Petition Of Arrow Generics Limited+organon Laboratories Limited And Others V. Norton Healthcare Limited
| Jurisdiction | Scotland |
| Judge | Lord Glennie |
| Neutral Citation | [2006] CSOH 146 |
| Court | Court of Session |
| Published date | 15 September 2006 |
| Year | 2006 |
| Date | 15 September 2006 |
| Docket Number | P1606/03 |
| OUTER HOUSE, COURT OF SESSION [2006] CSOH 146 | |
| P1606/03 P1031/03 A652/04 | OPINION OF LORD GLENNIE in the Petitions of ARROW GENERICS LIMITED Petitioners and in the case ORGANON LABORATORIES LIMITED AND OTHERS Pursuers against NORTON HEALTHCARE LIMITED Defenders ________________ |
Petitioners: Currie QC, Higgins; Maclay, Murray & Spens
Respondents: Davidson QC, Delibegović-Broome; McClure Naismith
Pursuers: Davidson QC, Delibegović-Broome; McClure Naismith
Defenders: C. Campbell QC, Clive; Morton Fraser
15 September 2006
Introduction[1] Akzo NV are the registered proprietors of patent EP 0 389 035 (hereafter "the 035 patent"). Akzo Nobel NV are the registered proprietors of patent EP 1 121 375 ("the 375 patent"). I shall refer to them collectively as "Akzo". They are represented in Scotland by Organon Laboratories Ltd ("Organon"). Both patents relate to a pharmaceutical product called tibolone. Tibolone has been known since the 1960s; and, since the 1980s, has been marketed as Livial. It has combined estrogenic, progestagenic and androgenic characteristics. In tablet form, it is used for treating menopausal complaints, for modulating the immune system, and for combating osteoporosis.
[2] The 035 patent is concerned with tibolone of a high degree of crystalline purity, whereas the 375 patent is concerned with tibolone of a high degree of chemical purity. In both cases the tibolone of the relevant purity is to be incorporated into a pharmaceutical composition.
The proceedings before the Court
[3] In these consolidated proceedings, there are challenges to both patents.
(a) By petition (P1606/03) lodged in November 2003, Arrow Generics Ltd ("Arrow") seek revocation of claims 1-3 and 5 of the 035 patent.
(b) There are two challenges to the 375 patent, by Arrow and by Norton Healthcare Ltd ("Norton"). By petition (P1031/03) lodged in July 2003, Arrow seek revocation of claims 1-3, 7 and 9-14 of the 375 patent. Norton's challenge, seeking revocation of the same claims of the 375 patent, arises by way of counterclaim in separate proceedings brought against them in 2004 by Akzo and Organon.
[4] The patents are European patents. They take effect in the United Kingdom as if granted by the UK Patents Office. They may therefore be challenged, as in this case, in the UK Courts. But they may also be challenged in the European Patent Office ("EPO"). The interrelationship between proceedings for revocation before the national court and opposition proceedings before the EPO is explained in ITP SA v Coflexip Stena Offshore Ltd 2005 SC 116. There are in this case concurrent proceedings before the EPO in respect of the 375 patent. It will be necessary to refer to those proceedings in the context of dealing with applications made by Akzo to amend the 375 patent.
The 035 Patent
[5] The 035 patent has a priority date of 18 March 1989. According to the description in the patent, the invention relates to "a pharmaceutical composition which contains a pharmaceutically suitable carrier and the compound having the structure (7α, 17α)-17-hydroxy-7-methyl-19-nor-17-pregn-5(10)-en-20-yn-3-one"; and also to "a method for the preparation of this compound for use in the pharmaceutical composition." The compound there referred to is tibolone.
[6] The patent recites that tibolone has been known for some time, for example from two American Patents, namely 3,340,279 ("the 279 patent") and 4,701,450 ("the 450 patent"). But the authors of the patent claim to have discovered that tibolone, prepared in accordance with the method described in those patents, "is polymorphous and consists of two crystalline pure forms." For pharmaceutical purposes, it would be desirable to use a pure rather than a polymorphic form of tibolone. As they explain:
"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."
[7] The authors go on to state that the aim of the invention covered by the 035 patent is:
"to obtain a pharmaceutical composition which contains a crystalline pure form ... which is completely or virtually free from the other crystalline form."
By this, as they explain, they mean one which contains less than 10%, and preferable less than 5%, of the other crystalline form.
[8] The authors of the patent claim to have found that by using specific crystallisation techniques, two crystalline pure forms (in the above sense) can be obtained. These are designated in the patent as "Form I", which is the monoclinic P21 form, and "Form II", the triclinic P1 form. They say that Form I is chemically much more stable than the already known polymorphous compound, with consequent advantages both in terms of the shelf-life of the pharmaceutical product and in terms of reproducibility. Against this background, the invention is described as relating to
"a pharmaceutical composition which contains a pharmaceutically suitable carrier and the compound having the structure (7α, 17α)-17-hydroxy-7-methyl-19-nor-17-pregn-5(10)-en-20-yn-3-one [i.e. tibolone], 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."
In light of the extended definition of "crystalline pure form" mentioned above, the word "virtually" would appear to add nothing of substance.
[9] The patent then sets out the following methods of producing Form I and Form II:
"Form I is obtained by crystallizing the polymorphous compound 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"
[10] The patent goes on to discuss the crystallisation process, the ability to differentiate between Forms I and II, and the advantage, from a pharmaceutical point of view, of the crystalline pure forms, particularly Form I. Various examples are given to illustrate the invention. From amongst these I need mention only two at present: Example 5, which described a process resulting in Form II tibolone of 100% crystalline purity; and Example 9, which identifies structural data from examples of the Form I and Form II.
The claims in the patent[11] It is convenient at this stage to set out the claims in patent 035. I shall quote them in full:
"1. A pharmaceutical composition which contains a pharmaceutically suitable solid carrier and the compound having the structure (7α, 17α)-17-hydroxy-7-methyl-19-nor-17-pregn-5(10)-en-20-yn-3-one [i.e. tibolone], 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 [i.e. Form I].
4. The pharmaceutical composition according to claim 1, characterized in that the crystalline pure compound had the triclinic P1 form [i.e. Form II].
5. A method for the preparation of a crystalline pure compound for use in the pharmaceutical composition according 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."
As can be seen, claims 1 and 2 relate to the crystalline purity of the compound (of whichever Form) in the pharmaceutical composition, while claims 3 and 4 relate to the crystalline form of the compound of a given purity. Claims 5 and 6 are claims to a method of preparation of the compound of the appropriate purity and form for use in the pharmaceutical compositions. Arrow's challenge in these proceedings - to claims 1, 2, 3 and 5 - does not include a challenge to any claims relating specifically and exclusively to Form II of the compound.
Arrow's case
[12] Arrow's primary case on Record is that the invention claimed in claims 1-3 was not patentable because it lacked novelty. During the hearing, it became clear that the patentability of the method claimed in claim 5 was also attacked on this ground. Their secondary case on Record is that the inventions in claims 1-3 and 5 were not patentable because they were...
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Arrow Generics Ltd v Akzo NV
...indicated his intention to grant the prayer of the petition and revoke claims 1 to 3 and 5 of the patent, and put the case out by order ([2006] CSOH 146). On 25 October 2006 the intellectual property judge revoked the patent in its entirety unless the respondent amended it within eight week......