T 0997/06 (Insulin Preparation/NOVO NORDISK) 14-12-2009

1. The appeal is admissible.

Main request - Claim 1

Amendments - Article 123(2) EPC

2. Amended claim 1 is based primarily on claims 1 and 17 of the application as published.

3. Claim 1 finds further direct basis in claims 4 and 5 of the application as published in the aspect of the specific Asp**(B28) human insulin whereby the concentration of the insulin compound is not indicated, in claim 14 in the aspect of the Zn content and on page 6, lines 1 to 3 in the aspect of the phosphate buffer.

4. In the context of Article 123(2) EPC, the parties have referred, besides to claims 15 and 16 of the application as published, to a passage on page 5, lines 18 to 25. This passage read:

"In a preferred embodiment of the invention the insulin preparation comprises:

60 to 3000 nmol/ml, preferably 240 to 1200 nmol/ml, of human insulin or insulin analogue or derivative,

10 to 40 myg Zn/100 U insulin, preferably 10 to 26 myg Zn/100 U insulin, and

0 to 5 mg/ml, preferably 0 to 4 mg/ml, of a phenolic compound.

As a phenolic compound, 0.5 to 4.0 mg/ml, preferably 0.6 to 4.0 mg/ml, of m-cresol or 0.5 to 4.0 mg/ml, preferably 1.4 to 4.0 mg/ml, of phenol, or a mixture thereof, is advantageously employed."

5. The board considers, however, that the subject-matter of claims 15 and 16 of the application as published suffices for the amendment concerning the mixture of phenolic compounds to comply with the requirements of Article 123(2) EPC. The dependency of claim 16 on claim 15 in the application as published and the explicit reference to a mixture of m-cresol and phenol unambiguously predetermine the notion "a phenolic compound" in claim 15 to be of generic nature and not to exclude the presence of different phenolic compounds in the insulin preparation.

6. In view of the above considerations, the board is satisfied that claim 1 complies with the requirements of Article 123(2) EPC.

Clarity - Article 84 EPC

7. The respondent has argued that claim 15 as originally filed and the passage on page 5, line 22, refer merely to "0 to 5 mg/ml, ..., of a phenolic compound". The upper range of 5 mg/ml in the amended claims 1 and 6 was therefore unclear as it referred to a total content of a mixture of more than one phenolic compounds (i.e. cresol and phenol).

8. The board considers, however, as reiterated in point 5, supra, that the dependency of claim 16 on claim 15 in the application as published and the explicit reference to a mixture of m-cresol and phenol in claim 16 predetermine the notion "a phenolic compound" in claim 15 unambiguously to be of generic nature and thus also to embrace different phenolic compounds present in the insulin preparation.

9. As follows from the above considerations claims 1 and 6 are clear pursuant to Article 84 EPC.

Inventive step - Article 56 EPC

10. The subject-matter of claim 1 pertains to an aqueous insulin preparation comprising, and being therefore not limited to, the following compounds: human Asp**(B28) insulin; glycerol; a halogenide (5 to 100 mM of e.g. NaCl); a mixture of m-cresol and phenol (at least 0.5 mg/ml each and maximum 5 mg/ml in total); 10 to 40 myg Zn/100 U insulin; and a phosphate buffer.

The goal of the invention in the patent in suit is set out in paragraph [0017]: "The ... insulin preparation has a high chemical stability which e.g. is reflected in a reduction in the formation of dimers and polymers and desamido insulins after storage. Furthermore, the physical stability is not deteriorated by the presence of the rather low amount of halogenide, and the insulin does not precipitate by long-term storage of the insulin preparations."

11. For assessing whether or not a claimed invention meets the requirements of Article 56 EPC, the boards of appeal apply the "problem and solution" approach, which requires as a first step the identification of the closest prior art. In accordance with the established case law of the boards of appeal, the closest prior art is a teaching in a document conceived for the same purpose or aiming at the same objective as the claimed invention and having the most relevant technical features in common, i.e. requiring the minimum of structural modifications to arrive at the claimed invention.

12. The parties to the present appeal have considered various documents during the appeal proceedings to represent the closest prior art.

13. The appellant considered document (D1) to represent the closest prior art. It discloses parenteral pharmaceutical preparations of insulin which are less prone to precipitate under constant delivery conditions.

In column 3, lines 35 to 40, the document discloses that "[p]referably, the total molar concentration of ... sodium salts, does not exceed 0.01 [molar] and the presence of calcium or magnesium precipitating or complexing anions, such as phosphate ..., is avoided in the insulin solutions of this invention.". The board therefore notes that document (D1) quite explicitly advises the skilled person not to use phosphate buffer, a feature of the claimed invention, in the insulin preparation.

14. The respondent has considered either of documents (D1), (D3) and (D12) to represent the closest prior art.

Document (D3) discloses methods for preventing denaturation of aqueous insulin in pharmaceutical preparations by the addition to the solution of a surface active polymeric substances with alternating hydrophobic and hydrophylic zones (see column 3, lines 16 to 22). The insulin solutions for therapeutic purposes in accordance with document (D3) are prepared by dissolving up to 1,500,000 I.U. of bovine, swine or human insulin and which contain up to 0.8% by weight of zinc in 400 ml of water with the addition of HCl. This solution is then mixed with 500 ml of a solution which contains a preservative, for example phenol, cresol or methyl p-hydroxybenzoate, an agent for rendering the solution isotonic, for example sodium chloride, glycerol, glucose, or a similar carbohydrate, and a salt for buffering the pH value, for example sodium phosphate, acetate, citrate, sodium veronal, or tris(hydroxymethyl)-aminomethane and the pH adjusted to 3.0-4.0 or 6.8-7.5. 50 ml of an aqueous solution containing 2 to 200 mg of a surface-active substance according to the invention are then added and the solution is made up to 1000 ml with water (column 5, lines 30 to 52). Example 9 of document (D3) specifies such a solution: "Amorphous bovine insulin (1,000,000 I.U.) containing 0.8 percent by weight of zinc was dissolved in 400 ml of water with the addition of 5 ml of 1N hydrochloric acid. 500 ml of a solution of 2.5 g of phenol, 16 g of glycerol and 1.78 g of Na2HPO4.2H2O were added to this solution. The pH of the solution was adjusted to 7.2-7.5. After adding 5 ml of an aqueous 0.1% strength solution of linear polypropylene glycol with an average molecular weight of 1.750 (Dalton), the mixture was made up to 1,000 ml with water and the solution was sterile-filtered.".

Document (D12) demonstrates by physico-chemical studies that the self-association of insulin can be drastically altered by substitution of one or more key amino acids (abstract, lines 21 to 23) which is said to be important for future diabetes therapy (page 527, right-hand column, lines 47 to 54). Association was studied by circular dichroism, size-exclusion chromatography and ultracentrifugation (abstract, lines 5 to 7). One of the low self-association insulins prepared was human Asp**(B28) insulin (see e.g. the section "Preparation of analogs" bridging the columns on page 528). The results show that certain analogs, including Asp**(B28) insulin, demonstrate significant Zn-induced association, but less than native insulin (see page 530, right-hand column, lines 28 to 30).

15. From the above analysis it can be taken that, rather than disclosing pharmaceutical preparations, (D12) discloses insulin preparations in a physico-chemical context. Both documents (D1) and (D3) on the other hand disclose pharmaceutical insulin preparations with an aim to improve the insulin stability characteristics. The board notes however that document (D1), in column 3, lines 35 to 40, advises explicitly against the use of phosphate in the disclosed pharmaceutical insulin preparations. Therefore, in view of the above principles, the board considers that the disclosure representing the closest prior art for the purpose of the assessment of inventive step of the subject-matter of claim 1 is document (D3).

16. The parties and the board are in agreement that the technical difference between the insulin preparation disclosed in document (D3) and the subject-matter of claim 1 are the presence in the claim of the human Asp**(B28) insulin analog as active ingredient and the addition of m-cresol.

17. In order to formulate the problem to be solved by the subject-matter of claim 1 it needs to be established what the effect is of the dual choice of the human AspB28 insulin and the addition of cresol over the insulin preparation disclosed in closest prior art disclosure document (D3).

18. Concerning the choice of the active insulin ingredient of the preparations of the invention, the patent in suits sets out in paragraphs [0020] and [0022] that either fast-acting insulin analogues, such as human AspB28 insulin, or insulin derivatives with a protracted profile of action can be used.

Concerning the phenolic compound in the preparation the patent in suit sets out in paragraph [0027] that either m-cresol, phenol or a mixture thereof is advantageously employed.

19. In its grounds of appeal the appellant has specifically addressed the effect of the combination of Zn-complexed AspB28 human insulin combined with phenol and m-cresol (final paragraph of page 11) and has thereby referred to document (D9), a post-published document. Document (D9) explained that the Asp**(B28) insulin analogue was a monomeric, rapid-acting hormone for therapeutic purposes having a mutation at the dimer-forming surface of the insulin monomer. The mutation was effective in destabilising the insulin dimer, giving rise to an essentially monomeric insulin at physiological concentrations. It was argued that the document thus confirmed that that the Zn-complexed Asp**(B28) human insulin in combination with phenol and m-cresol provided a rapid-acting preparation. As far as stability was concerned phenol was the preferred additive. However, considering the requirements for a satisfactory preservation, its sole use did not provide a sufficient effect. Hence it had been found that a combination of phenol and m-cresol gave a satisfactory result. The latter statement was essentially repeated in later stages of the proceedings (e.g. letter dated 6 February 2008, point 6.3, 3rd paragraph) when stating that a combination of phenol and m-cresol had been found to be necessary for a satisfactory preservation of the Zn-complexed Asp**(B28) human insulin.

20. In view of the above submissions by the appellant the problem to be solved by the claimed subject-matter must therefore be to provide for an alternative insulin preparation to the preparation disclosed in example 9 of document (D3) having improved stability characteristics and having satisfactory preservation characteristics in terms of anti-microbial action.

21. Human AspB28 insulin had been known in the prior art as an insulin with a diminished self-association, and a higher stability, i.e. an important feature for future diabetes therapy (see e.g. document (12), page 527, right hand column, lines 47 to page 528, left hand column, line 2).

The appellant has however argued that the choice of human Asp**(B28) insulin for parenteral insulin preparations was not obvious in the light of the document (D6), disclosing insulin analogues with a low ability to associate with a positively charged amino acid at the B28 position, rather than e.g. a negatively charged Asp.

The board notes however in this context that in view of the disclosure in document (D12), the skilled person would find itself not being confronted with a prejudice in the art which would prevent experimentation with the Asp**(B28) human insulin analog disclosed therein.

22. From document (D11), a review article on the topic of the galenics of insulin, especially from its tables 4 and 8, it can be taken that the preserving agents in therapeutic insulin preparations vary and range routinely from the use of methylparaben over the use of phenol alone or in combination with the former with m-cresol. The board notes that this fact finds confirmation in document (D8) on page 425, left hand column, lines 38 to 48, where it is stated that newly registered human insulin preparations contain powerful phenol derivatives (addition of 0,06% Phenol and 0,15-0,25% m-cresol), which had already at an early time been applied as anti-bacterial agents.

23. Hence, for the formulation of therapeutic insulin preparations as well the use of human Asp**(B28) insulin as the combined use of anti-bacterial agents phenol and m-cresol was known in the prior art.

24. It is established case law of the boards of appeal (see Case Law of the Boards of Appeal, 2006, I.D.8.2.1) that in assessing the inventive step involved in an invention based on a combination of features, consideration must be given to whether or not the state of the art was such as to suggest to a skilled person precisely the combination of features claimed. The fact that an individual feature or a number of features were known does not conclusively show the obviousness of a combination. The question is not whether the skilled person, with access to the entire prior art, could have made the combination according to the invention, but whether he actually would have done so in expectation of an improvement. Indeed, were this not so, it would be impossible for a combination consisting of known individual features to involve an inventive step. The existence of a combination invention requires that the relationship between the features or groups of features be one of functional reciprocity or that they show a combinative effect beyond the sum of their individual effects.

A mere aggregation of features must, however, be distinguished from a combination invention. Indeed, it has been established by the boards (see Case Law of the Boards of Appeal, 2006, I.D.8.2.2) that in patent law terms, the existence of a combination of features, i.e. of a combination invention, is to be viewed differently from the mere existence of partial problems, i.e. of an aggregation of features. According to current case law, partial problems exist if the features or sets of features of a claim are a mere aggregation of these features or sets of features which are not functionally interdependent, i.e. do not mutually influence each other to achieve a technical success over and above the sum of their respective individual effects, in contrast to what is assumed in the case of a combination of features.

25. The board notes that none of the experimental reports submitted by the appellant constitute, nor that the patent in suit discloses, comparative tests representing a fair comparison of the claimed subject-matter with respect to the closest prior art evidencing a mutual influence of both features leading to a technical success over and above the sum of the respective individual effects.

26. Accordingly, the board cannot identify a relationship between the features distinguishing the subject-matter of claim 1 from the insulin preparation defined in example 9 of the document representing the closest prior art which could be defined as one of functional reciprocity or that they show a combinative effect beyond the sum of their individual effects. Indeed, both the selection of the human Asp**(B28) insulin as more stable insulin as the native bovine insulin of document (D3) and the combined use of phenol and m-cresol as preservative had plainly been suggested in the art in the context of pharmaceutical insulin preparations. The combination of these features in claim 1 therefore constitutes a mere aggregation of features which cannot form the basis for the acknowledgement of an inventive step.

27. In view of the above considerations, the subject-matter of claim 1 of the main request lacks an inventive step (Article 56 EPC).

First auxiliary request

Amendments - Article 123(2) EPC

28. Claims 1 to 5 are identical to claims 1 to 5 of the main request but for the wording "1. A parenteral pharmaceutical formulation consisting of an aqueous insulin preparation consisting of: ..." (emphasis added by the board) in claim 1, i.e. a change of the "comprising" wording to the "consisting of" wording.

29. The meaning of the word "comprising" is generally interpreted as encompassing all the specifically mentioned features as well as optional, additional unspecified ones, whereas the term "consisting of" only includes those features as specified in the claim. Therefore, "comprising" includes as a limiting case the composition specified by "consisting of". The board is satisfied, therefore, that the amendment from the former into the latter does not extend beyond the content of the application as originally filed (see also e.g. decisions T 457/98 of 6 February 2001, point 2.1.1 and T 425/98 of 12 March 2002, point 3.1).

Inventive step (Article 56) EPC

30. Document (D1) discloses in example 1 a porcine Zn-insulin preparation, NaCl, glycerol and phenol and the pH was adjusted by NaOH. The parenteral preparation of claim 1 differs therefore from this disclosure in the aspects of the specific use of the human AspB28 analogue instead of the bovine insulin, the addition of m-cresol and use of a phosphate in the preparation. On the other hand, the wording "consisting" causes the subject-matter of claim 1 to differ from the insulin preparation in document (D3), by the substitution of the bovine insulin for the human AspB28 analogue, by the omission of the polypropylene glycol and by the addition of m-cresol.

31. Accordingly the change starting from document (D1) is the substitution of the active compound and the addition of two compounds, whereas the change starting from the disclosure in (D3), representing the closest prior art for the assessment of the invention in the main request, is the substitution of the active compound, the addition of one compound and the omission of an other compound. In view of the prudent nature of the skilled person when setting out to experiment with modifying the state of the art to solve technical problems encountered, the board considers that, rather than omitting specific compounds from prior art preparations, he would experiment with gradually adding further compounds to existing preparations, with a view of not generating unforeseen adverse effects created by the absence of compound though necessary in the prior art preparations. In case of the present invention therefore the board considers document (D1) to represent the closest prior art.

32. Starting from document (D1) the board considers the problem to be solved as the provision of alternative human insulin preparations having improved stability characteristics over those disclosed in document (D1).

33. As reiterated before, the board notes that in column 3, lines 35 to 40, document (D1) explicitly advises the skilled person not to use phosphate buffer in the human insulin preparations disclosed.

34. The board therefore considers that the skilled person, when starting from the disclosure of document (D1) would not as a matter of routine experimentation both change the active ingredient of the insulin preparation and, against the explicit advice in document (D1) itself, buffer the solution with a phosphate buffer in order to solve the problem to be solved.

35. In view of the above considerations the subject-matter of claim 1 was not rendered obvious by the prior art. Seeing that claims 2 to 5 depend on claim 1, their subject-matter is neither rendered obvious. The subject-matter of claims 1 to 5 therefore involves an inventive step.

Sufficiency of disclosure

36. The respondent has argued that from Figure 4 in document (D4) it could be taken that the formation of covalent dimer and polymers of insulin was highly dependent on the pH of the preparation. Therefore claim 1 should contain an indication of the pH of the parenteral insulin preparation claimed.

37. The board construes this objection as one that claim 1 lacks essential technical features. However, such an objection pertains not to the question of reproducibility of the invention and therefore sufficiency of disclosure within the meaning of Article 83 EPC, for which the disclosure as a whole is the criterion, but to an objection under Article 84 EPC, which is not a ground for opposition. Only for this reason this objection must fail.

38. In view of the above considerations the board is satisfied that claims 1 to 5 of auxiliary request 1 satisfy the requirements of the EPC.