T 0229/20 (Stabilizing proteins/MERZ) 24-11-2022

Main request, patent as granted

1. Added subject-matter

1.1 Claim 1 as originally filed defines:

"A formulation free of proteins comprising

(a) a mixture of a hydrophilic polymer and a non-ionic detergent, wherein the weight ratio between the hydrophilic polymer and the detergent is from 18:1 to 22:1 (wt-%),

(b) a mixture of a polyalcohol and a sugar, wherein the weight ratio of polyalcohol to sugar is from 2:1 to 5:1 (wt-%),

c) and wherein the non-ionic detergent is present in said fonnulation in an amount between 0.2 and 0.01 mg/g."

Claim 2 as originally filed defines:

"A formulation free of comprising

(d) a mixture of a hydrophilic polymer and a non-ionic detergent, wherein the weight ratio between the hydrophilic polymer and the detergent is from 2:1

to 30:1 (wt-%), and wherein the non-ionic detergent is present in said formulation in an amount between 0.2 and 0.01 mg/g;

(e) a sugar; and

(f) wherein no polyalcohol is present."

As explained in the decision under appeal (see page 5, lines 21-23) and not contested by the parties claim 2 as originally filed should be read to define a formulation free of proteins.

Claim 7 as originally filed defines a composition comprising the formulation according to any of the preceding claims, which further comprises a pharmaceutically active peptide, a protein or a mixture thereof.

Paragraph [0017] of the application as filed presents the following explanations as to the term "free of ..." used in original claims 1 and 2:

"The term "free of proteins" hereinunder refers to a formulation which is free of any protein and/or peptide which is not the pharmaceutical active protein, peptide or mixture of thereof. In particular it is meant that the formulation is free of stabilizing proteins such as animal or human serum albumin (HSA), gelatine, amino acids such as histidine, lysine, methionine and/or immunoglobulins." [underlining by the Board]

Paragraph [0031] of the application as filed specifically discloses the proviso of granted claim 2 in an embodiment of a formulation as defined in claim 2 as originally filed.

1.2 As pointed out in the decision under appeal (see pages 5-6 section A.1.3) the features of claim 1 as granted derive from claims 1 and 7 in combination with paragraph [0017] of the application as filed and the features of claim 2 as granted derive from original claims 2 and 7 in combination with paragraphs [0017] and [0031] of the application as filed.

The application as filed presents in paragraph [0017] the listed agents including animal or human serum albumin as examples of the "stabilizing proteins" which the defined formulations are defined to be free of. Contrary to the appellant-opponent's argument the Board therefore considers that the feature "free of..." in the granted claims relates to a group of agents which is per definition included in the term "stabilizing proteins" as used in paragraph [0017] in the application as filed.

The Board further agrees with the decision under appeal (see page 5 paragraph 3) that no added matter results from the definition of the ratio between the hydrophilic polymer and the non-ionic detergent in the claims as granted, because "the detergent" in original claim 1 under (a) and in original claim 2 under (d) finds its only antecedent in the terms "a non-ionic detergent".

The Board observes that paragraph [0017] of the application as filed presents an explanation of the meaning of the term "free of proteins" in original claims 1 and 2 and therein specifically points to the embodiment of original claim 7 involving a pharmaceutically active protein or peptide. The Board therefore also agrees with the decision under appeal (see page 5 paragraphs 8-9) that the combination of features from original claim 7 and paragraphs [0017] and [0031] does not give rise to subject-matter which had not been originally disclosed.

1.3 Accordingly, the Board concludes that the patent as granted does not comprise subject-matter extending beyond the content of the application as originally filed.

2. Sufficiency

2.1 The appellant-opponent contested the finding in the decision under appeal that it had not discharged the burden of proof regarding the ground of lack of sufficient disclosure.

2.2 With the statement of grounds of appeal the appellant-opponent filed documents D9 and D10 and referred to the US Food and Drug Administration IIG database to support the argument that claim 11 of the request upheld by the opposition division does not meet the requirement of sufficient disclosure, because certain excipients are not suitable for the purpose of preparing pharmaceutical compositions, including compositions for administration by injection, as tought in the patent. According to the appellant-opponent documents D1 and D6 further demonstrated that certain types of sugar, such as cellobiose, are unsuitable as Botulinum toxin stabilisers. Moreover documents D4 and D5 demonstrated that the weight ratio between the hydrophilic polymer and the detergent required for stabilization of Botulinum toxin depends on the specific components used. Document D5 further showed that Botulinum toxin is highly sensitive to factors such as the pH and the nature of the used buffer (see statement of grounds of appeal, pages 6-12, section 5).

The appellant-opponent justified the filing of the new facts, arguments and documents in view of the conclusion in the decision under appeal (see page 6 section A.2.3) that the appellant-opponent had not discharged the burden of proof on insufficiency (see statement of grounds of appeal pages 6-12 section 5).

The Board observes that the appellant-opponent had argued before the opposition division that claims 13-14 as granted did not meet the requirement of sufficiency of disclosure, because these claims relate to the stabilisation of pharmaceutically active proteins or peptides in general, whereas it was well known that different proteins have significantly different stability profiles (see notice of opposition page 6 section 6; see letter of 23 July 2010 page 3 section 3; see minutes of the oral proceedings of 27 July 2019 bridging section pages 1-2). In fact, the appellant-opponent had not maintained the objection of lack of sufficient disclosure against claim 11 of the auxiliary request upheld by the opposition division, which was limited to the stabilisation of Botulinium toxin (see minutes of the oral proceedings of 27 July 2019 page final sentence; see also decision under appeal, page 15, section C.3).

Accordingly, the appellant-opponent's objection concerning the suitability of the excipients for the purpose of preparing pharmaceutical compositions or stabilizing Botulinum toxin do not address the considerations which led to the decision under appeal, but rather change the dimension of the objection to the extent that it confronts the appellant-patent proprietor and the Board with a fresh case. The Board does therefore not admit these new facts, arguments and evidence into the appeal proceedings under Articles 12(2), 12(4) and 12(6) RPBA 2020.

2.3 The appellant-opponent further maintained that different proteins have different stability profiles and that from the examples in the patent relating to the stabilization of Botulinum toxin no conclusions can be drawn regarding the stabilization of pharmaceutically active proteins and peptides in general. According to the appellant-opponent the examples in the patent did actually not even demonstrate the stabilization in the claimed compositions, because the tested compositions in the patent were lyophilised and therefore comprised higher concentrations of the excipients than the compositions as claimed.

The Board agrees with the finding in the decision under appeal (see page 6, section A.2) that the appellant-opponent has not supported its contention that the experimental results reported in the patent regarding Botulinum toxin cannot be extrapolated to other proteins with any verifiable facts. In this context the Board observes that example 1 of the patent (see paragraphs [0141]-[0143] and figure 1) demonstrates the stability of a lyophilized composition, in which the relative amount of the non-ionic detergent may indeed surpass the 0.2 mg/g as defined in the claim due to solvent removal. However, as observed in the decision under appeal (see page 18 paragraph 8) example 1 still demonstrates that a composition as defined in the claims leads after solvent removal to a stable lyophilised Botulinum toxin formulation and can thus be used for the purpose of stabilization as defined in claims 13 and 14.

2.4 Accordingly, the Board concludes that the patent as granted fulfills the requirement of sufficient disclosure of the claimed invention.

3. Inventive step

3.1 The compositions of claims 1 and 2 as granted comprise in addition to the pharmaceutically active protein or peptide a mixture of a hydrophilic polymer and a non-ionic detergent as well as a sugar. The claims define a specific concentration range of 0.01-0.2 mg/g for the non-ionic detergent. Due to the defined weight ratios of the hydrophilic polymer in relation to the detergent the claims also require specific concentration ranges for the hydrophilic polymer. In accordance with the broad definition of the ratio in claim 2 as granted (2:1 to 30:1) the concentration of the hydrophilic polymer ranges from 0.02-6 mg/g. The narrowly defined concentration of claim 1 as granted falls within this range. Claim 1 as granted further defines the presence of a polyalcohol in a defined weight ratio to the sugar, whereas claim 2 as granted excludes the presence of a polyalcohol.

3.2 Document D2 describes stabilized compositions for Clostridium difficile toxin, including a "PSW" composition comprising the hydrophile polymer PVP, the sugar sucrose and the non-ionic detergent Tween 80 which the appellant-opponent relied upon as suitable starting point. This "PSW" composition differs from the compositions of claims 1 and 2 as granted in the higher content of the hydrophile polymer, namely 40 g/L corresponding to 40 mg/g instead of the maximum of 6 mg/g as defined in the claims as granted.

Document D5 describes a variety of stabilized compositions for Botulinum toxin, including the following compositions specifically relied upon by the appellant-opponent:

- compositions comprising 20-24 mg/mL of the sugar sucrose, 20 mg/mL of the hydrophile polymer PVP and 5 mg/mL of the non-ionic detergent Poloxamer-188 (see D5, page 86, Table 6, compositions 5-8)

- a composition containing 60 mg/mL of the hydrophile polymer PEG-3350 and 3 mg/mL of the non-ionic detergent Poloxamer-188 (see D5, page 77, Table 4, composition 19)

- a composition comprising 15 mg/mL sucrose, 45 mg/mL of the polyalcohol mannitol and 0.2 mL/mL of the non-ionic detergent Polysorbate 20 (see D5, page 97, Table 8, composition 5); in line with the finding in the decision under appeal (see page 18 lines 2-3) 0.2 mL/mL approximately corresponds to an amount as high as 200 mg/g for the detergent.

Document D1 describes stabilized Botulinum toxin formulations comprising 20 mg sucrose, 20 mg of the hydrophile polymer PVP and 20 mg of the non-ionic detergent poloxamer (see D1, page 42,Table 6).

The indicated compositions from documents D5 and D1 thus differ from the compositions defined in the claims as granted in the substantially higher content of the non-ionic detergent and the hydrophile polymer and their ratio or the drastically higher content of the ionic detergent in the absence of a hydrophile polymer.

3.3 The patent reports in its experimental section (see pages 14-15, examples 1 and 2 with reference to figures 1 and 2) that compositions in accordance with claims 1 and 2 which are lyophilized show stability over 12 months storage.

The appellant-opponent argued that the patent only demonstrated stability for lyophilized compositions not covered by the claims and that the stability profiles of proteins depend on the nature of the protein and the excipients. In its view it was therefore not credible that a stabilizing effect is achieved over the whole scope of the claim.

As explained in section 2.3 the Board considers that the patent substantiates in the experimental section that exemplified compositions covered by the claims allow for the preparation of stable lyophilised Botulinum toxin formulations.

In line with the finding in the decision under appeal (see page 18, final paragraph) the Board further agrees that, in the absence of substantiated arguments from the appellant-opponent to the contrary, this effect may be considered representative for the whole scope of the claims.

In this context the Board notes that document D1 (see page 17, lines 4-5) and document D6 (see paragraph [0013] only mention that the disaccharide cellobiose had in previous compositions not been found effective for stabilizing Botulinum. Moreover, document D4 (page 13, examples 1-4) and document D5 (see page 99, Table 188) merely report the use of different amounts for different surfactants in stabilized botulin toxin compositions. Document D5 further shows that in certain compositions (see D5, page 78) the stability of Botulinum compositions also depends on the pH and the nature of the buffer. However, such information does not affect the teaching in the patent regarding the stabilizing effect of the compositions as defined in the claims as granted, which are concerned with particular new combinations of the defined excipients.

In line with the finding in the decision under appeal (see page 9, lines 4-6) the Board therefore considers that the problem to be solved may be formulated as the provision of an alternative composition for stabilizing a pharmaceutically active protein or peptide.

3.4 For the assessment of inventive step of claims 1 and 2 as granted it is therefore decisive whether or not the skilled person would have expected that the protein stabilisation in the compositions as described in documents D5, D2 or D1 would be retained in compositions as defined in claims 1 and 2 as granted.

The Board observes that according to the appellant-opponent it is evident from document D5 that protein compositions such as Botulinum toxin are highly sensitive and that the stability of such compositions depends on a variety of factors (see statement of grounds of appeal, page 8). This sensitivity is confirmed by the results from example 1 of the patent, which show that a change in the ratio between the hydrophilic polymer and the detergent already affects the stability of the resulting formulation. In view of this sensitivity it would not have been obvious to the skilled person that the compositions with the reduced detergent concentration and the changed content of hydrophile polymer as defined in the claims of the patent represent a solution to the problem of providing an alternative composition for stabilizing a pharmaceutically active protein or peptide.

3.5 Accordingly, the Board concludes that the patent as granted fulfills the requirement of inventive step.