Actavis UK Ltd. v Merck & Co. Inc Rev 1

In this action, the Claimant (“Actavis”) seeks revocation of the Defendant’s (“Merck”) European Patent (UK) 0724 444 (the “Patent”). The Patent concerns the use of a drug called finasteride. At the priority date (the earliest claimed priority date is 15 October 1993), finasteride was marketed by Merck in tablet form, under the name PROSCAR, for the treatment of a condition known as benign prostatic hyperplasia (“BPH”). The conventional dose for treatment of BPH is 5mg daily. The basic patent for finasteride was EP 004 949 with a priority date of 13 April 1978.

The Patent relates to the use of a low dose of finasteride for the treatment of androgenic alopecia in humans, a condition which includes both male pattern baldness (“MPB”) and female pattern baldness. The Patent discloses the result that low doses of finasteride are effective in treating androgenic alopecia, a result which Mr Watson QC and Mr Hinchliffe, who appear for Merck, describe very early in their skeleton argument as “surprising”. The focus of the argument has been on Claim 1 of the Patent which I will come to. No separate point is made in relation to Claims 2 and 3. All three Claims stand or fall together.

Merck were also the applicants for European Patent (UK) 285 382 which is relevant to the state of the art.

Androgens are a class of steroid hormones which are responsible for the development and maintenance of masculine characteristics eg male sexual organs, deepened voice, facial hair, baldness and so on. Testosterone is the major circulating androgen in men. In certain tissues, the principal mediator of androgenic activity is not testosterone but one of its metabolites, dihydrotestosterone (“DHT”). Testosterone is converted to DHT by the action of a membrane bound enzyme called 5α-reductase. This enzyme is present in a number of adult tissues including prostate, liver and skin.

It is now accepted science that there are two forms (“isozymes”) of 5α-reductase, which I shall refer to simply as “type 1” and “type 2”. Isozymes are variants of the same enzyme. They differ in amino acid sequence but catalyse the same reaction – in this case the conversion of testosterone to DHT. Mr Watson says that, at the priority date, type 1 was thought to be the enzyme present in the scalp, whilst type 2 was thought to be the enzyme present in the prostate. The precise state of the common general knowledge with regard to the properties of the two types is in dispute.

Finasteride is one of a class of compounds known as a 4-azasteroids. It is a strong inhibitor of type 2 but not of type 1. It is now known that type 2 is the relevant isozyme in relation to BPH; finasteride is therefore a suitable treatment for BPH, inhibiting reduction of testosterone to DHT in the prostate. Finasteride was first administered to humans in 1986 and was shown to cause a marked reduction in plasma levels of DHT. Subsequent clinical trials demonstrated that the drug was effective in reducing the size of the prostate. In 1992 finasteride was first licensed for use in the treatment of BPH at an oral dose of 5mg per day.

However, according to Mr Watson, it could not, at the priority date have been generally seen as a treatment, particularly in low doses, for MPB given that it is not a strong inhibitor of type 1.

Nonetheless, Merck discovered that finasteride in small doses is an effective treatment for MPB and is sufficient to make a marked impact on the condition. Finasteride is marketed by Merck in tablet form, under the name PROPECIA, for the treatment of MPB. The conventional dose for treatment of MPB is 1mg daily.

The Patent specification describes a “method of treating androgenic alopecia with 5α-reductase inhibitors”. The actual Claims are as follows:

Merck says that, as a matter of construction, Claim 1 of the Patent is limited to the stated dosage of finasteride per day. If the entire Patent is read, there is material in the description which supports that conclusion. However, that construction is disputed by Actavis, relying on the definition of the invention which makes no reference to dosage. However, Actavis does not oppose the amendment so that the dispute about construction is largely academic. I do not propose to decide the question of construction but instead allow the amendment for the purpose of these proceedings.

It will be seen that Claim 1 is in “Swiss form” (for a general description of which see Terrell on the Law of Patents (16^th ed) at 6-122ff). I do not embark on an explanation of the justification for upholding patents in this form. But I should mention the legislation and a bit of history.

Sections 4(2) and 4(3) of the Patents Act 1977, which are derived from Article 52(4) of the Convention on the Grant of European Patents (the European Patent Convention) (“EPC”), state:

“(2)

An invention of a method of treatment of the human or animal body by surgery or therapy or of diagnosis practised on the human or animal body shall not be taken to be capable of industrial application.

(3)

Subsection 2 above shall not prevent a product consisting of a substance or composition being treated as capable of industrial application merely because it is invented for use in any such method.”

Section 2(6) of the 1977 Act, which is derived from Article 54(5) of the EPC, states:

“(6)

In the case of an invention consisting of a substance or composition for use in a method of treatment of the human or animal body by surgery or therapy or of diagnosis practised on the human or animal body, the fact that the substance or composition forms part of the state of the art shall not prevent the invention from being taken to be new if the use of the substance or composition in any such method does not form part of the state of the art.”

The result is that it is possible to obtain a patent for the first medical use of a known substance or composition, where this substance or composition was not previously known to have any medical application: see Sopharma SA’s Application [1983] RPC 195.

Owing to the prohibition on method of treatment claims in Article 52(4) of the EPC (which corresponds to sections 4(2) and 4(3) of the 1977 Act), the Enlarged Board of the European Patent Office has held that a European patent may notbe granted for the use of a substance or composition for the treatment of the human or animal body by therapy.

However, it has also accepted, on policy grounds, and following the practice of the Swiss Federal Intellectual Property Office, that a European patent may be granted with claims directed to the use of a substance or composition for the manufacture of a medicament for a specified new and inventive therapeutic application. This gave rise to the now widely used form of the second medical use, or so-called “Swiss form” claim: see Eisai/Second Medical Indication (1985) OJEPO, 64 (“Eisai”).

Accordingly, a claim in the form: “Use of [X] for treatment of [Y]” would not be accepted, whereas a claim “Use of [X] for the manufacture of a medicament for treatment of [Y]” would be accepted.

Claims in the Swiss form have been considered by the UK courts in a number of cases. I need only consider the decision of the Court of Appeal in Bristol-Myers Squibb v Baker Norton [2001] RPC 1.

In that case, the pharmaceutical in question (taxol) was used in the treatment of cancer. Claim 1 read as follows:

“use of taxol and sufficient medications to prevent severe anaphylactic reactions, for manufacturing a medicamentation for simultaneous, separate or sequential application for the administration of from 135mg/m₂ up to 175mg/m₂ taxol over a period of about 3 hours or less as a means for treating cancer and simultaneously reducing neutropenia”.

The use of taxol in combination with other medications was known as a treatment for cancer. It was common ground that the only difference between the claim of the patent in suit in Bristol-Myers and the previously disclosed treatment regimen for using it lay in the dosing protocol. Previously the treatment had been for 24 hours, which involved an overnight stay in hospital. The claimed treatment reduced this period to 3 hours so that the treatment could take place on an out patient basis and, yet, the accelerated treatment reduced neutropenia (suppression of the rapid division of white blood cells).

The judge had held the patent to be invalid on the grounds of lack of novelty and obviousness. The proprietor of the patent appealed submitting that the Claim 1 was a valid “Swiss-type” claim as allowed by Eisai based on the previously unknown suitability of taxol for treating cancer when infused in the claimed amount of 3 hours and the reduction of neutropenia; the appellants also submitted that in any case novelty did not need to reside in a second, or subsequent, therapeutic use.

The Court of Appeal held that, in so far as Swiss-type claims were permissible at all, they must be limited to a therapeutic application which was not only inventive but new; novelty must reside in the new second, or subsequent, therapeutic use. The reasoning of the judges is set out at paragraphs 34-49 and paragraphs 54-63 (Aldous LJ), paragraphs 76-88 and 90-94 (Buxton LJ) and paragraphs 107-112 (Holman J). I would cite the following passages:

Mr Thorley submits that the present case is indistinguishable from Bristol-Myers (which is of course binding on me). Dealing first with lack of novelty he says that, in order to be a valid Swiss-type claim, the novelty must lie in the new therapeutic application: novelty cannot reside in a new dosing regimen for treatment of the same disorder as previously treated. In the present case, he submits that EP 0 285 382 discloses the therapeutic application, namely, the treatment of androgenic alopecia. The fact that the dosage levels are changed cannot afford novelty. The Claim accordingly lacks novelty in the light of the reasoning in Bristol-Myers.

I need to say something at this stage about that EP 0 285 382. This application was published in October 1988. It is entitled “Methods of treating androgenic alopecia with 17β-N-monosubstituted-carbomyl-4-aza-5α-androst-1-en-3-ones”. One of the compounds in question is finasteride.

As with the Patent, 382 begins with a reference to a number of hyperandrogenic conditions including male pattern baldness and BPH (page 2_11-13). At the foot of page 2, it refers to the new class of compounds as active ingredients and methods of inhibiting 5α-reductase and of treating androgenic sensitive conditions.

Having described the underlying chemistry, the specification states as follows:

“Accordingly, the present invention is particularly concerned with providing a method of treating the hyperandrogenic conditions of androgenic alopecia, including male pattern alopecia, acne vulgaris, seborrhea, and female hirsutism by topical administration, and a method of treating all of the above conditions as well as benign hypertrophy, by systemic administration, of the novel compounds of the present invention.

The compositions containing the compounds of the present invention is [query should be “which are”] the active ingredient for use in the treatment of benign prostatic hypertrophy can be administered in a wide variety of therapeutic dosage forms in conventional vehicles for systemic administration, as for example, by oral administration in the form of tablets, capsules, solutions, or suspensions, o[r] by intravenous injection. The daily dosage of the products may be varied over a wide range varying from 5 to 2,000 mg, preferably from 5 to 200 mg.”

In the light of that, it seems to be clear that there is no novelty in the use of finasteride as a possible treatment for MPB. It may be novel to use it in the small dosage which it is now apparent can result in successful treatment, rather than the much larger doses mentioned in EP 0 285 382. But this is simply a different dosing regime and is thus precisely the same as the situation in Bristol-Myers.

So far as concerns industrial application and method of treatment, Mr Thorley submits that, by parity of reasoning, the decision to treat a patient using the dosage range specified in Claim 1 of the Patent rather than the dosing range specified in EP 0 285 382 is a matter of judgment by the doctor as to the method by which he wishes to treat the patient. It would make no therapeutic difference to a patient who was being treated under the dosage levels of EP 0 285 382 (eg 5 mg per day) whether he was given five 1 mg tablet 5 times a day or five 1mg or one 5mg tablet tablets at the same time. Equally it would make no difference to the patient treated under the dosage range of the Patent (eg. 1mg under Claim 2) whether he was given 1 tablet of 1mg or 1/5^th of a larger tablet of 5mg. The Patent itself makes no distinction as to the form of administration, referring to the possible administration in a wide variety of therapeutic doses.

In these circumstances, Mr Thorley’s contention is that each of the Claims is invalid as being a method of medical treatment in respect of which a patent would be impermissible by reason of the disclosure in EP 0 285 382.

Mr Watson relies, against that conclusion, on a number of decisions of the Technical Board of Appeal, in particular Genentech (T1020/03), which show, he says, that an important gap has opened between the EPO jurisprudence on second medical use and the approach of the English courts. He submits that Bristol-Myers ought no longer to be regarded as good law. He does not, however, seriously contest that I am bound by the approach in Bristol-Myers but reserves his position should this case go further.

I consider that I am bound by it and, seeing no material distinction between it and the present case, I agree with Mr Thorley’s conclusion.

That is enough to dispose of the case. However, the parties are concerned to have my decision on obviousness as well. I have received full evidence and received detailed argument on this aspect of the case. Obviousness will clearly be of decisive importance should Merck succeed on any appeal in relation to second medical use. I propose therefore to deal with the issue.

In that context, I have been referred to a number of scientific papers concerning 5α-reductase and the development of the understanding about type 1 and type 2 and where it is found. I will need to refer to a considerable number of them, although not at length.

I have received evidence from three experts. There has been a marked absence of controversy between the experts, all of whom were clearly trying to assist the court and were perfectly candid about what did and did not fall within their fields of expertise. There is really no significant challenge to what any of them said, or did not say. The question is where all this evidence takes one in the light of the applicable law. I would, however, say a few words about each of the witnesses at this stage.

Actavis originally obtained expert evidence from one expert, Dr Eve. His experience and expertise is in designing clinical trials but he was not an expert in the field of 5α-reductase or MPB. His evidence was clear and fair. It assisted me in understanding how clinical trials would be designed and implemented once a decision had been made to investigate the use of finasteride in the treatment of androgenic alopecia.

Merck obtained expert evidence from only one expert, Professor Russell. He was, as Mr Thorley accepts, clear, lucid and well informed. He is clearly a leading authority with perhaps an unrivalled depth of knowledge and experience as a molecular biologist in the field of 5α-reductase. He and his team at the University of Texas were, as Mr Thorley points out, at the cutting edge of the ongoing investigations into the existence and nature of the 5α-reductase isozymes and privy to unpublished work of all the leading commercial workers in the field. I accordingly take on board the note of caution sounded by Mr Thorley when he says that care must be taken in attributing the breadth and depth of Professor Russell’s knowledge to the notional scientist with knowledge of 5α-reductase who would form part of the skilled team which one is required to assume exists. Professor Russell made no claim to any particular expertise in hair biology or in the design of clinical trials, although it would be idle to suggest that he was not generally knowledgeable about both.

Perhaps having seen how the case was developing in the light of Professor Russell’s expert report, Actavis obtained further expert evidence from Dr Thornton. She has been closely involved in research into androgenic alopecia and was involved in it at the relevant time in 1992-4. She did not, and does not have, the extensive experience of Professor Russell in relation to the genetics and biochemistry of 5α-reductase. But she was, and is, a member of a very small community of scientists with a particular interest in androgenic alopecia and, as one would expect, became familiar with all the published material as and when it became available. She was able to give an account of her contemporaneous reaction to the relevant papers. She, too, gave her evidence clearly and fairly.

The structured approach to obviousness is set out in Windsurfing International v Tabur Marine [1985] RPC 59 at 73; it is not a compulsory approach but is useful in its application in many cases:

The Court must be particularly careful not to allow hindsight to colour its judgment when considering the fourth step. Oliver LJ himself stressed this in Windsurfing as have many other cases. I do not need to cite further authority but refer again to Terrell, at paragraph 7-67.

There is, unsurprisingly, a substantial area of common ground between the parties about the applicable law. Mr Thorley and Mr Acland put forward the following propositions in their skeleton argument with which I agree and gratefully adopt:

Cases concerning obviousness frequently give rise to what has been described as the “obvious to try” argument. In the present case, a central area of dispute between the parties is whether, at the priority date, it would have been obvious to a person skilled in the art to undertake clinical trials of finasteride for the treatment of MPB. Mr Watson accepts that, if it had been “obvious to try” an oral dose of finasteride at about 5mg daily, there would be bound to have been a trial at smaller doses which would have led to the discovery that small doses were effective in the treatment of MPB. The point, therefore, is that if Mr Thorley is correct in saying, as he does, that it was “obvious to try” then he succeeds in his case on obviousness. Mr Watson, of course, rejects the premise: there was “a lion in the path”. But he concedes that if, contrary to that, the premise is correct then the conclusion follows: if it were obvious to try the oral route at about 5mg daily, Merck loses. Mr Thorley would say that this lion is tiny and has no teeth: it would flee away as Dr Eve and Dr Thornton approach.

In their skeleton argument, Mr Watson and Mr Hinchliffe refer, in the context of “obvious to try”, to the expectation the skilled man would have of the success of his postulated trials as a relevant consideration. They cite Saint-Gobain PAM SA v Fusion Provida Ltd [2005] EWCA Civ 177, where Jacob LJ said this about such arguments in paragraph 35 of his judgment:

“35.

None of this to my mind remotely makes the idea of using Zn/Al alloy for pipes obvious – as something which is simply self-evident to the unimaginative man skilled in the art. Mere possible inclusion of something within a research programme on the basis you will find out more and something might turn up is not enough. If it were otherwise there would be few inventions that were patentable. The only research which would be worthwhile (because of the prospect of protection) would be into areas totally devoid of prospect. The "obvious to try" test really only works where it is more-or-less self-evident that what is being tested ought to work”.

It is often dangerous to take short passages from a judgment out of context, and what Jacob LJ says here really needs to be read in the context of the facts of the case. In any event, at the end of the day, the “obvious to try” argument is directed at, and is only one component in answering, the single question whether the invention was obvious. As Jacob LJ himself put it, after citing St Gobain, in his judgment in Angiotech Pharmaceuticals v Conor Medsystems Inc [2007] EWCA Civ 5, at paragraph 45:

“In the end the question is simply "was the invention obvious?" This involves taking into account a number of factors, for instance the attributes and cgk of the skilled man, the difference between what is claimed and the prior art, whether there is a motive provided or hinted by the prior art and so on. Some factors are more important than others. Sometimes commercial success can demonstrate that an idea was a good one. In others "obvious to try" may come into the assessment. But such a formula cannot itself necessarily provide the answer. Of particular importance is of course the nature of the invention itself.”

It is worth noting that in Angiotech, Jacob LJ goes back to the source of the expression “obvious to try” in relation to obviousness which is found in the judgment of Diplock LJ in the Johns-Manville case, [1967] RPC 479. He says:

“The facts were simple: there was a known process. The patent was for the old process using the new agent. It was held obvious as being “well worth trying out”. Diplock LJ said:

‘It is enough that the person versed in the art would assess the likelihood of success as sufficient to warrant actual trial.’

There is, of course, a difference of emphasis, at least, between “well worth trying out” and “ought to work”. But in the context of the ultimate question, Was the invention obvious?, the difference may come to nothing. I do not think that Jacob LJ can be read of saying that they are inconsistent.

Mr Watson points out, correctly, that invention may lie in overcoming the preconceptions and prejudices of the skilled workers in the field and in showing that that which was thought would not work (and therefore not worth bothering with) in fact would work. He refers to the comments of Pumfrey J in Glaxo’s Patent [2004] RPC 43 at paragraphs 27-33. This point is of importance in the present case because the science, today, explains why a type 2 inhibitor such as finasteride is effective in the treatment of MPB whereas, according to Mr Watson, nobody would have thought, at the priority date, that a type 2 inhibitor would be relevant to MPB when it was type 1 which was thought to be present in the scalp.

In addressing the question of obviousness, the Court is concerned with the position of the skilled addressee. The approach of the skilled addressee informs the approach which the Court must take to the patent in suit and the prior art. A patent specification is “addressed to those likely to have a practical interest in the subject matter of the invention (ie ‘skilled in the art’)”: see Catnic v Hill and Smith [1982] RPC 183 at 242 per Lord Diplock. Thus, in order to identify whether an invention is obvious, one has to consider what the invention is and then determine what the attributes of somebody interested in that invention would be. Mr Thorley refers me also to Aldous LJ in Richardson Vicks Patent [1997] RPC 888 at 895 in the passage cited in paragraph 6-32 of Terrell:

“There is no basis in law or in logic for including within the concept of “a person skilled in the art” a person who is not directly involved in producing the product in question in the patent or in carrying out the process of production”

The proper identification of the skilled addressee is crucial to obviousness – as Mr Watson says “everything (or on the other hand nothing) will be obvious to an incorrectly identified skilled addressee”. Pumfrey J made it clear in Mayne Pharma v. Debiopharm SA [2006] EWHC 1123 (Pat) at paragraphs 3 and 4, that the notional skilled addressee for the purposes of a patent action must include those who were actually in the field.

The skilled addressee can be, and in many cases will be, a team where more than one set of skills would be required in order to consider implementing the teaching of the patent in the field in question. But, the fact that the skilled addressee can be considered to be a team and that the team may be made up of people having expertise in refined areas of science, does not mean that the skilled team is possessed of the inventive capacity which undoubtedly most people with expertise in that field would have. The team possess the “common general knowledge” of each of the members of the team but none of them possess inventive capacity: see generally Technip France SA at paragraphs 6-15.

“Common general knowledge” is described in Terrell at 6-36 to 6-39. The general statements there are not controversial and I do not need to set them out. It is not the law that only that which the skilled man can hold in his head is common general knowledge. In Raychem’s Patent [1998] RPC 31 at 40, Laddie J said this:

“The Court is trying to determine in a common sense way how the average skilled but non-inventive technician would have reacted to the pleaded prior art if it had been put before him in his work place or laboratory. The common general knowledge is the technical background of the notional man in the art against which the prior art must be considered. This is not limited to material he has memorised and has at the front of his mind. It includes all that material in the field he is working in which he knows exists, which he would refer to as a matter of course if he cannot remember it and which he understands is generally regarded as sufficiently reliable to use as a foundation for further work or to help understand the prior art.”

A theory does not have to be proved to be correct before it can become common general knowledge. If the evidence shows that a person knows that people are looking at, for instance, the particular use of a drug or piece of equipment as a way forward to solving a problem, then even if it has not been proved to work, it is nonetheless part of his mental equipment, not on the basis that he knows that it will work but on the basis that it may: see Jacob LJ in Angiotech v Conor [2007] EWCA Civ 5 at paragraph 18.

There is a distinction, which is of relevance in the present case, between the knowledge obtained from reading cited prior art and the knowledge which forms part of the background technical knowledge of the skilled team. The question of obviousness must be assessed through the eyes of the skilled but non-inventive man in the art. This is the reflection of the policy which affords protection to inventiveness, not for the discovery and wider dissemination of public material and what is obvious over it. On the one hand, the hypothetical skilled person will see all routes to a desired goal where a particular real worker (even a real expert) might not. On the other hand, experts come to the issues not only with a profound understanding of the technology but also, frequently, with knowledge of information which is not deemed to be known to the skilled person. Information which is publicly available is not necessarily to be treated as known: there is, as Mr Thorley says, a distinction between common general knowledge and a specialist knowledge which would only be obtained by the notional skilled team on doing an extensive literature search or on focusing in detail on papers which, although read by the skilled addressee, would not have had the contents absorbed at any level of detail.

Mr Thorley and Mr Acland have identified a number of dicta from a number of authorities which they submit are of assistance in identifying where the line is to be drawn between background knowledge and specialist knowledge. They conclude that the law does not presume, but rather, rejects the concept that the skilled addressee will automatically indulge in a thorough literature search in order to determine whether a proposal put forward in a piece of prior art is or is not “generally regarded as a good basis for further action”. He takes the document as he finds it and if, in the light of his common general knowledge, it proposes to him a good basis for further action, that is an end of the matter. The further action is obvious.

They rely in particular on these dicta:

I consider that the approach of Mr Thorley and Mr Acland is established by these dicta.

This aspect of obviousness is dealt with in Terrell at 7-68. Patents are granted for technical advances, not for appreciating that a technically obvious development can be exploited commercially. The paragraph in Terrell cites from the judgment of Aldous J at first instance in Hallen Company v Brabantia (UK) Ltd [1989] RPC 307 at 327 which itself starts with the proposition that the word “obvious” (in section 3 Patents Act 1977) is directed at whether an advance is practically or technically obvious and not to whether it is commercially obvious. In the Court of Appeal, Slade LJ commented on this agreeing that it was not necessary that the hypothetical technician must be taken as applying his mind to the commercial consequences which might follow if the step or process in question were found in practice to achieve or assist the objective which he had in view. But those principles must be understood in the light of the later cases regarding the mindset of the skilled addressee as explained in that paragraph of Terrell. Arden LJ puts it succinctly, in Dyson v Hoover [2001] RPC26 where she says that “…commercial motivation or “mindset” may have some indirect relevance to the issue of obviousness…”.

In the present case, Merck held a patent in respect of finasteride as a compound, making its commercial exploitation by anyone else unrealistic. But that fact does not impact on the question whether the claimed invention was obvious.

I was referred by Mr Thorley and Mr Watson to a considerable number of papers. Some were published before and some after the priority date (15 October 1993). They include the following:

Actavis relies particularly on Sudduth and Diani. There had been reliance also on Gormley 1990. At this stage, I mention the last of those simply to get it out of the way. Mr Thorley relied on it to inform the skilled reader that there were good grounds for believing that a dosage of less than 5mg daily would in fact serve to inhibit the production of DHT. In the light of Mr Watson’s acceptance that if an oral dose of 5mg were to be trialled, so too would a smaller dose, Mr Thorley no longer needs Gormley 1990 and does not need to establish that the skilled addressee would have turned to it. Mr Watson accepts that the skilled addressee would turn to Diani. He in turn relies particularly on Harris and Thigpen which, according to him, brought about a major shift in the landscape rendering Actavis’ case on obviousness unsustainable whatever the position may have been prior to their publication. It is common ground that Sudduth and Diani formed part of the common general knowledge at the priority date. I would nonetheless add that Professor Russell accepted that Gormley 1990 would have been one of the papers that would have been consulted in order to determine the therapeutic window, but that was on the assumption that he was part of a team considering developing finasteride as a potential treatment for androgenic alopecia. Mr Watson’s acceptance described above does not answer the question whether it is obvious that the skilled team would have embarked on an investigation of finasteride for the treatment of MPB in the first place.

Imperato-McGinley: this paper, together with another paper [Walsh et al., Familial incomplete male pseudohermaphroditism type 2: Decreased dihydrotestosterone formation in pseudovaginal perineoscrotal hypospadias New England Journal of Medicine, 291, 944-949 (1974)], sets the background to later development. Although Mr Watson seeks to down play its significance in relation to the state of knowledge in 1993, it is cited in every (or almost every) relevant paper since its publication. It was also referred to by Merck in a confidential document as suggesting that DHT and not testosterone was the androgen necessary for the development of MPB. I hope, therefore, that I will be forgiven if I lengthen this long judgment even more by setting out some interesting paragraphs from Professor Russell’s report where he deals with it:

“…….In summary, they reported the biochemical basis of a rare human genetic disease in which affected males were born without prostates and with female external genitalia. As adults, these subjects were said to have normal male libido, deep voices and male musculature but not to develop acne or exhibit male pattern baldness. The two teams of investigators used different experimental methods to show that these patients failed to synthesise DHT in certain tissues because they had inherited defects in the gene that specified 5α-reductase. The striking presentation of these individuals suggested that testosterone and DHT had different physiological effects. Testosterone was required for some aspects of the male phenotype, including libido, vocal cord maturation and muscle development at puberty, whereas DHT was required for the development and growth of the external genitalia and the prostate. Furthermore, the failure to develop acne suggested that DHT controlled the activity of sebaceous glands, which are responsible for secreting skin oil. The fact that affected males had a full head of hair as adults appeared to indicate that DHT contributed to the development of male pattern baldness.

The latter activity deserves further consideration given the present case. A role for androgens in hair growth was recorded by Aristotle who wrote in describing men castrated as youths “The congenital growth of hair never falls out, for a eunuch never goes bald”……. More recent studies done by Hamilton on mentally defective men in the 1940s who were castrated based on eugenics principles, confirmed and extended Aristotle’s conclusions. Hamilton had access to purified testosterone and showed that administration of this androgen to eunuchs sterilised as boys caused them to develop male pattern balding ……. Although the anatomy of the hair follicle was well-established by Hamilton’s time (see Figure 1), experiments to determine which cells in the structure responded to androgen and whether testosterone or DHT was the active hormone were not forthcoming until the papers of Walsh and Imperato-McGinley in the 1970s.

The findings presented in the Walsh and Imperato-McGinley papers caught the attention of pharmacologists at several universities and large pharmaceutical companies who reasoned that if inhibitors of 5α-reductase could be identified, then these might be useful as drugs for the treatment of benign growth of the prostate, acne and baldness. When an enzyme catalyses a reaction, it binds the starting compound, referred to as the substrate, and then transforms the substrate into a product. In the case of 5α-reductase, the enzyme binds testosterone and then converts this substrate into the product DHT. To stop or block this enzyme, a pharmacologist attempts to identify molecules, typically small molecules, which bind to the enzyme and prevent it from transforming the substrate into product. Such inhibitors are known to act in different ways. Sometimes, an inhibitor will compete with the substrate for binding to the enzyme. In other cases, such as with finasteride, the small molecule inhibitor developed by Merck to block 5α-reductase, more complicated mechanisms of inhibition take place. During the late 1970s and 1980s, many different inhibitors of 5α-reductase were identified in academia and industry, and their use in the treatment of human disease began to be established in clinical trials.”

Imperato-McGinley describes 13 families from the Dominican Republic in which there were 24 male pseudohermaphrodites. The affected males were born with ambiguous external genitalia and were raised as girls. At puberty they developed a typical male phenotype. Male puberty without breast development precluded a complete absence of androgen action, and Imperato-McGinley therefore suggested that the abnormality was due to a defect in the metabolism of testosterone, in particular the transformation of testosterone to DHT by 5α-reductase. Chemical analysis showed a defect in 5α-reductase action resulting in a decreased conversion of testosterone to DHT. Imperato-McGinley reported that in affected males “Prostate growth, facial hair, temporal recession of the hairline, and acne do not occur and appear to be mediated by dihydrotestosterone”. Although the paper comments on facial hair, acne and temporal recession of the hairline, no data are presented to these ends. Professor Russell points out that this work was all carried out on related individuals. Within any individual, the activity of a particular gene may be affected by interactions with other genes. Where such interactions occur, they may well also occur in related individuals. This should be taken into account where observations are made of related subjects, as they may not occur with other, unrelated individuals. Imperato-McGinley’s comment on balding in 5α-reductase males are not a formal finding. It has, however, been propagated in the literature, including in Professor Russell’s own published papers. A formal finding of defective 5α-reductase deficiency in male pattern baldness would require detailed measurements and dermatological examinations followed over a period of time.

Harris is a paper from within Merck. It suggests that the scalp contains the type 1 5α-reductase and not the type 2 5α-reductase as seen in the prostate. It starts from the position that although two genes coding the 5α-reductase enzyme are known, no tissue distribution of the enzyme encoded by the 5α-reductase enzyme 1 gene has been reported. The paper reports a pharmacological characterisation of an isozyme present in the human scalp which appears to be the type 1 isozyme on the basis of its basic (alkaline) pH optimum. The discussion suggests that “The results reported in this paper may have important implication in pursuing steroid 5α-reductase as a therapeutic target. An inhibitor of 5α-reductase has been shown to be useful in the treatment of benign prostatic hyperplasia. Reductase inhibitors may also be useful in treating male pattern baldness, acne, and hirsutism, as these disorders also appear to be DHT dependent. However, the results of our study indicate that a single inhibitor may not be suitable, given the differences in the enzymes”.

Diani reports work done by a group at Upjohn. The group worked with, and maintained, a colony of stumptail macaques. These monkeys show balding similar to that seen in humans. It is not identical, however, since unlike humans, both the female and male macaque show similar balding. Stumptail macaque balding is partially reversible by chronic topical administration of minoxidil.

In the study, 21 macaques weighing between 9.5 and 15.4 kgs were used in a 20-week hair growth study. The animals were divided into four groups. Six monkeys were treated with a placebo, 5 with topical 2% minoxidil, 5 with 0.5 mg oral finasteride in combination with a topical vehicle and 5 with a combination of 0.5 mg oral finasteride in combination with topical 2% minoxidil. Monkeys treated with oral finasteride alone (ignoring one of the individuals which did not respond) exhibited comparable hair growth to animals treated with minoxidil. The combination of finasteride and minoxidil produced a highly significant promotion of hair growth.

There is considerable dispute between the parties about the account which would have been taken of Diani by the skilled team given that the size of the monkey sample was small (only 5 in number) and there was one non-responder. To exclude the non-responder would be improper as a matter of statistics and, according to Mr Watson, no conclusion can be drawn from the results of the group as a whole about the effectiveness of finasteride. That, however, seems to me skirt round the real point which is whether the limited results would indicate that further investigations might be valuable, or whether they give no indication at all, an issue highlighted by Dr Eve’s evidence to the effect that, in most clinical studies/situations, an 80% response rate would be considered clinically significant and acceptable. Occurring in an early, exploratory animal study, he would have regarded this result as highly encouraging and strongly supportive of ongoing development for this indication.

Dr Eve’s view was that although the data were equivocal they were certainly an indicator of finasteride’s potential. Mr Thorley says that Professor Russell’s evidence was to the same effect: he expressed misgivings, in his report, about the significance of the Diani results but readily accepted that even if one took the non-responder into account, Diani provided grounds for further investigation. Further, there were reasons to be encouraged that finasteride alone might work.

I do not think that this is a fair characterisation of what Professor Russell actually said. His report does rather more than express misgivings. It is not just that he is concerned about the size of the group; it is also that the dosage used in the finasteride-alone group corresponded, he says, to a dosage of at least 10mg for an adult human male and that Diani did not demonstrate a significant effect in treating MPB even at that dosage. Thus, he says, it could not be expected from Diani that finasteride at a low dosage of 1 mg/day or less would be effective for the treatment of male pattern balding. It is true that, in cross-examination, he accepted that the positive results with 4 monkeys would have been taken into account in deciding on whether to proceed with further investigation. But, in response to questions about Sudduth, he said that the reasons why Sudduth could say that one could be encouraged to think that finasteride might work as a treatment for MPB depended on personal communications that the authors had received from Merck: there was no proven data statistically documented to suggest that finasteride alone would be useful in MPB.

Professor Russell reaches his figures of 10mg per day by reference to Diani where it is explained that this dosage for monkeys was extrapolated from the clinical trial for humans in Rittmaster. This human trial had used oral doses of 10, 20, 50 and 100 mg. This indicates that the authors’ dosage of 0.5 mg for 10 kg monkeys corresponds to 10-100 mg for an adult human male However, as Dr Eve points out, it is not clear how this extrapolation was done but a standard man is typically taken to weigh 70 kg so a straight mathematical comparison would suggest a 0.5 mg dose in a 10 kg macaque to be equivalent to a 3.5 mg dose in a 70 kg man.

Professor Russell was also taken to part of the conclusion in Diani as follows:

In any event, so far as anyone interested in investigating finasteride further is concerned, a possible route forward would have been to undertake a further monkey study for example at higher doses. However, at the end of the day, monkeys are merely an indicator of what happens in humans. The only way of finding out what happens in humans is to test in humans.

Thigpen: This paper was published by Professor Russell’s team and reports data concerning 5α-reductase present in the organs of foetal, newborn and adult humans. Professor Russell summarises it (and his conclusions) this way:

“The data in this paper are more rigorous than those of the slightly earlier Harris paper (which Thigpen cites at reference 32) in that they are derived not only from the pharmacological method used in Harris, ie. pH dependence, but also from an immunological method and a molecular biological method. Thigpen shows developmental expression patterns of the two 5α-reductase isozymes in the liver, skin and scalp. In the liver, the two isozymes had an identical temporal pattern of expression. However, in the skin, the two isozymes differed in their expression patterns. Both were detected in the dermis of neonates through age 3 years; thereafter, expression of both isozymes is extinguished until puberty (around age 15) at which time expression of the type 1 isozyme is induced to high levels (no type 2 isozyme was detected). The finding of the type 1 isozyme in the scalp is surprising given the reported absence of hair loss in type 2 deficient subjects. Thigpen speculates that the pulse of type 2 expression near birth may influence the development of baldness in later life. Thigpen found no qualitative differences in the steady state levels of type 1 reductase in the scalps of balding and non-balding men, nor were there any regional expressional differences detected across the balding scalp. Thus, at the level of resolution afforded by this study, no evidence for abnormal expression of type 1 isozyme as a feature of male pattern balding was found.

Thigpen thus suggests that balding might be treated by a type 1 inhibitor while a type 2 inhibitor is unlikely to be effective in scalp skin (since the data suggested the type 2 isozyme is absent in the adult scalp). In my discussions as a consultant to Merck, I therefore suggested to Dr Ed Scolnick around the time of publication of Thigpen that Merck should concentrate on developing a type 1 inhibitor for male pattern baldness.”

The short message from Harris and Thigpen according to Professor Russell is that the scalp contains the type 1 not type 2. Professor Russell’s conclusions are however a matter of controversy. As Dr Thornton was at pains to point out, these studies do not tell you anything about which isozyme was to be found, or to be found predominately, in the hair follicle. The tests carried out had been on scalp, and it was not known what part of the scalp had been taken.

Sudduth is a review article published in August 1993 based upon two sources of information: (1) a Medline search of the scientific literature published between 1986 and November 1992 and (2) data supplied by Merck. It does not take account of Harris or Thigpen which came later. The authors explain that the purpose of the exercise was “to assess finasteride’s potential role in the treatment of a variety of DHT-mediated processes”. The introductory passage refers to the phenotypic consequences of DHT deficiency in men as suggesting “potential clinical utility of a 5α-reductase inhibitor drug in the treatment of [BPH], acne vulgaris, [MPB] and prostate cancer”. Finasteride is said to be the first such agent to be marketed commercially. Mr Thorley says that the suggestion that finasteride might have a role in the treatment of these conditions (including MPB) is entirely rational, something accepted by Professor Russell in cross-examination and with which I certainly agree.

Sudduth discusses, in succeeding sections of the paper, the chemistry, pharmacology and pharmacokinetics of finasteride. In the section entitled “Mechanism of Action”, two isozymes of 5α-reductase are described in the following terms:

“In humans, two 5α-reductase isoenzymes have been identified, numbered 1 and 2. Their tissue distribution in humans has not been determined. In the rat model 5α-reductase-1 is in all tissues at very low concentrations, and 5α-reductase-2 is limited largely to the urogenital tract. Finasteride is much more specific to inhibition of 5α-reductase-2 than 5α-reductase-1, although it works with both.”

The statement as to tissue distribution in humans was, according to Mr Thorley, an accurate reflection of the literature on which Sudduth is based (January 1986 to November 1992). Although Professor Russell said that this statement was not correct as at October 1993, he accepted that as at August 1993 relatively little was known about the relative tissue distribution of two isozymes. Indeed, this was the state of knowledge at the time of Thigpen, August 1993, a paper of which Professor Russell was a co-author. As Mr Thorley put it to him, and he accepted, the purposes of Thigpen was to move the state of knowledge forward from “little is known” to “a bit more is known”.

Under the heading “Prostate Cancer”, Sudduth explains that:

“The role of 5α-reductase inhibitors may not be limited to treatment of BPH. [DHT receptors] and 5α-reductase enzyme systems are located in the prostate, as well as in the skin and sebaceous glands. The former may play a major role in prostate cancer, male-pattern baldness, female hirsuitism, and acne. Recent research has focused on finasteride’s potential use in several of these conditions, including prostate cancer and male-pattern baldness; Merck presently has no plans for clinical trials in female hirsuitism or acne”

The bulk of Sudduth is concerned with clinical uses of finasteride, in particular the treatment of BPH and prostatic cancer. But it also includes a section devoted to hair growth. It is somewhat speculative stating:

“Androgens play a role in male-pattern baldness and female hirsutism. Dihydrotestosterone appears to be the active androgen in the balding scalp. Thus, preventing DHT formation by inhibiting 5α-reductase may be a viable treatment option”.

This section also includes a summary of Diani. In the light of Diani, Sudduth concludes as follows:

“Results from this study suggest a role for finasteride in reversing established baldness. It also appears that the combination of finasteride and minoxidil may be more effective than either agent alone. Development of a topical finasteride product would allow local treatment of baldness without significant systemic alteration of androgens. Clinical trials in humans are planned to establish the drug’s role as either single-agent therapy or in combination with minoxidil in the treatment of male-pattern baldness.”

I agree with Mr Thorley when he says that anyone reading Sudduth would therefore appreciate that Merck were conducting research into finasteride’s potential for treating MPB and the skilled person would readily infer that Merck was planning to undertake the clinical trials in question. When I asked Mr Thorley whether it was known by whom the clinical trials in humans referred to in Sudduth were to be undertaken, he answered that it was not stated in the paper but that the deduction must be that it was Merck; Professor Russell volunteered that he agreed with that. Mr Watson has made no comment. I infer that it must have been Merck.

In contrast, the take home message which Mr Watson derives is that topical finasteride might have a role to play in the treatment of MPB. If he is saying that the reference to topical finasteride is to be taken as a rejection of oral finasteride, I would reject the suggestion. The earlier discussion of Diani recognises that oral finasteride formed part of the testing carried out; and the conclusion that results from the Diani study “suggest a role for finasteride in reversing established baldness” cannot be seen as restricted to topical finasteride. Moreover, as I will explain later, there would be good reasons for trialling oral finasteride before trialling topical finasteride even if one was looking to develop a topical treatment.

In that context, it is to be noted that the safety profile of oral finasteride was already well established. Sudduth itself provides information regarding that safety profile. I agree with Mr Thorley when he says that the message could not be clearer – finasteride is extremely well tolerated, even at very high doses:

“The adverse events associated with finasteride are limited and predictable due to its specificity as an inhibitor of 5α-reductase. Unpublished manufacturer reports summarising adverse events in approximately 2500 patients demonstrate the drug’s excellent clinical tolerance and safety profile. Safety experience to date includes single-dose therapy (up to 400 mg), dose-ranging therapy (0.2-80 mg) for 3 months, and 3 years’ experience with the currently approved dosage of 5 mg once/day.

No reports exist in the published literature of finasteride overdose, although in clinical trials patients received single doses as high as 400 mg and multiple doses of up to 80 mg/day for 3 months continuously without any drug-related adverse event.

…

In summary the drug has an excellent safety and tolerability profile. The overall frequency of adverse events is low. Most are sex related and may require discontinuation of therapy in a small number of patients; however these symptoms may be transient, as demonstrated in clinical trials”

Nonetheless, as I have already mentioned, Diani translated (at least in Professor Russell’s analysis) into a human dosage of at least 10mg for an adult. That might have been regarded as an unacceptably high dosage for an essentially cosmetic treatment. Perhaps that is why we find this in Diani itself:

“In the current investigation, finasteride was administered orally to insure delivery and replicate the depression of serum DHT that was reported in clinical trials. It would be prudent to develop a topical formulation to target the drug to the skin, thereby lowering DHT in the hair follicle without systemic alteration of androgens”.

Mr Watson submits that the level of DHT in the circulation is not indicative of the level of DHT in any particular target organ. As such, it is not possible to predict the effect of finasteride on inhibition of 5α-reductase and hence DHT levels in the scalp in contrast with the prostate. He relies on Gormley 1992 concerning the PROSCAR clinical trial (which is also referred to in Sudduth, but which Dr Eve did not rely upon), which he submits indicated that in BPH a 5mg dose was superior to a 1 mg dose, not withstanding that both reduced serum DHT levels to the same extent. Thus the fact that a dose reduces serum DHT levels cannot be taken as an indictor of likely efficacy in the target tissue.

Dr Eve expressed his view that changes in serum level of DHT are a good indicator of changes in tissue level in the prostate. He supported that view by reference to McConnell; and it was accepted by Professor Russell that McConnell did support that view. In addition, other workers including Rittmaster together with Merck itself were measuring serum DHT as an indicator of the effect of finasteride in suppressing 5α-reductase. There is nothing in the Rittmaster, Gormley or McConnell to suggest that the levels of DHT in a tissue would not be reduced by administration of oral finasteride.

Further, he receives a rather different message from Gormley 1992 from that which Mr Watson detects. Dr Eve reads the paper as showing that 1 mg/day and 5 mg/day were equally efficacious in terms of objective measures (prostatic volume and maximal urinary flow-rate); the higher dose was chosen on the basis of urinary symptom scores. Dr Eve was firm that it would not have been assumed that Merck arrived at what they believed was the lowest effective therapeutic dose. I prefer Dr Eve’s view.