T 0115/18 (Alpha-1 proteinase inhibitor/GRIFOLS) 30-07-2020

Reasons for the Decision

Admissibility of the appeal

1. The appeal complies with Articles 106 to 108 and Rule 99 EPC and is therefore admissible.

Request for postponement of the oral proceedings

2. The respondent requested postponement of the oral proceedings. The reasons indicated were a very general reference to the ongoing COVID-19 pandemic and expected travel restrictions.

3. However, the board was not presented with information on travel restrictions between The Netherlands, where the representative for the respondent was located, and Munich or Munich and The Netherlands in force at the time the request was filed or up to the date of the oral proceedings. Therefore the request was not allowed and the oral proceedings were not postponed.

Party not represented at oral proceedings

4. As announced by letter of 29 July 2020, opponent 2, a party as of right, did not attend the oral proceedings (see section XI.). In accordance with Rule 115(2) EPC and Article 15(3) RPBA 2020, the oral proceedings were held without it. By its decision not to attend the oral proceedings, this party chose not to make any submissions during such proceedings.

Main request - claim 1

5. Inventive step - Article 56 EPC

Closest prior art

5.1 There was disagreement between the parties as to which disclosure represented the closest prior art to the subject-matter of claim 1. The appellant submitted lines of argument starting from each of documents D4 and D5; the respondent considered the disclosure of document D11 to constitute the closest prior art.

5.2 Document D4 discloses a method of purifying alpha-1 proteinase inhibitor (alpha1-PI) comprising steps of PEG precipitation, dilution and anion exchange chromatography. It thus addresses the same purpose as, and discloses a method having several steps in common with, the claimed method. The board holds this to be a suitable starting point for the assessment of inventive step.

The respondent argued that document D11 represented an even closer disclosure to the claimed subject-matter. However, whether other documents constitute a more promising starting point for the assessment of inventive step than a given document is considered immaterial in the present case, since the board holds that the claimed invention is obvious when starting from the disclosure in document D4.

Objective technical problem - partial problems

5.3 It was common ground that document D4 disclosed a method of purifying alpha1-PI comprising steps (a), (c), (d) and part of step (b) (the dilution) as defined in the claim.

The claimed method differs therefrom by the additional method steps of the virus inactivation part of step (b) and steps (e) to (g) defining a cation exchange chromatography step.

5.4 As regards the technical effect associated with these distinguishing features, it was reasoned by the appellant that each feature should be analysed in isolation since they were not technically interrelated. The respondent conceded that there was no technical interrelation between the virus inactivation and the cation exchange chromatography. A technical interrelation between the virus inactivation and the cation exchange chromatography is not apparent to the board either. In view of the above, the board will address the technical effect resulting from each feature in turn.

The respondent submitted that the first distinguishing feature - the detergent virus inactivation step - and the absence of a second PEG precipitation step (i.e. precipitation of alpha1-PI) in the method were technically interrelated. The board notes, however, that the absence of a second PEG precipitation step is not a feature which distinguishes claim 1 from the method disclosed in document D4. Thus such a technical interrelation is immaterial for the present analysis, which relies on the technical effects that can be attributed to the features distinguishing the claimed subject-matter from the closest prior art.

First partial technical problem and obviousness - virus inactivation step

Objective technical problem

5.5 With regard to the step of virus inactivation by detergent, no technical effect has been demonstrated beyond that already achieved by the method disclosed in document D4. The board therefore formulates the partial objective technical problem as the provision of an alternative method for purifying alpha1-PI including virus reduction.

5.6 The respondent reasoned that the experimental report document D35 showed a method of purifying alpha1-PI according to the patent which involved a step of detergent virus inactivation taking 5 hours. Thus the objective technical problem solved was the provision of a method for purifying alpha1-PI with a shorter production time.

5.7 The board notes, however, that according to the patent the solvent-detergent virus inactivation step takes between 8 and 10 hours (column 10, line 1). On the other hand, document D4 discloses that the heat inactivation step takes up to 10 hours (column 5, line 45). Although document D35 shows an example involving a shorter step of virus inactivation, the claimed method is not restricted to said example.

Thus the duration of the solvent-detergent virus inactivation as disclosed in the patent is not shorter than that of the heat inactivation used in the prior art method under discussion. Therefore the board cannot accept the respondent's reasoning.

Obviousness

5.8 It is established case law of the boards of appeal of the EPO that, when the objective technical problem addressed is the provision of an alternative, as in the case at hand, an arbitrary selection from amongst a number of known possible solutions cannot be considered to involve an inventive step (see for example decision T 939/92, reasons 2.5.3).

5.9 The skilled person would have been aware of the contents of document D8, which is directed to the purification of the same product by means of a method involving PEG precipitation and anion exchange chromatography. This document aims at improving prior methods comprising various combinations of one or more PEG precipitation steps, one or more chromatographic steps and phase separations (column 2, lines 25 to 27). It discloses a method involving a first precipitation step using PEG, which results in precipitation of contaminating proteins, and a second precipitation step using ZnCl2, which results in precipitation of alpha1-PI. These steps are followed by re-solubilisation of alpha1-PI and by virus inactivation. This latter step involves the addition of a solvent-detergent containing Tween 80 in TNBP. The resulting solution is used directly in the anion exchange chromatography step (column 2, lines 40 to 65).

5.10 Document D8 thus taught the skilled person that, in a multi-step process for alpha1-PI purification, one possibility of carrying out virus inactivation was by using the detergent Tween 80.

5.11 The skilled person seeking to provide an alternative method for purifying alpha1-PI including virus reduction would thus introduce the virus inactivation step by detergent Tween 80 before dilution of the solution for anion exchange chromatography, as disclosed in document D8, in the method as disclosed in document D4. It follows that the skilled person would arrive at the claimed subject-matter in an obvious way.

5.12 The respondent submitted that the skilled person would not arrive at the claimed method in an obvious way, based on the following, similar, arguments: document D4 provided no indication of the solution because it mentioned only heat inactivation; the skilled person would not isolate one method step from the method disclosed in document D8 and apply it to a different method; the skilled person would not combine the two teachings because the method disclosed in document D8 involves precipitation of the product, which is excluded by the claimed method; the skilled person would have been dissuaded from isolating the virus inactivation step from the ZnCl2 precipitation step and would thus at best have applied both steps as disclosed in document D8 to the method disclosed in document D4.

5.13 To the person skilled in the field of downstream processing of biological molecules, various unit operations are tools of which use can be made depending on the objective in terms of yield and purity. Beyond that, the choice of unit operations as well as their sequence is limited only insofar as each input stream needs to be compatible with the corresponding unit operation. Thus to the skilled person the unit operations virus inactivation, precipitation, filtration and ion exchange chromatography are not undissociable as submitted by the respondent. Therefore the board takes the view that the skilled person would recognise that the solvent-detergent virus inactivation used in the method disclosed in document D8 was a possible solution for carrying out virus inactivation in other purification methods, and in particular in the method disclosed in document D4, all the more so since in the method disclosed in document D8 the virus inactivation step is directly followed by the anion exchange chromatography without any technical difficulties being reported. This is precisely the sequence of steps in the method as claimed. In light of the above and in the absence of reasons specific to the unit operations of viral inactivation and anion exchange chromatography, the respondent's argument that the skilled person would not take a single step from one method and include it in a different method or use it in a different order of steps is not held to be convincing.

Second partial technical problem and obviousness - cation exchange chromatography steps

Objective technical problem

5.14 The respondent relied on document D35 to demonstrate that the effect of the cation exchange chromatography steps is to increase both purity and yield of the product.

This document is an experimental report submitted by the respondent, providing results in relation to the product purity and yield of two methods of alpha1-PI purification: a first method according to experiment 1, which represents the method disclosed in document D11, and a second method according to experiments 2 and 3, which falls within the scope of claim 1.

The board observes that the protocols used in experiment 1 on the one hand and experiments 2 and 3 on the other hand differ in a number of parameters, including the input solution into the PEG precipitation, the number of PEG precipitation operations, the anion exchange column used and corresponding buffer elution conditions, and the number of filtration operations. Indeed, whereas all the experiments have Cohn fraction IV-1 paste as input, the preparation of the starting aqueous solution differs between the experiments. The same applies to the column used for anion exchange chromatography - in the case of experiment 1 a weak anion exchange column and in the case of experiment 2 a strong one - the elution conditions hence differing between the experiments. However, the column and the elution conditions affect the purity and yield of the product. The board further notes that in experiments 2 and 3, which represent the claimed method, there are a number of filtration steps not present in experiment 1, which represents the method of document D11, such as a diafiltration step after the anion exchange chromatography and additional nanofiltration and ultrafiltration steps after the cation exchange chromatography. Such steps have an impact on the purity of the final product and the yield of the method.

5.15 To be able to draw conclusions about the technical effect of a given feature, the experiments submitted must be designed such that the results are truly comparable. In the present case, experiments 2 and 3 should differ from experiment 1 only by the steps of cation exchange chromatography. However, as listed above, the experiments differ in method steps which are not technically related to this step, namely the starting aqueous solution, and the anion exchange chromatography and filtration steps downstream from the cation exchange chromatography. These differences have an impact on the yield and purity of the product. Therefore the board cannot conclude from the content of document D35 that the cation exchange chromatography steps lead to an increase in both purity and yield of the product.

5.16 In an auxiliary line of argument, the respondent submitted that the objective technical problem solved by the claimed method was the provision of a method of purifying alpha1-PI with improved purity.

Obviousness

5.17 Document D5, which deals with the purification of the very same product, discloses the use of cation exchange chromatography as a technical development. Cation exchange chromatography is disclosed for use with a number of starting materials (including Cohn fraction IV-1 paste and purified alpha1-PI) and in combination with a number of other unit operations (column 3, lines 35 to 58). In example 1, cation exchange chromatography is used in combination with a number of other unit operations, following anion exchange chromatography; in example 3 it is applied directly to Prolastin, a commercially-available product containing alpha1-PI. This document reports that 90% yield and 95% purity can be achieved after two cation exchange chromatography steps (column 2, lines 27 to 36).

In view of the expected improvements in purity as reported in document D5, the skilled person, starting from the method of purifying alpha1-PI disclosed in document D4 and seeking to improve the purity achieved, would thus have used cation exchange chromatography as an additional method step. Thus the claimed method was obvious to the skilled person.

5.18 In view of the conclusions reached in points 5.11, 5.13 and 5.17, each of the features distinguishing the claimed method from the method of purifying alpha1-PI disclosed in document D4 is obvious to the skilled person. The claimed subject-matter therefore lacks inventive step as required by Article 56 EPC.

Auxiliary request 1 - claims 1 and 2

6. Inventive step - Article 56 EPC

6.1 The claimed methods differ from those of claims 1 and 2 of the main request, respectively, in that the non-ionic detergent in auxiliary request 1 is specified to be Tween 20 (see section V.).

Closest prior art

6.2 The appellant reasoned that the claimed methods did not involve an inventive step when starting from either one of document D4 and document D5 as representing the closest prior art to the claimed subject-matter.

Closest prior art document D4

6.3 Compared with the technical effects as discussed with regard to the main request (see points 5.4, 5.5, 5.15 and 5.16), no additional technical effects due to the use of Tween 20 have been put forward by the respondent.

Thus the partial objective technical problem that can be derived from the detergent virus inactivation step remains the provision of an alternative method for purifying alpha1-PI including virus reduction.

6.4 Document D8 discloses (see points 5.9 and 5.10) a method involving detergent virus inactivation using a non-ionic detergent - Tween 80 - without mentioning other detergents, such as Tween 20. The question to be addressed is thus whether the skilled person seeking to solve the technical problem would have modified the method disclosed in document D4 by introducing a step of detergent virus inactivation prior to the anion exchange chromatography and would have modified that step so as to use a different detergent.

In the board's view, in the absence of any identified pointer to Tween 20, the claimed solution was not obvious to the skilled person unless, as was argued by the appellant with reference to document D24, Tween 80 and Tween 20 were known to the skilled person as being equally suitable for virus inactivation in protein production processes.

The passage from document D24 cited by the appellant (paragraph bridging columns 7 and 8) reads: "Preferred wetting agents are non-toxic detergents. [...] In particular there is contemplated detergents which include polyoxyethylene derivatives of fatty acids, partial esters of sorbitol anhydrides, for example, those products known commercially as "Tween 80", "Tween 20" and "polysorbate 80" and nonionic oil soluble water detergents such as that sold commercially under the trademark "Triton X 100" [...]". The board therefore notes that the references in this passage to the use of Tween 20 do not concern a virus inactivation activity but rather its use as a wetting agent. Document D24 is therefore silent on the appellant's allegation that the detergents are equivalent for the purpose they serve in the method claimed, i.e. virus inactivation.

6.5 The appellant further submitted that in addition to the use of the specific compound Tween 80 in column 4, lines 17 and 27, document D8 also generically discloses the use of "solvent-detergent treatment" in virus inactivation (column 4, lines 15 to 16).

The passage referred to reads: "The alpha-1-PI-containing solution is virus inactivated by solvent-detergent treatment. A solution of 10±1% wt/v polysorbitol 80 and 3±0.31% wt/wt tri-n-butyl phosphate is added to the alpha-1-PI solution to a final concentration of [...]". In the board's reading this passage leaves no room for an alternative detergent to be selected. The board therefore cannot agree with the appellant that the cited passage conveys the teaching that inactivation may be carried out with any given detergent or one chosen from a general class of detergents.

6.6 In view of the above, the board has come to the conclusion that the skilled person seeking to provide an alternative to the method disclosed in document D4 had no reason to modify it by introducing virus inactivation by the use of Tween 20.

6.7 Thus the claimed solutions were not obvious to the skilled person when starting from the disclosure in document D4.

Closest prior art document D5

6.8 There was disagreement between the parties as to the disclosure content of document D5.

6.9 In the appellant's view, document D5 in example 3 disclosed a method from which the claimed method differed merely by a detergent virus inactivation step with Tween 20. Specifically, example 3 described in column 6, lines 49 to 56 a method of preparing alpha1-PI starting from the commercially available product Prolastin. The method involved steps (e), (f) and (g) according to the claims at issue. In turn, Prolastin was prepared by a method disclosed in each of documents D4, D9, D10 and D11. Such method included steps (a), (c) and (d), as well as the part of step (b) consisting of dilution.

6.10 According to the board's established case law, a prior art document anticipates claimed subject-matter if the latter is directly and unambiguously derivable from that document. An implicit disclosure is one the skilled person would objectively consider as necessarily implied in what is explicit in the document.

6.11 While document D5 does not refer to either of documents D4 and D9 to D11, the appellant rather argued that the skilled person knew from the common general knowledge, as represented by documents D37 to D41, that the method of preparing commercially-available Prolastin was as described in any of those documents. This argument is however not deemed convincing. Firstly, the board is not convinced that the skilled person would necessarily read into the method any additional method steps for the production of Prolastin instead of a method having Prolastin as the input. Secondly, if method steps were implied by the Prolastin, it cannot be said that they would inevitably be those disclosed in any of documents D4, D9, D10 and D11.

6.12 Thus the board comes to the conclusion that the method disclosed in example 3 of document D5 does not implicitly include the steps of PEG precipitation and anion exchange chromatography in addition to the explicitly-disclosed steps of cation exchange chromatography. This being the conclusion of the board, the appellant did not pursue their inventive-step attack starting from document D5 as closest prior art any further.

7. Amendments - Extension of protection conferred by the patent - Article 123(3) EPC

7.1 This objection was put forward in the context of the main request, but applies equally to auxiliary request 1.

7.2 The parties disagreed on the construction of the claim. According to the appellant, the claim allowed for e.g. the forming of an intermediate paste between the precipitation of alpha1-PI in step (a) and the anion exchange chromatography. Should the board take the view that step (b) immediately followed step (a) in claims 1 and 2 as granted, in other words that the solution resulting from step (a) was the same as that being processed in step (b), then the claims did not allow for additional intermediate steps such as the virus inactivation step. Consequently, the inclusion of a virus inactivation step amounted to an extension of the protection conferred by the patent.

7.3 The issue of whether or not claim 1 allows for the forming of an intermediate paste is not relevant to the present decision and can thus be left undecided. The board came to the view that, due to the word 'comprising', it cannot be concluded that in general further method steps are excluded from the claimed method and that the solution resulting from step (a) is therefore necessarily identical to that being processed in step (b). It follows that the condition on which the appellant's objection is dependent, i.e. that in the claimed method in the granted patent there could be no additional steps between steps (a) and (b), does not apply. In light of the above, the board sees no reason to find that the introduction of the virus inactivation step led to an extension of the protection conferred by the patent as granted.