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 obvious and involved no inventive step. In support of both lines of attack, Arrow rely upon a paper by J.-P. Declercq and M. van Meersche published in the Journal of the Royal Netherlands Chemical Society, 103/5, May 1984 entitled "Conformational analysis of 3-oxo 5(10)-unsaturated steroids. Single-crystal X-ray structure analysis of 17-hydroxy-7α-methyl-19-nor-17α-pregn-5(10)-en-20-yn-3-one (Org OD 14)". I shall refer to this paper as "Declercq" or "the Declercq paper". Their case on lack of novelty is that tibolone of the requisite crystalline purity, which is the subject of claims 1-2, is disclosed in the monoclinic form, Form I, in Declercq in Table 1 (at p.146 of the Journal). Those claims, and also claim 3, were therefore anticipated. Although the claims were to a pharmaceutical composition rather than simply to the compound, tibolone, that added nothing: the pharmaceutical composition was merely the combination of the compound with a pharmaceutically suitable solid carrier. The method, in claim 5, was also disclosed. In support of their case based on obviousness, Arrow also rely on two other patents, the 279 patent and a United Kingdom patent, GB1,177,845 ("the 845 patent"), and on the Common General Knowledge which, they say, is exemplified by a number of publications. The compound is disclosed in the 279 patent and, in its monoclinic form and of the relevant purity, in Declercq. It is a steroid, and the majority of steroids are polymorphic. They say that at the priority date of the patent it was standard practice for those skilled in the art to conduct polymorphic screens on proposed drug substances, in particular on those likely to be polymorphic. It would have been obvious to the man skilled in the art at the priority date of the patent: (i) to ascertain whether there were polymorphs present in the active compound; (ii) where such polymorphs were present, to identify the most stable polymorphic form of the compound; and (iii) to obtain and use that that polymorph in its pure crystalline form. The solvents used in the method claimed at claim 5 are examples of solvents which, at the priority date, would routinely have been used by the skilled man to conduct a polymorph screen; but in any event the use of such solvents was disclosed in the 845 patent and in Declercq. It would have been obvious to use a solvent screen comprising acetone and water.

 

Akzo's case

[13] Akzo's answer on Record consisted of bare denials and calls for further specification. It is convenient to refer to the arguments advanced on their behalf at the proof in the course of discussing the particular issues.

Anticipation/ Lack of novelty

[14] Section 1(1) of the Patents Act 1977 provides as follows:

"A patent may be granted only for an invention in respect of which the following conditions are satisfied, that is to say -

(a) the invention is new;

(b) it involves an inventive step ..."

I am not here concerned with paras. (c) and (d). A patentable invention is one for which these conditions are satisfied. Section 2(1) of the Act provides that an invention shall be taken to be new "if it does not form part of the state of the art". In terms of section 2(2), the state of the art comprises all matter "which has at any time before the priority date of that invention been made available to the public (whether in the United Kingdom or elsewhere) by written or oral description, by use or in any other way." As I have said, Arrow contend that the inventions disclosed by claims 1-3 and 5 are not new and do not satisfy the test in section 1(1)(a) of the Act. They say that those claims have been anticipated by prior publication.

[15] The classic statement of the test of anticipation, or lack of novelty, remains that of the Court of Appeal in General Tyre & Rubber Company v The Firestone Tyre and Rubber Company Ltd [1972] RPC 457 at 485, albeit that that judgment was given under reference to the previous Act:

"To determine whether a patentee's claim has been anticipated by an earlier publication it is necessary to compare the earlier publication with the patentee's claim. The earlier publication must, for this purpose, be interpreted as at the date of its publication, having regard to the relevant surrounding circumstances which then existed, and without regard to subsequent events. The patentee's invention must similarly be construed as at its own date of publication having regard to the relevant surrounding circumstances then existing. If the earlier publication, so construed, discloses the same device as the device which the patentee by his claim, so construed, asserts that he has invented, the patentee's claim has been anticipated, but not otherwise. In such circumstances the patentee is not the true and first inventor of the device and his claimed invention is not new ..."

Later on the same page the test is put in this way:

"... the question whether the patentee's claim is new ... falls to be decided as a question of fact. If the prior inventor's publication contains a clear description of ... something that would infringe the patentee's claim if carried out after the grant of the patentee's patent, the patentee's claim will have been shown to lack the necessary novelty, that it to say, it will have been anticipated."

The Court went on to say this:

"The prior inventor, however, and the patentee may have approached the same device from different starting points and may for this reason, or it may be for other reasons, have so described their devices that it cannot be immediately discerned from a reading of the language which they have respectively used that they have discovered in truth the same device; but if carrying out the directions contained in the prior inventor's publication will inevitably result in something being made or done which, if the patentee's patent were valid, would constitute an infringement of the patentee's claim, this circumstance demonstrates that the patentee's claim has in fact been anticipated.

If, on the other hand, the prior publication contains a direction which is capable of being carried out in a manner which would infringe the patentee's claim, but would be at least as likely to be carried out in a way which would not do so, the patentee's claims will not have been anticipated, although it may fail on the ground of obviousness. To anticipate the patentee's claim the prior publication must contain clear and unmistakeable directions to do what the patentee claims to have invented: ... A signpost, however clear, upon the road to the patentee's invention will not suffice. The prior inventor must be clearly shown to have planted his flag at the precise destination before the patentee."

[16] It is useful also to refer to a short passage from the speech of Lord Hoffman in Merrell Dow Pharmaceuticals Inc. v H.N. Norton & Co. Ltd [1996] RPC 76 at 82-3. For the purpose of considering infringement, he said

"It does not matter how the product is made or what form it takes. The monopoly covers every method of manufacture and every form which comes within the description in the claim. So claim 24 includes the making of the acid metabolite in one's liver just as much as making it by synthetic process; in the body as well as in isolation. Nor does it matter that the infringer knows that he is making, using etc. the patented product. Liability is absolute

The corollary of this principle is that the novelty of the invention must be co-extensive with the monopoly. If there is any method of manufacture or form of the product which is part of the state of the art, then to that extent the invention is not new. As the Enlarged Board of Appeal of the EPO said in its MOBIL/Friction reducing additive Decision G02/88 [1990] E.P.O.R. 73, 83:

'It is generally accepted as a principle underlying the EPC that a patent which claims a physical entity per se, confers absolute protection upon such physical entity; that is, wherever it exists and whatever its context. ... It follows that if it can be shown that such physical entity (that is, a compound) is already in the state of the art (for example in the context of a particular activity), then a claim to the physical entity per se lacks novelty'"

[17] Two points of particular relevance to the arguments in the present case emerge from these passages. First, any prior existence of the product is sufficient to defeat a product claim on grounds of anticipation, regardless of how it was produced and the context in which it is found. Thus, for example, the reason why Declercq was looking at the sample before him is irrelevant - it is irrelevant even to ask whether he knew what the compound was or what, if any, medicinal values it might have. Secondly, any consideration of the quantity in which the product was previously identified is also irrelevant unless, of course, some quantitative criterion is present, expressly or by implication, in the definition of the claim limiting the extent of the monopoly sought by the patentee.

 

Claims 1-3

[18] Claims 1-3 (and also claim 4) are claims to a product, in each case a pharmaceutical composition containing tibolone. In claims 1 and 2, that tibolone is of a particular crystalline purity; in claims 3 and 4, the tibolone of that purity is of a particular form. Arrow's anticipation attack on claims 1-3 is based on pure Form 1 tibolone having been revealed in Declercq.

[19] I heard evidence in relation to the issue of novelty from Dr Roger Newton, who was called on behalf of Arrow, and Professor Joel Bernstein, who was called by Akzo. Both gave evidence in chief by reference to their Reports lodged in process. It goes without saying that both were impressive witnesses with impressive credentials, though their respective backgrounds and experiences differed. In attempting a brief summary, I am conscious of doing each of them an injustice. Dr Newton has recently retired as resident medicinal chemist in the chemistry department of the University of Cambridge, a position he held since 1996, and he is visiting professor at the University of Sussex. He holds a number of posts with various scientific companies and, possibly most relevant to the present proceedings, was employed by Glaxo from 1971 to 1996, originally as a senior research chemist and subsequently as director of various research projects. Professor Bernstein is and has been since 1971 professor of chemistry at Ben-Gurion University of the Negev, Beersheva, Israel. He teaches courses in general chemistry, crystallography and organic state chemistry, including polymorphism and crystallisation. He has specialised and built an international reputation in the field of crystallography and has participated in a large number of conferences on the subject. Indeed, Dr Newton was willing to defer to Professor Bernstein on matters of pure crystallography.

[20] In relation to the question whether tibolone of the claimed purity and form was revealed in Declercq, however, there was nothing between the experts on the points that mattered. Dr Newton stated that data recorded in Table 1 of the Declercq paper showed that the compound under discussion there was the monoclinic form of tibolone (i.e. Form I). Further, being a single crystal, it was by definition 100% pure. Professor Bernstein agreed. In his first Report he said: "The Declercq paper does describe the crystal structure of the material that later became known as Form 1 in the Patent". Later in that Report he said: "The nature of the structure determination is such that the experiment is done on a single crystal, which by definition of a crystal is comprised of a pure substance". In his evidence, under cross-examination he confirmed that claim 3 of the patent was for a pharmaceutical composition containing tibolone with the crystal structure disclosed in Declercq, and that the single crystal analysed by Declercq had a crystalline purity greater than that claimed in claims 1 and 2.

[21] The agreement between the experts that Declercq did in fact refer to the monoclinic (Form 1) form of tibolone, and that it was of 100% crystalline purity, enables Arrow to say, simply, that claims 1-3 were anticipated by Declercq. Akzo dispute this. They advance a number of arguments in support of their submission that the invention was, none the less, patentable. The first, which is directed only to the validity of claim 3, is that spoken to by Professor Bernstein and first articulated by him, so far as I am aware, in para. 63 of his Report, beginning with the sentence already quoted:

"The Declercq paper does describe the crystal structure of the material that later became known as Form 1 in the Patent. But at the time of the Declercq paper the existence of polymorphism of Tibolone had not been discovered. The structure determined by Declercq et al., could not be called that of Form I until Form II was discovered, in the same way that there was no Queen Elizabeth I until Queen Elizabeth II ascended to the throne."

I cannot accept this argument. It confuses the existence of a particular thing with the name given to it. Professor Bernstein is wrong to say that there was no Queen Elizabeth I before Queen Elizabeth II ascended the throne. There was a Queen Elizabeth I, at least in England, albeit she was then simply called Queen Elizabeth. Similarly, Form I tibolone existed at the time of Declercq's work and was identified by him in Table 1 of his paper, but it was not then called "Form I". When considering a challenge to a claim in the patent to Form I tibolone, it does not matter that no one knew of Form II. Knowledge of Form II would, of course, be relevant if there were a challenge to claim 4 of the patent, but there is no such challenge. Only the claim to Form I is challenged, and that challenge must succeed because Form I, albeit without that name, is revealed in Declercq.

[22] It may be that Akzo's argument on this point is not best served by the particular analogy with Queen Elizabeth. The substance of the argument may be more directly focused in Professor Bernstein's unchallenged evidence, both in that passage and elsewhere, that at the time of the Declercq paper it had not been discovered that tibolone was polymorphous. This was a point developed by Mr Davidson in his submissions. He submitted that the patent teaches that tibolone is polymorphous, and that the claims are concerned with methods of producing one or other form of tibolone. It is unrealistic, therefore, he argued, to regard any part of the invention relating to the two polymorphic Forms of tibolone as having been anticipated by a paper which reveals nothing about polymorphism in tibolone.

[23] I do not agree. I accept, of course, that the patent teaches that tibolone is polymorphous. But claim 3 is a claim to a particular product, namely tibolone of a particular crystalline structure. The answer to the question of whether that product has or has not been anticipated must depend on whether that product is revealed in the prior art. It cannot be affected by the state of knowledge about the existence of other crystalline forms. Such knowledge might be relevant to a claim to a method of producing Form I tibolone, for example claim 5, in so far as it is necessary for a method of producing the one Form of tibolone to exclude production of the other. But I am not concerned with that question at this stage. In relation to claim 3, I am concerned with a claim not to a method of production but to a product, namely the monoclinic form of tibolone. That monoclinic form of tibolone was revealed in Declercq. Whether or not Declercq knew that tibolone was polymorphous, his paper reveals what we now know as Form I. The claim to Form I per se therefore lacks novelty.

[24] Akzo's second argument was that the fact that Declercq revealed a single crystal of Form I, which was by definition 100% pure, was irrelevant on a proper construction of claims 1-3. The claims in the patent were to a "pharmaceutical composition" containing the compound, i.e. tibolone. That must involve a recognition that a single crystal is not sufficient: a pharmaceutical compound clearly cannot be made of a single crystal. Declercq only analysed a single crystal from the sample he was given. There is no reason to believe that the whole sample was pure Form I; or at least Arrow cannot show that it was, since no analysis of the whole sample was carried out. Many of the crystals may have been what we now know to be Form II. The Declercq paper, therefore, only reveals the composition of the single crystal chosen for analysis, which happens to be pure Form I (and it could just as easily have been pure Form II). This does not reveal how to obtain Form I in sufficient quantities or with sufficient repeatability to use in a pharmaceutical compound. It therefore makes no practical sense to speak of Declercq having anticipated the claim to a composition containing pure Form I tibolone.

[25] There was some dispute on the evidence as to whether the sample, from which the single crystal analysed by Declercq was selected, was likely to have been made up wholly of Form I crystals or from a mixture of Forms I and II. The Declercq paper is silent on the point. Dr Newton suggested that since acetone was the medium used it was likely that the whole sample comprised Form I. Further, it was suggested that if there had been any Form II present in the sample, Declercq would probably have noticed and recorded it. Such speculation seems to me to go beyond what is justified by the evidence. Although various scenarios were suggested as to what might have happened, we in fact know nothing about how, or even by whom, the single crystal was selected. We do not know whether Declercq would have been interested in observing different crystalline forms or referring to them in his paper if he did observe them. I therefore do not find it established on the evidence that the whole sample was Form I tibolone. Indeed, since none of Examples 1-3 in the patent resulted in 100% crystalline purity despite the use of acetone as the solvent, I consider it unlikely that the sample before Declercq would be made up entirely of Form I crystals.

[26] Nonetheless, there are, in my opinion, two quite separate answers to Akzo's argument. The first is this: that part of the argument which focuses on the omission from Declercq of any method of obtaining Form I in sufficient quantities has nothing at all to do with claims 1-4. Those claims are claims to a product. The methods of obtaining the product, i.e. tibolone of the requisite form and purity, if new, is protected by claims 5 and 6 of the patent, which claims may, indeed, reflect the "teaching" of the patent as explained by Mr Davidson. The "single crystal" argument is not relied on by Arrow in relation to claims 5 and 6 - it impacts, if at all, only on claims 1-4. In this respect Akzo's argument confuses the claims to the method, on the one hand, with the product claims on the other.

[27] The second answer is that it would have been open to Akzo to attempt to limit claims 1-4 by reference to some quantitative criteria. But, for whatever reason, they have not done so. It was not suggested that, even adopting a purposive construction, those claims should be read as incorporating some such criteria capable of being expressed with sufficient precision. Even if it had been so argued, I would have felt unable to construe the relevant claims as being restricted to pure Form I tibolone in some quantity greater than a single crystal. On that basis, the prior disclosure in Declercq of a single crystal of what we now know to be Form I tibolone and which, being a single crystal, is by definition 100% pure, is sufficient to invalidate claims 1-3.

[28] The fact that claims 1-4 were claims to a pharmaceutical composition, rather than simply to tibolone of certain forms and purity gave rise to another argument on behalf of Akzo. Mr. Davidson argued that whatever the Declercq paper showed in terms of the form or purity of the crystal, it said nothing about a pharmaceutical composition. There was no Record, he submitted, for an attack on novelty in respect of the pharmaceutical composition (though he made it clear that he was not submitting that the point was not open to Arrow). More substantively, he submitted that any challenge to claims 1-3 on grounds of lack of novelty would have to demonstrate not just that the form and purity of the crystal were anticipated but also that the incorporation of the tibolone of the requisite form and purity into the pharmaceutical composition similarly lacked novelty. They had not sought to do this. The incorporation of the tibolone into a pharmaceutical composition was not anticipated in Declercq. A challenge to the whole of claims 1-3, properly construed, would, he submitted, involve Arrow in "mosaicing", i.e. building a case on anticipation by putting together a mosaic of different sources of prior disclosure: see Terrell on the Law of Patents, 16th ed. at para. 7-26, Von Heyden v Neustadt (1880) 50 L.J.Ch. 126, 128. In this case it would mean putting together the prior disclosure of crystalline pure Form I tibolone (i.e. Declercq) with the prior art of making a pharmaceutical composition.

[29] I do not accept this argument. Tibolone has been in use in pharmaceutical compositions for many years. This is made clear in the patent itself, as well as, for example, in Declercq. It cannot be, and was not, suggested that there is anything novel about the making of a pharmaceutical composition incorporating tibolone. As the descriptive part of the patent explains, the discovery claimed by Akzo is not that tibolone can be used in a pharmaceutical composition but that tibolone is polymorphous; and the claimed invention relates, not to any particular method of combining tibolone with a suitable carrier to make the pharmaceutical composition, but to particular forms and purity of tibolone to be so combined. It is not suggested in the patent that the incorporation of such a compound into a pharmaceutical composition involves any inventive step. Nor was it suggested in evidence that this could or would have been understood to have been part of the invention. The claims in the patent have to be construed in their context, that context including the description in the patent and the state of surrounding knowledge: see s.125 of the Patent Act 1977, Article 69 of the European Patents Convention and the Protocol on the Interpretation of Article 69, Lubrizol Corp. v Esso Petroleum Co. Ltd [1998] RPC 727, 737-8 and 742, Mayne Pharma Pty. Ltd v Pharmacia Italia Spa [2005] EWCA Civ. 137 (unreported 17 February 2005). Further, the claims must be construed from the standpoint of the notional addressee of the patent, i.e. the skilled man reasonably well versed in the relevant art. In a highly developed industry such as this, the "skilled man" can, and will often be a "composite entity" or a "team" working within the particular field: see e.g. General Tyre & Rubber company v The Firestone Tyre and Rubber Company Ltd [1972] RPC 457, 482, 485. In the context of the 035 patent, there was little or no difference between the parties on the identity of the skilled man. Adopting Professor Bernstein's description, with which Dr Newton broadly agreed, the skilled person here is "a process research chemist working with an analytical chemist in the pharmaceutical industry", having a batchelor's degree in chemistry and about 2-3 years experience (perhaps more) in the industry, and having some familiarity and experience in dealing with solids and the analytical techniques used to characterise and distinguish the two forms of tibolone under discussion. I consider that the addressee of the patent would not understand the incorporation of the compound into the pharmaceutical composition to be part of the invention claimed by the patent. Nor is this a realistic interpretation of the claims read in context, even if construed by the Court without looking through the eyes of the notional addressee. I should add that this argument by Akzo was wholly at odds with the stance which they themselves adopted in relation to the 375 patent, where they accepted that the claim to a pharmaceutical composition incorporating tibolone of a particular chemical purity stood or fell with the claims to tibolone of that purity, the incorporation of the tibolone into the pharmaceutical compound not in itself being an inventive step (see paras. 96 and 107 below).

 

Claim 5

[30] Claim 5 is a claim to a method for the preparation of the Form I crystalline pure compound for use in the pharmaceutical composition, the characteristic feature of the method ("characterized in that") being that the polymorphous tibolone is crystallised from "mixtures of water and acetone or ethanol" or from other solvents. In other words, in order to produce Form I tibolone, a polar solvent is used, one such solvent being a mixture of water and acetone. An apolar solvent, according to the patent and claim 6, results in Form II.

[31] It is Arrow's contention that this method of producing Form I tibolone is anticipated in the prior art. They say that the re-crystallisation process claimed in claim 5 is clearly disclosed in Declercq and in patent GB1,177,845 ("the 845 patent"). The 845 patent is entitled "New process for the preparation of D5(10)-3-Keto-19-nor-steroids". It has a priority date of June 1967. This patent discloses a synthetic method for making steroids, including tibolone. Tibolone is specifically mentioned (though not by name). The patent describes the process of synthesis and purification. In Example II of that patent it is stated: "The crude product is re-crystallised from acetone with one drop of pyridine". According to Dr Newton, the re-crystallisation conditions that we now know lead to pure Form I tibolone are clearly disclosed in this patent. Further, it is to be noted that acetone was also the crystallisation medium identified in the Declercq paper. We know that the particular crystal analysed by Declercq was Form I tibolone. It follows that Declercq teaches that acetone is the solvent used to produce Form I. Accordingly, it is argued, both the 845 patent and Declercq anticipate the method of producing Form I tibolone which is claimed in claim 5.

[32] For Akzo, Mr Davidson submitted that in order to succeed Arrow had to show that crystallisation (or recrystallisation - I shall refer to them generally as "crystallisation" unless it is necessary to differentiate) from acetone inevitably gives Form I tibolone of the requisite purity. On the evidence, Arrow failed to show this. They could have submitted experimental data to the court, but had not done so. It is not the case (or at least is not shown to be the case) that any crystallisation using acetone will produce Form I tibolone - fine tuning, particularly in terms of temperature and timing, is required. The patent shows this. There may, for example, be different results depending on the amount of water used in the solution, or the temperature and rate at which the crystallisation is carried out.

[33] I am not persuaded, on the evidence, that every crystallisation using acetone, will necessarily produce Form I tibolone. Arrow sought to find assistance in the Declercq paper, in which the single crystal analysed was taken from a sample produced using acetone as the medium; but I have already found that the evidence is insufficient to enable me to conclude that the sample was comprised entirely of Form I. Nor does the 845 patent assist, since it does not identify the crystalline form of the tibolone produced by the crystallisation. Examples 1-3 of the 035 patent, however, provide support for the fact that the use of an acetone solvent will tend to produce high purity Form I tibolone. There was some debate about whether the acetone used in Example I was anhydrous. Professor Bernstein suggested that a passage at lines 6-7 on p.3 of the patent encouraged the use of anhydrous, rather than "bench" acetone (which would have some water in it), particularly at low temperatures, and that this in turn enabled one to infer that the acetone used in Example I (which was carried out at a low temperature) was anhydrous. I do not accept this, since Professor Bernstein's view appeared to me to be based on a clear misreading of lines 6-7. Far from encouraging the use of anhydrous acetone, those lines in fact suggest that its use will not lead to good results unless the crystallisation is carried out at relatively low temperature. I read the patent as referring to ordinary bench acetone unless anhydrous acetone is specifically identified. I do, however, accept Professor Bernstein's evidence that it cannot be inferred from the material before the court that any use of acetone will inevitably give Form I. The amount of water and the temperature and rate of the crystallisation may impact upon the result, and the serendipitous nature of the discovery of different polymorphic forms means that one can, in any event, never have absolute certainty in this field. The more sensible question, however, seems to me to be whether the use of acetone as a solvent will normally result in Form I tibolone. In his evidence, both in chief and cross-examination, Professor Bernstein accepted that if you crystallise from acetone you would expect to get Form I tibolone. It seems to me that this correctly states the position. In the event, therefore, on the important question, he was not in disagreement with Dr Newton.

[34] To my mind, however, this discussion of the evidence is academic, since I consider that Mr Davidson's argument is mistaken in its premise. I do not accept the submission that, to succeed, Arrow must show that re-crystallisation from acetone inevitably gives Form I tibolone (I leave to one side the question of the relevant purity, since, if a single crystal is analysed, purity as an issue disappears). If the relevant claim under attack in the patent is a product claim, and the anticipation attack on that claim is by reference to a previously published method, then the argument that the product itself is anticipated by the previously disclosed method depends for its success upon it being shown that the previously disclosed method inevitably, or usually, leads to the product in question - see General Tyre & Rubber Company v The Firestone Tyre and Rubber Company Ltd at p.486. Had that been the issue here, my finding in the previous paragraph (that one would expect to get Form I by crystallising with acetone) would have been sufficient for Arrow to satisfy that test. But that is not the issue with which I am here concerned. I have dealt with the product claims (claims 1-3) on the basis that the product is anticipated by prior disclosure of the product rather than by derivation from an already disclosed method; though if that reasoning is wrong, Arrow would succeed in their challenge to those claims by an argument along these lines. In considering claim 5, however, the court is concerned with a different question, namely whether a claim to a method is anticipated by prior publication of a method. The question to be answered in that context has nothing to do with whether the method previously published always, usually or seldom achieves a particular result. Rather, it is whether someone now carrying out a crystallisation using that method, i.e. using acetone in accordance with the 845 patent or in accordance with Declercq (those materials, on this hypothesis, not having previously been published), would infringe the patent in issue here: see General Tyre & Rubber Company v The Firestone Tyre and Rubber Company Ltd at p.485. It seems to me clear that such a person would infringe the patent; and would do so whether or not he actually achieved the result he was striving for, i.e. Form I tibolone. This is because claim 5 claims a monopoly over every process of crystallising the polymorphous compound using acetone. Crystallising raw "tibolone" using acetone is certainly disclosed in the 845 patent and in Declercq, and, if done now, would be an infringement.

[35] Arrow's attack on claim 5 on grounds of anticipation or lack of novelty therefore succeeds.

 

Obviousness/ lack of inventive step

[36] Section 3 of the Patent Act 1977 states: "An invention shall be taken to involve an inventive step if it is not obvious to a person skilled in the art, having regard to any matter which forms part of the state of the art by virtue only of section 2(2) above ...". The argument that the invention claimed in the patent did not involve any inventive step is sometimes described as one of "obviousness".

[37] I was referred to certain authorities on the test to be applied. I should mention two in particular. The first is Windsurfing International Inc. v Tabur Marine (G.B.) Ltd [1985] RPC 59, a decision of the Court of Appeal decided under the 1949 Act but which, it was agreed, was directly applicable to disputes arising under the 1977 Act. At p.73, Oliver LJ, giving the Judgment of the Court, set out four steps which required to be taken in answering what he called the "jury question" whether the alleged inventive step was obvious to a normally skilled addressee in the art:

"The first is to identify the inventive concept embodied in the patent in suit. Thereafter, the court has to assume the mantle of the normally skilled but unimaginative addressee in the art at the priority date and to impute to him what was, at that date, common general knowledge in the art in question. The third step is to identify what, if any, differences exist between the matter cited as being "known or used" and the alleged invention. Finally the court has to ask itself whether, viewed without any knowledge of the alleged invention, those differences constitute steps which would have been obvious to the skilled man or whether they require any degree of invention."

The second authority is the decision of the Court of Appeal in Beloit Technologies Inc. v Valmet Paper Machinery Inc. [1997] RPC 489. In identifying the test for obviousness, Aldous LJ at pp.493-4 emphasised the objective nature of the test and warned against looking back with hindsight. He added:

"It has never been easy to differentiate between common general knowledge and that which is known by some. It has become particularly difficult with the modern ability to circulate and retrieve information. Employees of some companies, with the use of libraries and patent departments, will become aware of information soon after it is published in a whole variety of documents; whereas others, without such advantages, may never do so until that information is accepted generally and put into practice. The notional skilled addressee is the ordinary man who may not have the advantages that some employees of large companies may have. The information in a patent specification is addressed to such a man and must contain sufficient details for him to understand and apply the invention. It will only lack an inventive step if it is obvious to such a man."

The cases often, correctly, refer to the hypothetical skilled man as "unimaginative". But that is not to say that he is to be regarded as "uninterested" in accomplishing the result. One must assume, I think, that he is at least sufficiently interested to address his mind to the subject and to consider the practical application of the information which he is taken to have: see Windsurfer at p.73, and see also Pharmacia Corp v Merck & Co. [2002] RPC 41 at para.124. Aldous LJ in Beloit added the reminder that the fact that something is well known to a witness does not establish that it forms part of the common general knowledge. Nor is it necessarily part of the common general knowledge just because it is recorded in a document, however widely read, unless it has become generally known and accepted at least to the extent of being regarded as a good basis for further action.

[38] As I have indicated, the parties were agreed that the person skilled in the art for the purpose of the 035 patent is a process research chemist working with an analytical chemist in the pharmaceutical industry.

[39] The common general knowledge in play here related to knowledge of polymorphism, that is to say the phenomenon of a substance crystallising in more than one crystal structure. The most commonly cited definition of polymorphism is that given by McCrone: "A polymorph is a solid crystalline phase of a given compound resulting from the possibility of at least two crystalline arrangements of the molecules of that compound in the solid state" (W.C.McCrone, Physics and Chemistry of the Organic Solid State, vol.2, 1965 at p.725). Different crystal forms of a compound may exhibit different properties

[40] Dr Newton gave evidence to the effect that polymorphism was well known. Having referred in his first Report (at paras. 5.1.8 and 5.1.9) to polymorphism being a very common phenomenon, and having referred in support of that proposition to numerous textbooks, he said this:

"7.6 A skilled man wishing to develop Tibolone as a pharmaceutical product would need to identify a robust and repeatable process for making a well defined stable form of the drug.

7.7 The synthetic route to the compound is described in the 279 [patent]. ... The skilled man would be well aware of the fact that most steroids exhibit polymorphism (see references to common general knowledge at paragraph 5.1.9). Since he would have known that different steroidal polymorphs may have different melting points, densities, spectroscopic properties, bio availabilities and stabilities ... he would want to define a single polymorph having suitable physical and bioavailability profiles.

7.8 The skilled man would have been aware of the prior art and of the 1984 [Declercq] Paper. The latter would have been a very important document since it teaches how to make a pure polymorph and defines it analytically. Thus, by following the teaching of the 279 to make the compound and then recrystallising it from acetone as taught by the 1984 [Declercq] Paper the skilled man would have a method of preparing pure form I polymorph.

7.9 For these reasons I think that claims 1 and 2 of the Patent are obvious since the 1984 [Declercq] Paper already described form I Tibolone. Claim 3 is likewise obvious since the 1984 [Declercq] Paper precisely describes the crystal structure referred to in the Patent as monoclinic P21 form. Claim 5 is also obvious because the 1984 [Declercq] Paper describes recrystallisation from acetone rather than anhydrous acetone and one would expect the former solvent to contain some water. In support of this the Patent examples 1, 2 and 3 do not mention adding water to the acetone. ... So although the Patent on page 2 line 53 talks about recrystallisation from mixtures of water and acetone none of the examples include specifically adding additional water to the acetone. However on page 3 line 6 the Patent says: "Thus, in general good results are obtained from anhydrous acetone only when the crystallisation is carried out at a relatively low temperature". Since the Patent talks specifically about anhydrous acetone and indicates that it is less satisfactory than mixtures of acetone and water it is logical to conclude that the acetone used in the examples to illustrate the invention, which the authors refer to as acetone, is the standard solvent found on any bench top. This will contain some water. Since water is a very polar solvent its presence in the acetone will increase the polarity of that solvent and favour the formation of form I."

He then gives his conclusion in relation to obviousness:

"7.10 In my opinion it would have been obvious at the priority date of the Patent to obtain and use the polymorph claimed at claims 1-3 in its pure crystalline form. Furthermore, the solvents claimed at claim 5 are examples of solvents routinely used to conduct a polymorph screen."

[41] Professor Bernstein took a different view. As I understood his evidence, the difference between him and Dr Newton lay in his assessment of the level of common awareness of polymorphism and the uncertainties in that aspect of the science. He considered that even today there was a general lack of awareness of polymorphism amongst chemists. Although chemistry textbooks tended to mention the best known form of polymorphism or allotropism - that of graphite and diamond, both polymorphic forms of carbon - "physical chemistry texts discuss polymorphism in the context of thermodynamics and the phase rule, but rarely as a more general phenomenon encountered, say, in the field of pharmaceuticals". In his first Report he expressed the opinion that "in their proper context the citations and quotations [relied on by Dr Newton] do not support his conclusion" that polymorphism in steroids is very well known. However, in cross-examination (very late in the afternoon of Day 9) he accepted that he had carried out no investigation as to whether people working in the pharmaceutical industry, and in particular process research chemists, would have been familiar with the texts to which Dr Newton referred. On resuming his evidence the next morning, he asked to be allowed to elaborate upon those answers. I allowed him to do so, despite opposition from Mr Currie, because giving evidence is tiring and a witness can often "flag" towards the end of the day. However, as Professor Bernstein began to elaborate, it emerged that he wished not simply to expand on his previous answers but to give further evidence by reference to enquiries he had made of colleagues overnight. This seemed to me to be going a step further, and I stopped him on the basis that if this line was to be developed it should be for counsel to take it up or not as they considered appropriate. In the event, Mr Davidson did not seek to bring out the evidence of these further enquiries. It did not seem to me, however, that Mr Currie's criticism of Professor Bernstein for having made these enquiries overnight was warranted. An expert witness will often, in the course of prolonged examination or cross-examination, wish to check references or consider other aspects of his expert evidence overnight, and may need assistance, away from home, in finding materials. Sometimes this may involve outlining the problem to, or discussing it with, a colleague. I see nothing wrong with this at all. It is quite different from discussing the matter with clients or solicitors. Indeed, it is usually of assistance to the court. In the instant case Professor Bernstein's enquiries went slightly further. He felt, in light of the cross-examination directed to him, that he ought to have made those enquiries earlier, and he sought to make good that omission. I do not consider that he should be criticised for that.

[42] Despite Professor Bernstein's undoubted eminence in his field, I prefer the evidence of Dr Newton to the effect that by the late 1980s polymorphism as a phenomenon would have been well-known to a process research chemist working in the pharmaceutical industry; and they would have known that it was widespread in pharmaceuticals, particularly steroids. The prevalence of polymorphism was vouched by Professor Bernstein's citation of McCrone's view, as early as 1965, that "every compound has different polymorphic forms and ... in general, the number of forms known for a given compound is proportional to the time and money spent in research on that compound." Whilst emphasising that considerable caution should be exercised in asserting that polymorphism is the rule rather than the exception, Professor Bernstein went on to say (at para. 31 of his Report) that it "appears to be true that instances of polymorphism are not uncommon in those industries where the preparation and characterisation of solid materials are integral aspects of the developing and manufacturing of products (i.e. those on which a great deal of time and money are spent)", thus endorsing McCrone. The extent to which the skilled man (as previously defined) would be expected to have this knowledge is, of course, a separate question. However, Dr Newton's references included student text books, which would (as I understood his evidence, which I accept) have been read by process research chemists and analytical chemists during their student days, and I have no difficulty in accepting that knowledge of polymorphism was part of the common general knowledge of the skilled addressee of the patent.

[43] But there is a difference between, on the one hand, knowing of polymorphism as a phenomenon, or even knowing that it is likely to be found in steroids; and, on the other hand, being able to use or apply that knowledge. The point Professor Bernstein was making, for example in para.12 of his Report, was that polymorphism in any particular compound was usually discovered by serendipity rather than by systematic research. The important conclusion from this was that set out at para.56 of that Report, that: "... even the skilled person could not know in advance that any steroid might be polymorphic. He certainly would not know in advance how to obtain it, or what its properties might be." Despite the existence of polymorphic screening - which was less common in the 1980s than it is today - I did not understand Dr Newton to disagree strongly with this opinion; and, in any event, I accept it as correct. Ultimately there did not seem to be as much between Dr Newton and Professor Bernstein as at first appeared. The relevant issue is not so much whether there was an awareness of polymorphism amongst the relevant people at the relevant time, but whether that knowledge pointed the way to a discovery of polymorphism in any particular case.

[44] The obviousness attack on the claims in the patent has to be considered against this background. Let it be assumed that the skilled but unimaginative addressee of the patent knows of tibolone, and knows that there is a likelihood that tibolone, being a steroid, is polymorphous. Without the benefit of hindsight, I do not see why he would want to look for a pure polymorphic form of tibolone. After all, tibolone had been known from the 1960s, and there was no evidence of any concerted effort to find out if it was polymorphous. Nor do I see how he would go about finding a new polymorphic form. He might know of the Declercq paper, which would tell him about what is now called Form I, and about the use of acetone, but not about tibolone being polymorphic. If he carried out a crystallisation using acetone, he would probably have produced what we now know as Form I tibolone. But that would support Arrow's argument on anticipation rather than obviousness (see para.34 above). It seems to me that the "obviousness" line of attack, as distinct from that based on anticipation, assumes that the skilled but unimaginative addressee of the patent would be looking to develop a pure polymorphic form of tibolone and would have had the knowledge of how to achieve it. Without the benefit of knowing (with hindsight) that such a form had been found, I do not consider that he would have had either the motivation or the means.

[45] Applying the four stage approach identified in the Windsurfing case, the question of obviousness can be considered in this way: (i) the inventive concept in the patent is the identification of a crystalline pure form of tibolone and a method of producing it; (ii) the skilled addressee would have known of tibolone and would have knowledge that steroids are likely, though not certain, to be polymorphous; (iii) the difference is the discovery of polymorphism in tibolone and the identification of the method of producing one of the two different polymorphic forms. Stage (iv) requires one to ask whether the steps required to achieve this would have been obvious to the skilled man. To that question the answer, in my opinion, is a clear: No.

[46] Accordingly, I would have rejected the attack on Claims 1-3 and 5 of the 035 patent if that attack had been based solely on obviousness. As it is, I shall uphold the attack based on anticipation or lack of novelty, so my rejection of this additional line of attack is immaterial.

 

The 375 Patent

[47] The 375 patent has a priority date of 16 October 1998. According to the description in the patent, the invention relates to "a high purity (7α,17α)-17-hydroxy-7-methyl-19-nor-17-pregn-5(10)-en-20-yn-3-one [i.e. tibolone], a method for the preparation of this compound for use in the pharmaceutical composition as well as a pharmaceutical composition prepared by admixing a pharmaceutically suitable carrier and the high purity composition." The high purity referred to is, in this case, a chemical purity.

[48] Under reference to the 035 patent, the 375 patent states that tablets, including Livial, which comprise tibolone and a pharmaceutically acceptable solid carrier, are available on the market. Such tablets can be stored for, typically, 2 years at ambient temperature. However, it is noted that during the preparation of pharmaceutical dosage units the relative amount of impurities in the compound may increase. In particular, one of the impurities already present in the bulk preparation, known as Org OM38, tends to increase during the process of making pharmaceutical dosage units. It is also known that the amounts of OM38 in compositions comprising Tibolone increase upon storage.

[49] The patent then states in para. [0006] that the end of shelf life specification with respect to the amount of OM38 formed during storage is 5%. A minimum acceptable shelf life period for these dosage units is 1 year. Accordingly,

"it is an object of the present invention to improve upon the storage stability i.e. to enhance the shelf-live (sic) of the dosage units."

The patent goes on to explain in paras. [0007] and [0008] other problems to do with shelf-life.

"[0007] The customary amount of Tibolone in the known dosage unit is 2.5mg in tablets or capsules of 100 mg i.e. 2.5%. For the sake of providing therapies better tailored to the individual woman's needs. It is desired to provide dosage units having a lower amount.

[0008] However, adaptation of a known formulation by simply including a lower amount of Tibolone further decreases the stability of the dosage unit substantially. E.g., if a 2.5mg Tibolone dosage unit has a shelf-life of, e.g., 2-3 years at room temperature, the same unit upon lowering the amount of Tibolone to e.g. 0.3 mg can only be kept at 4C for a period of 6-12 months. Such a lower stability is unacceptable in daily practice. It is a further object of the invention to provide dosage forms having a lower content of Tibolone (which are more prone to stability problems than regular dosage forms) and that can be suitably kept for a prolonged period of time."

The authors explain that one of the possible ways of keeping the amount of OM38 below a desired level after a prolonged storage time is to limit the amount initially present in the bulk preparation. Thus they say in para. [0009]:

"there is a need to synthesize high purity Tibolone batches with a low contamination content of OM38. It is an object of the present invention to provide for such high purity batches of Tibolone."

They explain in the next paragraph that during the last step of the synthesis of tibolone, a solution of (7α17α)-3.3-dimethoxy-17-hydroxy-7-methyl-19-norpregn-5(10)-en-20-yn-3-one in a mixture of pyridine and ethanol is mixed with a solution of oxalic acid in water and the mixture is stirred for 3 hours at approximately 30C. The solution is then poured out in a mixture of pyridine and water and the resulting suspension is filtered. The crystals are washed with a mixture of water and pyridine and subsequently, the crystals are dried under vacuum at 40C to give (7α17α)-17-hydroxy-7-methyl-19-norpregn-5(10)-en-20-yn-3-one. The authors refer to a 1986 paper by van Vliet et al, "An alternative synthesis of 17β-hydroxy-7α-methyl-19-nor-17α-pregn-5(10)-en-20-yn-3-one (Org OD 14)" ("van Vliet" or "the van Vliet paper"). As tibolone has a lower stability than the corresponding OM38, a small percentage of OM38 forms in the compound via acid catalysed isomerisation. Furthermore, this isomerisation takes place at higher temperature and upon long term storage of the crystals.

[50] The authors then proceed to identify the discovery underlying the invention claimed in the patent.

"[0012] Unexpectedly, it now has been found that the rate of formation of OM38 during drying and storage in a specific batch can be decreased if crystals of Tibolone are washed with water and are allowed to age for at least 24 hours in the presence of water. Thus, the Tibolone is left for at least 24 hours under wet conditions. Preferentially the crystals are left under these conditions for a period of at least 3 days. There is no limit to a maximum period but a period of 3-6 days is best suited. The aging temperature preferentially is room temperature.

[0013] Thus according to the procedure of the present invention highly pure Tibolone with a low OM38 impurity is obtained by including a delay of several days before drying. The procedure reliably results in batches of Tibolone having a low OM38 content. A further advantage is that these batches have an excellent stability. Furthermore, these batches do not form additional amounts of the latter compound upon heating or long term storage."

[51] It is convenient at this stage to set out in full certain other paragraphs of the descriptive part of the patent before identifying the claims made by the patentees.

"[0014] The crystal formation procedure of the present invention can perfectly well be combined with the last step of the Tibolone synthesis wherein (7α17α)-3-3-dimethoxy-17-hydroxy-7-methyl-19-norpregn-5(10)- en-20-yn-3-one in a mixture of pyridine and ethanol is mixed with a solution of oxalic acid in water. In general, this reaction proceeds under mild acidic conditions in the presence of an organic solvent and water within a pH range of 5-3, preferentially 3.5-4.5. The acid preferentially is a weak organic acid having a pKa value in the range 1-5 such as citric acid, malonic acid, oxalic acid, dichloracetic acid and acetic acid, optionally buffered with a base such as pyridine. As organic solvent e.g. ethanol, methanol, acetone, 2-propanol or tetrahydrofuran can be used. The solution is then poured out in water, which is made slightly alkaline by addition e.g. of a low amount of pyridine. After filtering the suspension the crystals are washed with a mixture of water made slightly alkaline by e.g. pyridine. Before drying the crystals are left wet for at least 24 hours.

[0015] Inclusion of the crystal aging step according to the invention results in bulk Tibolone batches with a low Org OM38 content. Routinely, batches are obtained with an Org OM38 content of less than 0.5%. Often even batches with less than 0.25% or even 0.1% of Org OM38 are obtained. Thus high purity compositions with Tibolone having less than 0.5% of Org OM38, preferably 0.25%, more preferably 0.10% of Org OM38 form part of the present invention. The amount of Org OM38 is calculated as the percentage (w/w) of the total amount of the bulk substance including some minor impurities. The amount of Tibolone usually is more than 98%.

[0016] The batches of these high purity Tibolone compositions with their low initial Org OM38 content are perfectly well suited to be used as a source for the preparations of pharmaceutical formulations. This guarantees a formulation with a low initial Org OM38 content and improves therefore its storage properties. Pharmaceutical preparations prepared with high purity Tibolone usually result in preparations with less than 1% of Org OM38, often even less than 0.7% of Org OM38 and these preparations are less prone to increase in Org OM38 content during storage.

[0017] As indicated before the amount of Org OM38 in a dosage form also depends upon the concentration of the active substance, the amount of impurity being higher as the amount of Tibolone in the dosage unit decreases. Therefore, using high purity Tibolone as the active substance, dosage units can now be prepared with a lower amount of Tibolone and still having an acceptable shelf life. Thus, the invention also relates to pharmaceutical dosage units, which can be prepared by admixture of a pharmaceutically suitable solid carrier and the high purity composition of the present invention.

[0018] A typical known formulation for Tibolone is a 100 mg dosage unit having 2.5 mg of Tibolone contained therein, a relatively small amount (e.g. approximately 1% by weight) of pharmaceutically acceptable auxiliaries, and a carrier making up the body of the tablet. The carrier typically is composed of 10% by weight of starch, e.g. potato starch, and 90% by weight of lactose.

[0019] Due to the excellent stability properties of dosage units with a lower amount of active substance than the present commercially available tablets of 2.5mg active substance, the present invention now makes it also possible to provide for stable dosage units comprising Tibolone in an amount of less than 2.50mg, preferably 1.25mg or less, more preferably 0.625mg or less. At a shelf life of 1.5 years, preferably 2 years these dosage units still comprise less than 5% of OM38 (relative to the amount of Tibolone).

[0020] It is another aspect of the present invention to provide dosage units comprising Tibolone in amounts of less than 2.50mg, preferably 1.25mg or less, more preferably 0.625mg or less and comprising at a shelf life of 6 months less than 3%, preferably 2% of OM38. The shelf life preferably is extended up to 1 year, preferably 1.5 year, more preferably 2 years.

[0021] As used herein shelf life means storage during a specified period under temperature conditions varying from 2.25C. Dosage units can be packed e.g. in push-through packs (PTP, blister) and are preferably stored in dark (e.g. enclosed in carton). Alternatively they might also be stored in bottles e.g. high-density polyethylene bottles.

[0022] The pharmaceutical dosage units of the present invention will generally take the form of tablets or capsules, but other solid or dry pharmaceutical preparations are included.

[0023] Methods for making such dosage units are well known. For example in the standard English language text, Gennaro et al, Remington's Pharmaceutical Sciences (18th ed. Mack Publishing Company, 1990, see especially Part 8: Pharmaceutical Preparations and Their Manufacture), methods of making tablets, capsules and pills and their respective components are described.

[0024] Tablets and capsules are prepared of granulates using dry or wet granulation techniques as disclosed in The Theory and Practice of Industrial Pharmacy (Third Edition) L Lachman, H A Liebeman and J L Kanig (1986) p1-99 and 293-345.

[0025] The aim of granulation is to improve the flowability and compressibility of the powder mixture. Wet granulation forms the granules by binding the powders (a mixture of a diluent and disintegrant) together with an adhesive. The wet granulation technique employs a solution, suspension or slurry containing a binder, which is usually added to the powder mixture; however the binder may be incorporated dry to the powder mix and the liquid may be added by itself. The wet granulation process is performed in mixers/kneaders or fluid bed systems.

[0026] Usually an amount of water is incorporated in the basic granulae ranging from 5.5 - 7%. Preferably the amount of water incorporated is at least 6%.

[0027] After granulation the mass is dried to the desired water content using fluid bed dryers, tray dryers, vacuum dryers or other suitable dryers.

[0028] To attain a good distribution of the active (Tibolone) over the total mass, the active is premixed with a part of the granulate, sieved using an oscillating sieve, a high speed sieve or other suitable sieving equipment. Next this mixture is mixed with the remaining part of the granulate and a lubricant. This mixture is compressed to tablets, or filled into capsules."

 

The claims in the patent

[52] Against this explanatory background I set out the claims made in the patent. Although not all of them are challenged in these proceedings, it is useful, in considering the arguments, to set them out in full.

"1. A high purity compound (7α17α)-17-hydroxy-7-methyl-19-nor-17-pregn-5(10)-en-20-yn-3-one [i.e. tibolone] characterised in that said compound comprises (7α17α)-17-hydroxy-7-methyl-19-nor-17-pregn-4-en-20-yn-3-one [i.e. OM38] in an amount less than 0.5%.

2. The compound according to claim 1 characterised in that the amount of [OM38] is 0.25% or less.

3. The compound according to claim 1 characterised in that the amount of [OM38] is 0.1% or less.

4. A process for preparing the high purity compound of claims 1-3 characterised in that crystals of [tibolone] are allowed to age in the presence of water for at least 24 hours.

5. The process according to claim 4 wherein the aging lasts 3-6 days.

6. The process according to claims 4 or 5 characterised in that the crystals are formed in the last step of the Tibolone synthesis comprising the steps of

a. reacting (7α17α)-3-3-dimethoxy-17-hydroxy-7-methyl-19-norpregn-5(10)-en-20-yn-3-one in an organic solvent with a weak acidic aqueous solution.

b. pouring out the solution in water which is made slightly alkaline.

c. washing the crystals with water which is made slightly alkaline.

7. A pharmaceutical dosage unit obtainable by admixture of a pharmaceutically suitable solid carrier and the compound according to any one of the claims 1-3.

8. A pharmaceutical dosage unit obtainable by admixture of a pharmaceutically suitable solid carrier and the compound obtainable by the process of claims 4-6.

9. A dosage unit comprising a pharmaceutically suitable solid carrier and [tibolone] in an amount of less than 2.50mg and comprising less than 5% of [OM38] at shelf life of at least 1.5 years.

10. The dosage unit according to claim 9 characterised in that [tibolone] is present in an amount of 1.25mg or less.

11. The dosage unit according to claim 9 characterised in that [tibolone] is present in a amount of 0.625mg or less.

12. The dosage unit according to claims 9-11 wherein the shelf life is 1.5 years, more preferably 2 years.

13. The dosage unit according to claim 9-11 wherein at a shelf life period of 6 months the amount of [OM38] is 3% or less, more preferably 2% or less.

14. The dosage unit according to claim 9-11 wherein at a shelf life period of 11/2 years, more preferably 2 years, the amount of [OM38] is 3% or less, more preferably 2% or less."

[53] The claims can, for convenience, be grouped together under four headings. The first group, comprising claims 1-3, is concerned only with the chemical purity of tibolone in terms of its contamination by OM38. Those claims are claims to tibolone in which the OM38 is present in only very small amounts (<0.5%, 0.25% or less and 0.1% or less). The claims in the second group, claims 4-6, are claims to a process (the "crystal ageing step" or more commonly referred to in evidence and submissions as the "ageing process") for preparing tibolone of the purity identified in claims 1-3. Though there was some argument about the precise ambit of claim 8, the third group, comprising claims 7-8, may be described in general terms as being concerned with claims to a pharmaceutical dosage unit combining a pharmaceutically solid carrier and tibolone of the requisite purity. The claims in the fourth group, claims 9-14, are claims to a pharmaceutical dosage unit combining a carrier and various quantities of tibolone and having a shelf life defined by reference to the amount of OM38 present after certain specified periods.

 

Amendment by Arrow and Norton

[54] The claims challenged by Arrow and Norton on Record are those numbered 1-3, 7 and 9-14. In their closing submissions Mr Currie QC for Arrow and Mr Campbell QC for Norton both sought leave to amend to include a challenge to claim 8 as well. This was opposed by Mr Davidson QC for Akzo. Having considered the application carefully, I am satisfied that it would be in the interests of justice to allow the amendment to be made, for reasons which will become apparent when I deal with that claim. I shall accordingly consider also the validity of claim 8. In the event, therefore, only the second group of claims, i.e. claims 4-6, which were concerned with the ageing process itself, was not challenged in these proceedings.

 

Proposed amendment by Akzo

[55] Mr Davidson moved the court in October 2005 to allow the claims in the patent to be amended. The amendments followed the terms of Akzo's Second Auxiliary Request in opposition proceedings before the EPO. Mr Davidson described the amendments as being by way of re-writing. He said that they were sought for the purposes of further defining the invention. They involved the deletion of claims 1-14 of the patent and their replacement with 13 new claims. I do not propose to set out the whole terms of the proposed amendment but the flavour of it can be gathered from the following. Claim 1 of the proposed amended claims read as follows:

"A high purity compound [tibolone] comprising [OM38] in an amount less than 0.5% obtainable by a process wherein crystals of tibolone are allowed to age in the presence of water for at least 24 hours."

Claims 2 and 3 were to a similar effect with different quantities of OM38. Claims 4-6 were again similar except for variations to the period of ageing and the temperature at which the ageing was carried out. Claims 7-9 were identical to Claims 4-6 of the unamended patent whilst Claims 10-13 were in broadly similar terms to Claims 7-11 of the unamended patent. The key difference was the introduction of the ageing process into the definition of the product in the product claims, i.e. claims 1-3 of the original patent and 1-6 of the proposed amended patent. Akzo's motion to amend was in a somewhat unusual form, in that it sought the amendment on a contingent basis, namely only if as a result of the proof before answer the court held that any of the claims of the unamended patent were subject to revocation.

[56] The motion came before me in November 2005 and was continued twice. It was opposed by Arrow and by Norton on essentially three grounds: first, that it was incompetent; second, that it was irrelevant, the proposed amendment being to introduce "product by process" claims (cf. Kirin-Amgen Inc. v Hoechst Marion Roussel Ltd [2005] RPC 169 per Lord Hoffman at paras. 91-101); and third, that it was too late, the new claim raising issues which could not properly be investigated and dealt with before the proof due to commence in January 2006.

[57] The question of competency was argued at some length. In view of its general importance, it is right that I should set out briefly my reasons for holding the motion to be competent. Section 75 of the Patents Act 1977 permits the court to allow the patentee to amend the specification of a patent in such manner and subject to such terms as to advertising and as to expenses or otherwise as the court thinks fit. Rule of Court 55.5 governs the procedure in Scotland. There are requirements for notice and advertisement. The advertisement allows persons who are not parties to the proceedings to become aware of the proposed amendment and to give notice of their intention to oppose it. Within 35 days after the appearance of the advertisement, the applicant for the amendment must apply to the court by a motion intimated to the Comptroller-General of Patents, Designs and Trade Marks ("the Comptroller"), the other parties to the action and to any person who has intimated his intention to oppose the amendment. At the hearing of the motion, where there is opposition to it, the court ordains the applicant to lodge a minute setting out the grounds of his application within such period as the court thinks fit and allows other parties to lodge answers to the minute. Within 7 days after the expiry of the time for lodging answers, the applicant is required to apply by motion for an order for further procedure. On the hearing of that motion the court may grant the application or determine whether the motion shall be heard at the same time as the hearing of the cause depending before it relating to the patent in question, or may lay down other procedure as it thinks fit. It was submitted on behalf of Arrow and Norton that the Rules of Court to which I have referred did not permit a contingent application such as the one intimated by Akzo. I see no reason why that should be so. The effect of Akzo's motion, which I allowed to be amended at the bar so that it could be clarified, was that they would wish to move the amendment only if they were unsuccessful in upholding the claims put in issue by Arrow and Norton. Such a position seems to me to be consistent with the terms of Rule 55.5(8)(b) entitling the court to order that the motion be heard at the same time as the hearing of the cause depending before the court. At that stage the issues relating to the validity of the unamended claims will be canvassed before the court; and it seems to me that it would be unrealistic, and contrary to common sense, to require the applicant to make an election before he knows what the court's answer to the challenges will be. Provided that all the material necessary for a consideration of both the existing claims and the proposed amended claims is before the court - and that is important - it causes no difficulty to any party to allow the applicant to defer making a final decision on whether to proceed with his motion.

[58] Nonetheless, I refused the motion to amend since it seemed to me to raise issues which were not covered by the existing dispute between the parties and which neither Arrow nor Norton could reasonably be expected to address in the relatively short time leading up to the proof. These issues related, in effect, to the ageing process and the product produced as a result of it. As I have already indicated, the ageing process itself was not in dispute before me. Although evidence was given about it and submissions were made, no party had prepared for the proof on the basis that there was to be a full examination of the ageing process and the tibolone produced by that process. Nor had the expert evidence been focused on what, if any, differences there were in the product of the ageing process as compared with that which had not been through that process. In consequence, it would have been virtually impossible, so it seemed to me, for Arrow or Norton to deal properly with the amended claims 1-6. Equally, although I would not have refused the amendment simply on the basis that it was arguably irrelevant having regard to the test for "product by process" claims set out in Kirin-Amgen, it seemed to me that the question whether that test was satisfied in relation to the proposed new claims 1-6 was something that required evidence - and it would have been unfair to Arrow and Norton to require them to deal with this matter at relatively short notice before the proof. In coming to this conclusion, I took into account the submissions made on behalf of Akzo to the effect that Arrow and Norton, through the opposition proceedings before the EPO and certain other matters, were or ought to have been aware of the desire on their part to make these amendments. However, this did not seem to me to address the relevant issue. I was told by counsel for Arrow and Norton that their respective experts had not addressed these issues in the detail that would be required if the amendments were allowed. That did not surprise me. Why should Arrow or Norton incur expenditure and divert their energies - in advance of the proof due to commence in January - preparing to deal with issues which had not been raised in proof.

[59] Accordingly, I refused the motion to amend. I indicated that it would, of course, be open to Akzo to make a new application to amend at the end of the proof. They duly did so. I shall deal with this renewed application at the end of this Opinion.

 

Expert evidence

[60] I heard expert evidence in relation to the subject matter of the 375 patent from Dr Newton (for Arrow), Dr Widdowson (for Norton) and Professor Pattenden (for Akzo). I have already identified Dr Newton's field of expertise. Dr Widdowson and Professor Pattenden were also similarly qualified. Professor Pattenden has recently stood down as the Sir Jesse Boot professor of organic chemistry at the University of Nottingham and is now professor of organic chemistry there. He was elected in 1991 to the Fellowship of the Royal Society. Dr Widdowson is currently reader (albeit now on a part-time basis) in Organic Chemistry in the department of chemistry, Imperial College London, and before that was a lecturer in the department of chemistry at Imperial College. In 1997 he was awarded the Bader prize of the Royal Society of Chemistry for "Eminence in Organic Chemistry". They all gave their evidence in a clear and helpful manner. I formed the view that they were all aware of their obligations as expert witnesses and were trying to assist the court to the best of their ability. Unsurprisingly, there were large areas on which they agreed. Where there were differences between them on which I am required to make a decision I do so not on the basis of any general preference for one expert over the other but because of my perception of the strengths and weaknesses of the particular arguments.

[61] In addition I heard evidence in relation to two series of tests or experiments. One was carried out by Resolution Chemicals Ltd ("Resolution") on 7 February and 18 August 2003 ("the Resolution experiments"). Resolution had attempted to replicate Example 5 of the 035 patent, though on a larger scale. The result of the experiments was tibolone of a chemical purity which met the claims in Claims 1-3 of the 375 patent. The other tests were carried out by Synnovation Ltd, according to a protocol set out in a document entitled "Notice of Experiments". These test were carried out at the instance of Norton and were, in effect, an attempt to re-run the exercise carried out by van Vliet to see whether the tibolone resulting therefrom was of the chemical purity to which Claims 1-3 of the patent referred.

 

OM38

[62] I did not understand there to be any significant difference between the expert witnesses on the basic science which forms the background to the patent in issue. I take the following brief summary from Dr Newton's report as amplified by the evidence. Compounds such as tibolone, which contain a double bond and a carbonyl group in a 6-membered ring, have a tendency to undergo a rearrangement so that the double bond moves into conjugation with the carbonyl group and, in the case of tibolone, forms OM38. The process is called isomerisation (and OM38 is sometimes referred to as "iso-tibolone"). The isomerisation process can be catalysed by acid. The strength of the acid affects the speed of the reaction. The stronger the acid, the faster the conversion. The removal of acid slows the process. Impurities such as OM38 will have a different biological activity from that of tibolone, which may have an effect on the shelf-life of the product. As the patent notes in para.[0006], a maximum of 5% OM38 is permitted in pharmaceutical compositions comprising tibolone at the end of their shelf life. It is important, therefore, to control the level of OM38 in tibolone insofar as that level affects the shelf life of the product. That is the problem which the 375 patent addresses.

[63] The patent claims to have achieved this by the ageing process. There was considerable discussion during the evidence about whether and, if so, how the ageing process worked. Although, as I have noted, the ageing process as disclosed in Claims 4-6 of the patent was not challenged, it is necessary to consider this issue in some detail since it informs an understanding of the patent and the issues (of anticipation and obviousness) relevant to the other Claims.

 

The ageing process

[64] The first mention of the ageing process in the patent appears at paras.[0012]-[0015] of the specification. I have already quoted those paragraphs (see paras.50-51 above). A number of examples are given in the patent to illustrate the effect of the ageing process and to invite conclusions from a comparison of "aged" and "un-aged" tibolone, using that terminology to mean, respectively, tibolone prepared by the ageing process and that prepared without using the ageing process. Thus, Example 1 did not include the ageing process, whereas Examples 2 and 3 did. Those Examples are as follows, substituting [tibolone] and [OM38] for the chemical expressions used in the Examples:

"Example 1

[0030] A solution of (7α,17α)-3,3-dimethoxy-17-hydroxy-7-methyl-19-norpregn-5(10)-en-20-yn-3-one (15kg) in a mixture of pyridine (630ml) and ethanol (315 litres) was mixed with a solution of oxalic acid (750gr) in water (90 litres) and the mixture was stirred for 2 hours at approximately 30C. The solution was poured out in a mixture of pyridine (1350ml) and water (300 litres) and the resulting suspension was filtered. The crystals were washed with a mixture of water and pyridine and dried under vacuum at 40C to give [tibolone] containing 0.6% of the corresponding [OM38] as indicated by HPLC analysis; a stress test at 45C (duration 1 month) indicated a 0.4% increase of the latter compound.

Example 2

[0031] A solution of (7α,17α)-3,3-dimethoxy-17-hydroxy-7-methyl-19-norpregn-5(10)-en-20-yn-3-one (15kg) in a mixture of pyridine (630ml) and ethanol (315 litres) was mixed with a solution of oxalic acid (375gr) in water (90 litres) and the mixture was stirred for 3 hours at approximately 30C. The solution was poured out in a mixture of pyridine (1350ml) and water (300 litres) and the resulting suspension is filtered. The crystals are washed with a mixture of water and pyridine and allowed to age for 3-6 days at room temperature. Subsequently, the crystals were dried under vacuum at 40C to give [tibolone] containing ≤ 0.1% of the corresponding [OM38] as indicated by HPLC analysis; a stress test at 45C (duration 1 week) indicated a < 0.1% increase of the latter compound.

Example 3

[0032] The preparation as described in example 2 was repeated. [Tibolone] was obtained which contained 0.2% of the corresponding [OM38] as indicated by HPLC analysis; a stress test at 45C (duration 1 week) indicated a 0.1% increase of the latte compound."

[65] Example 4 set out a method of producing tablets. There was nothing either novel or inventive about that method. The text was silent on the question whether the tablets were made from aged or un-aged tibolone, and I do not think there was any consensus on which it was. For my part I consider it more likely that it was un-aged. The stability of the tablets thus made was determined and the results set out in Table 1.

Table 1:

Content of decomposition product (Org OM38) in percentage of the declared amount of Tibolone per tablet, in tablets containing a various amount of Tibolone, after storage at 25C and 60% relative humidity

Storage time (months)

Concentration of Tibolone per tablet

0.46

0.96

1.92

2.5

 

Amount of Org OM38 formed during storage (in percentage of the declared amount of Tibolone)

0

1.2

0.8

0.5

0.4

6

6.5

3.5

1.8

1.6

12

9.5

5.1

2.7

2.2

18

12.2

6.1

3.3

2.7

 

The figures against a storage time of 0 (zero) months indicated the amount of OM38 in the tibolone after tabletting, rather than when the tibolone was made. As can be seen, the concentration of tibolone in the tablets tested in Table 1 varied.

[66] Examples 5 and 6 set out to measure the OM38 content of tablets containing 1.25 mg tibolone over different lengths of storage time. I set out those examples below, since much discussion focussed on them.

"Example 5

[0036] Tablets of 1.25mg of Tibolone have been prepared as described in example 4. The tablets were stored at 25C and 60% relative humidity and the decomposition product (Org OM38) was measured.

Table 2: Content of decomposition product (Org OM38) in percentage of the declared amount of Tibolone per tablet. Stability of three development tablet batches (1.25mg of Tibolone per 65mg) was assessed (storage at 25C and 60% relative humidity)

Storage time (months)

Batch no

049514001

049515001

049516001

 

Amount of Org OM38 formed during storage (in percentage of the declared amount of Tibolone)

0

0.7

1.0

1.3

6

2.3

2.6

2.9

12

3.5

3.7

3.8

18

4.3

4.2

4.3

24

5.1

4.9

4.9

 

[0037] It can be concluded that the shelf life of tablets containing 1.25mg of Tibolone per tablet of 65mg is borderline."

There was some debate as to whether the tibolone used in Example 5 was aged or un-aged. Although the text is silent on this point, it seems to me that the context shows it to have been un-aged, since the clear intention behind setting out the results in this form was to compare the shelf-life of un-aged tibolone (Example 5) and aged tibolone (Example 6).

[67] The tibolone in Example 6 was prepared as in Example 2, and was, therefore, aged tibolone.

"Example 6

[0038] Tibolone as prepared as in example 2 was used as the active compound to prepare tablets as described in example 4. The amount of Org OM38 formed in several batches during storage was determined.

Table 3

The stability of six tablet batches (1.25mg of Tibolone per 65mg) was assessed (storage at 25C and 60% relative humidity). The amount of water incorporated in the basic granulate was varied from 6.0% to 6.5%

 

Storage time (months)

Batch No.

TD96.1128

TD96.1132

TD96.1133

162454001

162455001

162456001

 

Amount of Org OM38 formed during storage (in percentage of the declared amount of Tibolone)

0

0.7

0.5

0.5

0.9

0.8

0.9

6

1.3

1.1

1.1

1.8

1.7

1.8

12

1.8

1.5

1.6

 

 

 

18

2.0

1.5

1.7

 

 

 

Water content of the basic granulate

6.5

6.5

6.5

6.3

6.1.

6.1

 

[68] The data in these Examples was the only material placed before the court relevant to the issue of whether or not the ageing process was effective to produce pure and stable tibolone. In saying this, I put to one side the evidence of Dr Vrijhof, who was called by Akzo and gave evidence that the ageing process had been observed to work in practice. Objection was made to his evidence, principally on the basis that there was no Record for it. In light of the fact that other witnesses had spoken to the question of whether the ageing process worked, I would not have rejected it simply on that ground. However, Dr Vrijhof began to explain how, in his opinion, the process worked. His evidence came after all the experts had given their evidence, and was not foreshadowed by any Report or statement either lodged in process or intimated to the other parties. I was concerned that evidence from him at that stage as to the way in which the ageing process might work presented a risk of re-opening the expert evidence. I would, on that ground, have excluded that part of his evidence, but in the event Mr Davidson accepted the validity of that concern and confirmed that he placed no reliance on it. The same concerns seem to me to apply to any detailed observation confirming the efficacy of the process - the experts might have had something to say about that had they been given the opportunity - and I propose to exclude such evidence also. What remains of Dr Vrijhof's evidence amounts to little more than anecdotal evidence of his belief that the process works, and whilst I repel the objection to its admissibility I do not think it proper to place any reliance on it.

[69] Professor Pattenden, in his evidence, enthusiastically supported Akzo's case that the ageing process worked. He considered that this conclusion was supported by the data. He compared Example 1 (un-aged) with Examples 2 and 3 (both aged). In Example 1, without the ageing step, the level of OM38 was 0.6% after drying, whereas in Examples 2 and 3, with the ageing step, it was only 0.1% and 0.2%. So also, in the stress tests, the aged tibolone in Examples 2 and 3 performed much better than the un-aged tibolone in Example 1. Under stress tests, the OM38 in the un-aged tibolone of Example 1 increased from 0.6% to 1.0%, an increase of 0.4%. In the aged tibolone of Example 2, the increase in OM38 was from 0.1% to <0.2%, an increase of 0.1%; whereas in Example 3 (also aged) it increased by 0.1% (from 0.2% to 0.3%). Professor Pattenden relied both upon the final reading for OM38 after the stress tests and also upon the rate of continuing isomerisation during those tests. He attributed all aspects of the better performance of Examples 2 and 3 to the introduction of the ageing step. The differences in the initial levels of OM38 in the Examples, and in the levels of OM38 after the tibolone had undergone stress tests, he said, "are very significant and must reflect the importance of the ageing process." He also compared the results in the Tables in Example 5 (un-aged) with Example 6 (aged). The tablets of aged tibolone (Example 6) gave better results in terms of OM38 content over the 24 month period that those containing the un-aged tibolone. This too could be attributed to the ageing process.

[70] Whilst Doctor Newton did not consider that the ageing process worked, Doctor Widdowson, in his first Report, took up what appeared to be a more qualified position. He said, at para.14: "The 375 process offers no explanation as to the nature of the ageing process but certain facts are indicative of the probable role". In his oral evidence, he qualified this by saying: "if it works at all". It was put to him in cross-examination that he had shifted his position. I did not think so. Taking his evidence as a whole, it seemed to me that he had at no stage accepted that the ageing process worked. He was simply speculating as to how it might work, if it did.

[71] It is worth considering this point further at this stage. Doctor Widdowson's suggestion as to how the ageing process might work was as follows: (a) the synthetic process which produces tibolone is catalysed by a mild acid; (b) the isomerisation process to OM38 is also acid catalysed but this is slow under the mildly acidic conditions used in the synthesis; (c) Tibolone and OM38 are insoluble in water and are precipitated initially by adding aqueous base to the reaction mixture - this should also prevent the conversion to OM38 but the rapid precipitation of the product brought about by the added water may occlude small amounts of the acid catalyst in the crystals, thereby preventing the neutralisation of that material by the base dissolved in the water which cannot penetrate the crystals on the short time-scale of the work-up, even though the bulk of the acid, in solution, is neutralised; (d) this occluded acid would explain the continued slow conversion of tibolone to OM38 in the solid state and hence the shortened shelf-life; (e) the ageing process, consisting of prolonged contact of the product crystals with water containing a small amount of a base, therefore can be interpreted as a leaching process for the slow removal of residual acid from the crystals; (f) the extended shelf life of the product would then be a consequence of the low to zero acid content of the crystals resulting from the ageing process. Professor Pattenden agreed with this explanation of the process. He described it as like marinading meat or fish. His opinion was that the water leached out the residual acid and, perhaps simultaneously, protected the keto group in the tibolone until the bulk of the acid was removed. Dr Newton, for his part, was prepared to agree that if the process worked then this leaching process was a possible explanation of how it did. But this involves further interpretation by the reader of the patent. The patent does not fully explain how the acid catalyst is removed. One possibility is that, after completion of the ageing process, the solvents are simply evaporated off the wet crystals, leaving the acid on the outside of the crystals where it will continue to have some, albeit reduced, effect. Another is that the wet crystal cake is filtered to remove the bulk of the solvents and then dried by evaporation of the residual solvents. A third possibility, perhaps the most likely, is that the wet crystal cake is washed with water to remove the acid solution and then filtered and dried by evaporation. Whichever the explanation, removal of the acid appears to be an essential part of the process.

[72] Over the course of the evidence there was considerable discussion about whether, if it worked, the ageing process did so simply by reducing the acid content in the tibolone crystals and slowing down the formation of OM38; or whether it added something extra, and indefinable, which helped achieve stability and the longer shelf life. In his report, Dr Widdowson concluded his examination of the ageing process by stating his opinion that the extended shelf life of the product would be a consequence of the low acid content of the crystals resulting from the ageing process. Professor Pattenden in his report appeared to agree with this. He confirmed his agreement in his examination-in-chief. I sought clarification and asked Professor Pattenden to confirm that he was saying that the extended shelf life arises from the low acid content. He confirmed that the ageing process for its own reasons leads to a product which has a very low amount of OM38. He continued: "As a consequence of that low amount you are starting off with a very good position. So, it should have an extended shelf life." I then asked him: "So, you could reach the lower mark by some other route and still have this same extended shelf life?" His reply was: "That is my conclusion." In cross-examination, Mr Currie asked Professor Pattenden if it was his position "that stability is always described as a function of or in terms of chemical purity". Professor Pattenden responded: "They go hand in hand, yes." Although it is fair to say that Professor Pattenden subsequently spoke in terms of the ageing process achieving something more than mere purity of the tibolone, I did not accept that it was shown that the extended shelf life was achieved other than by achieving an initial purity in the tibolone. Insofar as it is necessary for me to make any finding, I am satisfied on the evidence before me that if the ageing process works - and I am not asked to decide this - it does so only by reducing the acid content and thereby reducing the rate of formation of OM38. This is of some importance in the discussion that follows.

[73] Professor Pattenden's interpretation of the Examples to which I have referred was the subject of criticism from both Dr Newton and Doctor Widdowson. Doctor Newton focused his attention on Examples 1-3. He suggested that the results were not directly comparable because the tibolone had not been treated in the same way. In each of those Examples oxalic acid was used, which he described as "fairly strong" (although he accepted Professor Pattenden's point that this description was appropriate only in the context of organic acids). Twice as much acid was used in Example 1 (un-aged tibolone) than was used in Examples 2 and 3 (aged tibolone), and the timings were different. He questioned whether the different amounts of OM38 resulting from the process in Example 1 could really be ascribed to the ageing process. In his opinion there was a direct correlation between the amount of acid and the level of impurity. He qualified this in is oral evidence, accepting Professor Pattenden's correction that it was the acidity of the medium that was important rather than the absolute amount of acid; and he accepted that there was no information in the Examples as to the acidity of the media used. However, he remained of the view that it was the reduction in the concentration of the acid, rather than some unexplained feature of the ageing process, which led to the purer product. He noted in passing that Example 3, which was apparently a repeat of Example 2, produced 0.2% OM38, which did not meet the levels in claim 3. This cast doubt upon the contention that the process was capable of reliably producing material according to claim 3. The three Examples taken together suggested that the process was not particularly robust or repeatable. Nor was Doctor Newton persuaded by Professor Pattenden's interpretation of the results of the stress tests. The small increase in the OM38 content of Examples 2 and 3 (aged tibolone) had been measured over only one week, whilst the larger increase in that of Example 1 (un-aged tibolone) was measured over a 4-week period. If the process was linear, that difference in time would account for the increase in the amount of OM38. Professor Pattenden said that he would have expected a faster rate of conversion to OM38 at the outset, tailing off over time, but he did not produce any justification for this. The data in the Tables in the patent did not help on the likely pattern of deterioration over the first 4 weeks, the relevant period for consideration of Examples 1-3, though from Tables 5 and 6 it appears that over a period of months the rate does slow down.

[74] Doctor Widdowson made similar points in a somewhat different way. He submitted that the attempt to draw any conclusions from a comparison of the Examples in the patent was flawed from the start. There was no basic data enabling any such comparison to be made. Part of the problem was the difference in the different batches of tibolone, in terms of their OM38 content, shown in the patent. The different examples did not bear meaningful comparison unless one knew the initial OM38 content. To carry out a proper experiment to see if the ageing process worked, one should start with the same batch of tibolone and split it three ways so as to remove the uncertainty as to possible differences in the starting points of the material. Thereafter, one part of the sample would undergo the ageing process; another would be re-crystallised (this was important, if it was being said that the ageing process gave an advantage in terms of purity and stability over other methods of purification); and the third would be dried un-aged. The drying process would then be the same for all three parts of the sample. The initial OM38 content in the three examples could then be compared. Such an experiment would have to be repeated on a number of occasions to provide robustness to the results. Without doing this, it was uncertain and potentially misleading to rely upon a comparison of the three examples.

[75] A detailed examination of Examples 1 to 3 illustrates this point. In Example 1 the crystals were dried under vacuum at 40C. In Examples 2 and 3 they were subjected to the ageing process and then dried under vacuum at the same temperature. The level of OM38 measured in Example 1 after drying was 0.6%. But there is no information as to the level of OM38 before drying. It was common ground between the experts that whatever the ageing process might do, if it did anything, it did not convert OM38 back into tibolone. All one can say, therefore, about the OM38 content before drying is that it could not have been any higher at that stage, i.e. it must have been 0.6% or less. In Example 2, after ageing and drying, tibolone was produced with 0.1% OM38. This means that before the sample was subjected to the ageing process, the OM38 level in Example 2 was no higher than 0.1%. Similarly, the OM38 level in Example 3 before the ageing step was no higher than 0.2%. In his Supplementary Report, Professor Pattenden assumed that the OM38 level in Example 1 at a similar stage, i.e. before drying, would have been similar to the level in Examples 2 and 3, i.e. about 0.1-0.2%; and from this draws the conclusion that the OM38 content of the un-aged tibolone in Example 1 increased markedly during the period up to the end of the drying process, whereas that of the tibolone in Examples 2 and 3, which underwent the ageing process, did not. This would be an important observation if justified from the material. But given the knowledge that different batches of tibolone show markedly different OM38 content, that observation could not be justified on the available information. It was, to my mind, pure speculation. While it is possible that Professor Pattenden is correct that that the level of OM38 in Example 1 before drying only about 0.1-0.2%, it is equally likely, as Doctor Widdowson suggested, that it was 0.5% or higher - in which case the increase in OM38 at the crucial period would be similar for each sample.

[76] The criticisms to which I have referred in para. [74] above bore also upon the comparison sought to be made between Examples 5 and 6. But in this case the objection about the lack of any comparison with tibolone which had been purified by conventional methods was particularly relevant. The comparison was designed to show that the ageing process produced tibolone having a greater stability over a 24-month period. Yet the un-aged tibolone tested in Example 5 had not been the subject of any conventional method of purification such as re-crystallisation. To compare the stability of aged tibolone only with that of un-aged and unpurified tibolone is to run the risk of comparing apples with pears. If Akzo had wanted to show that the ageing process produced tibolone not just of high purity but with some additional (as yet unidentified) characteristic that made it more stable, the way to do that would have been to test over the 24 month period aged tibolone against un-aged tibolone that had been purified by a conventional method such as re-crystallisation. Doctor Widdowson's evidence, to which I have referred, that on any meaningful test one should start with the same batch of tibolone and then treat it in the relevant different ways, envisaged that one part of the batch would be re-crystallised. This evidence is in point here. No such comparison was done.

[77] Professor Pattenden was pressed in cross-examination by Mr Campbell about the flawed methodology in attempting any meaningful comparison between the un-aged and aged tibolone from the data in the Examples set out in the patent. At times he appeared to accept the criticisms, at least to the extent of recognising that he would not have been happy with a paper submitted along those lines had he been acting as the referee of a learned journal. Yet he did not appear to accept that these matters in any way undermined his reliance upon a comparison of the Examples. I have to say that I found this aspect of his evidence unsatisfactory. For whatever reason, and it may be that it simply stemmed from his enthusiastic support for the ageing process, Professor Pattenden did not appear to be as rigorous in his analysis of the results as one might have expected. The criticisms of the exercise of comparing the three examples which Dr Widdowson advanced were, to my mind, obviously well founded; and, indeed, would have been apparent to any reasonably informed and objective person seeking to see the limits of that exercise. In the results, therefore, I was unpersuaded by Professor Pattenden's evidence that a comparison of Examples 1-3 showed anything of value about the efficacy of the ageing process.

[78] I accept the validity of the criticisms spoken to by Doctor Newton and Doctor Widdowson. I consider that Examples 1-3 are an insufficient basis for the inference that the ageing process produced tibolone of greater purity as compared either with "raw" un-aged tibolone or with un-aged tibolone which had been purified by well-known methods. So also, I do not accept that the comparison of the results set out in Tables 2 and 3 (Examples 5 and 6), whether taken by themselves or together with a comparison of the results in Examples 1, 2 and 3, was a sufficient basis for any inference that the ageing process resulted in the production of tibolone which, in some other (undefined) way had a greater stability or an increased shelf life (compared with tibolone purified by conventional methods).

[79] A final point should be noted in connection with the results of the tests shown in the Examples. Certain of the results set out in Table 2 (Example 5) showed that some of the claims in the patent were achieved with un-aged tibolone, even without purification by a conventional means such as re-crystallisation. Thus, claim 9 of the patent is for a dosage unit with tablets of less than 2.50mg of tibolone comprising less than 5% OM38 at a shelf life of 18 months. Table 2 shows that all three batches of unaged tibolone in tablet form (the tablets containing only 1.25mg of tibolone) were well within this figure after 18 months. These same results also meant that un-aged tibolone fell within claim 10. Two of the batches of un-aged tibolone tested in Table 2 achieved claim 12, having a shelf life (i.e. the period before the regulatory limit of 5% OM38 was reached) of two years. The three batches of unaged tibolone also met the requirements of claim 13 (3% or less OM38 at a shelf life of 6 months). It should be added that if Table 1 was for un-aged tibolone, then two of the batches tested met claim 9 and also claims 12 and 13, and one satisfied claim 14. (If, on the other hand, that Table set out results for aged tibolone, then some of the results from the samples in the two left-hand columns did not satisfy certain of the claims in the patent.)

 

Evidence relating to the arguments on anticipation

[80] A number of different issues were raised by Arrow and Norton in developing their case that Claims 1-3 of the 375 patent had been anticipated by the prior art. The first, and in some ways the most straightforward, was something upon which all the experts were agreed. This was that there were well known techniques for purifying compounds such as tibolone. Of these, the discussion tended to concentrate on re-crystallisation. It was accepted that if one re-crystallised tibolone one could achieve purity levels consistent with those identified in Claims 1-3 of the patent. This might involve two or more re-crystallisations, but there was no dispute that the purity levels in those claims could be achieved by this method. Further, it was agreed that the crystallisation technique could work to achieve the removal of acid from the tibolone. It followed that tibolone with a low OM38 content and low levels of acidity such as could be achieved by use of the ageing process could also be achieved by re-crystallisation. Tibolone of the purity claimed in Claims 1-3, for example, could be produced by the re-crystallisation method. Further, insofar as shelf life was a product of initial purity and a low level of acidity, this too could be achieved easily by the re-crystallisation process. Akzo argued that such techniques were inefficient and produced a low yield. However, Professor Pattenden agreed with the other experts that re-crystallisation could be carried out at production scale, and he presumed that crystallisation was the process used, at any rate originally, to produce livial. As I understood his evidence, however, he drew a distinction between this and the bulk production of pure tibolone achievable, as he would have it, by the ageing process.

[81] Dr Newton discussed the question of whether Claims 1-3 were anticipated by the prior art by reference to one of the Examples in the 035 patent. There is no doubt that this patent was part of the prior art. Although the 035 patent was concerned with crystalline purity, the single crystals of 100% crystalline purity would also be chemically pure. In terms of larger scale production, Dr Newton referred to Example 5 of the 035 patent. In that Example, 5.0g of tibolone had been dissolved in 50ml of ethyl acetate, to which a trace of pyridine had been added, at 40C. 300ml of hexane at about 35C were added whilst stirring vigorously, after which the mixture was cooled to 0C and stirred for a further 30 minutes. The crystals were filtered and washed off with hexane at 0C. This produced a yield of 4.25g of form II (i.e. the triclinic form of tibolone) with a polymorphic purity according to the DRIFT method of 100%. In his evidence, Dr Newton referred to experiments carried out by Resolution Chemicals Ltd. ("Resolution") on 7 February and 18 August 2003 ("the Resolution experiments"). Those experiments had followed Example 5 of the 035 patent, though on a larger scale. There had been minor differences in temperature, he said, and the product was dried in vacuo, but in Dr Newton's opinion these differences did not materially affect the experiment or invalidate the result. In each case the result of the experiment was tibolone of a chemical purity which met the claims in Claims 1-3 of the 375 patent.

[82] Doctor Widdowson referred in his evidence to the van Vliet paper, which described a synthesis of tibolone, i.e. a method of producing tibolone from a precursor. So far as concerned the 375 patent, only the final stage of the van Vliet procedure, whereby tibolone is generated with only low levels of iso-tibolone (OM38), was relevant. He summarised this passage in his Report in the following way:

"(a) a precursor ... is hydrolysed in aqueous ethanolic solution under mild acid conditions to generate tibolone;

(b) the tibolone and the by-products are precipitated from solution, and the acid catalyst concurrently neutralised, by the addition of 5% aqueous sodium hydrogen carbonade, a mild base;

(c) the precipitated product is filtered, washed with water and dried;

(d) the method of drying is unstated in the paper but normal practice is to remove the residual solvent by placing the crystals in a vacuum oven and applying slight warming if necessary;

(e) this produces the crude product which was further purified by van Vliet by crystallisation from di-isoropyl ether containing a little pyridine ...;

(f) the resulting crystals had a melting point in accord with prior reports and were shown to contain <1% iso-tibolone as judged by quantitative thin layer chromatography ..., a technique still in use in 1998 but considered less accurate than the analytical High Pressure Liquid Chromatography (HPLC) ..."

Doctor Widdowson said that the reader of the van Vliet paper in 1986, as in 1998, would have understood from that passage that, by carrying out that protocol, tibolone could be produced with low levels of OM38.

[83] In order to test this, the protocol described by van Vliet was re-run at the instance of Norton by Synnovation Ltd. Doctor Widdowson approved in advance the protocol that Synnovation proposed to use. This protocol was set out in a document called the "Notice of Experiments". It proposed the use of HPLC to determine the chemical purity of the product, and crystallisation of the crude product for the final purification. Doctor Widdowson said that this represented the steps that a skilled person would have taken at the priority date of the 375 patent. Having reviewed the experiments carried out, Doctor Widdowson concluded that direct crystallisation of the crude product obtained by the van Vliet process was effective to produce tibolone with less than 0.1% OM38. Further re-crystallisation would reduce the OM38 content still further.

[84] According to Dr Newton, Claims 7 and 9-14 were all concerned with combinations of the compound and pharmaceutically acceptable solid carriers, and they did not add anything. A skilled man would be well aware of the use of tibolone in tablet form. Doctor Widdowson put it even more robustly. He said that although claims to pharmaceutical compositions fell outside his areas of expertise, it seemed to him that once tibolone of sufficient purity had been obtained in accordance with claims 1-3, "it would appear perfectly obvious to use the material in a pharmaceutical formulation as claimed".

 

Arrow's submissions

[85] Arrow's case on Record attacked the validity of the claims not only on grounds of lack of novelty (anticipation) and lack of inventive step (obviousness), as in the case of the 035 patent, but also on the basis of insufficiency. In developing his argument under these heads, Mr Currie reminded me that tibolone had been known since the 279 and 450 patents, and the process of producing tibolone was acid catalysed. Its tendency to isomerise into OM38 was also acid catalysed.

[86] In support of his case on anticipation, he advanced two propositions: (1) that conventional methods for purification of organic compounds are within the common general knowledge of the skilled man; and accordingly, (2), that a document disclosing such a compound and its manufacture makes the compound available to the public in all grades of purity - or at least all grades of purity achievable by those conventional methods. The qualification to that second proposition is mine, but I think is implicit in the two propositions taken together. As authority for this he cited two decisions of the Technical Board of Appeal of the EPO, Decisions T990/96 and T728/98. The speech of Lord Hoffman in Merrell Dow recognised that such decisions are of great persuasive authority. He submitted that, since tibolone had been disclosed by the 279 and 450 patents. Akzo were not entitled thereafter to patent tibolone of a particular purity. Put another way, any claims to particular levels of chemical purity have been anticipated by those earlier patents. Further, he submitted that the Resolution experiments, involving a re-working of Example 5 of the 035 patent, produced tibolone of the purity levels claimed in the 375 patent. On this basis also the claims to tibolone of a particular chemical purity were anticipated.

[87] Turning to his case on obviousness, Mr Currie relied on Dr Newton's evidence that claims 1-3, 7 and 9-14 would have been obvious to the skilled man. The skilled man, he submitted, was either a medicinal chemist or a process research chemist working in the pharmaceutical industry. The difference between the experts on this was really just a matter of emphasis. It would be the goal of any medicinal chemist to avoid impurities occurring or to reduce them as much as possible. In the case of tibolone, a straightforward recrystallisation would produce tibolone with less that 0.1% OM38, as would other standard purification techniques such as HPLC. Separately, the correlation between the amount of concentration of acid and the level of impurity in tibolone would have been obvious to the skilled man. He would seek to avoid or reduce the formation of OM38 by lowering the concentration of acid used. He would also wash the product to remove as much as possible of the acid, since residual acid would encourage the continued formation of OM38 and reduce shelf life. Mr Currie pointed out that Professor Pattenden had agreed that shelf life was a product of initial purity levels: shelf life and stability go hand in hand. It followed, he submitted, that claims 1-3 are anticipated, or alternatively are obvious, and should be revoked. Claim 7 simply put the tibolone of the requisite purity into a pharmaceutical compound. There was nothing inventive in this. Therefore claim 7 (and claim 8) stood or fell with claims 1-3. Since shelf life was simply a function of initial purity, claims 9-14 also stood or fell with claims 1-3.

[88] Mr Currie developed his case on insufficiency by submitting, in accordance with Arrow's case on Record, that the specification of the patent did not disclose the invention in claims 1-3 and 7-14 clearly enough and completely enough for it to be performed by a person skilled in the art across the whole width of the claims. These claims were claims to a product, namely tibolone of varying degrees of purity and stability for use in pharmaceutical compounds. According to the evidence, these products could be made by a wide range of processes. Yet the technical contribution revealed in the patent was only the ageing process. It followed that the claims to the product extended well beyond the technical contribution to the art revealed by the patent. He referred to Biogen Inc. v. Medeva plc [1997] RPC 1, 47, Merrell Dow (supra) at p.82 and Pharmacia Corp. v. Merck (supra) at p.798. If, however, the product claims were taken as limited to tibolone produced by the ageing process, the patent was insufficiently detailed to enable a skilled man to achieve the claimed result. He referred to Edison and Swan Electric Light Co. v. Holland (1889) 6RPC 243. None of the experts thought that the ageing process was described in sufficient detail.

 

Norton's submissions

[89] For Norton, Mr Campbell developed his case by reference to detailed written submissions. He adopted much of what Mr. Currie had said. He focussed first on the ageing process. This, he said, was the only invention disclosed in the 375 patent. Whilst Norton did not concede that the ageing process worked, or produced the benefits claimed in the patent, the efficacy of that process was not challenged in these proceedings. There was no challenge in these proceedings to claims 4-6 of the patent. However, the claims in the patent went far beyond that ageing process. None of these claims could be justified, in that none of them related to anything invented by Akzo in this patent. As it stands, the patent prevents competition from others who seek to make or market tibolone and who might wish to use their own methods of making tibolone of a particular purity. In the context of an old product, it was hard to envisage how this could ever be justified by the invention of a new step in the process of making an old product. Mr Campbell also founded upon EPO jurisprudence to the effect that once a product is revealed it is revealed in all degrees of purity, since purification techniques (such as recrystallisation) are common practice and a well-established part of basic practical chemistry. Simply to come up with a new step in making or purifying tibolone could not justify a patent over the product itself. The most that Akzo could hope for was a patent over the new process. There is no sound basis for any of the product claims. Akzo's patent over tibolone had now expired, but the effect of the product claims, if not revoked, would be to resuscitate and prolong the life of the old patent.

[90] If, contrary to the above, the tibolone produced by the ageing process is claimed to have some special feature, then that special feature has not been disclosed in the patent, neither in terms of what it is or how it works or how it is obtained. No one can know in the future whether or not they are infringing the patent. On this basis, all of the product claims would be invalid for insufficiency of disclosure. However, he submitted, there was no evidence that tibolone produced by the ageing process had any special feature. Professor Pattenden agreed with Dr Widdowson that if the ageing process achieved anything, and Professor Pattenden thought that it did, it did so by removing acid from the tibolone, and therefore had the same effect as crystallisation. It did not create a different product.

[91] Addressing the question of obviousness, Mr Campbell submitted that the skilled person was assumed to be addressing the issue addressed in the patent, i.e. the issues of purity and shelf life. He would be able to achieve the desired outcome by well-established and, indeed, obvious techniques. The patent does not add anything new and necessary for the production of pure tibolone with sufficient shelf life. A skilled person using the prior art and his knowledge of obvious and standard techniques would be able to create a product which infringed the product claims.

[92] Mr Campbell referred to the van Vliet paper and the Synnovation experiments carried out in an attempt to repeat the final step in his synthesis. He submitted that those experiments showed that van Vliet disclosed a method for obtaining highly pure and stable tibolone.

[93] In summary, Mr Campbell submitted that claims 1-3 lacked novelty, being anticipated in the prior art and in particular in van Vliet. Those claims also failed on grounds of obviousness. Tibolone of the required chemical purity could be achieved by well-known purification methods such as recrystallisation. Claim 7 (and claim 8) fell on the same basis. Claims 9-14 also fell for the same reason. There was nothing new about the concept of tibolone in a pharmaceutical composition. In addition, however, Akzo's own results set out in Table 2 of the patent, based on un-aged tibolone, showed that tibolone of the required purity and shelf life could be obtained by conventional means.

 

Akzo's submissions

[94] Mr Davidson also advanced his arguments by reference to written submissions. After submitting that the attacks as developed at the Proof went further than their cases on Record, he reminded me that the burden of proof lay on Arrow and Norton. I, of course, accept that that is so. He was concerned, as I understood it, that they were seeking to cast doubt upon the efficacy of the ageing process without assuming the burden of disproving it.

[95] He then turned to the teaching and contribution of the 375 patent. He accepted that tibolone and its uses had been known for decades. However, none of the teaching in the patent about the actual or desired pill size and the shelf-life problems associated therewith was even alleged to be part of the common general knowledge. He took me through the patent, explaining that the concepts of purity and shelf-life, though related, were separate. The patent explained how materials prepared by the ageing process could be used in various dosage quantities with various shelf-lives. This, he submitted, had not been challenged.

[96] Turning to the particular claims, he submitted that the challenge to claims 1-3 raised an issue of construction: would those claims be understood to include tibolone, admittedly of high purity, but produced by a very low-yield process in such small quantities as to be of no practical use for making pills? He submitted that the answer was: No. The claims had to be construed purposively, in light of the specification: see Kirin-Amgen. Everything in the specification was against the literal construction adopted by Arrow and Norton. The patent had nothing to do with the preparation of highly pure but very small amounts of tibolone. In this context he referred me to the references in the specification to "pharmaceutical preparations", which typically required large batches of product, references to commercial compounds and storage of tablets, many references to "bulk" and "batch", and the fact that the Examples in the specification related to the use of large quantities, much larger than the quantities which would be used in an analytical laboratory. Claim 7, he accepted, was just the combination of claims 1-3 and a conventional carrier. Akzo did not contend that claim 7 was valid if claims 1-3 were not. However, he did not accept that claims 9-14 fell to be treated in the same way as claim 7. There was a point of construction involved here as well: are these claims merely to a combination of claims 1-3 with an appropriate carrier, as Arrow and Norton allege? Obviously not: these claims were much more specific, going into such details as dosage amounts, shelf-life and purity at the end of the specified period.

[97] Mr Davidson submitted that, given that the focus of the specification was on large quantities for use in pharmaceutical preparations, there could be little doubt that the skilled addressee was a process chemist seeking to make tibolone in bulk quantities for practical commercial purposes. He would have yield and stability in mind, as well as purity. He submitted that there was no justification for Dr Newton's view that the skilled addressee was a medicinal chemist, particularly because the medicinal chemistry of tibolone is decades old.

[98] Mr Davidson accepted that Livial was common general knowledge. He further accepted that "if the skilled person wanted to prepare highly pure tibolone, and purity was the only requirement, he or she could prepare it to the levels of purity of the claims." However, he did not accept that, using only common general knowledge, tibolone at those levels of purity could be prepared in good yield and/or with any degree of stability other than that which follows merely from purity. Nor did he accept that common general knowledge would provide any motivation for making high purity tibolone unless yield and stability would follow at the same time. He submitted that a comparison of Examples 5 and 6 of the patent showed that stability was not simply a product of initial purity. Tibolone produced by the ageing process showed a greater stability, possibly because the ageing process had the effect of removing the occluded acid and thereby reduced the possibility of further isomerisation to OM38. He submitted that on the evidence there was no doubt that the ageing process did work.

[99] In addressing the question of novelty, Mr Davidson submitted that the case made against him was one of "inevitable result". He referred to Synthon BV v. Smithkline Beecham plc [2005] UKHL 59, in particular the passage in the speech of Lord Hoffman at paras.23-24, to Mayne Pharma Pty Ltd v Debiopharm S.A. [2006] EWHC 164 at para.5 and to Inhale Therapeutic Systems Inc. v Quadrant Healthcare plc [2002] RPC 21 at para.43. The prior disclosure did not identify the product of the purity claimed in claims 1-3. Van Vliet simply identified an OM38 level of less than 1%, whereas the levels in claims 1-3 were below 0.5%. Example 5 of the 035 patent did not teach any particular level of OM38. In order for an anticipation argument to succeed, Arrow and Norton had to show that those processes inevitably led to tibolone of the purity claimed in claims 1-3. The Resolution experiments did not accurately repeat the 035 patent. Nor did the van Vliet paper contain sufficient detail to enable an exact repetition by Synnovation. Neither could support a case of anticipation. So far as Arrow and Norton relied on the EPO jurisprudence to the effect that a claim to a particular level of purity of a known compound lacks novelty unless that product cannot be purified to that level by conventional methods, Mr Davidson submitted that the Courts in the United Kingdom should not "slavishly" follow EPO decisions. The EPO does not have a doctrine of precedent as it is understood here, except to the extent that there has been established a long line of unbroken and consistent authority. There were only two decisions of the EPO relied on here, and they should not be followed. Even if that line of authority were good, it would be relevant here only if the patent was solely concerned with purity. But it was not: it was concerned with bulk and dosage units and shelf life as well. The conventional methods of purification did not touch on those issues.

[100] Turning to deal with obviousness, Mr Davidson submitted that claims 9-14 were concerned with dosage units and shelf-life as well as purity. These aspects were not attacked on grounds of obviousness. Even if claims 1-3 were concerned simply with purity, there was no evidence that coupling such tibolone with a pharmaceutical carrier would give the shelf lives stated in claims 9-14. In respect of claims 1-3, it was accepted that a skilled man who wanted to achieve the levels of purity there claimed could do so by conventional techniques. But even if, as contended for by Arrow and Norton, the claims were construed as covering small scale production of high purity tibolone, the arguments on obviousness did not address the question of motivation. Under reference to the Windsurfing case (supra), Mr Davidson identified four steps that needed to be addressed. Step 1 was to identify the inventive concept. That was to achieve purity at the levels stated on a manufacturing scale. Step 2 was to identify the relevant prior art. The relevant prior art was the commercial product, Livial, or possibly tibolone with less than 0.1% OM38 as identified in Van Vliet. Step 3 was to identify the relevant difference between the prior art and the invention. That difference was the increase in purity. Step 4 was to ask: was it obvious to increase the purity? Mr Davidson submitted that no expert had explained why it would be obvious to take the step of increasing purity. Livial was already successful at a lower level of purity; why should one seek to increase the level of purity when the drug could already be sold and the improvement in purity would be expensive to achieve and maintain by the conventional methods? By contrast, the 375 patent offers a motive to improve purity in that it can be achieved on a manufacturing scale and produces a product having a stability which enables smaller doses to be put into tablets with an acceptable shelf-life. There is no evidence that the problem was generally known or the solution obvious.

[101] Finally, on the question of insufficiency, Mr Davidson argued that Arrow and Norton did not show by evidence that there were other processes for the production of bulk tibolone. But even if an insufficiency attack could be made against claims 1-3, it could not succeed against claims 9-14. For Biogen to apply, it had to be shown that there were other ways of achieving the result without using the invention claimed in the patent. There was no evidence hat those claims could be achieved in any other way. This is because shelf life is not simply a product of purity. It is the product of the ageing process. Further, the inventive concept in those claims included achieving a shelf life with different and smaller dosages.

 

Discussion

[102] In considering these arguments in the light of the evidence adduced at the proof, it is necessary first to identify the person to whom the patent is addressed. It was not, I think, in dispute that the addressee would be an organic synthetic chemist. The dispute was as to whether this organic synthetic chemist was a process chemist, working as part of a large team seeking to make tibolone in bulk quantities for practical commercial purposes, or was a medicinal chemist, interested in the development of the science of purifying tibolone. To my mind this is a false dichotomy, and I think Mr Currie was correct in submitting that it amounted more to a difference in emphasis that to one of kind. It is true, as Mr Davidson emphasised, that the patent is concerned with production of pure tibolone in bulk. That bulk production clearly engages the intention of a process chemist. But the patent claims also a new way of achieving pure tibolone, and tibolone of greater stability and longer shelf life. It seems to me to be clear that this claim to an invention of, in effect, a new technique, if not a new product, would be directed as much to the medicinal chemist in the first instance at least. In any event, I was left unsure as to the real significance of this. It seemed clear on the evidence that the addressee of the patent, at whichever end of the spectrum of organic synthetic chemists he might be, would have the same awareness of standard purification techniques, including re-crystallisation. And before concerning himself with the question whether the ageing process was effective to ensure mass production he would want to be satisfied that it was a robust and repeatable method for the production of chemically pure and stable tibolone on a smaller scale.

[103] The only question of construction between the parties was as to the proper interpretation of claims 1-3. I accept that a purposive construction has to be adopted. I accept also, as I have indicated earlier, that the patent is directed to a large extent towards the production of pure and stable tibolone in bulk. But it does not follow from that that claims 1-3 must be read in this way. The ability to produce pure and stable tibolone in bulk is said to be a result of the ageing process. The ageing process is the subject of quite separate claims, namely the process claims in claims 4-6 of the patent. If the ageing process works, it may give Akzo particular commercial advantages, in enabling them to produce pure and stable tibolone more economically than those who depend upon other, more traditional, methods. On their case, the bulk production towards which the patent is directed is achieved by the ageing process. Claims 1-3, however, do not require to be read as referring to bulk quantities of pure tibolone in order for the aim of the patent to be fulfilled. To my mind the patent claims to have achieved tibolone of a particular purity in claims 1-3; and, in claims 4-6, claims to have found a method for achieving that in a particular manner with certain advantages. The two claims are distinct.

[104] Accordingly, claims 1-3 of the patent are to be read straightforwardly as claims to tibolone of high chemical purity, namely tibolone in which the amount of OM38 is less than 0.5%, 0.25% and 0.1% respectively.

[105] I am satisfied on the evidence that tibolone of this purity is readily achievable by conventional methods such as re-crystallisation. I also accept that such methods of purification are within the common general knowledge of the skilled man, whether that skilled man be the process chemist or the medicinal chemist. I accept Mr Currie's argument, under reference to Technical Board of Appeal Decisions T990/96 and T728/98, that a document disclosing a compound and its manufacture makes available that compound to the public in all grades of purity which are achievable by conventional methods such are within the common general knowledge of those skilled in the art. Put another way, a particular level of purity of a known compound cannot, as a general rule, entail novelty, since conventional methods for its purification are within the common general knowledge of the skilled person. It seems to me that the courts should follow such decisions of the EPO unless persuaded that they cannot be supported. In the present case, far from being persuaded that they should not be followed, I am satisfied that they make good sense. I have some doubt as to whether, as it appears to be put in those decisions, the claim fails in consequence for lack of novelty; or whether, as I tend to think, it should be regarded rather as a case of obviousness or lack of an inventive step. But this makes no difference to the result, since the argument can be made to fit into both categories. Tibolone as a compound was disclosed by the 279 and 450 patents, as well as by the 035 patent. It seems to me to follow that there can be no novelty in a claim, such as is found in claims 1-3 of the patent, to tibolone of any particular chemical purity which is achievable by well-known means. This seems to me also to be the answer to Mr. Davidson's reliance on the 4-stage Windsurfing test (see para. [100] above). He asked rhetorically: was it obvious to increase the purity? This question is answered clearly in the affirmative where the method of achieving the purity is tried and tested.

[106] I would, therefore, uphold the challenge to Claims 1-3 of the patent on this basis. Had it been necessary for me to do so, I would also have upheld the challenge based upon the experiments carried out by Resolution and by Synnovation. Those experiments seemed to demonstrate convincingly that a re-working of Example 5 of the 035 patent, and an attempted reconstruction of the Van Vliet process, led to tibolone of the requisite chemical purity. I accept the accuracy of Mr Davidson's criticisms of those exercises. Both required interpretation by the person or persons carrying out the exercise. They were not precise copies of what had gone before, nor could they have been given the lack of relevant information as to what had earlier been done. Nonetheless, they appeared to me to demonstrate that it was a simple and obvious matter to use what had been done as a means of obtaining tibolone of the necessary chemical purity. It may well be that the exercises carried out by Resolution and Synnovation, not being precise re-enactments of what had gone before, failed to support a case on anticipation. The test of "inevitable result" is not satisfied. But to my mind they did support an argument that there was no inventive step in producing tibolone of the chemical purity claimed. Mr Hoptroff was, by his own admission, the archetypal unimaginative addressee of the patent. He simply took Example 5 from the 035 patent and attempted to replicate it, recognising that, from time to time, he would have to apply his own common sense as to temperatures, quantities etc. It was his very lack of curiosity which, in my opinion, vividly demonstrated that producing tibolone of that chemical purity claimed in the patent involved no inventive step once one had knowledge of van Vliet and the 035 patent.

[107] Mr Davidson conceded that, if the challenge to claims 1-3 were successful, he could not resist the challenge also to claim 7. As he put it in his written submission: "It is immediately apparent that this claim [claim 7] ... is just the combination of claims 1-3 and a conventional carrier". This concession was, in my opinion, correctly made. But I think it must carry over to claim 8 as well. Claims 7 and 8 were to a pharmaceutical dosage unit obtainable by an admixture of a pharmaceutically suitable solid carrier and the compound. In the case of claim 7, the compound was "the compound according to any one of claims 1-3". In the case of claim 8, the compound was "the compound obtainable by the process of claims 4-6". But claim 4 is itself "a process for preparing the high purity compound of claims 1-3". It follows that claim 8 is a claim to a dosage unit obtainable by admixture of a carrier with, inter alia the compound in claims 1, 2 and 3, those being compounds obtainable by the process of claim 4. On this basis, claim 8 must be treated in the same way as claim 7. For this reason I took the view that allowing Arrow and Norton to amend their pleadings to attack claim 8 added nothing new to the process and caused no disadvantage to Akzo. I therefore uphold the challenges to claims 7 and 8.

[108] If I were wrong on my interpretation of claim 8, then that claim would read as a claim to a pharmaceutical dosage unit which was an admixture of a carrier with a compound "obtainable by" the ageing process. That would be a classic case of a "product by process" claim. I have, earlier in this opinion, rejected the theory that the ageing process, if it works, works in a way which creates something indefinable in the resulting tibolone. It follows from that that the test set out in Kirin-Amgen for the validity of a product by process claim in a patent is not satisfied. I would therefore have found against Akzo on claim 8 on this ground also.

[109] Claims 9-14 are claims to dosage units comprising a carrier and tibolone of different quantities. The claims made are in respect of the amount of OM38 present in the tibolone after various periods defined in the claims. As I have indicated earlier, I am satisfied on the evidence that stability and shelf life, that is to say the amount of OM38 appearing in the tibolone after a particular period, is a product of initial purity and removal of acid. It follows from my earlier findings in respect of claims 1-3, that there is nothing novel in tibolone of a high purity, that the products claimed in claims 9-14 are also achievable by conventional methods. Nor was it disputed that it was well known that the production of OM38 in tibolone is acid catalysed, so that to achieve pure tibolone and to keep the tibolone pure over a long period would involve the removal, so far as possible, of acid from the tibolone. It was well known that the removal of acid could be achieved by conventional methods such as re-crystallisation. Whilst there was no evidence that others had addressed their minds to the particular dosage units identified in claims 9-14, it does not seem to me that these can properly be regarded as inventive steps sufficient to found the claims in the patent. To put it another way, it would be obvious to all those involved in a pharmaceutical business that tablets could be created using different amounts of tibolone, and obvious also that it was desirable to maximise shelf life. This is achieved simply by combining tibolone of the purity claimed in claims 1-3 with a conventional carrier. If there is nothing inventive in tibolone of that purity, there is nothing inventive in the particular combinations. To my mind, these claims are to be treated in the same way as claim 7. Further, as was demonstrated by the results in Tables 2 and 3 in the patent (in Examples 5 and 6), tablets of the different sizes claimed and with initial purity levels and shelf life meeting the criteria claimed in claims 9-14, were achievable (and indeed achieved) by conventional methods. In my opinion the attack on these claims succeeds on the grounds of obviousness or lack of an inventive step.

[110] In light of my conclusions, it is not necessary to deal with the arguments advanced under the heading of specification or insufficiency of disclosure. That is because if claims 1-3 are claims only to tibolone of a high purity, and claims 7-14 are simply claims to a combination of tibolone of that purity with a carrier, no question of lack of specification arises. But if I am wrong on this analysis of the claims, and they are claims to a compound and/or a pharmaceutical composition with a purity and/or a stability borne of some different characteristic, then I would have accepted the submissions for Arrow and Norton which I have summarised at paras. [88] and [90] above.

[111] As had been earlier anticipated, at the end of the proof, Mr Davidson made a new application to amend the patent in terms of the Second Auxiliary Request to which I have already referred, he having of new complied with the terms of Rule of Court 55.5. I indicated that I would deal with this motion in the course of this opinion. Having considered the matter carefully, I refuse the motion. I do so because in terms particularly of the amendments to claims 1-3, the amended claims would focus on tibolone not of any specific purity but such as resulted from the ageing process. I full accept that the ageing process was gone into in some detail, but this was largely as background to the other matters under discussion. To allow the patent now to be amended in the manner suggested would, in effect, require the proof to be reopened; and further would require the experts to research and give evidence upon matters which were tangential to the issues canvassed to date before the court. When refusing the motion in December, I had left open the possibility that Mr Davidson might wish to renew it but I in no way encouraged this course and the motion made to me at the end of the proof seemed to me inevitably to fail for the same reasons as I had rejected the earlier motion.

[112] In addition, I should say that in light of my determination earlier in this opinion that the ageing process, if it worked, did not do so by creating a product with some unidentifiable characteristic, I would have found it difficult to see how the proposed amended claims met the tests laid down in Kirin-Amgen for product by process claims.

[113] As it transpired, matters had moved on since the earlier application to amend. Akzo's Second Auxiliary Request before the EPO had been replaced by a Third and ultimately a Fourth. As matters stood, Akzo were no longer moving the EPO to allow amendment in terms of the proposed amended claims put before the court, i.e. those in the Second auxiliary Request. Further, I was told that the EPO had found against Akzo in the opposition proceedings, though the possibility of an appeal was still open. Clearly it was not possible for Akzo to move the court to allow an amendment in terms of the Fourth Auxiliary Request, since that would require them first to go through the process laid down by Rule of Court 55.5 all over again. Equally, it seemed to me that there were great difficulties in them moving to amend in terms of the Second Auxiliary Request if this was no longer part of their motion before the EPO. I would have refused the renewed motion to amend on this ground also.

[114] I was asked to put the cases out By Order for further procedure. I shall do so. It is appropriate that I should formally pronounce interlocutors dealing with the motions to amend, granting leave to Arrow and Norton to amend in respect of the 375 patent to include a challenge to claim 8, and refusing Akzo leave to amend the 375 patent. Subject to further argument, I would be minded to dispose of the various proceedings in the following ways: in petition P1606/03, which is Arrow's petition in respect of the 035 patent, to grant the prayer of the petition and revoke claims 1-3 and 5 the 035 patent; in petition P1031/03, which is Arrow's petition in respect of the 375 patent, to grant the prayer of the petition, as now amended, and revoke claims 1-3, 7, 8 and 9-14 of the 375 patent; and in respect of action A652/2004, to uphold the plea-in-law for the defenders in counterclaim and make an order for revocation of claims 1-3, 7, 8 and 9-14 of the 035 patent in terms of the first conclusion for the defenders in the counterclaim as now amended. But apart from dealing with the amendments, I shall not make any orders at this stage but simply put the cases out By Order.