Arrow Generics Limited V. Azko Nb (represented In Scotland By Organon Laboratories Limited For Revocation Of Claims 1-3 And 5 Of European Patent Eo 0 389 035
| Jurisdiction | Scotland |
| Judge | Lord President,Lord Kingarth,Lord Clarke |
| Neutral Citation | [2008] CSIH31 |
| Date | 20 May 2008 |
| Court | Court of Session |
| Published date | 20 May 2008 |
| FIRST DIVISION, INNER HOUSE, COURT OF SESSION | |
| Lord President Lord Kingarth Lord Clarke | [2008] CSIH31 OPINION OF THE LORD PRESIDENT in RECLAIMING MOTION by ARROW GENERICS LIMITED Petitioner and Respondent; against AKZO NB (Represented in Scotland by ORGANON LABORATORIES LIMITED Respondent and Reclaimer: for Revocation of claims 1-3 and 5 of European Patent EP 0 389 035 _______ |
Act: Currie, Q.C., Higgins; Maclay Murray & Spens (Petitioners and Respondents)
Alt: McNeill, Q.C., Delibegović-Broome; McClure Naismith (Respondents and Reclaimer)
20 May 2008
Introduction
[1] In these proceedings the petitioner (the respondent in the reclaiming motion), which I shall refer to as "Arrow", seeks revocation of claims 1 to 3 and 5 of European Patent 0 389 035 ("the patent") granted to the respondent (the reclaimer in this reclaiming motion), which I shall refer to as "Akzo". Akzo is represented in Scotland by Organon Laboratories Limited. The patent has as its active ingredient the steroid known conventionally as tibolone. That compound has been known since the 1960s and, since about 1988, has in one composition been marketed as Livial. It has combined oestrogenic, progestagenic and androgenic characteristics. In tablet form, it is used for treating menopausal complaints, for modulating the immune system and for combating osteoporosis. The patent is concerned with tibolone in a high degree of crystalline purity, that is, with a high degree of one form as against any other form of the crystals of that compound. The priority date of the patent is 18 March 1989.
The patent
[2] The claims in the patent are, in their English language version, in the following terms:
"1. A pharmaceutical composition which contains a pharmaceutically suitable solid carrier and the compound having the structure (7ά, 17ά) - 17 - hydroxy-7-methyl-19-nor-17-pregn-5(10)-en-20-yn-3-one, characterized in that the compound is crystalline pure, which purity is greater than 90%.
2. The pharmaceutical composition of claim 1, characterized in that the crystalline purity is greater than 95%.
3. The pharmaceutical composition according to claim 1, characterized in that the crystalline pure compound has the monoclinic P21 form.
4. The pharmaceutical composition according to claim 1, characterized in that the crystalline pure compound has the triclinic P1 form.
5. A method for the preparation of a crystalline pure compound for use in a pharmaceutical composition accordingly to claim 3, characterized in that the polymorphous compound is crystallized from mixtures of water and acetone or ethanol, or from ethyl acetate, acetonitrile, or acetone-hexane mixtures.
6. A method for the preparation of a crystalline pure compound for use in a pharmaceutical composition according to claim 4, characterized in that the polymorphous compound is crystallized from an apolar solvent."
[3] Claims 4 and 6 are not challenged in these proceedings. Of the challenged claims, claims 1, 2 and 3 are claims to a product; claim 5 is a claim to a process (for the preparation of the monoclinic crystalline form).
[4] In the Description of the patent the patentee narrates that the compound in question, its chemical and structural formulae being given, is known from two American patents, which are identified. The method described in these patents has, it is narrated, led to a compound having certain characteristics, which have led to its use in medicaments having gonadomimetic, ovulation-inhibiting or immuno-modulating action.
[5] The Description continues:
"Surprisingly, it has now been found that the compound having the formula [in question] prepared in accordance with the method described in the above-mentioned patents, is polymorphous and consists of two crystalline pure forms.
It may be expected of polymorphous compounds that their biological activity is comparable or identical to the biological activities of the crystalline pure forms of which the polymorphous compound consists. Nevertheless, if the polymorphous compound is used as a medicament great drawbacks are associated therewith compared with its crystalline pure components. The differences in crystal structure can lead to a difference in physico-chemical parameters such as stability, rate of dissolution, melting point, analytical data and the like, which frequently are strongly influenced by the crystal forms in the polymorphous compound. This is all the more obvious since in practice it is virtually impossible to make each batch of a polymorphous compound exactly identical in respect of composition. As a consequence of these differences, it is frequently regarded as undesirable to incorporate polymorphous compounds in medicaments and it is sometimes demanded that only one of the crystalline pure components of the polymorphous compound is used.
The aim of the present invention is, therefore, to obtain a pharmaceutical composition which contains a crystalline pure form according to the formula [in question], which is completely or virtually completely free from the other crystalline form.
The term 'crystalline pure form which is virtually completely free from the other crystalline form' denotes a form which contains less than 10% and preferably less than 5% of the other crystalline form.
It has now been found that by using specific crystallization techniques two crystalline pure forms, which here are designated form I and II respectively, can be obtained from the polymorphous compound [in question].
It has moreover been found that form I is chemically appreciably more stable than the already known polymorphous compound [in question]. This improvement in stability yields great advantages in respect of the shelf-life of the pharmaceutical product in which form I is incorporated.
The invention therefore relates to a pharmaceutical composition which contains a pharmaceutically suitable carrier and the compound having the structure [in question], characterized in that the said compound is a crystalline pure or virtually pure form which is completely or virtually completely free from the other crystalline form.
A pharmaceutical composition of this type has the advantage that the reproducibility is appreciably increased and that the physical data, within acceptable limits, are always identical.
The pure crystalline compounds, and in particular the compound with form I, are suitable for treating menopausal complaints or for modulating the immune system, and also for combating osteoporosis.
Form I is obtained by crystallizing the polymorphous compound [in question] from mixtures of water and acetone or ethanol. A suitable method is to dissolve the polymorphous compound in acetone or ethanol, after which the solution is added to water. Conversely, water can also be added to a solution of the polymorphous compound in acetone or ethanol. Other suitable solvents are, for example, ethyl acetate, acetonitrile and acetone/hexane mixtures. Mixtures of methanol and water, from which only mixtures of the two crystalline forms always crystallize, are unsuitable.
Form II can be obtained by crystallizing the polymorphous compound from a selection of apolar solvents. Toluene is very suitable, as is also hexane to which a little ethyl acetate has been added. Another suitable solvent is trichloroethylene.
The rate of crystallization, which is influenced most strongly by the crystallization temperature, can also play a role in obtaining crystalline pure forms. Thus, in general good results are obtained from anhydrous acetone only when the crystallization is carried out at a relatively low temperature."
The patentee then explains that forms I and II can readily be differentiated from one another - in particular by three methods, which are then described.
[6] The Description continues:
"Each of the crystalline pure forms is mixed with a suitable pharmaceutical carrier and administered parenterally or orally, for example as a solid pharmaceutical administration form, such as a tablet, pill, capsule or suppository.
The dosage schemes are the same as described in the abovementioned patents. An oral daily dose of 1-5 mg is particularly suitable for administration to humans.
A pharmaceutical composition in which form I is incorporated is preferred. A composition of this type has the additional advantage that a much better stability is obtained, so that the shelf-life, even under changing storage conditions, is notably improved."
[7] Nine Examples by way of illustration are then set out. As certain of these were discussed before us it is convenient to narrate them at this stage. Since Example 9, which relates to determination of structural data, is not material, it may be omitted. The other Examples are as follows:
"Example 1
4.0 g of the polymorphous compound [in question] were recrystallized under nitrogen from 20ml of acetone to which a trace of pyridine had been added. During this operation the temperature was slowly brought from room temperature to - 10 ºC. The crystals were filtered off and washed with acetone at -20 ºC and dried under vacuum at 40-45 ºC. Yield 3.0g of form I (purity according to DRIFT 94%, calculated from [a certain relationship]) ... .
Example 2
1 kg of the polymorphous compound [in question] was dissolved at 20-25 ºC in a mixture of 23 l of acetone and 6 ml of pyridine. The solution was filtered dust-free and the filter was washed twice with 1 l of acetone. At a temperature of 15-20 ºC the filtrate was poured as rapidly as possible, under nitrogen, into 25 l of dust-free distilled water, to which seed crystals of form I had been added. The suspension was cooled to 0-5 ºC and stirred for one hour at this temperature. The crystals were filtered off, washed with dust-free distilled water and dried under vacuum at 40 ºC. Yield 0.95 kg of form I (purity according to DRIFT 97.2%).
Example 3
In a manner comparable to that described in Example 2, four batches of form I were obtained with a purity of,...
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