D15, but there remains a contradiction in the teaching as to which of the two binders must have the higher affinity, i.e. the lower KD (see document D15, column 2, lines 41 to 51).

9. On purely precautionary grounds, given that the inconsistencies in document D15 were arguably even more serious than in document D1, and since document D1 is the original text, the opposition division decided to choose the lesser of two evils. D1 was taken as the closest prior art. The findings on inventive step were in any event based on the sections of document D1 that were not changed in document D15.

10. In view of the above the board considers that document D15 was part of the decision under appeal and that, given the circumstances, the appellant has addressed document D15 in the statement of grounds of appeal in a reasonable manner. Therefore, the inventive step reasoning based on document D15 is admissible.

Document D1 as the closest prior art

11. Document D1 discloses bispecific binding agents (bsBAs) with an improved ability to bind to target cells without binding to non-target cells with the aim of increasing or decreasing the biological activity of a target molecule on the target cell and thereby providing an improved ability to modulate biological activity of target cells with reduced, if any, effect on the corresponding activity of non-target cells. The specificity of targeting diseased cells by the bispecific binding agents can be increased by controlling the differences in the binding affinities of the two binding domains of the bsBAs (see paragraphs [0017] and [0018]). Paragraph [0043] explains that the use of bsBAs with a single high-affinity binding domain is sufficient to provide specific binding to cells of interest. According to paragraph [0056] the term "binding agent" may include antibodies, antibody fragments, aptamers, peptides, antibody mimetics or also a natural ligand for a receptor. Paragraphs [0049], [0067] and [0070] define "antibody fragments" and "univalent binding agent" as encompassing e.g. Fab, Fab', F(ab')2, Fv, etc., or single domain antibodies. According to paragraph [0090] the affinities of the binding domains of the bsBA are determined after the bsBA is formed so that the relative affinity of the binding domains can be determined.

Document D1 provides in silico-based predictions, but no in vitro or in vivo experimental results.

It is noted that document D1 provides technically correct definitions for "affinity" and the associated "dissociation constant (KD)" in paragraphs [0047] and [0065].

11.1 However, the teaching in document D1 is contradictory as far as the affinity distribution between the two binding domains is concerned, to such an extent that the skilled person would not have derived clear teaching of whether the targeting domain or the domain which is to inhibit the biological activity is to have a higher binding affinity (i.e. a lower KD value).

Paragraphs [0014], [0023] and [0026] to [0028] disclose that a higher-affinity (i.e. a lower KD value) second (targeting) domain targeted to receptor A (present on tumour cells) and a lower-affinity (i.e. a higher KD value) first (effector) domain targeted to receptor B (also present on non-tumour cells), and having an affinity that is 5, 10, 20, 30, or even 100 or more times higher for receptor A than for receptor B, will preferentially bind to the cancer cells, and by normal kinetic interactions, will bind in larger numbers to the cancer cells as compared with normal cells.

11.2 Claims 1, 11 and 24 of document D1 require exactly the opposite affinity distribution, i.e. the first binding domain has to bind to the first target molecule (the tumour antigen) with a KD of at least 100 nM or greater, and the second (effector) binding domain binds to the second target molecule (also expressed on normal cells) with an at least 10- or 20-times lower affinity, which can be calculated to correspond to a KD >= 1 myM, than the KD of said first binding domain.

A corresponding disclosure can also be found in paragraphs [0011] to [0013], [0015] or [0016] of document D1. Paragraph [0011], for example, discloses a bispecific binding agent having a first binding domain having a KD between 10**(-8) to 10**(-12)M, i.e. 10 nM to 1 pM, for the first target molecule and a second binding domain (targeting the molecule with biological activity) having a KD for the second target molecule that is at least 20 times lower than the KD of the first binding domain and can be calculated to correspond to a KD between 500 pM to 0.05 pM, which represents a higher relative affinity (see page 4, lines 9 to 12).

11.3 Furthermore, dependent claim 10 is also inconsistent with the teaching of its independent claim 1 in that it requires the first (tumour-cell-specific) binding domain to have a KD in the range between 10**(-8) and 10**(-12)M, i.e. 10 nM to 1 pM, which is inconsistent with the at least 10**(-7)M, i.e. 100 nM, or greater required by independent claim 1.

11.4 The computational modelling in document D1 predicts that, in the bispecific construct having a first (targeting) domain with an affinity of KD = 1 nM, the second (effector) domain with 1 myM affinity would be "as effective" as an effector domain that binds with a KD = 1 nM affinity (see paragraph [0190]).

Difference, its technical effect, and objective technical problem

12. The subject-matter of claim 1 differs from the teaching in claim 1 of document D1 in that

(a) it specifically utilises a bispecific polypeptide comprising two ISVs as binding arms;

(b) the second (targeting) ISV binds with an affinity defined by a KD in the range between 10 nM and 0.1 pM and the first (effector) ISV binds with an affinity defined by a KD in the range between 10 nM and 200 nM, i.e. with an affinity that is between equal to and up to 2x10**(7) times weaker compared with the second (targeting) ISV, wherein said second (targeting) ISV has to enhance the binding of the first (effector) ISV;

(c) the effector first ISV inhibits the function of its target; and

(d) on account of the list of targets selected for the targeting second ISV and the effector first ISV.

13. The patent provides different examples demonstrating that the claimed concept of using a second (targeting) ISV with higher affinity to enhance the binding of the first (effector) ISV with lower affinity, with both targets being present on the same cell, works (see e.g. Tables 4.1 and 4.4 (summarised in Annex 1 as attached to the respondent's reply to the statement of grounds of appeal) and Figure 4.5).

The functional requirement that the second ISV must enhance the binding of the first ISV rules out situations in which two ISVs are used that do not result in the binding of the first ISV being enhanced.

14. The objective technical problem in the decision under appeal was defined as "[...] to find concrete conditions where a bispecific construct along the lines of D1 and based on ISVs actually works to some reasonable degree of potency and selectivity."

15. Based on the parties' arguments and the analysis above, the board finds it necessary to reformulate the objective technical problem.

The phrase "actually works to some reasonable degree of potency and selectivity" has been reformulated to read "allow for a preferential and enhanced inhibition..." to avoid reference to the closest prior art in the objective technical problem.

Cells that express the first and second target antigens are already part of the disclosure in the closest prior art and therefore need to be included in the objective technical problem.

Given difference (a) (see point 12. above), it is inappropriate to incorporate an element of the solution - specifically, the use of ISVs - into the objective technical problem. Consequently, it was necessary to formulate this aspect more generally.

16. Therefore, the objective technical problem is to provide constructs that allow for a preferential and enhanced inhibition of the function of a first target molecule only on cells that express both the first and second target antigens.

17. The solution is as defined in claim 1.

Obviousness - starting from document D1 alone

18. Starting from the bispecific binding agent in claim 1, in document D1 several selections are necessary to arrive at the claimed subject-matter.

ISV format

18.1 Document D1 exemplifies bispecific binding agents as being constructs containing two scFvs ((scFv)2 and diabodies; Example 1). To arrive at the ISV-antibody format for both the targeting and effector domains, a two-step selection is needed based on the options outlined in paragraphs [0049] and [0067] of document D1 for the binding-agent format of the first and second binding domain; however, document D1 provides no specific guidance for making this selection.

Affinities

19. Due to the contradictory teaching in document D1 regarding the affinity distribution between the two binding domains (see points 11.1 to 11.3 above), a skilled person would only understand that a certain affinity difference is necessary between the targeting and effector domains, but would not know which domain should bind its target structure with higher affinity.

20. However, even if the contradictory passages regarding the affinity differences were read in favour of the appellant - the targeting domain binding with higher affinity than the effector domain - document D1 provides no clear guidance in the direction of the claimed affinity ranges.

20.1 Document D1 defines, for the first (targeting) domain, an affinity of at least 100 nM (see e.g. claim 1; paragraph [0011]) or a range between 10 nM and 1 pM (see e.g. claim 10; paragraphs [0011] and [0034]), and, for the second (effector) domain, an upwardly open affinity difference of at least 10 times, 15 times, 20 times, etc. (see point 11.1 above). The only disclosure of a concrete affinity combination can be found in Example 6 in paragraph [0190], in which the targeting domain has an affinity of KD = 1 nM and the effector domain has an affinity of KD = 1 myM. A KD of 100 nM for the targeting domain and a KD of 1 myM are outside the ranges in claim 1 of the main request, i.e. 10 nM to 0.1 pM for the targeting ISV and 10 nM to 200 nM for the effector ISV.

20.2 With reference to Table 4.4 in the patent in suit (summarised in Annex 1 as provided in the now respondent's response to the notice of opposition), the appellant argued that the data in the patent in suit did not support a clear distinction in potency or selectivity for the claimed bispecific constructs compared with those disclosed in document D1. Therefore, there was no unexpected technical improvement over the disclosure in document D1.

20.3 However, document D1 first does not disclose or point to the specific combination of affinity ranges for the effector ISV (KD = 10 to 200 nM) and targeting ISV (KD = 10 nM to 0.1 pM) as claimed, not even in the in silico simulations in the examples (see point 20.1 above). A selection is thus required to arrive at the claimed affinity ranges.

Second, and contrary to the lack of any experimental evidence in document D1, Table 4.4 and Figures 4.4 and 4.5 of the patent in suit show that using bispecific constructs as claimed results in dose-dependent increased binding to and a potency shift in the inhibition of EGFR phosphorylation in EGFR+/CEA+ double positive Lovo cells compared with EGFR+/CEA- HER14 cells.

Type of effectors

21. A further selection needs to be made regarding the activity of the effector domain. While document D1 refers to the modulation of a biological activity, i.e. increasing or inhibiting the biological activity, without preference for one of the two options (paragraphs [0019] or [0061]), the claimed effector ISV has to inhibit a function of its target.

Lists of targets

22. The list of targets selected for the targeting second ISV and the effector first ISV in claim 1 differs from those in claims 5 to 9 of document D1 for the first (targeting) and second (effector) binding domains. While some targets, such as CEA, MART-1, MAGE-1, Lewis Y, Her2 (ErbB2), EpCAM, and PSMA for the targeting domain, and receptor tyrosine kinases (e.g., ErbB3, ErbB4), FGFR-1, and FGFR-3 for the effector domain, are identical to those in claim 1 of the main request, claim 1 also lists several alternative targets for both domains that are not mentioned in document D1.

Consequently, at least formally, further selections must be made in order to arrive at the lists of targets for the effector and the target domain as claimed.

23. In summary, multiple selections, at least for the antibody format used for each of the targeting and the effector domain, their affinities, and the type of effectors are necessary to arrive at the claimed subject-matter. In the absence of any pointer in document D1 to the claimed combination of features, a skilled person would not have arrived at the subject-matter of claim 1 in an obvious way. Therefore, the subject-matter of claim 1 is considered to involve an inventive step in view of the teaching within document D1.

Obviousness - combination of document D1 and D11

24. The board also considers that a skilled person would not have been motivated to combine the teaching of document D1 with that of document D11.

25. Document D11 shows that co-targeting the preferred ErbB2/ErbB3 heterodimer with a bispecific construct comprising two scFvs promotes increased targeting selectivity over antibodies specific for one of the two tumour-associated antigens (TAA) alone. This bispecific construct, comprising scFvs that bind ErbB3 and ErbB2, respectively, exhibits selective targeting of tumour cells in vitro and in vivo co-expressing both antigens, compared with tumour cells expressing only one antigen or normal cells expressing low levels of both antigens {see e.g. title and abstract). The ErbB3 binding arm has an affinity of KD = 160 nM, while the KD of the ErbB2 binding arm is 1 nM (see page 1418, left-hand column, paragraph 2). Fusing the two scFvs into the bispecific format does not dramatically alter the KDs of the individual scFv (see page 1418, right-hand column, paragraph 1). In vitro tests demonstrate that the bispecific scFv construct has intrinsic anti-cancer activity, which is mediated by the anti-ErbB3 arm (see abstract).

26. The teaching of document D11 differs from the subject-matter of claim 1 in that an ErbB2xErbB3 receptor heterodimer is targeted as a single "effector" target, rather than using a separate anchor. The improved selectivity observed in document D11 is not based on quantitative factors, such as avoiding off-target effects through differential KD values. Document D11 also fails to disclose bispecific ISV constructs.

27. Therefore, the subject-matter of claim 1 is not obvious when considering a combination of the teaching of document D1 and document D11, either.

Document D15

28. In view of the considerations in point 8. above, starting from document D15 as the closest prior art, the subject-matter of the main request does involve an inventive step for the same reasons, mutatis mutandis, as given in points 18. to 27. above.

Admittance of the line of argument starting from document D11 as the closest prior art

29. The respondent objected to the admittance of the additional line of attack of lack of inventive step of the subject-matter of claim 1 starting from D11 as the closest prior art.

It was submitted that this attack was presented for the first time at the very end of the oral proceedings in opposition.

30. The board agrees with the respondent's view that admittance of the objection of lack of inventive step starting from document D11 as the closest prior art is indeed still an open issue in the present case.

30.1 The line of argument starting from D11 as the closest prior art was brought up again in the statement of grounds of appeal, in which the appellant provided full inventive step reasoning against claim 1 of the main request starting from document D1/D15 or D11 as the closest prior art. The same objections were maintained against some of the auxiliary requests with the appellant's submissions of 22 December 2022; however, none of these submissions addressed the procedural aspect of admitting the inventive step argument based on document D11 as the closest prior art.

30.2 During the written opposition proceedings, claim 1 was attacked in view of document D11 only for novelty and inventive step, with document D11 being treated as a secondary document. Document D11 was merely mentioned as the closest prior art for an inventive step attack against claims 8 to 10 (see page 15, last paragraph of the notice of opposition: "Similar arguments for lack of inventive step of claim 8 to 10 can be made using D2, D3 or D11 as starting point").

30.3 Despite the opposition division's preliminary opinion, which concluded that document D11 could not be considered the closest prior art due to its different purpose (see page 18), the opponent's subsequent written submissions still discussed inventive step for claim 1 only based on documents D1, D2 or D15, but not document D11.

30.4 During the oral proceedings in opposition, at the very end of the discussion of inventive step, after the relevant decision on inventive step starting from document D1/D15 had been announced, the appellant brought up an objection of lack of inventive step starting from document D11 as an alternative closest prior art document against the subject-matter of claim 1.

30.5 Both the decision under appeal and the minutes of the oral proceedings before the opposition division fail to indicate whether a procedural decision was taken on the admittance of the line of argument under inventive step starting from document D11 as the closest prior art.

30.6 The minutes just mention that "The opposition division asked both parties which document they consider the closest prior art. D11 was not brought forward as potential closest prior art at that time. The discussion of which document is the closest prior art has become final as the opposition division has already decided that D1 is the closest prior art" (see page 4, last paragraph).

30.7 In point 9.3.3 of the decision under appeal, the opposition division stated that "Aside from procedural issues which could make such a request inadmissible, the Division finds that in any event D11 does not provide a suitable "springboard" for arriving at the invention claimed in the opposed patent."

In the subsequent paragraphs of point 9.3.3 of the decision under appeal, the opposition division analysed the disclosure of document D11 as the closest prior art and concluded that document D1 "is closer than D11 in terms of relevance".

31. These passages from the minutes and the decision make no mention whatsoever of whether the parties were heard on the admittance of this line of attack and on the substantive inventive step issues starting from document D11 as the closest prior art for claim 1.

31.1 At the oral proceedings before the board the respondent submitted that the appealed decision mixed up issues which had been discussed with those which had not. The respondent had not been heard on D11 for the question of inventive step, nor could it appeal the decision on those points as it was not negatively affected. It could have requested a correction of the minutes, but it did not.

31.2 On the other hand, by not participating in the oral proceedings, the appellant did not make any contribution to reconstructing the discussion before the opposition division. It is therefore not possible for the board to draw a final conclusion on whether the considerations made by the opposition division in the cited passages were based on any of the parties' submissions.

32. The decision under appeal also contains an obiter dictum in point 9.10, which does not provide further clarification in this respect. To the contrary, it creates uncertainty as to whether the question of inventive step had been conclusively decided upon.

32.1 In this section the opposition division mentioned that document D11 was not the closest prior art, and thus it would not be necessary to decide on its basis. For the sake of completeness, however, and at the request of the opponent, an assessment of inventive step had also been provided on the basis of document D11. In that assessment, the opposition division found that the subject-matter of claim 1 was inventive over the disclosure of document D11.

32.2 No mention is made of whether the line of argument starting from document D11 as the closest prior art had been admitted into the proceedings, a fact which was brought into question by the opposition division in the previous point 9.3.3 of the decision. It is even less clear whether the parties were heard on the admittance and the substance of inventive step based on document D11.

33. The board finds that the use of an obiter dictum was not correct in the present circumstances.

33.1 An obiter dictum is any general statement, either implicit or explicit, in a decision which does not constitute a ratio decidendi of said decision.

33.2 Accordingly, in decisions of the boards of appeal it was stated that observations in an obiter dictum do not, by definition, form part of a decision (see

T 802/97, point 3 of the Reasons; T 2238/11, point 5 of the Reasons) and that obiter dicta are sometimes included in decisions of the examining and opposition divisions in order to avoid remittal (see decision T 473/98, Headnote I).

33.3 Form a purely legal point of view obiter dicta have no significance for the decision of the specific case and have no binding force. They normally deal with issues that were not raised in the proceedings as a whole, or on which a decision does not actually have to be made.

33.4 Accordingly, if a legal opinion expressed as an obiter dictum has no influence on the legal dispute, it cannot, by itself, constitute an infringement of one party's rights.

33.5 In particular, as a party's right to be heard pursuant to Article 113(1) EPC is satisfied if it has had an opportunity to present its comments on all grounds or evidence on which a decision is based, this right is not violated if a party did not have the opportunity to comment on observations in an obiter dictum (cf. e.g.

T 726/10, point 9 of the Reasons and T 725/05, point 6 of the Reasons).

33.6 The requirements of Article 113(1) EPC are instead contravened if the decision is subsequently based on an "omitted" ground which is contained in an obiter dictum.

34. On account of these considerations of principle, it is apparent that the use of an obiter dictum in the present case was not appropriate, at least owing to the fact that it contained a part of the finding on which the decision was based, namely that the claimed subject-matter was considered inventive. Both the decision and the obiter dictum related to the same ground for opposition, lack of inventive step, and therefore the statement contained in the obiter dictum had been "omitted" from the formal decision.

34.1 After having decided that the subject-matter of claim 1 was inventive starting from document D1, the opposition division should have addressed further objections of lack of inventive step, if any were on file. Therefore, the opposition division should first have taken a decision on the admittance of the inventive step attack starting from document D11. Only if admitted, it should have then fully decided upon inventive step by also taking into account document D11 as the closest prior art after having heard both parties. Had the opposition division formally decided not to admit the attack based on document D11, there would have been no need for an obiter dictum.

34.2 In this context the board also notes that in cases in which the skilled person has a choice of several workable routes, i.e. routes starting from different documents, which might lead to the invention, the rationale of the problem-solution approach requires that the invention be assessed relative to all these possible routes, before an inventive step could be acknowledged (see e.g. T 967/97, point 3.2 of the Reasons and T 21/08, point 1.2.3 of the Reasons).

35. Therefore, for this reason too, the inclusion of an obiter dictum in the decision to deal with the question of inventive step starting from document D11 creates uncertainty as to whether the case was actually fully decided at that stage.

35.1 This legal uncertainty is confirmed by the fact that the respondent felt that an attack which should not have been admitted into the proceedings was apparently introduced by means of an "obiter". Legal uncertainty is also confirmed by the fact that the appellant felt the need to file additional evidence, namely document D16, to support the objection of lack of inventive step starting from document D11 with its statement of grounds of appeal. A genuine obiter dictum does not make it necessary to file additional evidence.

36. The board has therefore come to the conclusion that it is not possible to infer from all of the procedural documents forming part of the opposition proceedings that document D11 as the closest prior art was not in the proceedings. Therefore, the line of argument concerning inventive step starting from document D11 is admitted.

37. However, the discussion in the opposition proceedings of document D11 as the closest prior art does not appear to have been complete and the board cannot ascertain that both parties have been heard on the substance of this issue.

The assessment of inventive step therefore seems to require further discussion.

In accordance with Article 111(1) EPC, it is left to the board to decide whether to exercise the competence

of the department which was responsible for the

appealed decision or to remit the case to that

department for further prosecution.

The board considers that, on their own, the facts of the case would favour remittal to the opposition division for further prosecution of document D11 as the closest prior art, in particular as it would allow the respondent to argue its case in this respect. The respondent did not object to the remittal, either. It is therefore decided that the case be remitted for further prosecution. A separate decision by the board on the admittance of document D16 is not required.