T 0943/01 (Aerosol formulations/BOEHRINGER) 23-03-2006

I. The appellant is proprietor of European patent No. 0 673 240 ("the patent"), which was granted with effect from 24 March 1999 on the basis of European patent application No. 94 903 467.2 (International application No. PCT/US93/11801, published under the PCT as WO 94/13262) filed on 6 December 1993, claiming two US priorities of 9 December 1992 (Serial No. 987 852) and 22 November 1993 (Serial No. 153 549). The patent as granted contained two independent claims reading as follows:

"1. An aerosol solution formulation comprising a medicament, selected from the group consisting of ipratropium bromide, oxitropium bromide, albuterol, tiotropium bromide and fenoterol, an HFC propellant, an organic cosolvent, and either an inorganic or an organic acid wherein the medicament chemically degrades or decomposes by interaction with the cosolvent or water or other mechanism, such chemical degradation having the capability of being reduced to acceptable levels by the addition of the inorganic or organic acid and wherein the acid is present in an amount sufficient to reduce the chemical degradation to an acceptable level.

9. An aerosol solution formulation comprising ipratropium bromide, an HFC propellant, ethyl alcohol and an inorganic acid or an organic acid wherein the ipratropium bromide chemical degradation by interaction with cosolvent or water is reduced to acceptable levels by the addition of the inorganic or organic acid to the aerosol solution formulation."

Dependent claims 2 to 8 related to specific embodiments of the aerosol solution formulation according to claim 1 and dependent claims 10 to 16 to specific embodiments of the aerosol solution formulation according to claim 9.

II. The respondent originally filed notice of opposition requesting revocation in full of the European patent pursuant to Article 100(a) EPC on the ground of lack of inventive step (Article 56 EPC) and pursuant to Article 100(b) EPC on the ground of insufficiency of disclosure (Article 83 EPC).

III. Of the numerous documents cited during the first-instance opposition and subsequent appeal proceedings against the patentability of the claimed subject-matter in the patent in suit, the following remain relevant to the present decision:

(4) K.L. Rominger (C.H. Boehringer Sohn, Department of Biochemistry, Ingelheim) "Chemistry and Pharmacokinetics of Ipratropium bromide", Scand. J. Resp. Dis. Suppl. 103, 1979, pages 116 to 126;

(5) Advances in Pharmaceutical Sciences, edited by H.S. Bean et al, Volume 2, 1967, Academic Press London and New York, pages 2-83;

(10) EP-A-3 72 777;

(11) ABPI Data Sheet Compendium, 1990-91, pages 215-216, Datapharm Publications Limited, 12 Whitehall, London SW 1A 2DY;

(12) Compendium Suisse des Médicaments 1991, edited by J. Morant et al, Documed, pages 1158-1159;

(13) Morrison/Boyd, Lehrbuch der Organischen Chemie, Dritte völlig neu bearbeitete Auflage, VCH, pages 939-942.

IV. During the oral proceedings before the opposition division, the proprietor presented as its new main request an amended set of claims which differed from those as granted only in that albuterol (i.e. a synonym for the medicament salbutamol mentioned in citation (10) - see page 5, lines 18-19; Example 5 and Example 24 with surfactant No. 6) - had been deleted from the list of the medicaments recited in claim 1 (see I above).

In addition to its main request, the proprietor presented at the hearing before the opposition division two auxiliary requests, designated auxiliary requests 2 and 3. The only difference between the above main request and auxiliary request 2 was that the organic cosolvent had been specified in claim 1 as being ethyl alcohol.

Claim 1 of the auxiliary request 3 read as follows:

"1. An aerosol solution formulation comprising a medicament, selected from the group consisting of fenoterol, ipratropium bromide, oxitropium bromide and tiotropium bromide, an HFC propellant, ethyl alcohol,

and either an inorganic or an organic acid wherein the medicament chemically degrades or decomposes by interaction with ethyl alcohol or water, such chemical degradation having the capability of being reduced to acceptable levels by the addition of the inorganic or organic acid in a range of about 0.10 - 0.000 0001 normal for the inorganic acids corresponding to an aqueous pH range of about 1.0 to 7.0 and which must be calculated for the organic acids depending on their pKa values, and wherein the acid is present in an amount sufficient to reduce the chemical degradation to an acceptable level."

V. The essence of the reasoning in the opposition division's decision to revoke the patent was as follows:

(a) As regards the admissibility of lack of novelty as a ground for opposition, the opposition division noted that this ground was invoked by the opponent for the first time in its letter of 20 February 2001, i.e. more than one year after the time limit set in Article 99(1) EPC for giving notice of opposition had expired. With reference to decisions G 9/91 (OJ EPO 1993, 408) and G 10/91 (OJ EPO 1993, 420), the opposition division pointed out that consideration of grounds not properly covered by the statement pursuant to Rule 55(c) EPC should only take place before it in cases where, prima facie, there were clear reasons to believe that such grounds were relevant and would in whole or in part prejudice the maintenance of the European patent. The possibility of disregarding facts and evidence in support of fresh grounds not submitted in due time under Article 114(2) EPC should of course also be kept in mind. Since, in the opposition division's judgment, the late-filed, allegedly novelty-destroying citation (10) was prima facie not prejudicial to the novelty of the claimed subject-matter in all three requests before it, it decided not to admit lack of novelty as a fresh ground of opposition into the proceedings.

(b) Although citation (10) was filed late together with the opponent's letter of 20 February 2001, and not relevant to the assessment of novelty, the opposition division found that this citation was of greater relevance to the assessment of inventive step than any of the prior-art documents already on file and decided to admit citation (10) into the proceedings.

(c) As regards inventive step, the decision under appeal stated that (10) taught aerosol formulations comprising an HCF propellant, a cosolvent, a medicament, preferably ipratropium bromide, and a surfactant (see (10), page 3, lines 16-17; page 5, lines 12-23). The opposition division did not share the opponent's submission, that (10) already taught the use of an acid for the stabilization of the aerosol formulation. It pointed out that the oleic acid mentioned in the cited document (see page 5, line 5; Example 24, page 9, No. 6; claim 10) was added in (10) as a surfactant and that (10) was silent about the possibility of using acids for stabilization of the aerosol formulation disclosed in (10).

(d), The opposition division referred, however, to citation (4), which disclosed that ipratropium bromide was in neutral and acid solutions rather stable, whereas the ester binding linking the two molecular parts of ipratropium bromide, namely the alcoholic N-isopropyl-noratropine moiety and the tropic acid part, was hydrolysed rapidly in alkaline solution. The logical inference was, in the opposition division's view, that those skilled in the art, faced with the problem of reducing the degradation or decomposition of ipratropium bromide resulting from interaction of the active agent with the cosolvent or water in aerosol formulations and knowing the teaching of (4) would try to keep the concentration of hydroxyl ions as low as possible in such formulations by the addition of an acid to lower the pH value of the formulation.

(e) The opposition division also did not accept the proprietor's argument that the beneficial effect of using an acidic pH on the stability of the active agent was not foreseeable for non-aqueous systems because, as pointed out by the opposition division, neither the claimed aerosol solution formulations were limited in the claims to non-aqueous systems nor the total exclusion of water from the claimed aerosol formulations was possible, particularly if ethanol was used as the cosolvent.

(f) The opposition division found that the above-mentioned arguments against the presence of an inventive step equally applied to auxiliary requests 2 and 3 and decided to revoke the patent.

VI. The appellant lodged an appeal against this decision, paid the appeal fee and submitted a statement setting out the grounds of appeal within the time limit set in Article 108 EPC. In addition to its main request that the decision under appeal be set aside and that the patent be maintained on the basis of the main request before the opposition division (see IV above), the appellant filed an auxiliary request, wherein in claim 1 the more general reference to "an organic cosolvent" was limited to "an alcohol cosolvent".

VII. In its reply, the respondent maintained its objections to the maintenance of the patent on the basis of the appellant's main request or auxiliary request on the grounds of lack of novelty and lack of inventive step and requested that the appeal be dismissed. At the appeal stage, the respondent did not maintain the ground for opposition under Article 100(b) EPC. Together with its reply, the respondent submitted the new citations (11) and (12).

VIII. In advance of the oral proceedings before the board, fixed for 23 March 2006, the appellant filed with its letter of 22 February 2006 further observations and submitted, in addition to its main request that the patent be maintained on the basis of the claims in the main request before the opposition division (see IV above), auxiliary requests 1 to 3.

Accordingly, claim 1 of the main request reads as follows:

"1. An aerosol solution formulation comprising a medicament, selected from the group consisting of ipratropium bromide, oxitropium bromide, tiotropium bromide and fenoterol, an HFC propellant, an organic cosolvent, and either an inorganic or an organic acid wherein ........... (see I above, claim 1 as granted) ......... acceptable level."

Claims 2 to 16 are identical to the corresponding claims in the patent as granted.

Claim 1 of the first auxiliary request reads as follows with the sole amendment to the main request (see VIII above) being indicated in bold italic letters:

"1. An aerosol solution formulation comprising a medicament, selected from the group consisting of ipratropium bromide, oxitropium bromide, tiotropium bromide and fenoterol, an HFC propellant, an alcohol cosolvent, and either an inorganic or an organic acid ........... (see I above, claim 1 as granted) ......... acceptable level."

As the second auxiliary request the appellant erroneously presented a set of claims which was identical to that in the first auxiliary request.

Claim 1 of the third auxiliary request reads as follows, the amendments to the main request (see VIII above) being indicated in bold italic letters:

"1. The use of an inorganic or an organic acid for reducing the chemical degradation or decomposition of the medicament in an aerosol solution formulation comprising a medicament, selected from the group consisting of ipratropium bromide, oxitropium bromide, tiotropium bromide and fenoterol, an HFC propellant, an alcohol cosolvent, wherein the medicament chemically degrades or decomposes by interaction with the cosolvent or water or other mechanism, such chemical degradation having the capability of being reduced to acceptable levels by the addition of the inorganic or organic acid and wherein the acid is used in an amount sufficient to reduce the chemical degradation to an acceptable level."

IX. In reply to the appellant's new submissions and requests filed on 22 February 2006, the respondent filed with its letter of 16 March 2006 observations of its own and maintained its request that the appeal be dismissed.

X. Oral proceedings were held on 23 March 2006 in the presence of the appellant and the respondent. At the beginning of the proceedings, the appellant filed an amended second auxiliary request to replace the second auxiliary request filed on 22 February 2006 (see VIII above).

Claim 1 of the amended second auxiliary request reads as follows, the sole amendment to the main request (see VIII above) being indicated in bold italic letters:

"1. An aerosol solution formulation comprising a medicament, selected from the group consisting of ipratropium bromide, oxitropium bromide, tiotropium bromide and fenoterol, an HFC propellant, ethyl alcohol, and either an inorganic or an organic acid wherein ........... (see I above, claim 1 as granted) ......... acceptable level."

Claims 2 to 16 are identical to the corresponding claims in the patent as granted.

XI. Towards the end of the oral proceedings, the appellant announced its intention to file certain new requests and asked for a short break of the proceedings, which was allowed. After the break, it sought to introduce new auxiliary requests 4 to 7.

Claim 1 of the fourth auxiliary request reads as follows, the sole amendment to the main request (see VIII above) being indicated in bold italic letters:

"1. An aerosol solution formulation comprising a medicament, selected from the group consisting of ipratropium bromide, oxitropium bromide, tiopropium bromide and fenoterol, an HFC propellant, an organic cosolvent, up to about 5% by weight of water and either an inorganic or an organic acid wherein ........... (see I above, claim 1 as granted) ......... acceptable level."

Claim 1 of the fifth auxiliary request reads as follows, the amendments to claim 1 of the main request (see VIII above) being indicated in bold italic letters:

"1. An aerosol solution formulation comprising a medicament, selected from the group consisting of ipratropium bromide, oxitropium bromide, tiotropium bromide and fenoterol, an HFC propellant, an organic cosolvent, up to about 5% by weight of water and either an inorganic acid selected from the group consisting of sulfuric acid, hydrochloric acid, nitric acid, and phosphoric acid, or an organic acid selected from the group consisting of ascorbic acid and citric acid, wherein ........... (see I above, claim 1 as granted) ......... acceptable level."

Claim 1 of the sixth auxiliary request reads as follows, the amendments to claim 9 as granted (see I above) and the identical claim 9 of the main request (VIII above) being indicated in bold italic letters:

"1. An aerosol solution formulation comprising ipratropium bromide, an HFC propellant, ethyl alcohol, up to about 5% by weight of water and an inorganic acid selected from the group consisting of hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid, or an organic acid selected from the group consisting of ascorbic acid and citric acid, wherein the ipratropium bromide chemical degradation by interaction with ethyl alcohol or water is reduced to acceptable levels by the addition of the inorganic or organic acid to the aerosol solution formulation."

Claim 1 of the seventh auxiliary request reads as follows the amendments to claim 9 as granted (see I above) and the identical claim 9 of the main request (see VIII above) being indicated in bold italic letters:

"1. An aerosol solution formulation comprising ipratropium bromide, an HFC propellant, ethyl alcohol, up to about 5% by weight of water, and about 0.0039 to 27.7 mg/ml of citric acid, wherein the ipratropium bromide chemical degradation by interaction with ethyl alcohol or water is reduced to acceptable levels by the addition of citric acid to the aerosol solution formulation."

XII. After deliberation on this point, the board announced its decision not to admit the late-filed auxiliary requests 4 to 7 into the proceedings.

XIII. The arguments presented by the appellant in its written and oral submissions, in so far as they are relevant to the present decision, are summarised below:

[1] It was recalled by the appellant that, in the notice of opposition pursuant to Rule 55(c) EPC, only lack of inventive step (Articles 100(a) and 56 EPC) and insufficiency of disclosure (Articles 100(b) and 83 EPC), but not lack of novelty (Articles 100(a) and 54 EPC), were invoked as grounds for opposition. It was also recalled that only more than one year after expiry of the time limit set in Article 99(1) EPC, i.e. with its letter of 20 February 2001, did the respondent introduce lack of novelty as a new ground for opposition based on citation (10), which was submitted together with the respondent's above-mentioned letter and was accordingly also filed late. The appellant also noted that, in the decision under appeal, the opposition division considered that the new ground for opposition was not admissible because it found that the content of (10) was prima facie irrelevant to the novelty of the claimed subject matter. In the appellants opinion, the respondent was now, at the appeal stage, making a second attempt to introduce lack of novelty as a fresh ground for opposition. According to the appellant, this attempt already had to fail for legal reasons in the light of decisions G 9/91 (loc. cit.) and G 10/91 (loc. cit.). Accordingly the respondent's request that this new ground for opposition be admitted had to be refused.

[2] Nevertheless, for illustration of the technical background, the appellant considered it useful and necessary to point out that, in referring to Examples 5 and 24 of (10) as the basis for attacking novelty, the respondent had apparently overlooked the fact that the claims in all current requests no longer covered salbutamol (i.e. a synonym for albuterol) as one of the medicaments comprised in the claimed aerosol solution formulations.

[3] In summary, on the basis of the observations in the foregoing points, it was, in the appellant's opinion, abundantly clear that novelty was neither on legal nor on technical grounds an issue to be treated in these appeal proceedings.

[4] As regards inventive step, the appellant stated that, as explained in section [0007] of the patent, the inventors of the claimed invention had found that the use of propellant systems containing an HFC propellant and an organic cosolvent in aerosol solution formulations presented a chemical stability problem that had neither been recognised previously nor resolved in the prior art. This chemical instability of certain medicaments, e.g. ipratropium bromide, in such HFC propellant/cosolvent systems resulted from a possible chemical interaction of the medicament with the cosolvent and/or traces of water present in the system to produce decomposition or degradation products. Accordingly, the technical problem to be solved was to provide an aerosol solution formulation containing a medicament selected from a specific group of drugs, including ipratropium bromide, oxitropium bromide, tiotropium bromide and fenoterol, said aerosol solution formulation being stable against chemical degradation and decomposition of the medicament. In the context of the present invention, "stable" meant "long-term stability" as required for drugs to be stored in pharmacies, hospitals, etc., and not short-term stability as would be sufficient for pharmacokinetic studies and the like.

[5] Citation (4), which was cited by the opposition division against the presence of an inventive step, was an article on the "Chemistry and Pharmacokinetics of Ipratropium bromide". The passage of interest was at the end of page 118 and read as follows: "Ipratropium bromide is a white, crystalline substance with a bitter taste. As a quaternary ammonium compound it is freely soluble in water and lower alcohols, but insoluble in lipophilic solvents, such as ether, chloroform and fluorohydrocarbons. In neutral and acid solutions the substance is rather stable; in alkaline solution the ester binding is hydrolysed rapidly." In this context the appellant observed that, as interpreted by the opposition division and the respondent, this passage motivated the expert to avoid alkaline media. Whilst the appellant admitted that this might possibly be true, it argued that the claimed invention was not about avoiding alkaline media. The present invention taught that, in order to stabilise certain medicaments in HFC/cosolvent aerosol solutions, one should add an inorganic or organic acid.

[6] In the appellant's opinion, the skilled person was not at all motivated by the teaching of citation (4) to add an inorganic or organic acid to a solution of ipratropium bromide because it had been demonstrated in the appellant's experimental report, submitted with its letter date 22 February 2006, that 0.01-0.1% aqueous solutions of ipratropium bromide themselves exhibited a slightly acidic pH value of between 5.07 to 5.31. In view of the teaching of citation (4) that "neutral and acid solutions of the substance are rather stable", those skilled in the art had, in the appellant's opinion, absolutely no reason to expect any particular benefit from adding additional acid to an already slightly acidic ipratropium bromide solution in order to improve the medicament's chemical stability. The appellant concluded that (4) simply did not provide or even suggest such a teaching.

[7] Citation (10) disclosed a self-propelling aerosol formulation which comprised a medicament, HFC-l34a as the propellant, a surface active agent and at least one compound having a higher polarity than HFC-134a as the cosolvent. In the appellant's view, citation (10) was primarily concerned with improving the physical dispersion stability of aerosol suspension formulations and did not disclose or suggest any solution to the problem of providing aerosol solution formulations stable against chemical degradation and decomposition of the medicament caused by interaction with the cosolvent or water. The "prophetic" sentence at page 3, lines 16-17, of (10) ("The presence of large amounts of solubilised surfactant may also assist in obtaining stable solution formulations of certain drugs.") was, in the appellant's opinion, not helpful either as it lead away from the technical solution proposed in the patent in suit, i.e. to employ an inorganic or organic acid as a stabiliser to reduce chemical degradation and decomposition of the medicament. Even if oleic acid was mentioned as an example of a suitable surfactant, this acid was used in (10) as a surface active agent rather than as an acidifier. Even if those skilled in the art had consulted the teaching of (10), they would not have had any incentive to select the surfactant in (10) given its acidic functionality, let alone to substitute an acid for the surfactant used in (10).

[8] Documents (11) and (l2) had been introduced by the respondent only at the appeal stage, together with its letter of 25 February 2002. Both these documents dealt with aqueous formulations of fenoterol hydrobromide and ipratropium bromide, respectively. Since neither of these documents related to HFC solution aerosol formulations, the appellant requested that these late-filed documents not be admitted into the proceedings as they were, in its opinion, irrelevant to the issues to be decided in the present case.

XIV. The respondent disagreed, relying in its written and oral submissions essentially on the following arguments:

[9] Aerosol solution formulations containing a broncho-dilator of the 2-phenylethylamine type as claimed (albuterol = salbutamol) as well as of the atropine type (ipratropium bromide), an HFC propellant, an organic cosolvent (ethanol) and an acid (oleic acid) were known from citation (10) - see Example 5 and Example 24 with surfactant No. 6, and claim 12 in combination with claims 10, 6 and 1. Contrary to the opinion of the opposition division in section 3.2 of the decision under appeal, it was irrelevant whether the function of oleic acid in the formulations of (10) was that of a surfactant. In any case, oleic acid was an acid. The "discovery" that oleic acid was also a "surfactant" could not establish the novelty of the claimed subject-matter in the patent. The respondent submitted that its opinion was also consistent with the principles set out in decision T 892/94 (OJ EPO 2000, pages 1 to 18, in particular sections 3.4 to 3.7 of the Reasons and Headnote II).

[10] In the contested patent itself, it was admitted, in sections [0005] to [0006] on page 2, that broncholytic aerosol solution formulations for inhalation containing as the medicament an atropine derivative or a phenylethylamine derivative (epinephrine; isproterenol HCl), a cosolvent, an HFC propellant and an acid were known in the state of the art. The respondent noted that in section [0007], on page 2, the patent alleged that the use of an HFC propellant and a cosolvent as the propellant system in aerosol solution formulations presented a chemical stability problem. In particular, the patent stated that in such HFC propellant/cosolvent systems, the medicament (the active compound) might interact with the cosolvent and/or water present in the system to produce decomposition or degradation products.

[11] It was pointed out by the respondent that the problem underlying the alleged invention as outlined in section [0007] of the patent was to provide such aerosol solution formulations having "the requisite chemical stability" of the active compound. The solution of this technical problem was formulated in the patent as follows: "the addition of an acid, either an inorganic acid or an organic acid, to the HFC propellant/cosolvent system provides the requisite chemical stability to the medicament" (see section [0007], last sentence).

[12] The respondent referred to the decision under appeal (see especially page 6, lines 4-9) where it was stated as a ground for the revocation: "When the patentee, starting from (10), is faced with the problem of increasing the stability of ipratropium bromide in solution aerosols, he would immediately try to provide for an acidic pH, i.e. to keep the concentration of OH ions as low as possible. Such a teaching is e.g. derivable from (4) (page 118, last complete paragraph), where the instability of ipratropium bromide in alkaline solution and its relative stability in neutral and acidic solution is clearly expressed." It concluded that it would have been obvious, when starting from the closest state of the art according to (10), in view of the teaching of (4), to add an acid or to use the medicament in the form of an acidic salt (acid addition salt; see patent description page 4, line 19) to provide stable solution formulations of ipratropium bromide or fenoterol containing an HFC propellant and a cosolvent. Citation (4) advised persons skilled in the art that an alkaline medium is strictly to be avoided to prevent degradation or decomposition of ipratropium bromide, which, in turn, provided the clear teaching to those persons to adjust the pH of a solution of ipratropium bromide to acidic conditions to be on the safe side. In this context, the respondent noted that the appellant's assertion that the claimed invention was not about avoiding alkaline media clearly contradicted the statement at page 5, lines 15 to 17, of the patent description that the pH of the claimed aerosol solution formulations should be adjusted to about 1.0-7.0 to effect an acceptable rate of decomposition of the medicaments.

[13] The respondent drew attention to citation (5), which gave a clear and complete explanation as to why, from a chemical point of view, ipratropium bromide was stable in acidic media, but unstable in alkaline media. Thus, citation (5) fully confirmed the teaching of (4) and taught that the concentration of hydroxyl ions should be kept as low as possible by adding an acid.

[14] The respondent submitted that, contrary to the appellant's opinion, the teaching of citations (l1) and (12) was also relevant to the claimed subject-matter and the decision to be taken in the present case. Citation (11) described an aqueous solution of fenoterol hydrobromide for administration by inhalation wherein the solution has a pH of approximately 3.2 and (12) described an aqueous solution of ipratropium bromide containing hydrochloric acid. In this context, the respondent referred to page 4, lines 29 to 34, of the patent description where it is stated: "In aqueous solution the rate of hydrolysis and esteriflcation is typically pH dependent. In aqueous solution, the degradation of ipratropium bromide exhibits a pH-rate minimum at pH 3.5. This corresponds to a hydrogen ion concentration of 3.2 x 1O-4molar (m) at 25(C. Although the concept of pH is poorly defined in non aqueous systems, formulation evaluation studies were conducted using this concentration of hydrochloric acid in the HFC-134(a)/ethanol system containing ipratropium bromide. Samples stored at 50(C for five and one-half months exhibited less than 5.5% loss of ipratropium bromide. A summary of these results is illustrated in Figure 1".

The respondent concluded therefrom that, at the appellant's own admission, the proposed solution of the stated problem simply required adding to the HFC-134(a)/ethanol system the same concentration of HCl that was known (e.g., from (11) and (12)) to be necessary to minimise the degradation of ipratropium bromide or fenoterol in an aqueous solution.

XV. The appellant requested that the decision under appeal be set aside and that the patent be maintained in amended form on the basis of one of the main, first or third auxiliary request, filed with letter dated 22 February 2006 or of the second auxiliary request filed in the oral proceedings, or, as a further auxiliary request, that the case be remitted to the first instance for further prosecution.

The respondent requested that the appeal be dismissed.