T 0715/10 (Stable liquid exendin formulations/Amylin Pharmaceuticals) 16-09-2014

Admissibility of the new main request

1. The appellant's auxiliary request 1 as filed with its letter of 21 August 2014 (i.e. its new main request, see sections IX and XI above) corresponds to auxiliary request 2 according to the notice of appeal and also to auxiliary request 2 which had been the subject of the decision of the opposition division, but with the following amendments in claim 1:

(1) The phrase "in an aqueous system" was inserted after the word "exendin";

(2) The phrase "leading to an isotonic or iso-osmolar solution in an aqueous continuous phase" was inserted after the term "iso-osmolality modifier".

2. In their decision, the opposition division had held auxiliary request 2 not to be allowable for the single reason that the feature "a stable parenteral liquid dosage form" was considered to extend the subject- matter claimed beyond the content of the application as filed, in contravention of Article 123(2) EPC (see point 13 of the reasons). In its statement of grounds of appeal the appellant duly gave reasons why it considered this part of the decision to have been wrong. In its reply respondent III raised inter alia further objections under Article 123(2) EPC (a) concerning the omission of the phrase "in an aqueous system" and (b) arguing that in relation to the iso-osmolality modifier, the dosage form according to the disclosure in the application as filed had to be an isotonic or an iso-osmolar solution in an aqueous continuous phase. Neither point had been the subject of the decision of the opposition division. In its communication pursuant to Article 15 RPBA the board indicated that in its view the feature "a stable parenteral liquid dosage form" was to be interpreted in a sense that all of the ingredients of the formulation were stable and that respondent III was correct about the omission of the phase "in an aqueous system" (see point (a), above). The board made no express comment on point (b), above. Auxiliary request 1 - the current new main request - was filed within the time limit set by the board for any response to its communication.

3. The board considers that the filing of the request was an appropriate response to the situation as it had developed. The request dealt with two of the points which had been raised in respondent III's reply, neither of which had played any role in the opposition division's decision, one of which the board had indicated as being possibly valid. It did not raise any new issue which could not be dealt with at the oral proceedings. The situation is quite different to that in decision T 1721/07 of 29 March 2012, point 13 of the reasons, where the board criticised the conduct of the appellant in waiting to see what the opinion of the board was before filing further requests. The relevant part of the decision reads as follows:

"13. Wie bereits angeführt ..., zeigen Zahl und Umfang der von den Beschwerdeführern im Laufe des Beschwerdeverfahrens eingereichten Schriftsätze, dass diese ausreichend Gelegenheit hatten, weitere Anträge zu einem früheren Zeitpunkt vorzulegen. Offenbar zogen es die Beschwerdeführer aber vor, abzuwarten, bis sie die Auffassung der Kammer zu den wenigen tatsächlich eingereichten Anträgen kannten, und erst dann - je nachdem, wie diese Auffassung ausfiel - Alternativen einzureichen. Wer als Beteiligter derart taktisch vorgeht, handelt unweigerlich auf eigenes Risiko; dies geht aus den Vorschriften der VOBK auch eindeutig hervor (wonach ein Beschwerdeführer beispielsweise mit seiner Beschwerdebegründung seinen vollständigen Sachvortrag einschließlich aller Anträge einreichen muss, Änderungen seines Vorbringens im Ermessen der Kammer stehen und eindringlich davon abgeraten wird, solche Änderungen nach Anberaumung der mündlichen Verhandlung oder gar - wie im vorliegenden Fall - während der mündlichen Verhandlung vorzunehmen (siehe Artikel 12(2), 13(1) und 13(3) VOBK)."

4. Clearly the later a party waits before filing requests the greater the risk that they will not be admitted. However, the board does not consider that the appellant overstepped the mark in the present case and in the exercise of its discretion therefore admitted the request (Articles 114(2) EPC in combination with Articles 12(1) and 12(3) RPBA).

Amendments (Article 123(2) EPC)

5. It is established case law that amendments are permitted within the limits of what a skilled person would derive directly and unambiguously, using common general knowledge, from the explicit or implicit disclosure of the application as filed as a whole. An implicit disclosure is what the skilled person would consider necessarily implied by what is explicitly disclosed (see Case Law of the Boards of Appeal, 7th edition, section II.E.1, page 361, fourth paragraph and page 362, sixth paragraph).

5.1 Claim 1 relates to a pharmaceutical formulation which is defined by the following features:

(i) it is a stable parenteral liquid dosage form;

(ii) its suitability for multi-use administration;

and the presence of

(iii) 0.005% to 0.4 % (w/v) of an exendin in an aqueous system; of

(iv) 0.02% to 0.5% (w/v) of an acetate, phosphate, citrate, or glutamate buffer, alone or in combination; of

(v) 1.0% to 10% (w/v) of a carbohydrate or polyhydric alcohol iso-osmolality modifier leading to an isotonic or iso-osmolar solution in an aqueous continuous phase; of

(vi) 0.005 to 1.0 % (w/v) of m-cresol; and

(vii) a pH between 4.0 and 6.0.

Thus the pharmaceutical formulation of claim 1 is in a "stable parenteral liquid dosage form" which contains exendin as active ingredient and a buffer, an iso-osmolality modifier and m-cresol as "inactive" ingredients, i.e. excipients.

5.2 It is uncontested by the parties that the application as filed explicitly only discloses that the active ingredient, i.e. exendin, is stable in this formulation. It is however an issue in the present case whether the application as filed also discloses that the formulation as a whole is stable.

5.3 In this respect the following passage can be found in the application as filed on page 43, line 1 to page 44, line 17:

"The formulation which best supports a parenteral liquid dosage form is one in which the active ingredient(s) is stable with adequate buffering capacity to maintain the pH of the solution over the intended shelf life of the product. The dosage form should be either an isotonic and/or an iso-osmolar solution to either facilitate stability of the active ingredient [...] If, however, the dosage form is packaged in a multi-use container, then a preservative is necessary. [...] Sodium chloride, as well as other excipients, may also be present, if desired. Such excipients, however, must maintain the overall stability of the active ingredient. Polyhydric alcohols and carbohydrates [...]. These two classes of compounds will also be effective in stabilizing protein against denaturation caused by elevated temperature and by freeze-thaw or freeze-drying processes." (Emphasis added by the board).

5.4 This passage explicitly discloses that the active ingredient exendin is stable and also that it is the function of the cited excipients to maintain the overall stability of the active ingredient (see the passages in bold).

5.5 In the board's judgement, the skilled person using common general knowledge would derive from the passage cited in point 5.3 above that the stability of exendin as active ingredient in the liquid formulation of claim 1 depends on the proper functioning of all the excipients present, or in other words, that the stability of exendin is the direct consequence of the activity of the individual excipients. This would be understood by the skilled person to mean that the formulation is stable. It follows therefore that the application as filed implicitly discloses a formulation which is stable as a whole.

6. The respondents further objected to the feature "suitable for multi-use administration" of claim 1. With reference to page 43, lines 12, 13 and 30 to page 44, line 1 of the application as filed they argued that a multi-use administration of the claimed formulation is only disclosed if it is packaged in a multi-use container (see the underlined passage in point 5.3 above).

6.1 However, the application as filed discloses on page 14, lines 3 to 8:

"The invention also includes lyophilized and liquid multi-dose formulations. As with the parenteral liquid and lyophilized unit-dosage formulations described above, the lyophilized multi-unit-dosage form should contain a bulking agent to facilitate cake formation. A preservative is included to facilitate multiple use by the patient." (Emphasis added by the board).

6.2 In the board's judgement this disclosure presents a direct and unambiguous disclosure for a parenteral liquid dosage form suitable for multi-use administration according to claim 1, i.e. for a multi-use administration without the concomitant requirement for the packaging of the formulation in a multi-use container.

7. The respondents further objected to the combination of m-cresol with the other features of claim 1 as being not disclosed in the application as filed.

7.1 The subject-matter of claim 1 as outlined in point 5.1 above concerns a pharmaceutical formulation which is defined by features (i) to (vii).

7.2 The application as filed discloses a formulation which is a stable parenteral liquid dosage form (i.e. feature (i)) and suitable for multi-use administrations (i.e. feature (ii)) for the reasons given in points 5.3 to 6.2 above.

7.3 Moreover, the application as filed discloses in the passage cited in point 5.3 above in the context of a formulation which best supports the parental liquid dosage form of the invention:

"0.005 to about 0.4% [...] (w/v), respectively of the active ingredient in an aqueous system" [i.e. feature iii]; "0.02 to 0.5% (w/v) of an acetate, phosphate, citrate or glutamate or similar buffer either alone or in combination" [i.e. feature iv]; "1.0 to 10% (w/v) of a carbohydrate or polyhydric alcohol iso-osmolality modifier (preferably mannitol) or up to about 0.9% saline or a combination of both leading to an isotonic or an iso-osmolar solution in an aqueous continuous phase" [i.e. feature v], "0.005 to 1.0% (w/v) [i.e. feature vi] of an anti-microbial preservative selected from the group consisting of m-cresol, benzyl alcohol, methyl ethyl, propyl and butyl parabens and phenol".

M-cresol [i.e. feature vi] is the preferred preservative in this list of preservatives (see page 14, lines 27 to 30 of the application as filed). The passage cited in point 5.4 above further discloses "4.0 to 6.0" [i.e. feature vii] (emphasis added by the board).

7.4 The board notes that m-cresol is not only disclosed in this passage as one of the suitable preservatives, but that it is also highlighted as the preferred one. In the board's view this passage thus discloses a combination of the features (iii) to (vii) of present claim 1 as outlined in point 5.1 above.

7.5 Hence, the board considers that in view of points 7.2 and 7.3 above that the application as filed discloses the combination of m-cresol with all the other features of claim 1.

8. The respondents have not raised objections pursuant to Article 123(2) EPC against the subject-matter of claims 2 to 11. Also the board has none. Thus, it is concluded that the subject-matter of claims 1 to 11 meets the requirements of Article 123(2) EPC.

Extension of protection (Article 123(3) EPC)

9. None of the respondents has raised an objection pursuant to Article 123(3) EPC against the amended subject-matter of claim 1. Also the board has none. The subject-matter of claim 1 thus meets the requirements of Article 123(3) EPC.