T 1544/16 (Induction of tolerance to egg proteins/NESTLÉ) 18-05-2021

Reasons for the Decision

1. The patent in suit

The patent in suit relates to the use of hydrolysed egg proteins to induce oral tolerance to intact egg proteins in mammals likely to be allergic to eggs. Oral tolerance involves administration of antigens through the oral route to prevent subsequent systemic immune responses to the same antigen given in an immunogenic form (paragraphs [0001] and [0004]). The solution entails the use of enzymatically hydrolysed egg proteins with a degree of hydrolysis between 15 and 28%.

2. Main request - inventive step

2.1 The appellant contested the opposition division's decision that the subject-matter of claim 1 (wording, see point VII) involved an inventive step. It argued that the subject-matter of claim 1 lacked inventive step, for instance starting from D11 as the closest prior art. It disagreed in particular with the opposition division's reasoning in the decision under appeal (page 9) that the skilled person "would not have been lead to the present invention, since the end result in terms of sufficiently low residual allergenicity, and sufficiently high capacity to induce oral tolerance at the DH [degree of hydrolysis - note by the board] required by the present claims, would not have been certain".

2.2 At the oral proceedings before the board, the respondent stated that, in its view, D11 was not the closest prior art, but it did not provide further explanations.

However, D11 relates to inducing oral tolerance to a native egg protein (ovalbumin) using egg protein hydrolysate. The patent in suit addresses at least a similar technical problem. In view of this alone, D11 is a promising springboard for assessing inventive step and is considered the closest prior art.

2.3 The closest prior art D11

2.3.1 In its abstract, D11 discloses that:

- peptides and protein hydrolysates are tools for the induction of tolerance or regulation of targeted B or T cell responses

- in vitro, peptides are produced by enzymatic digestion and chemical hydrolysis of proteins

- the publication investigates the potential of CNBr-hydrolysed ovalbumin fractions to induce oral tolerance to native ovalbumin

- CNBr-hydrolysis releases several peptides with stimulatory effect on native ovalbumin-specific T cells

- a peptide fragment which induces oral tolerance to native ovalbumin is identified

2.3.2 Furthermore, the introduction of D11 describes that peptides represent an attractive strategy for the manipulation of unwanted immune responses to food proteins. In this context, D11 refers to a publication addressing tolerance to milk proteins following oral administration of partially hydrolysed milk proteins. The publication is D3 in these proceedings.

2.3.3 In summary, D11 discloses that a hydrolysed egg protein, namely ovalbumin, induces oral tolerance to native ovalbumin. The fact that the disclosure of D11 goes beyond that - it even identifies a specific peptide which suppresses ovalbumin-specific IgE responses - does not render D11 less relevant. On the contrary, D11 shows that the principle of providing a hydrolysed protein for inducing oral tolerance works also for egg protein ovalbumin, a major allergen of hen egg white.

2.4 The distinguishing features are that in claim 1 the use involves enzymatically hydrolysed egg proteins with a degree of hydrolysis between 15 and 28%.

This is not in dispute.

2.5 The problem stated in the patent (paragraph [0001]) is to induce oral tolerance to intact egg proteins in mammals likely to be allergic to eggs.

2.5.1 There is no reason to believe that the subject-matter of claim 1 would not solve this problem.

2.5.2 Therefore, the technical problem set out in the patent need not be reformulated.

2.6 Obviousness

2.6.1 The respondent argued that the skilled person starting from D11 would not have considered D3 because it was from a remote technical field and did not belong to a neighbouring technical field. On this aspect, both parties referred to Case Law of the Boards of Appeal of the EPO, 9th edition, 2019 (Chapter I.D.8.2, first paragraph).

2.6.2 Before turning to neighbouring fields, the skilled person would have considered the state of the art in the specific technical field in question and, in particular, would have studied the closest prior art's disclosure. In the case at hand, the authors of D11 themselves place the publication's disclosure in the context of peptides and protein hydrolysates as tools for the induction of tolerance. It is in this context that D11 explicitly refers to the results discussed in D3.

2.6.3 Therefore, the question of how remote the disclosure of D3 is to the technical field of D11 does not arise. D11 refers to a method applicable across several technical fields to induce tolerance, namely by using peptides, and also points to the disclosure of D3. The skilled person reading the closest prior art would have been directly made aware of D3 and its teaching on induction of oral tolerance. Consequently, they would have turned to D3.

2.6.4 D3 discloses the following.

In its abstract, it is stated that:

- the purpose of the study is to determine whether oral tolerance can be induced with protein peptides

- partially hydrolysed and extensively hydrolysed cow's milk formulas are compared for their capacity to induce tolerance

- in conclusion, partially hydrolysed proteins are able to induce oral tolerance whereas extensively hydrolysed proteins are not

In the study's experiments, the partially hydrolysed formula used is an enzymatically (trypsin) hydrolysed whey formula (hydrolysis 18%), and the extensively hydrolysed formula is based on a pancreatic hydrolysate of isolated whey proteins (hydrolysis 28%). Whey proteins comprise the protein beta-lactoglobulin, a potent allergen of cow's milk. The overall conclusion in D3 is that partially hydrolysed formulas are more suited than extensively hydrolysed formulas for actively inducing oral tolerance to cow's milk proteins.

2.6.5 The respondent argued that the skilled person would have refrained from applying a teaching valid for milk protein to egg proteins because the proteins were different. In its view, induction of oral tolerance using a partially hydrolysed whey-based formula prevented the immune system from developing allergic reaction to whey proteins but not to egg proteins.

However, the skilled person would know that allergenic and tolerogenic peptides are specific to the protein. Contrary to what the respondent appears to suggest, the skilled person would not have expected that partially hydrolysed whey-based formula induces oral tolerance to egg proteins. But they would have been aware of the immunological mechanism behind allergy and induction of tolerance. As the appellant pointed out, induction of oral tolerance involves low dose antigen exposure that favours the induction of regulatory T cells. In view of the immunological mechanisms involved, the skilled person would not have restricted themselves solely to the knowledge on egg proteins.

2.6.6 Consequently, the skilled person would have applied the knowledge from D3 (i.e. to enzymatically hydrolyse proteins to obtain partially hydrolysed proteins) to induce oral tolerance. With regard to the teaching in both D11 and D3, the skilled person would have expected this to solve the technical problem.

2.6.7 As to the degree of hydrolysis, D3 instructs the skilled person to use partially hydrolysed proteins. The degree of hydrolysis exemplified is of 18%. The skilled person would have been aware that this specific value relates to whey proteins which have been hydrolysed enzymatically with trypsin. Nevertheless, this value would have provided the skilled person with a starting point as to what partially hydrolysed means. This value is fully within the range for the degree of hydrolysis called for in claim 1.

2.6.8 Furthermore, as the respondent itself pointed out, reduced allergenicity is a prerequisite for any agent to be used for inducing oral tolerance. While extensively hydrolysed proteins have low allergenic potential (e.g. D3, page 268, right column; patent in suit, paragraph [0006]), they do not induce oral tolerance, as D3 teaches. The skilled person would therefore have provided an enzymatically produced partial hydrolysate of egg proteins with a degree of hydrolysis high enough to have reduced allergenicity and low enough to induce oral tolerance.

2.6.9 Therefore, the board cannot agree with the opposition division that the skilled person would not have been led to the current invention, in particular to the sufficiently low residual allergenicity and sufficiently high capacity to induce oral tolerance at the degree of hydrolysis called for in claim 1.

2.7 To conclude, the subject-matter of claim 1 of the main request does not involve an inventive step (Article 56 EPC).

3. Auxiliary requests - admission and order of requests

As will be shown below, none of the auxiliary requests is allowable. Therefore, it is not necessary to assess whether these requests are to be admitted into the proceedings. Likewise, the specific order in which the respondent requested that the auxiliary requests be dealt with is immaterial for the present decision.

4. Auxiliary requests AR 1A to 1C and 2

4.1 In auxiliary requests AR 1A to 1C and 2, the degree of hydrolysis is restricted, compared to that of claim 1 of the main request (wording, see point VII). All these requests encompass a value for the degree of hydrolysis of 23%.

4.2 The respondent did not argue that additional technical effects occur in the more restricted value ranges called for in the auxiliary request. The respondent's argument was that arriving at a degree of hydrolysis within the more restricted value ranges would have been even less obvious to the skilled person.

4.3 Therefore, no rephrasing of the technical problem is required.

4.4 As explained above (see point 2.6.8), extensively hydrolysed proteins have low allergenic potential, but they do not induce oral tolerance. The skilled person would have worked in a range that provides partially hydrolysed proteins with a degree of hydrolysis high enough to reduce allergenicity and low enough to induce oral tolerance. Contrary to what the respondent argued, the skilled person would have had a motivation to work above a degree of hydrolysis of 18%. It is not convincing that the skilled person - when applying the teaching of D3 and carrying out corresponding experiments - would only have adopted the specific value disclosed in D3, i.e. 18%, and have stopped the partial hydrolysation of proteins at a degree of hydrolysis of below 20 or 23%.

4.5 The respondent, referring to paragraph 5.6.4 of T 230/07, argued that when a prior art document disclosed ranges or values close to the claimed ones, this did not render obvious how to proceed to arrive at the claimed subject-matter.

4.5.1 In the case underlying the cited decision, the technical problem was to provide an alternative method of preparing a stable colloidal silicate binder dispersion. The closest prior art (D13) referred to an intermediate product (a specified solution) to which ammonia or ammonium hydroxide was added to form a gel. The competent board considered with regard to intermediate silicate solution of D13 that "there is however no time left in the process of D13 for the further steps defined in claim 1 at issue" (Reasons for the decision, point 4.5.2). Under these circumstances, where the process disclosed gives no room for carrying out further steps, the competent board concluded that there was no indication how the skilled person would have to proceed in order to arrive at a colloidal silicate dispersion.

4.5.2 In the case at hand, the situation is different. D3 presents a teaching to the skilled person, namely to provide partially hydrolysed proteins - not extensively hydrolysed proteins - and exemplifies values for the degree of hydrolysis. Therefore, the skilled person would have found instruction on how to proceed to solve the technical problem.

4.6 Thus, none of auxiliary requests AR 1A to 1C and 2 involves an inventive step (Article 56 EPC).

5. Auxiliary requests AR 9A to 9E

5.1 In claim 1 of these request (wording, see point VII), the feature two stage enzymatic hydrolysis has been added. This feature is not in the claims as granted and is disclosed on page 5, lines 10 and 11, of the application as filed. The amendment is based on the description and may be examined under Article 84 EPC (G 3/14).

5.2 Article 84 EPC sets out: "The claims shall define the matter for which protection is sought. They shall be clear and concise and be supported by the description."

5.3 The feature added to claim 1 is a process feature. Claim 1 is not directed to a production process. Instead, it concerns a second medical use of a composition. The respondent has not explained what is the impact of the added feature on the matter for which protection is sought. Possibly, the added feature aims at further characterising or restricting the composition (or the enzymatically hydrolysed egg proteins) of claim 1.

5.4 However, the feature added to claim 1 blurs the matter for which protection is sought. First, it is not specified what kind of steps the two stage enzymatic hydrolysis involves. Second, and more important, it is not clear if, and then by how far, the added feature restricts the subject-matter of claim 1 as granted, in particular the composition (or the enzymatically hydrolysed egg proteins) referred to in claim 1.

5.5 The board concurs here with decision T 1661/16 (Reasons for the decision, point 1.4.4): "The meaning, in terms of the limiting effect, of features introduced into a claim must be clear in order that the claim as a whole is clear. To argue ... that it is not relevant whether a limitation might or might not be present, does not overcome such objection, it simply emphasises ... that the claim is not clear."

5.6 Therefore, claim 1 as amended fails to clearly define the matter for which protection is sought. None of auxiliary requests AR 9A to 9E fulfils the requirements of Article 84 EPC.

6. Auxiliary requests AR 4A and 7A to 7D

6.1 The amendment in claim 1 of auxiliary requests AR 4A and 7A to 7D (wording, see point IX) is based on page 5, lines 10 to 21, of the application as filed.

6.2 In the application as filed, the step of raising the temperature to between 85°C and 95°C and holding it there for about up to 30 minutes is disclosed only in combination with "to inactivate the enzymes and terminate the hydrolysis" (application as filed, page 5, line 21). The amendment in claim 1 adds subject-matter because the inactivation of enzymes, which is disclosed as a mandatory result of the process, is no longer required. Moreover, inactivation of the enzymes is also not obtained implicitly because claim 1 also encompasses situations where the heating step is carried out for too short a period.

Thus, the amendment in claim 1 encompasses added subject-matter.

6.3 To conclude, auxiliary requests AR 4A and 7A to 7D are not allowable because they do not fulfil the requirement of Article 123(2).

7. Auxiliary requests AR 3, 6A to 6D

7.1 In claim 1 of auxiliary requests AR 3 and 6A to 6D (wording, see point VII), it is specified that egg proteins have been hydrolysed using the bacterial serine endoprotease subtilisin.

7.2 In the application as filed, the only disclosure of subtilisin is found in a sentence on page 5, lines 13 to 15, which reads:

"A protease such as the bacterial serine endoprotease subtilisin (sold for example under the trade mark Alcalase**(®)) is added and the mixture is maintained at about 55°C for at least two hours to effect a partial hydrolysis."

7.3 The respondent argued that according to the application as filed (page 5, lines 9 to 10), the egg proteins may be enzymatically hydrolysed by any suitable process known in the art. Therefore, the skilled person would have understood that the bacterial serine endoprotease subtilisin is disclosed in this passage as an example of a protease.

7.4 This is not convincing. The sentence in which the bacterial serine endoprotease subtilisin is disclosed belongs to a defined process according to which any of the proteases used (including the bacterial serine endoprotease subtilisin) is added to a specified mixture (the mixture), at a specified temperature and for a specified duration. Therefore, there is no direct and unambiguous disclosure of the feature added to claim 1 without the specified process conditions in the application as filed.

7.5 Thus, auxiliary requests AR 3 and 6A to 6D include added subject-matter (Article 123(2) EPC).

8. Auxiliary requests AR 5A and 8A to 8D

8.1 Claim 1 of auxiliary requests AR 5A and 8A to 8D (wording, see point VII) is based on claim 1 of auxiliary request AR 4A, but the protease is defined to be the bacterial serine endoprotease subtilisin.

8.2 The objection of added subject-matter set out above with respect to auxiliary request AR 4A and 7A to 7D applies also for these requests. The respondent did not provide any further comment with respect to these requests.

8.3 To conclude, auxiliary requests AR 5A and 8A to 8D are not allowable because they do not fulfil the requirement of Article 123(2) EPC.