T 0360/07 (Magnesium omeprazole/SHERMAN) 09-02-2010

1. The appeal is admissible.

2. Article 123 EPC

2.1 Neither were the present claims objected to under Article 123 EPC, nor was the opposition based on grounds under Article 100(c) EPC.

2.2 Main Request / Fifth Auxiliary Request

Claims 1 to 13 of the Main Request, namely the claims as granted, are based on claims 1-3 and 5-14 as originally filed.

Claims 1 to 3 of the Main Request are identical to the claims of the Fifth Auxiliary Request.

2.3 First Auxiliary Request

Claims 1 to 13 as granted are based on claims 1-3 and 5-14 as originally filed, with amendments in claims 1 and 4 which are based on page 10, lines 18-21 of the application as filed.

2.4 Second Auxiliary Request

Claim 1 is based on original claim 1 and page 10, lines 9-10 ("having a degree of crystallinity of under 25%") and page 10, lines 18-21 of the application as filed. Claim 4 is based on original claim 5 and page 10, lines 9-10 and 18-21 of the application as filed. Claims 2, 3, and 5-10 are based on original claims 2, 3, 6-8 and 12-14.

2.5 Third Auxiliary Request

Claim 1 is based on original claims 1 and 3 and page 10, lines 9-10 ("having a degree of crystallinity of under 25%") and page 10, lines 18-21 of the application as filed. Claim 3 is based on original claim 5 and page 10, lines 9-10 and page 10, lines 18-21 of the application as filed. Claims 2 and 4-9 are based on original claims 2, 6-8 and 12-14.

2.6 Fourth Auxiliary Request

Claim 1 is based on original claim 1 and page 10, lines 9-10 ("having a degree of crystallinity of under 25%") and page 10, lines 18-21 of the application as filed. Claim 4 is based on original claim 7 and page 10, lines 9-10 and 18-21 of the application as filed. Claims 2, 3, and 5-8 are based on original claims 2, 3, 8 and 12-14.

2.7 All the amendments limit the scope of the claims.

2.8 Hence, the claims satisfy the requirements of Article 123 EPC.

3. Main Request / Novelty

3.1 The Respondent deemed the subject-matter of claim 4 not to be novel in view of document (D3). This document is a patent application published after the priority date of the patent in suit. Therefore, it has to be assessed to which extent document (D3) forms part of the prior art.

The patent in suit is based on an application filed on 04 August 2000, claiming the priority of an application filed on 16 November 1999. The validity of this priority was not disputed. It is based on the fact that the wording of the specification and the claims of the priority document is identical with the one of the application as originally filed.

Document (D3) was published on 02 June 2000. It is based on an application filed on 22 November 1999, claiming the priority of application (D4) filed on 23 November 1998.

The Appellant contended that the priority claimed in document (D3) was valid (see above under point VIII(a)). The Board is satisfied that the wording of document (D3) relevant for this decision, including the examples and claims of (D3), is identical with the one of the priority document (D4).

For these reasons, the relevant parts of document (D3) have a valid priority date prior to the one of the patent in suit and thus form part of the state of the art under Article 54(3).

In this context Article 54(3) EPC 2000 and Article 54(4) EPC 1973 apply (see the Decision of the Administrative Council of 28 June 2001 on the transitional provisions under Article 7 of the Act revising the European Patent Convention of 29 November 2000, special edition no. 1 OJ EPO 2007, 197, Article 1, paragraph 1).

3.2 Document (D3) discloses in example 2, experiment 2-1a the production of amorphous (s)-omeprazole magnesium salt by dissolving (s)-omeprazole magnesium salt in ethanol and introducing the solution into CO2 as an antisolvent.

3.3 Whereas claim 4 of the Main Request requires that the magnesium omeprazole has "a residual organic solvent content of less than 7% by weight", document (D3) does not specify the organic solvent content of the products disclosed therein.

Therefore, it is to be assessed whether or not this feature of claim 4 renders its subject-matter novel.

3.4 The Appellant considered decision T 0142/06 of 11 March 2008 to apply to this case rather than T 0990/96 (OJ EPO 1998, 489)(see under point VIII(a) above).

3.4.1 Decision T 0990/96 states that "... a document disclosing a low molecular chemical compound and its manufacture makes available this compound to the public in the sense of Article 54 EPC in all grades of purity as desired by a person skilled in the art" if "Conventional methods for the purification ... such as recrystallisation, distillation, chromatography, etc., which normally can be successfully applied in purification steps, are within the common general knowledge of those skilled in the art." (see point 7 of the reasons).

This statement is preceded by the following:

"It is common general knowledge that any chemical compound obtained by a chemical reaction will normally contain impurities for various reasons, such as side-reactions, incomplete conversion of starting materials, etc., and that it is not possible for thermodynamical reasons to obtain a compound, which is - in the strict sense - completely pure, i.e. totally free of any impurity." (see point 6 of the reasons).

This clearly indicates that the conclusion drawn in point 7 of the reasons for the decision not only applies to the type of impurity of the specific case (here the threo isomer in the respective erythro isomer) but to impurities in general, namely to any undesired compound present in the desired product.

3.4.2 The Appellant considered residual solvent not to be an impurity. It referred to US patent (D20) which defines that "references herein to 'impurities' are to be understood as not including residual solvents ..." (see column 2, lines 36-40). However, the word "herein" in this citation indicates that said definition was made only for the purpose of this document, possibly in contrast to the general meaning of the term "impurity".

Magnesium omeprazole is used as an active agent in pharmaceutical compositions (see document (D7), claims 8 to 11). High contents of organic solvents in general are undesirable and even moderate contents of methanol (the most preferred solvent according to the patent in suit) inacceptable in pharmaceutical compositions (see document (D22), the abstract and Table 1 on page 216; compare paragraphs [0001] and [0008] and claim 2 of the patent in suit).

Consequently, residual organic solvents in general and methanol in particular are to be regarded as impurities whenever present in magnesium omeprazole. Hence, the decision T 0990/96 might be relevant for the present case.

3.4.3 Decision T 0142/06 refers to T 0990/96 (see points 3.27 to 3.3.2 of the reasons). Under point 3.29 of the reasons it bases its deviation from T 0990/96 on the fact that only the low content of chlorine in the latex enables the production of films of the desired oxygen barrier and boil blushing properties. The present case differs from the one of T 0142/06 in that here the desired therapeutical effect is only based on magnesium omeprazole as such. Therefore, the reasons to deviate from T 0990/96 indicated in T 0142/06 do not apply to the present case. Consequently, there is no reason to apply the conclusions drawn in T 0142/06 to the present case.

3.4.4 Decision T 0990/96 states that the absence of impurities cannot contribute to novelty only if said purification can be achieved by conventional means (see point 7 of the reasons). Such conventional means include the evaporation of the solvent as suggested in example 6 of document (D7). Furthermore, detailed methods for the effective removal of residual solvents by drying were known from the review article (D22)(see chapter 3.2 on pages 236-237).

3.4.5 Consequently, there is no reason to deviate from the decision T 0990/96. All the features of claim 4 are explicitly disclosed in example 2, experiment 2-1a, of document (D3) except the requirement that the residual organic solvent content has to be less than 7% by weight. As this range for the organic solvent content cannot contribute to novelty, the subject-matter of claim 4 of the Main Request lacks novelty under Article 54(3) EPC 2000 for the contracting states designated both in document (D3) and in the patent in suit (see Article 54(4) EPC 1973), namely for all the states designated in the patent in suit.

3.4.6 The Board can only decide on a request as a whole. Hence, the Main Request is rejected.

4. First to Fourth Auxiliary Requests

4.1 Claim 4 of the First, Second and Fourth Auxiliary Requests and claim 3 of the Third Auxiliary Request differ from claim 4 as granted by the additional feature "an equilibrium water content of 5% to 8% depending on the relative humidity of the air" (see under point VII(b) and (c) above). It was under dispute whether or not this feature renders the claim unclear (see under point VIII(b) and IX(b) above).

4.2 Lack of clarity is no ground for opposition under Article 100 EPC. Nevertheless, the compliance with Article 84 EPC is to be examined in opposition and opposition appeal proceedings if an alleged lack of clarity arises from amendments after grant.

4.3 It was not under dispute that the "equilibrium water content" was to be interpreted as the property of the product to reach a certain water content if contacted with air. Hence, a magnesium omeprazole satisfying said requirement may have a water content outside the range of 5% to 8% if it is within that range after being equilibrated in humid air.

4.4 Neither does the patent disclose any details as to the relative humidity at which the "equilibrium water content" is to be determined nor did the Appellant claim that there was a standard method for its measurement.

4.5 It was undisputed that the "equilibrium water content" varied with the humidity of the air in which the sample was equilibrated. The claimed products are preferably substantially amorphous and thus do not contain or absorb any considerable amount of water of crystallisation. Consequently, their "equilibrium water content" will increase continuously with increasing humidity of the surrounding air.

4.6 For these reasons, the equilibrium water content of an amorphous magnesium omeprazole may be within the range of 5% to 8% if determined in relatively humid air, and may be below said range (and thus outside the scope of the claims) if measured in less humid air. Hence, the parameter "equilibrium water content" cannot be clearly and reliably determined. This renders the claims relating to this parameter unclear.

4.7 Therefore, the First to Fourth Auxiliary Request were rejected.

5. Fifth Auxiliary Request

The claims of this request are identical to claims 1 to 3 as granted. Hence, their examination is limited to the grounds for opposition under Article 100 EPC.

5.1 Novelty

The Respondent did not argue that the subject-matter of the claims of this request lacked novelty. It differs from the disclosure in documents (D3) and (D7) which do not teach the flash evaporation of the solvent. Hence, the Board is satisfied that the subject-matter of these claims is indeed novel.

5.2 Inventive step

5.2.1 The closest prior art

Document (D3) forms part of the state of the art under Article 54(3) EPC and thus shall not be considered when assessing inventive step (see Article 56 EPC).

Therefore, the Board concurs with the parties that document (D7) may be regarded as the closest prior art.

This document discloses in example 6 steps (i) and (ii) of the process of present claim 1, namely

i) reacting magnesium with methanol to produce magnesium methoxide in solution in methanol,

ii) adding omeprazole to the solution, the amount of omeprazole being 2 moles per mole of magnesium.

The magnesium omeprazole is recovered by "Evaporation". No details are given as to the temperature, pressure and duration of said "Evaporation".

5.2.2 The problem to be solved

One of the problems addressed in the patent in suit was "... to produce magnesium omeprazole that has acceptable low levels of methanol, ... by a simple process." (see paragraph [0014]). A comparison between examples 2 and 3 of the patent in suit shows that spray drying the reaction mixture (see example 3) may produce a magnesium omeprazole having a methanol content of 0.7 % whereas drying the same reaction mixture under vacuum at 50 ºC for four hours (see example 2) yields a product still containing 7.2 % by weight of methanol.

Example 2 of the patent in suit is supposed to be a comparative example according to example 6 of document (D7). This requires that the drying under vacuum at 50 ºC for four hours in example 2 can be considered as an appropriate "Evaporation" in the sense of example 6 of document (D7). Taking into account that the magnesium omeprazole is isolated in example 5 of document (D7) from its aqueous solution by "drying in vacuum at 40º for 24h", and that methanol is more readily evaporated than water due to its much lower boiling point (i.e. about 65 ºC at a pressure of 0.1 MPa), the evaporation step in example 2 of the patent in suit, namely drying in vacuum at 50 ºC for four hours to evaporate the methanol, appears to be appropriate when repeating example 6 of document (D7). Therefore, the comparison between examples 2 and 3 of the patent in suit allows for a proper comparison between the process of example 6 of document (D7) with the one of claim 1 of the patent in suit. Consequently, that comparison shows that the problem mentioned above is solved in view of document (D7) by the features of present claim 1.

In view of the outcome of this decision it is not necessary to decide whether or not a more ambitious problem was solved.

5.2.3 The solution

Document (D7) indicates the temperature and duration of the drying step in examples 1, 4 and 5 where the product is treated under reduced pressure at 40 ºC "over night", "for 20h" or "for 24h", respectively. Hence, this document discloses drying at low temperatures for extended periods of time. In contrast to this, flash evaporation as required in present claim 1 means evaporation at high temperatures for short periods of time. Therefore, document (D7) as such does not render the subject-matter of claim 1 obvious.

Document (D8) discloses spray drying of pharmaceutical starting materials and of drug extracts (see the left column, the first sentence under the heading "Sprühtrockner"). Documents (D19) and (D28) mention that spray drying is a common method in the manufacture of pharmaceutical dosage forms (see the abstract of (D19); see (D28), pages 3 and 4). Neither of these documents indicates that organic solvent might be more efficiently evaporated from a solid product by spray drying.

Document (D20) discloses to decrease the residual solvent content of Cefuroxamine Axetil either by evaporation in vacuo of the solvent from its solution in a mixture of diisopropyl ether and ethyl acetate (see preparation 2 in column 7) or by spray drying of its solution in acetone (see examples 1 to 3 and 18). The residual solvent content after evaporation in vacuo (0.2 % by weight) was almost as low as the best results achieved by spray drying (see examples 1 and 18: 0.15 % by weight) and considerably smaller than that of the other spray dried products (see examples 2 and 3). On the one hand these results cannot be compared because the solvents are different (and so are their boiling points). On the other hand, neither these examples nor the general teaching of the documents indicates that spray drying might more efficiently decrease the residual organic solvent content than evaporation in vacuo.

Document (D22) reports on the drying of pharmaceutical products in order to reduce their residual solvent content (see the first and last sentences of the abstract). It mentions that the residual methylene chloride content in microspheres was 2.1 % when prepared by the solvent evaporation method and 0.3 % when prepared by spray drying (see page 237, right column, lines 14-18). However, these microspheres have walls made of a polymer which may hinder the escape of solvent and thus requires special drying techniques (see page 236, right column, lines 2-3). Hence, the person skilled in the art could not have expected that the same effect occurred when drying magnesium omeprazole.

5.2.4 For these reasons, the subject-matter of claim 1 of the Fifth Auxiliary Request involves an inventive step. The same applies to the subject-matter of claims 2 and 3 which are dependent from claim 1.

6. Neither did the Appellant argue that the claims of the Fifth Auxiliary Request contravened the requirements of any other provision of the EPC nor has the Board found any reason to do so.

Hence, the claims of the Fifth Auxiliary Request meet the requirements of the EPC.

7. Remittal

The claims of the Fifth Auxiliary Request reduce the scope of the claims as granted considerably. In order to ensure that the description be properly adapted under Rule 42(1)(c) EPC to the claims thus amended, the Board exercises its discretion under Article 111(1) EPC by remitting the case to the department of first instance.