In a patent dispute between innovator Akzo and generic manufacturer Arrow (in Scottish court), the generic player seeks revocation of claims 1 to 3 and 5 of EP0389 035. The patent covers various crystalline forms of 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. Following are the claims
"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.
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).
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."
During trial only claims 1-3 and 5 were in dispute. Arrow challenges the validity of the patent on grounds both of anticipation and of obviousness. The Lord Ordinary upheld that challenge on the basis of anticipation but rejected it on the ground of obviousness. Akzo has reclaimed against the Lord Ordinary's interlocutor. It contends that, properly construed, the patent was not anticipated by any relevant prior art. Arrow resists that contention and further cross-appeals, contending that the Lord Ordinary erred in holding that the invention was not obvious.
The prior art upon which Arrow primarily, but not exclusively, relies is an article published in May 1984 in the Annual of the Royal Netherlands Chemical Society. The title of the article is in the following terms:"Conformational analysis of 3-oxo 5(10)-unsaturated steroids. Single-crystal X-ray structure analysis of 17-hydroxy-7ά-methyl-19-nor-17ά-pregn-5(10)-en-20-yn-3-one (Org OD 14)". Its authors were J.-P. Declercq and M. Van Meerssche
The question was whether the Lord Ordinary at the first instance had been correct in determining that the claims were not obvious in light of one particular prior art document disclosing tibolone in a crystalline form. The prior art document did not disclose that tibolone occurred in more than one crystalline form, as the discovery that tibolone was in fact polymorphic was made only later on. The Lord President, in judgment, considered that this did not make the claimed invention obvious:
The circumstance that following the experimental parameters described by Declercq et al. the skilled person would ordinarily obtain crystals, some at least of which were monoclinic, does not entail that 'the invention' would thereby be performed. The invention, properly understood, was constituted by a pharmaceutical composition having a high degree of crystalline purity in the active ingredient. While the skilled person, following Declercq, might be expected to obtain a mixture of crystalline forms (including some monoclinic), from which a particular crystal might by some process under the laboratory microscope have been isolated, Declercq did not teach how to obtain a product of high crystalline purity for pharmaceutical use - even if the skilled person for some reason was alert to the need to isolate a particular form, notwithstanding his ignorance of polymorphism in tibolone.In these circumstances, while Declercq enabled the skilled person to take certain steps, it did not enable him 'to perform the invention
Lord President Opinion : The Lord President considered that the use of tibolone to a high degree of crystalline purity as the active ingredient in a pharmaceutical composition was not obvious. Preliminary to that inventive step was the discovery by Akzo (not itself an invention, according to the Lord President) that tibolone was in fact polymorphous, i.e. with at least two crystalline forms. That discovery led in turn to the practical identification of the product, involving use in a pharmaceutical composition of crystalline pure tibolone having distinct advantages over a general mixture of forms, these advantages being stability and reproducibility. The skilled but unimaginative man would not have taken these steps or any of them.That was effectively the end of the story, as far as the patent was concerned, since Lord Kingarth agreed with the Lord President's conclusions. Lord Clarke, however, did not agree entirely and considered that claims 1-3 were not inventive:
Lord Clarke opinion: On discovery of the polymorphous character of tibolone, the patentee, no doubt, sought to address the consequences of that discovery. In my judgment, however, they did so by virtue of what is addressed in claims 4, 5 and 6. In claims 1-3, however, as they are worded, what was being claimed was the incorporation of monoclinic P21 form tibolone, up to a level of purity greater than 90%, which would include 100%. Claims 1-3 do not address the means (whether robust or otherwise) whereby a purity of more than 90% of monoclinic P2 tibolone is to be produced. They are, as previously noted, product claims, not process claims. They seek a monopoly in the product so described. My acceptance, shared by all members of this court, of Arrow's submission that these claims required to be read as embracing single crystal pharmaceutical compositions has to be kept in mind. The composition, tibolone, had been known since the 1960s. I accept that the skilled man would, at the priority date, have known that it was being developed by a drug company and was of particular interest in relation to the treatment of menopausal complaints. After Declercq, he knew also that the crystalline structure had been discovered as monoclinic form. Prior to the priority date tibolone had been put on the market in pill form. The question then comes to be, whether it would have been an inventive step to do what claims 1-3 embrace. [...] I repeat that the knowledge, or otherwise, of the discovery of the polymorphous character of tibolone seems to me to have bedevilled the discussion of this question and certainly led, in my view, the Lord Ordinary to misdirect himself when dealing with the matter. On this branch of the case, it seems to me that the question is, can it be said to be inventive to place a single crystal of monoclinic form 1 tibolone in a pill, tablet or capsule? Judging matters from the viewpoint of the skilled man who was aware of only Form 1 monoclinic tibolone as at the priority date, I agree with Arrow that, on the evidence, it cannot
Opinion of court
"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.
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).
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."
During trial only claims 1-3 and 5 were in dispute. Arrow challenges the validity of the patent on grounds both of anticipation and of obviousness. The Lord Ordinary upheld that challenge on the basis of anticipation but rejected it on the ground of obviousness. Akzo has reclaimed against the Lord Ordinary's interlocutor. It contends that, properly construed, the patent was not anticipated by any relevant prior art. Arrow resists that contention and further cross-appeals, contending that the Lord Ordinary erred in holding that the invention was not obvious.
The prior art upon which Arrow primarily, but not exclusively, relies is an article published in May 1984 in the Annual of the Royal Netherlands Chemical Society. The title of the article is in the following terms:"Conformational analysis of 3-oxo 5(10)-unsaturated steroids. Single-crystal X-ray structure analysis of 17-hydroxy-7ά-methyl-19-nor-17ά-pregn-5(10)-en-20-yn-3-one (Org OD 14)". Its authors were J.-P. Declercq and M. Van Meerssche
The question was whether the Lord Ordinary at the first instance had been correct in determining that the claims were not obvious in light of one particular prior art document disclosing tibolone in a crystalline form. The prior art document did not disclose that tibolone occurred in more than one crystalline form, as the discovery that tibolone was in fact polymorphic was made only later on. The Lord President, in judgment, considered that this did not make the claimed invention obvious:
The circumstance that following the experimental parameters described by Declercq et al. the skilled person would ordinarily obtain crystals, some at least of which were monoclinic, does not entail that 'the invention' would thereby be performed. The invention, properly understood, was constituted by a pharmaceutical composition having a high degree of crystalline purity in the active ingredient. While the skilled person, following Declercq, might be expected to obtain a mixture of crystalline forms (including some monoclinic), from which a particular crystal might by some process under the laboratory microscope have been isolated, Declercq did not teach how to obtain a product of high crystalline purity for pharmaceutical use - even if the skilled person for some reason was alert to the need to isolate a particular form, notwithstanding his ignorance of polymorphism in tibolone.In these circumstances, while Declercq enabled the skilled person to take certain steps, it did not enable him 'to perform the invention
Lord President Opinion : The Lord President considered that the use of tibolone to a high degree of crystalline purity as the active ingredient in a pharmaceutical composition was not obvious. Preliminary to that inventive step was the discovery by Akzo (not itself an invention, according to the Lord President) that tibolone was in fact polymorphous, i.e. with at least two crystalline forms. That discovery led in turn to the practical identification of the product, involving use in a pharmaceutical composition of crystalline pure tibolone having distinct advantages over a general mixture of forms, these advantages being stability and reproducibility. The skilled but unimaginative man would not have taken these steps or any of them.That was effectively the end of the story, as far as the patent was concerned, since Lord Kingarth agreed with the Lord President's conclusions. Lord Clarke, however, did not agree entirely and considered that claims 1-3 were not inventive:
Lord Clarke opinion: On discovery of the polymorphous character of tibolone, the patentee, no doubt, sought to address the consequences of that discovery. In my judgment, however, they did so by virtue of what is addressed in claims 4, 5 and 6. In claims 1-3, however, as they are worded, what was being claimed was the incorporation of monoclinic P21 form tibolone, up to a level of purity greater than 90%, which would include 100%. Claims 1-3 do not address the means (whether robust or otherwise) whereby a purity of more than 90% of monoclinic P2 tibolone is to be produced. They are, as previously noted, product claims, not process claims. They seek a monopoly in the product so described. My acceptance, shared by all members of this court, of Arrow's submission that these claims required to be read as embracing single crystal pharmaceutical compositions has to be kept in mind. The composition, tibolone, had been known since the 1960s. I accept that the skilled man would, at the priority date, have known that it was being developed by a drug company and was of particular interest in relation to the treatment of menopausal complaints. After Declercq, he knew also that the crystalline structure had been discovered as monoclinic form. Prior to the priority date tibolone had been put on the market in pill form. The question then comes to be, whether it would have been an inventive step to do what claims 1-3 embrace. [...] I repeat that the knowledge, or otherwise, of the discovery of the polymorphous character of tibolone seems to me to have bedevilled the discussion of this question and certainly led, in my view, the Lord Ordinary to misdirect himself when dealing with the matter. On this branch of the case, it seems to me that the question is, can it be said to be inventive to place a single crystal of monoclinic form 1 tibolone in a pill, tablet or capsule? Judging matters from the viewpoint of the skilled man who was aware of only Form 1 monoclinic tibolone as at the priority date, I agree with Arrow that, on the evidence, it cannot
Opinion of court
