T 1772/06 (Clarithromycin/ABBOTT) 16-10-2007

I. European patent No. 0 915 899 with the title "Preparation of crystal Form II of clarithromycin" based on European patent application No. 97 934 319.1 (published as WO 98/04574) was granted with 19 claims.

II. The patent was opposed by nine parties on the grounds of Article 100(a) EPC 1973, in particular lack of novelty (Article 54 EPC 1973), lack of inventive step (Article 56 EPC 1973) and non-patentable discovery (Article 52(2)(a) EPC 1973), as well as on the grounds of Article 100(b) and (c) EPC 1973. Opponent 8 withdrew its opposition on 4 April 2006.

III. In a decision announced at the end of the oral proceedings on 29 June 2006 and issued in writing on 12 September 2006, the opposition division found that none of the seven sets of amended claims then on file fulfilled the formal requirements of the EPC 1973. In particular, the sets of claims corresponding to the main request and the second, third and fourth auxiliary requests then on file were found to offend against Article 123(2) EPC 1973, because the feature "solvent free" present in, inter alia, claim 1 of each of these requests was not clearly and unambiguously disclosed in the original application. The opposition division held that, by introducing the feature "solvent free" into the claims, the patent had been amended in such a way that it contained subject-matter which extended beyond the content of the application as filed (cf. Article 123(2) EPC 1973). Consequently, the patent was revoked pursuant to Article 102(1) EPC 1973.

IV. The proprietor of the patent (appellant) lodged an appeal against the decision of the opposition division. With its statement setting out the grounds of appeal, the appellant filed five sets of claims, a main request and four auxiliary requests, which replaced the requests considered by the opposition division. New evidence in the form of a declaration and a scientific publication was also filed. In the event that the board was not minded to allow the main request, the appellant requested oral proceedings.

V. The respondents were given the opportunity to comment on the statement setting out the grounds of appeal. The board nevertheless considered it expedient to summon the parties to oral proceedings even prior to expiry of the time limit set for filing comments.

VI. All respondents except for respondent II (opponent 2) submitted observations to the grounds of appeal and/or the amended requests. Respondent V (opponent 5) filed additional documentary evidence. Respondent II announced that it would not attend and would not be represented at the oral proceedings.

VII. In a communication under Article 11(1) of the Rules of Procedure of the Boards of Appeal (RPBA) as it entered into force on 1 May 2003 (OJ EPO 2003, 60), the board provided comments on the amendments introduced into the sets of claims filed with the statement of grounds of appeal, as well as on some of the issues decided upon in the decision under appeal.

VIII. By letter dated 26 September 2007, the appellant withdrew all sets of claims then on file and submitted six sets of amended claims, a main request and five auxiliary requests, for consideration by the board.

IX. Claims 1 and 17 of the main request read as follows:

"1. A method of preparing solvent free 6-O-methylerythromycin A crystal Form II comprising

(a) treating 6-O-methylerythromycin A with a solvent selected from the group consisting of

(i) an alkanol of from 1 to 5 carbon atoms, provided said alkanol is not ethanol or isopropanol

(ii) a hydrocarbon of from 5 to 12 carbon atoms,

(iii) a ketone of from 3 to 12 carbon atoms,

(iv) a carboxylic ester of from 3 to 12 carbon atoms, provided said carboxylic ester is not isopropyl acetate,

(v) an ether of from 4 to 10 carbon atoms of formula ROR', where R and R´ are straight or branched alkyl,

(vi) benzene,

(vii) benzene substituted with one or more substituents selected from the group consisting of

alkyl or from one to four carbon atoms,

alkoxy of from one to four carbon atoms,

nitro, and

halogen,

(viii) a polar aprotic solvent,

(ix) a compound having the formula HNR1R2 wherein R1 and R2 are independently selected from hydrogen and alkyl of one to four carbon atoms, provided that R1 and R2 are not both hydrogen,

(x) water and a water miscible solvent selected from the group consisting of a water miscible organic solvent and a water miscible alkanol,

(xi) methanol and a second solvent selected from the group consisting of

a hydrocarbon of from 5 to 12 carbon atoms,

an alkanol of from 2 to 5 carbon atoms,

a ketone of from 3 to 12 carbon atoms,

a carboxylic ester of from 3 to 12 carbon atoms,

an ether of from 4 to 10 carbon atoms,

benzene, and

benzene substituted with one or more substituents selected from the group consisting of

alkyl of from one to four carbon atoms,

alkoxy of from one to four carbon atoms,

nitro, and

halogen

and

(b) isolating the 6-O-methyl erythromycin A Form II crystals to separate them and remove any remaining solvents.

17. Solvent free 6-O-methylerythromycin A crystal Form II having the following characterizing x-ray 2-theta angle positions: 8.39 ± 0.20, 9.33 ± 0,20, 10.72 ± 0.20, 11.33 ± 0.20, 11.74 ± 0.20,12.24 ± 0.20, 13.62 ± 0.20,13.97 ± 0.20, 15.03 ± 0.20, 16.37 ± 0.20, 16.80 ± 0.20, 17.16 ± 0.20, 17.38 ± 0.20, 17.97 ± 0.20, 18.20 ± 0.20, 18.91 ± 0.20, 19.75 ± 0.20, 20.34 ± 0.20, 22.08 ± 0.20 and 24.79 ± 0.20."

Claims 2 to 16, 18 and 19 were identical to the corresponding claims as granted, and concerned particular embodiments of the method of claim 1 (claims 2 to 16) and specific medical uses of the compound of claim 17 (claims 18 and 19).

X. At the oral proceedings, which took place as scheduled on 16 October 2007, all parties to the appeal except for respondent II were represented.

XI. The parties presented their arguments on issues related to Article 123(2) EPC 1973 with respect to the main request. After the discussion, the appellant submitted an amended set of claims as auxiliary request 1 which replaced the auxiliary requests previously on file. Claim 1 of this request differed from the corresponding claim of the main request in that the claimed method comprised the additional step of "(a) converting erythromycin A to 6-O-methylerythromycin A;", the previous step (a) becoming step (b), and that step (c) (previous step (b)) read:

"1. ...

(c) isolating the 6-O-methylerythromycin A Form II crystals by filtration and drying in a vacuum oven at a temperature of between ambient temperature (from 20 to 25ºC) and 50ºC, and a pressure of between 6.8 kPa [2 inches of mercury] and atmospheric pressure to remove any remaining solvent."

Additionally, claim 17 was amended to insert the phrase "... obtainable by the method of any one of claims 1 to 16" at the end of the claim. Dependent claims 2 to 16 and independent claims 18 and 19 remained as granted.

XII. The following documents are referred to in the present decision:

D11: Iwasaki et al., 1993, Acta Cryst. C49, pages 1227 to 1230;

D14: ICH Harmonised Tripartite Guideline "Impurities: Residual Solvents", CPMP/ICH/283/95, published on September 1997, pages 1/18 to 18/18;

D42: WO 98/31699, published on 23 July 1998;

AP2: Witness Statement of Dr Cynthia B. Curty dated 25 September 2007.

XIII. The submissions made by the appellant, as far as they are relevant to this decision, may be summarized as follows:

In coming to the erroneous conclusion that the application did not teach the removal of solvent from a solvate of clarithromycin (6-O-methylerythromycin A) Form II, the opposition division made a distinction between "solvent free" and "solvate free" that was present neither in the application nor in the patent. In the context of the patent, "solvent" referred to the liquid medium used to prepare a supersaturated solution of clarithromycin, from which clarithromycin Form II could be isolated. It was the common practice of the person skilled in the art to dry pharmaceutical active ingredients so that they were essentially free of residual solvents. This was described in various textbooks of practical organic chemistry cited in opposition proceedings.

However, when concluding that the term "solvent free" could not encompass "solvate free", the opposition division seemed to have assumed that, first, solvates would inevitably be formed by clarithromycin and the solvents mentioned in the process claim, and, second, that under the conditions generally used by the skilled person, this "bound" solvent could not be removed. However, no evidence on the formation of solvates of clarithromycin was filed in opposition proceedings. Although D11 described a methanolate solvate of clarithromycin, this document did not describe how the solvate was produced. Moreover, no evidence was presented showing that "bound" solvent could not easily be removed from a solvate.

The opposition division seemed to have assumed that different conditions were required to remove "bound" solvent from a solvate, relative to the normal conditions for removing "non-bound" solvent from a solid pharmaceutical substance. However, the conditions for removing "unbound" solvent and "bound" solvent could be the same. The ease of removal of solvent depended, amongst other things, on the crystal structure of the pharmaceutical products and on the solvent. The sole document on file describing the preparation of solvates of clarithromycin was D42, and the results therein showed that solvates of clarithromycin could be readily desolvated to give a solvent free form of clarithromycin Form I, under drying conditions which were commonplace for pharmaceutical products and identical to the general conditions taught in the application as filed, at the top of page 8.

The disclosure of the application, in particular the passage on page 8, lines 1 to 3 left the skilled person in no doubt that clarithromycin Form II was to be dried to remove any remaining solvent. However, the skilled person knew that it was not practicable to remove all remaining traces of solvent. In the context of the patent, the skilled person would construe "dried ... to remove any remaining solvent" to mean remove, as far as practicable, solvent from the clarithromycin. The products obtained in the experiments described in declaration AP2, which corresponded to Examples 8 and 10 of the patent, would be considered by the person skilled in the art to be "solvent free" and to comply with the guidelines for residual solvents set out in D14.

XIV. The submissions by the respondents were as follows:

The term "solvent free" had not been disclosed, let alone defined in the original application. This term was introduced into the claims during the examination proceedings in order to delimit the claimed subject-matter against a prior art document cited by the examining division. During the oral proceedings before the opposition division, the proprietor (appellant) contended that the term "solvent free" was to be construed to indicate that all solvent, ie. not only the free solvent, but also the solvent bound in a solvate had to be eliminated. Thus, independently from the crystal form and the solvent used, the term "solvent free" had to be understood as "completely free of solvent".

If so construed, the feature "solvent free" could not be clearly and unambiguously derived from the original application. There was neither an explicit nor an implicit disclosure which could serve as a basis for the amended claims 1 and 17. Neither the intended use of 6-O-methylerythromycin A crystal Form II for the manufacture of a medicament nor the drying conditions described in the application implied that the compound must be completely free of solvent. According to D14,

crystals of an active substance did not need to be completely free of solvent; rather, residual solvents were often present in medicaments, eg. when the active substance was a hydrate.

XV. The appellant (patentee) requested that the decision under appeal be set aside and the patent be maintained on the basis of the main request filed on 26 September 2007 or auxiliary request 1 filed during the oral proceedings.

XVI. The respondents (opponents) requested that the appeal be dismissed.