England and Wales High Court (Chancery Division) Decisions

IN THE HIGH COURT OF JUSTICE
CHANCERY DIVISION
PATENTS COURT

		Royal Courts of Justice Strand, London, WC2A 2LL
		22/05/2006

Mr Justice Lewison:

Background	3
General	3
The skilled addressee	6
Common general knowledge	7
Routine steps in drug formulation	10
General	10
Pre-formulation	11
Testing	12
Are polymorphous compounds a problem?	14
Regulatory considerations	21
The pleaded prior art	24
The '035 Patent	24
European Patent EP 0 613 687	27
The patent in suit	28
Obviousness: the legal test	36
General	36
The relevance of regulation	41
The relevance of '035	44
What would the skilled addressee know about tibolone?	50
In the real world	50
Common general knowledge	52
The pleaded prior art	56
Obviousness: application to the facts	59
What is the inventive concept said to be embodied in the patent?	59
What was the state of knowledge of the skilled person?	61
What is the difference between the claimed inventive concept and the state of the art?	65
What is the end to be accomplished?	66
Was formulating polymorphous tibolone obvious?	67
Result	73

Introduction

1. Tibolone is a steroid; and is used in hormone replacement therapy for women and in connection with other problems associated with the menopause. It mimics the effect of female hormones. Fortunately its exact chemical structure and properties are not directly relevant to these proceedings. Tibolone is a polymorphous compound: that is to say that it exists in more than one crystalline form. Each crystalline form (a "polymorph") has the same chemical composition, but will normally have different physicochemical properties, such as melting point, solubility, vapour pressure and density.
2. The dispute in the present case is about a patent which claims a monopoly for polymorphous tibolone of a specified mean particle size. Akzo is the patentee. Arrow and Ivax attack the patent on the ground that the claimed invention is obvious, both in the light of common general knowledge at its priority date; and also in the light of particular prior art. Although Akzo originally applied to amend the patent, just in case, it withdrew that application. Mr Waugh QC, appearing for Akzo, also decided not to call Akzo's expert, Professor Davis. In consequence, I heard oral evidence only from Professor Newton, who was called as an expert by Mr Thorley QC for Arrow and Ivax. Professor Newton has been both a distinguished academic, and a research scientist in industry. He was an impressive witness; and I accept his evidence.

Background

General

3. Tibolone was, I believe, invented by Akzo in the 1960s. It has been widely marketed under the trade name "Livial". Tibolone was originally patented under patent US 3 340 279 ("'279"). That had a priority date of 1964 and has now expired. '279 described the compound and said that it had valuable biological properties, including estrogenic, gonad-inhibiting and ovulation-inhibiting properties. It also said that the compound could be administered parenterally or orally in the form of suspensions, solutions, emulsions or solid pharmaceutical dosage forms. A second generation formulation patent was published in 1990 (E P 0 389 035) ("'035"). That patent revealed that tibolone was a polymorphous compound, of which there were two (or two principal) forms. It claimed a monopoly in the formulation of tibolone in both forms, each crystalline pure.
4. Sometimes a drug does not directly achieve the pharmaceutical effect for which it is administered. Instead, after the drug has absorbed into the body the drug is changed by the body's chemical processes into another compound and it is that other compound which has the desired effect. This process of change is called metabolizing; and the changed compound which results from the process is called a metabolite. Sometimes a drug has multiple metabolites; and sometimes both the drug and its metabolites have a pharmaceutical effect. Tibolone has two main metabolites, called 3a-OH tibolone and 3ß-OH tibolone (3a- and 3ß- hydroxytibolone).
5. One of the important characteristics of any drug is its bioavailability. This is the extent to which, and rate at which, a drug appears in the bloodstream after administration in dosage form. Where the bioavailability of one drug and another drug (or the bioavailability of two different formulations of the same drug) are the same, they are said to be bioequivalent.

The skilled addressee

6. There is no significant dispute about the kind of person to whom the patent in suit is addressed. The target readership consists of persons in the pharmaceutical industry interested in formulating drugs. That person would have a degree in chemistry, pharmaceutical sciences or formulation science. He or she would have several (three to five) years' post-graduate experience in a laboratory, with experience in the formulation and development of solid dosage forms intended for oral administration. He or she would be assisted by a team of graduates and technicians; and would have access to analytical laboratories. The addressee could be a non-graduate, with longer practical experience.

Common general knowledge

7. The skilled addressee's common stock of knowledge would include the following:

i) The dissolution rate of a drug affects its bioavailability.

ii) If a drug has a low aqueous solubility it will have a low dissolution rate.

iii) The dissolution rate of a drug is directly related to its solubility. Solubility is affected by the chemical nature of the drug and also its salt form.

iv) The dissolution rate of a drug is affected by particle size, because dissolution is directly related to surface area. The greater the surface area of the particles, the faster a drug dissolves.

v) What would be a suitable particle size varies from drug to drug, but typical limits would be sizes from 5 µm to 40 µm.

vi) Different physical states of a drug can have an effect on the apparent solubility. These physical states include the formation of solvates (particularly hydrates) and whether the drug is in crystalline or amorphous form.

vii) Different crystalline forms of a drug (polymorphs) can have different energy states. As a result different polymorphs can display different physical properties.

viii) The differing properties of different polymorphs can include different apparent solubilities; and thus have different rates of dissolution, which can affect the bioavailability of the drug.

ix) However, if a drug has a high solubility in water, then the pharmokinetic properties of the drug are not affected by particle size, or by polymorphic form, because in those circumstances the rate of absorption of the drug is controlled by the permeability of the drug across the gastrointestinal tract.

x) Normally the most stable polymorph is selected for drug development. This is generally the polymorph with the lowest thermodynamic energy state. The polymorph with the lowest energy state will also be expected to be more stable chemically, because of a higher crystal density.

xi) It is important to screen for polymorphs both during processing and during storage, since changes can occur at both stages.

8. The skilled addressee would also know about the different types of dosage forms in use at the priority date. These included:

i) Tablets, including coated and uncoated tablets and their components;

ii) Capsules, in which solid powders or granules are encased in a hard gelatine capsule;

iii) Liquid formulations, in which drugs are suspended or stabilised in solution.

9. The skilled addressee would also be familiar, in general terms, with the properties of steroids. These properties would include the fact that steroids are frequently polymorphous; that most steroids are poorly soluble, and that they are administered in low dosages. There is, however, a dispute about whether the skilled addressee would know about tibolone specifically. I return to this point after I have considered the law.

Routine steps in drug formulation

General

10. The process of drug formulation is empirical. It is not possible to predict with certainty what the characteristics of any particular drug formulation will be. It is therefore necessary to carry out tests, both in vitro and in vivo. Professor Newton described the routine steps involved in formulating a new dosage form of a drug. His description was uncontroversial in so far as it described what happens in the real world; although there is some dispute about the extent to which the world of patents corresponds to the real world.

Pre-formulation

11. The process begins with pre-formulation. The formulator will be given an appropriate specification. This would, for example, define the drug dosage to be incorporated and whether the formulations should provide for the immediate release of the drug or a more controlled release. He would be given (or ascertain from the literature) basic information about the physicochemical properties of the drug. These properties would include information about the solubility of the drug in aqueous and other media, the stability of the drug in solution; and interactions between the drug and excipients that might be required in preparation of the dosage form. This information would be gathered in a pre-formulation study.

Testing

12. The formulator would perform dissolution studies in order to ascertain the dissolution rate of the drug. These studies would give an indication of the likely bioavailability of the drug. Where the drug had a slow dissolution rate, the formulator would know that it was likely to have poor bioavailability. If the drug had a slow dissolution rate, the formulator would know techniques to improve it. These included:

i) Reducing the particle size of the drug; and

ii) Using excipients (inert substances) to ensure that the dosage form is wetted easily and quickly breaks up to release the drug into the surrounding fluids.

13. Reducing the particle size of the drug would have been the simpler technique. Methods of reducing particle size were well-known at the priority date. However, in reducing particle size, the skilled person would have wanted to ensure that the reduction in particle size did not create handling problems. In addition, the application of energy to fracture the crystals in order to reduce particle size may carry the risk of converting one polymorph into another. The formulator would therefore have carried out routine experiments in order to determine the effect of a reduction in particle size on test formulations. An alternative well-known method of reducing particle size without fracturing the crystals would have been to sieve them; but this method may result in wastage of material.

Are polymorphous compounds a problem?

14. Knowing that polymorphs can exhibit different physicochemical properties, the formulator would also test for polymorphs. This is particularly important in the case of a poorly soluble drug. As I have said the skilled addressee would have known that steroids, in general, are both poorly soluble and frequently polymorphous. Dissolution studies would have revealed whether a drug was poorly soluble or not. The more insoluble the drug, the greater the implications are for bioavailability. Whether differences in solubility are attributable to differences between polymorphs depends on the degree of difference. There are instances (referred to in standard textbooks) where different polymorphs exhibit no differences in bioavailability.
15. One of the standard textbooks (Florence and Attwood: Physicochemical Principles of Pharmacy) regards polymorphous compounds as a potential problem; and states that the normal way of overcoming the effects of polymorphism is to convert polymorphs into the same form by re-crystallisation from the same solvent.
16. In drug development it is normal to select a polymorph with the lowest thermodynamic energy state since this will provide a consistent material without the problem of conversion to a more stable and less soluble form. Moreover it is to be expected that the polymorph with the lowest energy state will be more stable chemically because of a higher crystal density. However, metastable polymorphic forms can sometimes be preferred for drug development. The metastable form can still be very stable and also, beneficially exhibit higher dissolution rates than the stable form. The less stable polymorph could still be used in a formulation. Its stability may be acceptable on an absolute basis i.e. either polymorph or both could be used in a medicament. There are also instances where different polymorphs exhibit no differences in bioavailability.
17. Professor Newton agreed with the following general propositions put to him by Mr Waugh:

i) As a matter of generality, it is virtually impossible to manufacture a polymorphous compound of identical composition as between the polymorphs;

ii) As a matter of generality, it is frequently regarded as undesirable to incorporate polymorphous compounds in medicaments;

iii) Hence, as a matter of generality, it is desirable to produce a medicament using only one polymorph.

18. However, Professor Newton said that this was only a preference; and there might be advantages in producing a polymorphous mixture: for example its lower cost and the avoidance of the need to carry out procedures to prepare a particular polymorphic form. His view was that if the two polymorphs are stable (and there is no suggestion in the patent in suit that they are not), both produce a reasonable biological effect (again the data in the patent in suit suggest that they do) and where there is a positive reason to use a polymorphous product, then it is not undesirable to use a polymorphous mixture. In the present case, he considered that there were two positive reasons why a polymorphous mixture might be preferred:

i) The existence of '279 which, in the light of '035, could be seen to have taught how to make a polymorphous mixture with pharmaceutical utility; and

ii) The existence of the monopoly claimed by '035 itself, which would block off development of a crystalline pure product.

19. Where the formulator is formulating a polymorphous product, he would wish to ensure that there were no problems of reproducibility (i.e. that the proportions of each polymorph were the same in each batch of the manufactured product); and no problem of stability (i.e. that one polymorph did not convert to another). He would also be concerned to ensure that there was no problem over chemical stability of the compound.
20. Professor Newton was firmly of the view that none of the perceived problems associated with polymorphous mixtures was insurmountable. He considered that, from the technical perspective, there was nothing inventive about formulating a polymorphous mixture.

Regulatory considerations

21. A drug cannot be marketed without regulatory approval. Accordingly, the formulator must satisfy the regulators. Where there is an established product on the market, any competitor must have essentially the same bioavailability as the established product. It must not have better bioavailability, nor worse bioavailability. Regulators are not, however, concerned with whether the same polymorph is used; or, indeed, whether a polymorphous mixture is used. Nor are they concerned with particle size, provided that there is bioequivalence. That said, however, a single polymorph is the simplest formulation; and that is what regulators tend to look for. Accordingly, that is what a pharmaceutical company would tend to present to the regulators. Practice in this respect differs between the UK and the USA. The regulators in the USA are less flexible than regulators in the UK. The latter will listen to a good argument, and will look at the evidence to see whether something that differs from the norm is acceptable. There are many instances of generic products on the market that consist of different polymorphs to the branded product.
22. The regulators need to be satisfied that there is no issue over reproducibility, phase transition, relative proportions and chemical stability. It is easier to convince them with a single polymorph; but if you can show the same effects with a polymorphous product, they will be quite happy.
23. It was not, I think, suggested that only an expert in regulatory matters would have known this. These matters would have been equally known to a skilled formulator.

The pleaded prior art

The '035 Patent

24. '035 begins by referring back to '279, which was the original patent for tibolone. It goes on to say that tibolone "is used in medicaments having gonadomimetic, ovulation-inhibiting or immuno-modulating action". As I have mentioned, '035 revealed that tibolone prepared in accordance with the method described in '279 was polymorphous, with two main polymorphs. The patent explains the deficiency as follows:

"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."

25. The aim of the invention described in '035 was a method of preparing a crystalline pure (or almost pure) form of one of the polymorphs. Crystalline pure, for this purpose, was defined as one crystalline form containing less than 10% of the other crystalline form. It then said that it had been found that by using specific crystallisation techniques two crystalline pure forms (forms I and II) can be obtained from the polymorphous compound. It explained that one of the two polymorphs was chemically appreciably more stable than the polymorphous compound. This in turn increased the shelf-life of the pharmaceutical product. A further advantage of the crystalline pure tibolone was that its reproducibility was appreciably increased. The patent goes on to explain how to produce each of the two polymorphs. Having described this, the patent says:

"Each of the crystalline pure forms is mixed with a suitable pharmaceutical carrier and administered parenterally or orally, for example as a solid pharmaceutical administration form, such as a tablet, pill, capsule or suppository."

26. The claims claimed both forms I and II. It is clear from the last quoted passage and the claims themselves that the patent regards each of the two polymorphs as having pharmaceutical utility.

European Patent EP 0 613 687

27. This patent ("687") relates to the use of pregnane derivatives for the treatment of tumours. The relevance of this patent was not pursued in argument; and I say no more about it.

The patent in suit

28. The patent in suit is European Patent (UK) No. 1 449 278 ("'278"). It has a priority date of 23 May 2003. It is entitled "Immediate-release pharmaceutical dosage form comprising polymorphous tibolone".
29. The specification begins by identifying tibolone and its applications (paragraphs [0001] to [0002]). Paragraph [0003] refers to tibolone's relatively complex metabolic pattern. It explains that the bioequivalence of a compound, which exerts its activity through a metabolite, can be measured by analysing the plasma levels of its metabolites in the blood. However, it goes on to say that this is more complex in the case of tibolone, which has more than one metabolite. Paragraph [0004] explains that one way of achieving maximum exposure to a drug is by providing that drug in the form of a solution and that the normal expectation is that the bioavailability of the drug in the solid form will be lower than that in solution.
30. Paragraph [0005] introduces the heart of the claimed invention. It says:

"It has now been found that in the case of tibolone, this experiment led to an unexpected result. For different solid formulations, an analysis was made of two of the main metabolites, viz. 3a-OH tibolone and 3ß-OH tibolone. The finding is that one of these, 3a-OH tibolone, turned out to become better bioavailable as compared to a solution of tibolone, dependent on the particle size of tibolone. As this increase in bioavailability does not hold for the other above-mentioned metabolite, 3ß-OH tibolone, obvious explanations could not be given."

31. Paragraph [0006] says that this is an improvement of the solid pharmaceutical product as 3a-OH tibolone is responsible for an important part of the estrogenic effect of tibolone. Paragraph [0008] refers to '035 and describes how '035 discloses the existence of polymorphous tibolone. It says that '035 indicates that if polymorphous tibolone is used as a medicament great drawbacks are associated with it; and that therefore a pure crystalline form should be used with a purity greater than 90%. Paragraph [0009] explains that the marketed product is in pure crystalline form. However, paragraph [0010] says that it is complex and cumbersome to prepare crystalline pure tibolone; and that it is therefore desirable to provide a pharmaceutical dosage unit comprising polymorphous tibolone. This dosage unit comprising polymorphous tibolone "should have a similar bioavailability of 3a-OH tibolone as the marketed product" (viz. Livial).
32. Paragraph [0011] says that polymorphous tibolone with a mean particle size of less than 22.8µm has a similar bioavailability of the 3a-OH tibolone as Livial. This allows the use of polymorphous tibolone as a pharmaceutical, which gives economic advantages. Paragraph [0012] describes the invention as follows:

"The invention thus resides in pharmaceutical dosage forms, comprising the active substance tibolone as a polymorphous compound, which show an improvement of 3a-OH tibolone availability as compared to a reference solution with maximum exposure, viz. a solution of tibolone, in a similar way as the marketed product."

33. Paragraph [0013] is the characterising clause:

"The immediate-release pharmaceutical dosage forms according to the present invention are characterized by comprising tibolone as a polymorphous compound in a mean particle size of below 22.8 µm in the dosage form as measured by the technique described hereinbelow. Preferably the mean particle size of the polymorphous tibolone in the dosage form is below 20 µm. Preferably the pharmaceutical dosage form is a solid, peroral dosage form."

34. Paragraphs [0015] to [0042] describe how to make tibolone and how to formulate the dosage forms of the claims. These are generally uncontroversial. Paragraph [0016] defines "polymorphous" as meaning that the active substance contains at least two different crystal structures each present in an about of at least 10% by weight. Paragraph [0023] states:

"If the polymorphous tibolone has been provided in the adequate particle size before mixing with excipients, it can thereafter be mixed with excipients. Eventually, the mixture of polymorphous tibolone and excipients (however obtained) can be incorporated into solid pharmaceutical dosage units in a known manner."

35. Having thus described the invention, the patent sets out the claims. The relevant claims are:

"1. An immediate release pharmaceutical dosage form comprising, as the active substance, polymorphous tibolone and pharmaceutically acceptable excipients, wherein the polymorphous tibolone has a mean particle size of below 22.8µm in the dosage form.

2. A pharmaceutical dosage form according to claim 1, wherein the mean particle size of the polymorphous tibolone in the dosage form is below 20µm.

7. Use of polymorphous tibolone for the manufacture of a medicament for the treatment or prevention of menopausal and post-menopausal complaints including osteoporosis, wherein the polymorphous tibolone has a mean particle size as defined in the specification of below 22.8µm in the dosage form."

Obviousness: the legal test

General

36. A patent may only be granted for an invention if it involves an inventive step: Patents Act 1977 s 1 (1) (b). An invention does not involve an inventive step if it is "obvious to a person skilled in the art": Patents Act 1977 s. 3. The question whether a step was obvious has been described as a jury question. In Windsurfing International Inc v. Tabor Marine (Great Britain) Ltd [1985] RPC 59, 73 Oliver LJ said:

"There are, we think, four steps which require to be taken in answering the jury question. 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."

37. This is the conventional approach.
38. In commenting on the last (and crucial) step, in Molnlycke AB v. Procter & Gamble Ltd [1994] RPC 49 Sir Donald Nicholls V-C said that:

"obviousness connotes something which would at once occur to a person skilled in the art who was desirous of accomplishing the end."

39. That leads on to the question: what is the end to be accomplished?
40. Before leaving the general approach, I should mention that it is trite law that if there is more than one possible development of the state of the art, each may be regarded as obvious, if the facts justify that conclusion: Brugger v Medic-Aid Ltd [1996] RPC 635, 661.

The relevance of regulation

41. The Court of Appeal considered the relevance of regulatory approval to an obviousness attack in Richardson-Vick's Inc's Patent [1997] RPC 888. The case concerned an over the counter preparation for coughs and colds. A typical preparation contained an analgesic and one or more of decongestants, antihistamines, cough suppressants and expectorants. The alleged invention was the substitution of a non-steroid analgesic drug (such as ibuprofen) for the previously used analgesic (such as aspirin or paracetamol). The patent was attacked as being obvious. It was not suggested that the substitution produced any synergy between the components of the preparation. The patentee argued that, in the absence of such synergy, it would not have been possible to obtain regulatory approval to the new preparation. Thus it would not have been obvious to try the substitution. In support of this argument, the patentee argued that the patent specification was addressed to a team, one member of which would have been an expert on drug regulation. At first instance Jacob J said:

"Even if it were true that is what the regulatory man would have said (and the evidence only goes as far as indicating that the regulatory pathway would have been seen as difficult, perhaps impossible) I cannot see that it has anything to do with obviousness. All the argument amounts to is that it would have been impossible or difficult to get permission lawfully to sell the mixtures of the alleged invention."

42. The Court of Appeal agreed. Aldous LJ said that it was illegitimate to include in the team to whom the patent was addressed someone who was not directly involved in producing the product described in the specification or in carrying out the process of production. He held that it had not been established on the evidence that knowledge of the regulatory requirements was part of the common general knowledge of the legitimate members of the team. He rejected reliance on regulatory approval in the following terms:

"Richardson-Vicks sought to avoid the conclusion that the patent was obvious by relying upon the difficulties of obtaining regulatory approval. That was an obstacle in the path along the road to the conclusion that the patent was obvious which, they submitted, meant that, even though it was obvious to consider substitution of ibuprofen for aspirin, a skilled addressee would have realised that it was not worth trying. They were the first to perceive that it was obvious to try the substitution and therefore, relying upon cases such as Johns-Manville Corporation's Patent ([1967] R.P.C. 479), there was invention.
That submission fails for four reasons. First the alleged obstacle in the path of the skilled addressee did not form part of his common general knowledge and therefore was not an obstacle in fact. Second, claim 1 of the patent purports to monopolise the manufacture of the combination of ibuprofen and a decongestant. The alleged obstacle was not an obstacle to manufacture. It was an obstacle to marketing the combination. Thus the alleged obstacle did not prevent the manufacture of the combination being obvious. Once it was conceded that it was obvious to consider the claimed combination and the way to manufacture the combination was well-known, the conclusion that the invention was obvious was inevitable. Third the alleged obstacle only prevents commercialisation being obvious. That is not relevant to the issue of obviousness. …
Fourth, the cases such as Johns-Mansville have no application. They were all concerned with patents where it was alleged that there was a technical difficulty in perceiving the result. In this case there was no such technical difficulty."

43. The first of these reasons may not be applicable to the facts of this case, for reasons that I will explain; but the remaining reasons are. It seems to me, therefore, that obstacles to regulatory approval of pharmaceutical products are not relevant obstacles to an obviousness attack. It is also worth drawing attention to the clear distinction drawn by Aldous LJ between obstacles to manufacture on the one hand, and obstacles to lawful sale on the other. Obstacles to lawful sale are not relevant to obviousness.

The relevance of '035

44. '035 is, of course, one of the pleaded instances of prior art. But it is also relied on for two other reasons. The claim made by '035 is a claim to a monopoly of tibolone in a pure crystalline form (or, at any rate, 90% pure). Mr Thorley therefore relies on '035 in support of the argument that a formulator, wanting to formulate a dosage of tibolone would find that the path to formulating a pure crystalline form was blocked by the claimed monopoly; and would, necessarily have gone down the path of formulating a polymorphous compound containing both polymorphs of tibolone. He would have been encouraged in this because '035 recognises the pharmaceutical utility of both polymorphs.
45. Mr Waugh attacks this line of argument. He submits that the fact that one potential route is patented is not relevant to obviousness as a matter of law. First, for the same reasons that led the Court of Appeal in Richardson-Vicks to conclude that regulatory obstacles to lawful marketing were not relevant to obviousness, so other legal obstacles to marketing (such as the existence of a patent) are also irrelevant. Obviousness in this context is about technical obviousness, not commercial obviousness. Second, he says, treating patents as factors going to obviousness is unworkable because they are limited geographically and temporally. If a change is obvious because a particular path is blocked by a patent, will it cease to be obvious when the patent expires? Suppose that a patent is registered in France but not Portugal, will the same change count as an obvious change in France but not in Portugal? Third, the skilled person would not be deterred by a patent which might be attacked in a claim for revocation of that patent. Thus an argument based on the existence of a patent either presupposes its validity; or requires the court to determine its validity.
46. In my judgment this argument turns Richardson-Vicks on its head. Richardson-Vicks was concerned with a case in which the technical solution was obvious but where it would not have been tried because of difficulties in marketing the result. This case is, in a sense, the converse. Obstacles to marketing are part of the reason why the skilled person would consider whether there is any technically obvious alternative to crystalline pure tibolone. It cannot, in my judgment, be said that commercial considerations are completely irrelevant to the world of patents. As Lord Hoffmann put it in Biogen Inc v Medeva plc [1997] RPC 1 at 44:

"The fact that a given experimental strategy was adopted for commercial reasons, because the anticipated rewards seemed to justify the necessary expenditure, is no reason why that strategy should not involve an inventive step. An inventor need not pursue his experiments untouched by thoughts of gain. Most patents are the result of research programmes undertaken on the basis of hard-headed cost-benefit analysis."

47. See also Dyson Appliances Ltd v Hoover Ltd [2002] RPC 22, [88] (per Sedley LJ) and [97] (per Arden LJ), where commercial considerations deterring a skilled person from following a particular path were said to be relevant to the question of obviousness. If commercial considerations may deter a person from following a particular path, why should they not be relevant in considering whether he would follow a particular path? Commercial reasons may, in my judgment, be sufficient reason to take a skilled person down a particular path. I see no reason why those commercial reasons should exclude the desire to emulate a successful product, without infringing a patent, if the means of doing so are technically obvious.
48. Mr Waugh also relies on '035, but for a different reason. He says that '035 both teaches and reflects a general prejudice against the formulations of polymorphous mixtures in general; and tibolone in particular. Thus, he said that the invention embodied in the patent in suit was the overcoming of an existing prejudice. There is no doubt that the overcoming of an existing prejudice is capable of being inventive. As Jacob J put it in Union Carbide Corp v BP Chemicals Ltd [1998] RPC 1, 13:

"Invention can lie in finding out that that which those in the art thought ought not be done, ought to be done. From the point of view of the purpose of patent law it would be odd if there were no patent incentive for those who investigate the prejudices of the prior art."

49. The real question, as it seems to me, is one of fact: was the alleged prejudice so strong that overcoming it is inventive?

What would the skilled addressee know about tibolone?

In the real world

50. Professor Newton was unfamiliar with tibolone or Livial before being instructed in this case. In the light of this evidence it is plain that specific knowledge of tibolone and its properties would not have been part of the general common knowledge which is to be attributed to the average formulator. Whether he had come across tibolone before would be entirely adventitious. However, Professor Newton said that it did not matter that in the real world the skilled addressee might never have heard of tibolone. That would be equally true of a host of other drugs. What matters is that the skilled addressee would apply ordinary principles of drug formulation to information he would acquire about tibolone. He would acquire this information either in the form of a pre-formulation brief which would tell him what drug he was required to formulate; or in the course of pre-formulation literature searches. This was part of the ordinary routine of a formulator. Having acquired or been given the requisite information about the drug, he would then perform routine tests to discover such properties as its rate of dissolution. The process of acquiring such information cannot realistically be described as "research". It is no more than preparation for the process of formulation. In addition the average formulator would know, in general terms, the properties of steroids, of which tibolone was one.
51. I agree with Professor Newton. The analogy may be made with a lawyer called upon to advise on a particular case. Although he may know the general principles of law applicable, there can (or should) be no question of giving advice until he has ascertained the facts of the case. The fact-finding process is no more than necessary preparation for the giving of the advice. The same, no doubt would be true of a doctor who, before prescribing treatment, must examine the patient and, perhaps, perform routine tests. It was, in addition, common ground that in the real world, the formulator would be given a specification of what it was he was required to do; and that the specification would include the physicochemical properties of the drug he was being asked to formulate.

Common general knowledge

52. Mr Waugh submitted that since the average formulator would never have heard of tibolone, it was illegitimate in considering obviousness to combine the ordinary skills and knowledge of a formulator with information specific to tibolone. Whatever might be the position in the real world, the law of patents forbade the combination. He relied on the observations of Jacob LJ in SmithKline Beecham plc and ors v Apotex Europe and ors [2005] FSR 23 at [96] - [100]:

96. I think the Judge erred in principle here. The skilled man has his common general knowledge – the mental tools of his trade – but no more. The law of obviousness supposes that he can be given any individual piece of prior art and read it with that knowledge. The piece of prior art forms part of the "state of the art". What he cannot do is to just link one piece of prior art with another, unless so to do would itself be uninventive. No-one disputes what Lord Reid said in Technograph v Mills & Rockley [1972] RPC 346 at page 355:

"In dealing with obviousness, unlike novelty, it is permissible to make a 'mosaic' out of the relevant documents, but it must be a mosaic which can be put together by an unimaginative man with no inventive capacity."

97. It is that which must be applied here. If one starts with the Buxton and Lynch paper there is nothing about bound IPA at all. Nor is there anything which would suggest that it should be read with the erythromycin patent. So just putting the two papers together is an obvious illegitimate mosaic.

98. That is not how Apotex put the case however. They suggest that it is legitimate to suppose that the skilled man tries Buxton and Lynch and discovers for himself the unbound solvent problem. He would then, it is suggested, be entitled to take the information from the erythromycin patent and say "displacement worked there, I should try it here".

99. Such an analysis does not comply, as the Judge seemed to think it did, with the Windsurfing analysis:

(i) The inventive concept of the claims is displacement of bound solvent.

(ii) The common general knowledge of the skilled man does not include knowledge of bound solvent as such.

(iii) (a) If one takes Buxton & Lynch as the starting point the difference is the unknown existence of the bound solvent coupled with the fact that displacement is possible.

(b) If one takes Buxton & Lynch plus an experiment the skilled man would learn about the unbound solvent for himself but there would be nothing to tell him about the possibility of a displacement step.

(c) If he started with the erythromycin patent he would have no common general knowledge of paroxetine, still less of any problem of bound solvate in the anhydrate.

(iv) Whether one uses cases (iii)(a), (iii)(b) or (iii)(c) the differences to arrive at the invention are not shown to be obvious.

100. In short, the argument based on the erythromycin patent involves combining two documents, the separate contents of which are not common general knowledge. Carrying out an experiment on one of them does not make an illegitimate mosaic legitimate."

53. In my judgment the observations of Jacob LJ are directed to a different point. He was dealing with a "step-by-step" argument of the kind deprecated by Lord Diplock in Technograph Printed Circuits Ltd v Rockley (Electronics) Ltd [1972] RPC 346; and to which Jacob LJ himself referred in Apotex at [65].
54. In Nutrinova Nutrition Specialties & Food Ingredients GmbH v Scanchem UK Ltd [2001] FSR 42 Pumfrey J considered the extent to which the notional addressee of a patent could inform himself before applying himself to the task in hand. The task in hand in that case was the need to find a commercially acceptable pathway for the synthesis of an artificial sweetener (acesulfame-K) for which no known process of manufacture existed. Pumfrey J said at [81]:

"Dr Tennant says, and I accept, that the first thing a chemist charged with such a task would do is to familiarise himself with existing synthetic routes to acesulfame-K. Dr Tennant expressed the view that such a chemist would do a literature search and would certainly come up [with a particular review article]. The German version of this article is referred to on page 6 of the translation of the patent in suit. If this is what the unimaginative chemist would do, the court must do it as well. The disclosure of a document is ascertained by looking at the document through the eyes of the unimaginative chemist, and the court must decide what is obvious, or insufficient, in the same way. This is not to say that the contents of the article amount to common general knowledge. … It is, in essence, the knowledge which the addressee of the specification can be expected to have as part of his ordinary professional knowledge. An organic chemist brings his general skills and knowledge as an organic chemist to the task, but he cannot be expected to know the contents of review articles. At the same time, he must be expected to discover such articles, since doing a literature search is something which every skilled man in this art would be expected to do. …

There is a category of information which would be accepted generally once discovered and which will certainly be discovered by the skilled unimaginative chemist doing his job, not as a matter of performing a diligent search, following all the leads and cross-references, but as a matter of identifying the publications which are necessary to use as a starting point for tackling the new problem. I have no doubt that publications of this sort must be pleaded, if only to avoid surprise, but if it is established that their disclosure would form the basis of the skilled man's approach to the new problem it seems to me that they will form part of the knowledge with which he will approach other disclosures. To this extent, the information which they disclose must be treated in the same way as information forming part of the common general knowledge."

55. I respectfully agree. If that is what would happen in the real world, as a matter of the routine of a skilled but unimaginative person, there is no reason why it should not happen in the world of patents. Although this information may not be part of the common general knowledge, as that expression is usually understood, it is nevertheless to be treated in the same way as common general knowledge. In so far as this process consists of linking one piece of existing knowledge with another, it is an uninventive linkage.

The pleaded prior art

56. Of course if the skilled addressee were presented with the pleaded prior art he would know about tibolone. He would know its chemical formula. He would know how to make it. He would know from '035 that if made in the manner taught by '279 it would be polymorphic. He would not find this at all surprising, because steroids are often polymorphic. But what else would he know? In particular, would he know that tibolone had a poor rate of solubility? And, perhaps more importantly, would '035 put him off attempting to formulate a polymorphous mixture?
57. Mr Waugh emphasises that '035:

i) contains no teaching about appropriate particle size.

ii) contains no teaching about metabolism of tibolone. It discloses neither what the metabolites are, nor their roles or levels.

iii) contains no teaching that the metabolism of tibolone can be affected by formulation, or how to do so, or that different metabolites can be affected differently by appropriate choice of formulation.

iv) contains no teaching about any issue or problem concerning either poor solubility or bioavailability of tibolone.

58. Again, I think that Professor Newton had the answer. It is part of routine formulation to carry out tests on the drug that the formulator is asked to formulate, in order to discover its properties. In the course of such routine work the formulator would discover all he needed to know about tibolone in order to put into effect the techniques of formulation that formed part of his stock in trade. This would include the bioavailability of both polymorphs.

Obviousness: application to the facts

What is the inventive concept said to be embodied in the patent?

59. Mr Waugh submitted that the inventive concept is the use of polymorphous tibolone in an immediate-release pharmaceutical dosage form of less than the specified particle sizes (22.8 µm in claims 1 and 7 and 20 µm in claim 8). Mr Thorley submitted that it was the formulation of polymorphous tibolone (of any ratio outside the claims of '035) with a particular particle size so that it had bioequivalence with Livial. The "invention" resides in seeking to formulate polymorphous tibolone; and then determining the particle size that gives equivalent bioavailability to Livial.
60. The claims themselves do not refer to bioequivalence with Livial; but it is clear from paragraphs [0010] and [0011] of the specification that the reason why this particular particle size was chosen was its bioequivalence with Livial. In my judgment bioequivalence with Livial was an important part of the claimed inventive concept. In my judgment Mr Thorley's characterisation of the claimed inventive concept is the correct one, although there is little difference between the two.

What was the state of knowledge of the skilled person?

61. I have phrased the question in this way because, for reasons I have explained, I consider that it is right to imbue the skilled formulator with knowledge of the properties of the drug to which he is to apply his ordinary and unimaginative formulation skills.
62. Mr Waugh, however, submits that part of the attributes of the skilled formulator is a strong prejudice against formulating a polymorphous mix. This, he submits, is part of the mindset of the skilled formulator.
63. Professor Newton disagreed with this. He said:

"I disagree that the skilled person reading the pleaded prior art would not attempt to use a polymorphous mixture of tibolone. The common general knowledge on mixed polymorph systems … was that the critical feature was to ensure stability of the mixture … There may be no discussion of this in the prior art, but the issues of particle size and bioavailability would flow from general principles of formulation unrelated to whether the material was polymorphous. The skilled person would be aware of these potential issues in formulating a polymorphous product, but would not be put off trying out a polymorphous formulation. That is why formulation work is done."

64. In the light of this evidence, which I accept, I do not consider that there was a prejudice against the formulation of a polymorphous mixture, such that the mindset of an unimaginative formulator would have been deterred by technical problems from formulating a polymorphous mixture. There was, as Professor Newton accepted, a preference for a single polymorph, but in my judgment the preference was not strong enough to amount to a prejudice; or, to put it another way, overcoming the preference was not inventive.

What is the difference between the claimed inventive concept and the state of the art?

65. This, I think, is common ground. The differences are the use of polymorphous tibolone instead of crystalline pure tibolone, and the specified particle sizes.

What is the end to be accomplished?

66. It is, in my judgment, indisputable that at least part of the end to be accomplished is the formulation of tibolone. But it would be known to the skilled addressee that tibolone was a marketed product. Both '035 and his pre-formulation studies would have told him that. He would therefore know that the object of the exercise would be to produce a formulation of tibolone with bioequivalence with the marketed product.

Was formulating polymorphous tibolone obvious?

67. Professor Newton accepted that if a formulator set out to emulate the marketed tibolone the obvious technical thing to do would be to formulate a single crystalline form. What, then, would be the trigger for attempting something different?
68. Professor Newton put it as follows. The literature search would reveal that tibolone as originally patented was a polymorphous product. But it would also reveal that there was a patent covering tibolone of pure (or almost pure) crystalline form. He continued:

"Taking all of the above into account, the skilled person would know that formulations of tibolone had proved to be a valuable medicament, that there was a route for making polymorphous tibolone and that there was a patent on the non-polymorphous product. This would, I believe, naturally cause him to turn his attention to formulating a polymorphous tibolone product – with the objective of having physical and biological characteristics at least as good as those of the Livial® product. The bioavailability of the product would also be a regulatory approval issue and it would need to have an "essentially similar" bioavailability to the Livial® product. Improvements to bioavailability could have the added benefit of enabling dose to be reduced."

69. Professor Newton also pointed out that the claim made in '035 was not a claim to tibolone in pure crystalline form. As he put it:

"The [patent in suit] refers to … '035 …in which a crystalline pure form exists where purity is greater than 90%. In my opinion, that (90% to 10% or 91% to 9%) would still be a mixture of polymorphs (as 89% to 11% would be) and I would not call it "pure"."

70. He also said:

"In giving my evidence in this case I have been asked to imagine that the skilled person wanted to make a new formulation of tibolone at the priority date. In that position, if he had been handed the 035 Patent (which itself refers to the marketed product Livial®) he would have been aware that tibolone existed in polymorphic forms. From this the skilled person would understand that he could make a new formulation using a polymorphic mixture, and if he encountered any problems with the bioavailability of his mixture compared to Livial®, he would expect to be able to improve that bioavailability by reducing the particle size."

71. I have already held that Professor Newton's starting point was the right one. Building on this evidence Mr Thorley submitted that although it might have been obvious (absent the monopoly claimed by '035) to formulate a crystalline pure form of tibolone, it was equally obvious to formulate a polymorphous mixture. Given these two equally obvious technical possibilities, which one was chosen might well depend on commercial considerations, which would, no doubt, include the monopoly claimed by '035. However, looked at purely from the technical perspective of a skilled but unimaginative formulator, the choice between the two was a matter of indifference. I accept this submission.
72. Once the decision had been taken to formulate polymorphous tibolone, finding a particle size with bioequivalence to the marketed product was no more than a matter of routine testing. The particle sizes claimed are nothing out of the ordinary. In my judgment it would have been obvious to the skilled but unimaginative formulator to have formulated polymorphous tibolone of the claimed particle sizes.

Result

73. The attack on the validity of the patent on the ground that the claimed inventive step was obvious to a person skilled in the art therefore succeeds. I will, in principle, revoke the patent. The precise terms of my order will be a matter for discussion, if they cannot be agreed.