Mr Justice Warren:
Introduction
- 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
- The Patent specification describes a "method of treating androgenic alopecia with 5α-reductase inhibitors". The actual Claims are as follows:
1. The use of [finasteride] for the preparation of a medicament for oral administration of androgenic alopecia in a person and wherein the dosage amount is about 0.05 to 1.0 mg
2. The use as claimed in claim 1 wherein the dosage is 1.0mg.
3. The use as claimed in claim 1 or 2 wherein the treatment is of male pattern baldness.
Amendment
- 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.
"Swiss form" and medical use
- It will be seen that Claim 1 is in "Swiss form" (for a general description of which see Terrell on the Law of Patents (16th 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 not be 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.
Lack of novelty, industrial application, method of medical treatment
- 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:
a. [Aldous LJ]
"42. ……The Judge was right to conclude that it [Claim 1] was not a claim for a second therapeutic use. The medicaments in question were known to be suitable for treating cancer. The remainder of the claim relates to the way that such a medicament was to be used….
63. In my view the form of claim 1 does not disguise its effect. The invention was the discovery that by changing the treatment from a 24 hour infusion to 3 hours a similar effect was obtained with less neutropenia. That was a discovery that a change in the method of treatment provided the result. The claim is an unsuccessful attempt to monopolise the new method of treatment by drafting it along the lines of the Swiss-type claim when analysed it was directed step by step to the treatment."
b. [Buxton LJ]
In considering second medical use claims, Buxton LJ referred to Wyeth and Schering's Applications [1985] RPC 545; he referred to the court there expressing the question as involving
"The allowability of claims directed to an invention based on the discovery of a second (or subsequent) pharmaceutical use of a known substance or composition, already known for a particular medical use (or particular medical uses), the new use being unconnected with the previously known use or uses" ([1985] RPC 546 at p556 line 24)" (emphasis supplied by Buxton LJ)
and he went on to say this at paragraph 87:
"The novelty of the second medical use, on which its patentability rests, must therefore be found in applications that are new in the terms used in Wyeth and Yew-tree. The novelty cannot lie in the method of use, but in the new therapeutic purpose for which the substance is used."
c. [Holman J]:
"108. I respectfully agree with the analysis by my Lord, Buxton LJ as to the limits of second medical use claims, the validity of which was recognised by the Enlarged Board in Eisai. The conclusion of the Enlarged Board, as expressed in the last paragraph (23) of their decision, clearly refers to "a specified new and inventive therapeutic application". So there must be a therapeutic application or purpose which is not only inventive but new……
109. In the present case, however, the drug, taxol, is exactly the same; the method of administration, by injection and infusion, is exactly the same; and the therapeutic application or purpose, namely the attempt to treat cancer, is exactly the same. The only difference is the discovery that if the drug is infused over a short period an undesirable side-effect, neutropenia, is less than it otherwise would be, whilst the therapeutic effect remains. No "previously unrecognised advantageous properties in the chemical compound have been discovered". All that has been discovered is that if the compound is administered over a shorter period, one of its disadvantageous side-effects will be less than it otherwise would be."
Lack of Novelty
- 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 211-13). 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.
Industrial application and method of treatment
- 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 1/5th 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.
Conclusion on second medical use and the Swiss form claim
- 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.
Obviousness
- 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.
The witnesses
- 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:
a. Identify the inventive concept embodied in the patent in suit.
b. Assume the mantle of the normally skilled but unimaginative addressee at the priority date imputed with the common general knowledge.
c. Identify the differences between the matter cited as "known or used" and the alleged invention.
d. Ask 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.
And see discussion in Terrell at paragraph 7-53ff.
- 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:
a. Obviousness is a question of fact. The primary evidence is that of properly qualified experts. All other evidence, such as, for example what persons in the art did or did not do, is secondary to that primary evidence.
b. The primary function of the expert witnesses is to educate the court in the technology – they come as teachers, as makers of the mantle for the court to don. It is permissible for the expert to opine on the 'ultimate question' ie whether or not the invention is obvious. However such conclusions in themselves are of little value. What matters are the reasons for the opinion. See Technip France SA's Patent [2004] RPC 46 at paragraphs 12-16.
c. Whether or not the invention is obvious involves taking into account a number of factors, for instance the attributes and common general knowledge of the skilled person, 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.
d. The skilled person is deemed to look at and read publicly available documents, however obscure they may be. He never misses the obvious, nor stumbles upon the inventive. He is deemed to be interested in the prior art, even if a real worker in the field would not be. This reflects the policy of the law, that anything which is obvious over what is available to the public cannot be the subject of valid patent protection. See Pfizer Ltd's Patent [2001] FSR 16 at paragraph 62 per Laddie J. Providing that the route in question is obvious, the claim is invalid. See Brugger v Medic-Aid Ltd [1996] RPC 635 at 661.
- 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.
The skilled addressee
- 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
- "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:
a. Luxmoore J in British Acoustic Films Ltd .v. Nettlefold Productions (1936) 53 RPC 221 at p 250 – cited with approval by the Court of Appeal in General Tire & Rubber Co v Firestone Tyre & Rubber Co Ltd [1972] RPC 457 at 482:
"In my judgment it is not sufficient to prove common general knowledge that a particular disclosure is made in an article, or series of articles, in a scientific journal, no matter how wide the circulation of that journal may be, in the absence of any evidence that the disclosure is accepted generally by those who are engaged in the art to which the disclosure relates. A piece of particular knowledge as disclosed in a scientific paper does not become common general knowledge merely because it is widely read, and still less because it is widely circulated. Such a piece of knowledge only becomes general knowledge when it is generally known and accepted without question by the bulk of those who are engaged in the particular art; in other words, when it becomes part of their common stock of knowledge relating to the art. Whatever else common general knowledge may be, it has never in my judgment included public knowledge of particular documents, reports or scientific papers and the like…..It is certainly difficult to appreciate how the use of something which has in fact never been used in a particular art can ever be held to be common general knowledge in the art".
That passage was accepted by the Court of Appeal in Beloit Technologies (see next paragraph) with the reservation for further consideration:
"whether the words "accepted without question" may not be putting the position rather high: for the purposes of this case we are disposed, without wishing to put forward any full definition, to substitute the words "generally regarded as a good basis for further action".
b. Aldous LJ in Beloit Technologies Inc v Valmet Paper Machinery Inc [1997] RPC 489 at 494:
"It has never been easy to differentiate between common general knowledge and that which is known by some. It has become particularly difficult with the modern ability to circulate and retrieve information. Employees of some companies, with the use of libraries and patent departments, will become aware of information soon after it is published in a whole variety of documents; whereas others, without such advantages, may never do so until that information is accepted generally and put into practice. The notional skilled addressee is the ordinary man who may not have the advantages that some employees of large companies may have. The information in a patent specification is addressed to such a man and must contain sufficient details for him to understand and apply the invention. It will only lack an inventive step if it is obvious to such a man."
c. Laddie J in Pfizer at paragraph 66 where he drew attention to the circumstances in which the common general knowledge of the skilled man would cause him to indulge in some form of literature search as a result of reading the prior art document in question:
"When any piece of prior art is considered for the purpose of an obviousness attack, the question asked is "what would the skilled addressee think and do on the basis of this disclosure?". He will consider the disclosure in the light of the common general knowledge and it may be that in some cases he will also think it obvious to supplement the disclosure by consulting other readily assessable publicly available information".
d. Jacob LJ in SmithKline Beecham plc v Apotex Europe Ltd [2004] EWCA Civ 1568, [2005] FSR 23 at paragraph 96 when he stated:
"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 to do is to just link one piece of art with another, unless so to do would itself be uninventive."
A mosaic is permissible but it must be one which the skilled person can put together with no invention.
- I consider that the approach of Mr Thorley and Mr Acland is established by these dicta.
Technical not commercial obviousness
- 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] RPC 26 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.
The published material and the experts' comments
- 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:
a. "Imperato-McGinley": Imperato-McGinley et al., Steroid 5α-reductase deficiency in man: An inherited form of male pseudohermaphroditism, Science, 186, 1213-1215 (1974)
b. "Rittmaster": Rittmaster et al., Effect of MK-906, a specific 5α-reductase inhibitor, on serum androgens and androgen conjugates in normal men, Journal of Andrology, 10, 259-262 (1989)
c. "McConnell": McConnell et al., Finasteride, an inhibitor of 5α-reductase, suppresses prostatic dihydrotestosterone in men with benign prostatic hyperplasia, Journal of Clinical Endocrinology and Metabolism, 74, 505-508 (1992)
d. "Andersson": Andersson et al., Deletion of steroid 5α-reductase 2 gene in male pseudohermaphroditism, Nature, 354, 159-161 (1991)
e. "Jenkins": Jenkins et al., Genetic and pharmacological evidence for more than one human steroid 5α-reductase, Journal of Clinical Investigation, 89, 293-300 (1992)
f. "Itami": Itami et al., Characterization of 5α-reductase in Cultured Human Dermal Papilla Cells from Beard and Occipital Scalp, The Journal of Investigative Dermatology (1990)
g. "Harris": Harris et al., Identification and selective inhibition of an isozyme of steroid 5α-reductase in human scalp, PNAS, 89, 10787-10791 (1992)
h. "Diani": Diani et al (Upjohn Laboratories) published in 1992 Diani et al., Hair growth effects of oral administration of finasteride, a steroid 5α-reductase inhibitor, alone and in combination with topical minoxidil in the balding stumptail macaque, The Journal of Clinical Endocrinology and Metabolism, 74, 345-350 (1992)
i. "Sudduth": Sudduth and Koronkowski, Finasteride: The First 5α-reductase Inhibitor, Pharmacotherapy, 13, 309-329 (1993)
j. "Thigpen": Thigpen et al., Tissue distribution and ontogeny of steroid 5α-reductase isozyme expression, Journal of Clinical Investigation, 92, 903-910 (1993)
k. "Gormley 1990": Gormley et al., Effects of finasteride (MK-906), a 5α-reductase inhibitor, on circulating androgens in male volunteers, Journal of Clinical Endocrinology and Metabolism, 70, 1136-1141 (1990)
l. "Gormley 1992": Gormley et al., The Effect of Finasteride in Men with Benign Prostatic Hyperplasia, The New England Journal of Medicine (22 October 1992)
m. I refer to some of these papers in the Annex to this Judgment. There are also a number of other papers which were put to Dr Thornton in cross-examination and which I also deal with in the Annex. Further, I was referred to some confidential material which I do not need to identify.
- 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.
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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:
"Therefore, retardation of the conversion of testosterone to DHT by 5 alpha-reductase inhibition seems to be not only an additional mechanism to stimulate hair regrowth, but also a potential conjunctive therapy to minoxidil as a remedy for male-pattern baldness."
He accepted that the take-home message from these authors is that you should be looking at both finasteride on its own and as a combination with minoxidil.
- 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.
Application of the legal principles in the present case
Skilled addressee
- The first issue is the identity of the skilled addressee. It is clearly a team. The patent itself is described, as I have said as a "method of treating androgenic alopecia with 5α-reductase inhibitors".
- Actavis' opening skeleton argument contained a brief description of the addressee of the Patent comprising a team of people with an interest in the treatment of androgenic alopecia using finasteride. The team would have included (amongst others) a clinical pharmacologist and a physician or scientist with a background in and/or knowledge of androgenic alopecia.
- In its closing submissions, this had been fleshed out in more detail. The team must have knowledge both in relation to androgenic alopecia and in relation to 5α-reductase inhibitors, of which finasteride was the only one which had been the subject of regulatory approval. The skilled team would have known that any method of treatment of the human using a drug such as a 5α-reductase inhibitor would require regulatory approval prior to being launched and that in order to obtain such approval, clinical trials would have to be conducted. The team must therefore contain scientists skilled in 5α-reductase inhibitors, androgenic dependent hair follicles and MPB. The team would also contain someone skilled in designing and conducting clinical trials.
- Mr Thorley points out that the Patent acknowledges that finasteride was already on the market at the priority date and had also been disclosed as being useful for treating androgenic alopecia. The alleged invention resides in determining the "lowest possible dosage" and thus comprises the use of finasteride to treat androgenic alopecia according to that particular dosing regimen. Accordingly, the relevant art ought to be characterised by reference to finasteride, and likewise the relevant skilled person. He submits that the skilled person would not include someone with the detailed knowledge of 5α-reductase possessed by Professor Russell.
- Merck's case is this:
a. The skilled person in this case is a team of people seeking to treat androgenic alopecia. A key person in this team would have been someone with knowledge of the biological pathways leading to androgenic alopecia, in particular 5α-reductase (and its isozymes), the role(s) it played and its inhibitors (including finasteride). Such views are essential for setting the direction of the skilled team. Reliance is placed on what Professor Russell had to say about this: he believed that the skilled addressee would be a team of people seeking to treat androgenic alopecia in a person. Given what was known about androgenic alopecia, he believed the team would have included someone with knowledge of 5α-reductase.
b. The scientist who understands the mechanism of action of MPB and 5α-reductase would plainly have a crucial role in setting the direction of the skilled team. He or she is the person who would most likely understand that which is most likely to be efficacious. Consistent with this was Actavis' late decision to call Dr Thornton to reply to Professor Russell's evidence as to the relevant common general knowledge.
c. Actavis' case, it is said, is that the hypothetical team is one looking to treat MPB with oral finasteride. Consistently with this Dr Eve's expert report is premised upon a decision having already been made to trial oral finasteride for MP. By assuming the team has already decided to opt for finasteride as the proposed treatment, Actavis has missed out a crucial part of the obviousness case they must establish. It is submitted that to get its case off the ground, it must be shown that it was obvious (a) to decide to research the use of finasteride further and (b) to conclude it was worth investigating low doses of oral finasteride. To assume that the decision to go forward with finasteride has been made is missing out a vital part of what Merck says is the inventive step. In relation to that, the real question, it seems to me, is point (a) at a dose of 5mg daily since, if it is decided to trial finasteride at doses of 5mg daily it is accepted that lower doses would also have been trialled.
- I am not sure that there is really a great deal of difference between these approaches. The important point is that the team includes the scientist knowledgeable in 5α-reductase, although I accept that it would not include a person with the unrivalled knowledge and insight of Professor Russell (or, at least, if he is there, he will have lost his talents of imagination). It does not matter whether that is because any team interested in the treatment of androgenic alopecia would contain such a person or because the Patent is directed at treatment of MPB with finasteride. I do not think it correct on either approach to regard the skilled team as one looking to treat MPB with finasteride. As Mr Watson points out, to identify the skilled team in that way is almost to answer the question of obviousness: it is obvious that a team whose agenda is to treat MPB with finasteride would carry out trials and reach the invention. But that is to beg the question whether it would be obvious to the skilled team – that is to say a team with the knowledge of the skilled person in the treatment of androgenic alopecia and in the use of 5α-reductase – actually to trial oral finasteride to treat MPB even at a dose of 5mg per day.
Common general knowledge
- Both Actavis and Merck have set out in their closing submissions what they say the state of common general knowledge was at the priority date. I set each of them out in full because it not only identifies the areas of disagreement, but also displays some differences of emphasis on what is, almost, common ground.
- Actavis identifies the following as common general knowledge:
a. DHT is the mediator of a number of androgenic conditions, including BPH and androgenic alopecia.
b. Hair follicles in the occipital region of the scalp are not affected in androgen dependent male pattern balding whereas hair follicles in other areas of the scalp such as the frontal region and crown/vertex are (subject to genetic predisposition).
c. DHT is derived from testosterone by the action of 5α-reductase.
d. It had recently been established that there are two isozymes of 5α-reductase, called type 1 and type 2. In the prostate the predominant enzyme is type 2. Any differences between the tissue distribution of the two isozymes was the subject of ongoing research.
e. Finasteride is a potent inhibitor of 5α-reductase – primarily a type 2 inhibitor in humans.
f. Finasteride was known to be effective in the treatment of BPH and was known to lower serum and intra-prostatic levels of DHT.
g. In administering any pharmaceutical, it was desirable to administer the lowest possible effective dose.
h. The nature of pre-clinical and clinical trials: nothing now turns on this.
- Merck identifies the following as common general knowledge:
a. There were two isozymes of 5α-reductase, known as type 1 and type 2.
b. The type 2 isozyme was present in prostate and was associated with BPH. BPH could be treated with a 5 mg/day dose of finasteride, which successfully lowered serum and intra-prostatic DHT.
c. The type 1 enzyme was around 100 times less inhibited by finasteride than the type 2 isozyme.
d. 5α-reductase from different species were not directly comparable.
e. Maximum reduction of the type 2 isozyme with finasteride led to a serum DHT concentration of about 20% initial concentration. It was not reduced to zero.
f. The macaque model of balding was the best available, but it was not perfect.
g. At the priority date, and indeed for a period of time thereafter, those actually working in the art thought that it was the type 1 in the scalp that was the relevant enzyme and that inhibitors of type 1 were what was needed to treat MPB.
- The main areas of dispute, it can be seen, are therefore over the extent to which the tissue distribution of the type 1 and 2 isozymes was common general knowledge, the relevance of that distribution and whether such distribution was subject to ongoing research. In this context, it is accepted by Actavis that the skilled person would be aware of Harris and Thigpen and would have read them. Indeed, Dr Thornton accepted that Harris and Thigpen would have attracted a lot of attention at the time they were published and would have been read with interest by those in the field. She also accepted that anyone interested in 5α-reductase would have been expected to know about them by October 1993. She also accepted that it was "certainly clear" that type 1 was present in the scalp whole tissue including the balding scalp although she said that there was little evidence to suggest which isozyme was present in the hair follicle.
- There is considerable disagreement about what it is proper to derive from Harris and Thigpen. Mr Watson says that the clear teaching in Harris and Thigpen is that type 1 was the predominant enzyme in the scalp and that Actavis' case comes down to the point that the skilled person would have a lingering residual doubt that there might still be very small amounts of type 2 present which might be important for MPB. He submits that all the contemporaneous evidence establishes that the views in Harris and Thigpen were generally accepted and that the lingering doubts postulated by Dr Thornton did not in fact exist as a matter of common general knowledge. In cross-examination Dr Thornton was taken to 9 papers, each of which referred to Harris and Thigpen without reservation. I consider those papers separately in the Annex to this judgment.
- Merck say that the cumulative weight of all these papers leads to only one conclusion: at the priority date, and indeed for a period of time thereafter, those actually working in the field thought that it was the type 1 in the scalp that was the relevant enzyme and that inhibitors of type 1 were what was needed to treat MPB. In other words, the skilled person would assume (wrongly) that finasteride would not be an effective treatment for androgenic alopecia and thus lead him to reject such invitation as can be found in Sudduth to investigate the use of finasteride for such treatment.
- On that basis, I am invited to conclude that Dr Thornton's views as to (i) her concerns over the methodology of Harris and Thigpen as regards taking whole skin samples and (ii) the continuing importance of type 2 based upon the 1974 Imperato-McGinley paper were not part of the common general knowledge for the following reasons:
a. None of the papers referred to above published after Harris and Thigpen questioned that type 1 was the relevant isozyme present in the balding scalp. To the contrary, many of them proposed the use of type 1 inhibitors for treating MPB.
b. Dr Thornton was not able to point to a single paper, published before or after the priority date (until Bayne et al in 1999, another Merck paper), which suggested that there was a question whether type 2 remained relevant; nor could she point to any paper which suggested that the approach of Harris and Thigpen was flawed because they had looked at the whole skin as opposed to hair follicles. That she, and possibly others, may have suspected that type 2 had a part to play may be so. But nothing was published until 1999. And she accepted that she could not answer the question of who was looking for type 2 in 1993 in the balding scalp unless it was published.
c. Further, Mr Watson says that her suggested theory that type 2 was to be found in the dermal papilla, extrapolating from Itami's work on dermal papilla cells in the beard, was tenuous and speculative. It is certainly her view that it had not been demonstrated that the dermal papilla contained type 2.
- Mr Watson does not, in any case, accept that the teaching of Sudduth, Diani and Gormley 1990 renders the Patent obvious.
- I now turn to how Mr Thorley deals with Mr Watson's submissions (and Professor Russell's conclusions) on Harris and Thigpen.
- Mr Thorley then says that, in considering Thigpen and Harris one should begin with Itami. This paper would, it is accepted, have been picked up in any literature search. I have already mentioned that Itami shows that the 5α-reductase present in dermal papilla cells from androgen dependent beard follicles was similar to that found in the prostate but dissimilar to that present in dermal papilla cells from the non-androgen dependent follicles of the occipital scalp. Dr Thornton explained this in her report and Professor Russell accepted in cross-examination that this was an interesting piece of information because the beard was known to be androgen responsive. But, as I have just mentioned, Dr Thornton accepted that it was not demonstrated that type 2 was present in the scalp.
- Professor Russell's experience of working with 5α-reductase was that the DHT diffused rapidly out of the cell. He therefore questioned whether the relevant enzyme was in the dermal papilla as opposed to some other cell type. Nonetheless, he did appreciate that in looking at the skin a whole, one would be looking at more than one cell type, but which cell type was responsible for making the DHT effective in MPB would not be known until the experiments were carried out.
- It must be remembered in this discussion that Itami dated from 1990. Even if, contrary to Mr Watson's submissions, the teaching of Sudduth read with Itami supports Mr Thorley's submissions, Actavis still needs to meet the case that Harris and Thigpen brought about a change in the common general knowledge as of October 1993.
- Harris and Thigpen would have been read by those skilled in the art (a proposition which is not controversial); that does not, Mr Thorley says, mean that the whole contents of the papers formed part of the common general knowledge nor that the conclusions which Professor Russell thought would be drawn from the papers were in fact the conclusions that would be drawn by the skilled addressee. He argues this way:
a. First, he refers to Dr. Thornton's reports where she says this:
"I can recall having such concerns [ie the usefulness of the scalp samples actually used in the studies] at the time and did not believe it was possible to draw any firm conclusions from them about the isozyme type expressed in the hair follicle and specifically the dermal papilla."
That Dr Thornton had some uncertainties I do not doubt. But she never published them nor is there any evidence that she discussed them with her peers at conferences and the like, as appears more fully from the discussion of the papers in the Annex to this judgment.
b. This uncertainty is in fact acknowledged in the papers themselves. In Harris, the authors specifically refer to the limitations on their current work because of the crude nature of the enzymes and expressly draw attention to the fact that the enzyme present in the dermal papilla cells of the beard resembles the prostatic reductase (type 2) whilst the enzyme present in the occipital scalp is similar to the scalp reductase described in the paper (type 1) and conclude: "Additional studies are required to fully characterise the skin reductase(s)". Further, as Professor Russell accepted, Harris suggests that further investigations should be carried out into the dermal papilla of the occipital and frontal follicles
c. On the basis of this teaching it cannot be suggested that the background knowledge of the skilled team was that androgenic alopecia was caused by type 1 rather than type 2.
d. In Thigpen (a paper of which Professor Russell is credited as a co-author), there was an acceptance (as Mr Thorley correctly states) that the type 2 isozyme might be an initiating factor in the development of male pattern baldness. Further, the paper accepted that little was known about the relative tissue distribution and developmental expression patterns of the 2 5-a reductase isozymes. The Discussion is replete with speculation. It states that at the level of resolution afforded by the studies no evidence for abnormal expression of the type 1 isozyme as a feature of male pattern baldness was found.
e. The most that can be said to be common general knowledge about tissue distribution was that it was an area of ongoing research as to which, at October 1993, no conclusions could be drawn in relation to the effect of either type 1 or type 2 on androgenic alopecia. In September 1993, Professor Russell submitted a paper which referred to Harris and Thigpen. It did not say unequivocally that type 2 should no longer be a focus of attention for the treatment of MPB. Indeed, he accepted in cross examination that it was not clear and that reasonable men could differ on their preferences.
f. Accordingly to Mr Thorley, Professor Russell accepted that one take home message of Thigpen was "watch this space". However, although it is true that he agreed that a message was indeed "watch this space", it is clear from reading the transcript and the relevant part of Thigpen that the space Professor Russell thought was being referred to was directed at something rather different from the implication of type 2 in MPB.
g. Professor Russell accepted that although inhibitors of the type 1 isozyme were a possible drug target, this was not to the exclusion of the possibility that the type 2 was also a possible drug target. This reinforces the correctness of the conclusion set out above on common general knowledge of tissue distribution.
h. So far as concerns Diani, whether or not this was common general knowledge is irrelevant since everybody accepts that on reading Sudduth, the skilled team would review Diani. The take home message from Diani however is not as recorded by Professor Russell in his report where he said this:
"Oral administration of finasteride at around 0.5 mg/day in an estimated 10 kg macaque, a balding animal model, in combination with topical minoxidil had been shown by Diani in a single experiment to increase hair weight more significantly than minoxidil alone. The data for administration of finasteride alone were not conclusive. The combination of topical minoxidil and oral finasteride was thus more promising."
i. Rather, according to Mr Thorley, the take home message included, as indicated in the abstract, that:
"finasteride increased hair weight in 4 out of 5 monkeys"
j. Indeed Professor Russell himself accepted in cross-examination that Diani provided grounds for further investigation of finasteride alone.
k. It is worth remembering, I would add, that all these issues arise in the context of what was recognised as something of a puzzle. In addressing Thigpen in cross-examination, Professor Russell was asked whether he was surprised to find type 1 present in the heads of potentially balding and potentially non-balding men and answered that he was surprised. When asked whether this did not indicate that type 1 was not playing a part in MPB he replied in this way:
"No. It illustrated the conundrum that you referred to earlier, and that was on the one hand you had the genetic results arguing that it should be type 2, and on the other hand we had strong biochemical and immunochemical data saying that type 1 was the major enzyme in the skin. That to us was hard to explain."
One sees in that reply the assumption, which Mr Watson says was indeed the common general knowledge, that the skin was perceived as the appropriate focus; in other words, that it was enzyme levels in the skin which would have to be reduced if an effective treatment for MPB was to be found.
Obviousness
- The central question, so far as concerns obviousness, is whether it would have been obvious to embark on trials involving the oral use of finasteride at a dosage of 5mg per day. In the light of Mr Watson's acceptance that a trial at 5mg per day would have led to a trial at smaller dosages, it is not necessary to start with the question whether it would have been obvious to start with trials at the smaller dosage indicated in the Patent.
The Windsurfing Approach
- The inventive concept, it is common ground, is the use of oral finasteride at between 0.05 – 1.00 mg per day to treat androgenic alopecia . The common general knowledge can be derived principally from Sudduth read with Diani and taking into account Harris and Thigpen.
- Mr Thorley puts forward the following formulation of the difference between Sudduth and the inventive concept of Claim 1:
"Sudduth teaches that finasteride is a promising treatment for androgenic alopecia. The difference between this and the inventive concept of claim 1 of the Patent is the discovery that oral finasteride is an effective treatment for androgenic alopecia at doses of between 0.05 – 1.0 mg per day."
- Mr Watson would rewrite that as follows:
"Sudduth suggests that topical finasteride at an unstated dosage may be a treatment for androgenic alopecia and suggests that the most promising treatment is a combination of finasteride and topical minoxidil. The difference between this and the inventive concept of claim 1 of the Patent is the discovery contrary to the common general knowledge at the priority date that oral finasteride is an effective treatment for androgenic alopecia at doses of between 0.05 – 1.0 mg per day
- Insofar as Mr Watson submits that it was common general knowledge at the priority date that oral finasteride was not an effective treatment for MPB at any dosage, I do not accept that that was so, at least ignoring Harris and Thigpen. The best evidence was, as Mr Thorley says, from Diani, which certainly did not prove that it was not an effective treatment. There is, however, something in Mr Watson's point that Sudduth suggests that the most promising treatment would be a combination of finasteride and minoxidil. I do not, however, think that he is correct is restricting that to topical finasteride. Moreover, even if one was to investigate the effectiveness of the combined treatment, it is clear from the evidence of Dr Eve (which I accept on this point) that one would carry out trials of oral finasteride on its own if for no reason other than to establish the effect, by itself, of each component of the proposed combination. Professor Russell agreed that, in relation to the combination therapy, there would first be a clinical assessment of the individual components by themselves so as to test for possible synergies. One would therefore reach the invention.
- Moreover, even if one were to investigate a combined treatment because that was regarded as obvious, it would not follow that investigation of finasteride alone would not also be obvious. There can be more than one obvious route.
- The fourth step in applying the Windsurfing approach is to ask whether viewed without any knowledge of the alleged invention, the differences constitutes a step which would have been obvious to the skilled man or whether it requires any degree of invention. Mr Thorley says not, for the following reasons:
a. The teaching of Sudduth that finasteride is a promising treatment for androgenic alopecia is entirely rational and is based upon sound scientific principles and the data referred to in the paper, in particular:
i. Finasteride is a potent inhibitor of 5α-reductase. The latter converts testosterone to DHT.
ii. Androgenic alopecia is mediated by DHT as is BPH.
iii. Oral finasteride is an existing treatment for BPH.
iv. Finasteride is exceptionally safe and well tolerated.
v. Oral finasteride appeared to promote hair growth in balding stumptail macaques.
b. In these circumstances an obvious, if not the obvious course of action, would have been to undertake clinical trials in humans to determine whether finasteride was effective against androgenic alopecia.
c. The fact that Merck was planning to undertake such trials would indicate to the skilled man the worth of trying finasteride himself as a treatment for MPB. As Professor Russell pointed out "They [the authors of Sudduth) are extrapolating from personal communications they got from Merck. I do not know what they were, but the mere fact that Merck were pursuing finasteride by itself would be an indication that that would be the thing to do."
d. Dr Eve explained (and I accept his evidence on this) that, having regard to the previous trials in relation to BPH, the clinical trial in question (assuming, I add, that a decision has been made to commence the investigation at all) would be Phase II study lasting around 6 months and involving patients with MPB of a defined severity. In terms of dosage amounts, he would have used an oral dosage form and would have tested 5 mg/day (the dose licensed for BPH), 1 mg/day and a lower dose of 0.2-0.5 mg/day. As is acknowledged in the Patent, it is desirable to administer the lowest possible dose and still maintain therapeutic efficacy. This is particularly true for the treatment of a condition such as MPB which is generally regarded as cosmetic. As Professor Russell acknowledged, for a cosmetic condition such as MPB, there is little incentive to develop new treatments if they also cause unacceptable side effects eg loss of sexual function: in relation to finasteride as a possible treatment for MPB, the attraction was that if it worked, it could be used without impairing sexual function.
e. The clinical trial for testing finasteride would be relatively short in duration and inexpensive because the drug already had a product licence and thus there would be no need to carry out animal or Phase I human trials.
f. In the light of Sudduth, it was obvious to investigate whether finasteride was effective against androgenic alopecia. Whilst a combination therapy (topical minoxidil together with oral finasteride) was a possible option, oral finasteride alone was equally, if not more attractive according to Dr Eve's evidence. Professor Russell's evidence was to the same effect – the take home message from Diani is to look at both finasteride on its own and as a combination. Oral finasteride would have scored very highly in terms of confidence in safety (because the drug was already on the market) and medium confidence in terms of rationale (absence of balding in pseudo-hermaphrodites and Diani).
g. In relation to the combination therapy, this would involve first a clinical assessment of the individual components by themselves so as to test for possible synergies (a point which I have already mentioned). Thus even if one opted for the combination, the efficacy of an oral dose of finasteride would inevitably reveal itself.
h. In terms of technical contribution to the art, it was already known that oral finasteride was useful for treating androgenic alopecia. The Patent properly acknowledges that it is desirable to administer the lowest possible dose and still maintain therapeutic efficacy. There is no teaching in the Patent as to any special way of testing the efficacy of lower dose finasteride – the methodology is entirely conventional ie treat for 6-12 months and see whether it works. Accordingly the alleged technical contribution to the art comprises no more than the consequence of Merck having done that which was obvious (testing low dose finasteride) in an obvious way (clinical trials using patients suffering from male pattern baldness).
- It has been suggested that, assuming trials were to go ahead at all, they would be of a topical formulation in preference to an oral formulation. I reject any such suggestion. At the very least, trials of an oral formulation would not be excluded. There are strong pointers to that conclusion. In particular:
a. Dr Eve's evidence shows that in circumstances where (i) there is an existing oral formulation which is shown to be safe and (ii) the pharmacokinetics are reasonably well understood and acceptable for oral use, it is very common to look at the proof of concept (ie see whether it works) rather than the trying to develop an alternative formulation.
b. The possibility of side effects caused by systemic finasteride would not have been a real concern given that the literature on BPH shows that adverse events are relatively uncommon, relatively minor and reversible, as Dr Eve explained in cross-examination. He also explained that developing a topical formulation might be a reasonable step to take at a later stage but first of all one would want to know whether or not finasteride has the desired effect; it would be a quick and easy first step. I accept his explanations.
c. Dr Eve gave further reasons for starting with an oral formulation, which again I accept as valid. For example it is frequently the case that topical administration does not achieve the same effect as oral administration; development of a topical formulation requires a limited amount of additional animal testing; and if the topical route did not work, the time effort and money involved in the development of the formulation would have been wasted. Further, as Professor Russell accepted, the benefit of an oral dose is that it ensures constant delivery of a given amount of drug whereas a topical administration is inherently more variable
- I have already looked at Itami, Harris and Thigpen in some detail. Mr Thorley's position is that it cannot be suggested on the basis of these papers that the background knowledge of the skilled team was that androgenic alopecia was caused by type 1 rather than type 2. But if that is putting matters too high, he says that, at best, Thigpen teaches that for treating DHT-mediated conditions, consideration should be given to the inhibition of both isozymes as well as one or the other. That message was confirmed by his cross-examination of Professor Russell. Further, as Professor Russell confirmed, Thigpen was not (nor would it have been understood to be) a definitive statement as to the role of the type 1 isozyme in MPB.
- Mr Thorley's submission in more detail is that these papers do not present a clear picture about the distribution of the two isozymes in the scalp, let alone the region of the scalp that matters ie the frontal area and crown/vertex. He submits that, if the skilled person had read Harris and Thigpen in October 1993, he would have concluded as follows:
a. The scalp appeared to contain type 1 enzyme. Although type 2 had not been found in the scalp, its presence had not been ruled out, as Professor Russell accepted.
b. The expectation was that the type 2 isozyme would have some function in terms of MPB because of its association with male pseudohermaphroditism. This was another proposition with which Professor Russell agreed although I must observe this was in relation to an earlier time, in late 1991.
c. The presence of type 1 as the predominant isozyme in the scalp was a conundrum since it had previously been thought that type 2 was associated with hair loss. The implications in terms of baldness were not clear.
d. Dr Thornton said that there was no clear evidence that the type 1 isozyme was expressed in the hair follicle and there were good grounds for thinking that male androgen dependent hair follicles might well be mediated by 5α-reductase type 2. What she said was this:
"As at 1993, whilst one could not rule out the possibility that a type 1 inhibitor would make a possible drug target for the treatment of MPB, there was no clear evidence that type 1 was expressed in the hair follicle. My own thinking at the time was that there were some parallels to be drawn between the prostate and androgen dependent hair follicles in terms of androgen action. This was based partly on the observations of prostate development and male hair distribution in 5α-reductase type 2 deficient men (Imperato-McGinley (1974)).
In addition, a study by Itami et al, had demonstrated that the 5α-reductase present in dermal papilla cells from androgen dependent beard follicles was similar to that found in the prostate but dissimilar to that present in dermal papilla cells from non-androgen dependent occipital scalp follicles.
Taken together these observations provided evidence that the 5α-reductase in the dermal papilla of the balding scalp follicles could also be the same as that present in the dermal papilla of the beard follicles and in the prostate, since all of them are androgen dependent tissues. Accordingly, in 1993 there were good grounds for believing that male androgen dependent hair follicles might well be mediated by the type 2 5α-reductase isozyme."
Some care must be taken with what Dr Thornton says. In particular, her own private, unpublished, thoughts (as these were) do not take the argument about what was and was not common general knowledge any further.
- Mr Thorley nonetheless submits that the only difference between the actual teaching of Sudduth and the knowledge that the skilled man might bring to bear on reading Sudduth in October 1993 lies in the question of tissue distribution of the two isozymes. Sudduth says that the tissue distribution was unknown whereas by October 1993, the matter was the subject of some limited and unproven speculation. The most, he says, that can be said is that this might have caused the skilled team to consider in addition to the plain teaching of Sudduth the possibility of research into a type 1 inhibitor. It does not render inventive following the teaching to investigate finasteride as a potential treatment for MPB. Accordingly, even if this route is followed, the conclusion is no different.
- Mr Watson submits that the Sudduth/Diani/Gormley 1990 combination does not render the use of low dosage oral finasteride obvious for the following reasons:
a. The prior art relied upon by Actavis is all prior to Harris and Thigpen (indeed neither Diani nor Gormley refer to types 1 and 2 at all). These papers indicated that type 1 was the isozyme of 5α-reductase present in the scalp.
b. In the light of these papers it would therefore not have been obvious to try to use finasteride, a selective inhibitor of type 2 but a poor inhibitor of type 1, to treat androgenic alopecia. A type 1 selective inhibitor would have been sought, as Eli Lilly did, as explained by Professor Russell in his report and as suggested by Rushton (in 1996). Alternatively a dual inhibitor (ie one that was equally effective at inhibiting type 1 and type 2) would have been tried. In this context, I quote a short part of the cross-examination of Dr Thornton when she was dealing with Harris:
Q. So do you agree that the take away message from this paper, particularly that last paragraph, is that single inhibitors may not be suitable for male-pattern baldness because you can now identify scalp selective, prostate selective, and dual active inhibitors.
A. The tissue you are looking at here is the scalp in its entirety. If you are interested in what is happening in the hair follicle, then you would look at the hair follicle. This is like taking the adrenal gland, the pancreas, thyroid, and mushing it all together and saying that this is an endocrine tissue. It is very difficult to draw a conclusion about what is happening in the hair follicle from this study.
Q. But these authors do draw the conclusion, do they not?
A. Yes, they do.
- Mr Watson then argues as follows (much of this material has already been mentioned but I bring it together here):
a. Dr Thornton repeatedly raised her personal concern over the scalp skin collection method used in those papers. However, this concern was not shared by any of the authors of any of the papers which have been shown to me. Accordingly, Mr Watson says that Dr Thornton's caution over the conclusions that can be taken from Harris and Thigpen regarding the enzyme distribution in the hair follicle itself (as opposed to the scalp in general), is irrelevant since it was not published or shared by others. Further, Dr Thornton's comments that notwithstanding that type 2 had not been detected in the scalp, inhibition of type 2 might still be important in treating MPB are, Mr Watson says, equally irrelevant: Dr Thornton was not able to point to a single paper after Harris and Thigpen where any such reservations were expressed or theories were put forward. A concern, he says, can hardly be common general knowledge if no one has expressed it.
b. The lack of a clear effect of finasteride in Diani would, it is said, have been seen as entirely consistent with this discovery. The results in Diani suggested that oral dosing with finasteride alone had no significant effect on hair growth. It is only if the results of the non-responder monkey are ignored that any effect is seen. However, this is bad science. It should be noted that the equivalent dose would need to be scaled up to a much higher dose.
c. In any event, even if (contrary to the above) finasteride was thought worth trying, topical administration would have been preferred over oral administration. This was the direction suggested in Sudduth in the light of the results in Diani. It is also the suggestion in Diani itself. It is also the route followed by Rushton. Topical administration would provide local delivery of the active agent to the required site of action and would avoid systemic side effects. This is an important factor when considering administering a compound that interferes with the product of the male virilising hormones. Minoxidil, a powerful anti-hypertensive, was applied topically to avoid side effects.
d. In contrast to the results in Diani for oral finasteride alone, a combination of finasteride and minoxidil did have a significant effect on hair growth. A topical combination therapy of minoxidil and finasteride would therefore have presented itself as the best way forward in the light of Diani. However, as it is not possible to correlate results in animal studies to humans, it could not be predicted whether these results would also be seen in humans.
e. If oral administration of finasteride was to be considered, given the view that it was type 1 which was present in the scalp and that finasteride was a poor inhibitor of this enzyme, the dose of finasteride chosen would have been a high one and higher than the 5 mg/day used to treat BPH. This is consistent with Diani, which used a dose of 0.5 mg for a 10 kg macaque. This is confirmed by Rhodes. In the light of the results of Diani, in 1994 Rhodes et al used a higher dose of finasteride.
f. High doses of a drug with potential to produce sexual side effects would be unlikely to be acceptable to the regulators (or patients) for treatment of non-life threatening cosmetic disorders. Dr Eve's evidence was that there would have been significant concerns about the use of the 70mg dose extrapolated from the Rhodes study for an essentially cosmetic application which required many years of administration. I conclude that a trial at that level would certainly not be "obvious to try".
g. Gormley 1990 only provides information as to the serum levels of DHT. These cannot be taken as an indication of the levels of DHT in the scalp or any indication that the doses employed in that trial would be useful to treat androgenic alopecia.
h. In summary, from Sudduth the skilled team would have no expectation whatsoever that 1 mg/day or less oral finasteride would be useful to treat androgenic alopecia in humans. It certainly was not "more or less self evident" (the test in St Gobain) that it would. To the contrary, the signposts were all pointing in a number of different directions. The recent disclosures in Thigpen and Harris (which everyone in the art would have been aware of) clearly indicated the inappropriateness of using finasteride to suppress levels of DHT in the scalp and were confirmative of the failure to achieve significant results referred to in Diani.
i. Further, Professor Russell made the point, which he maintained in cross-examination, that even if some type 2 was present in the scalp, the preponderance of type 1 would mean that type 1 would have to be inhibited in any event, otherwise one source of DHT would be reduced but the other would remain, leaving large quantities to migrate to all areas surrounding the hair follicle.
- Before expressing my conclusions, there is one other matter I would mention. As revealed in Sudduth, Merck was itself carrying out studies in humans. The detail was not in the public domain, nor was any clinical development plan for the treatment of MPB. On the basis of material placed before me Activis submit that experiments on men started in November 1992. This was at a time after the publication of Harris and Thigpen and, in any case, well after the time when Merck would have known about the results of Harris since that was a Merck paper. Mr Thorley asks why, if the work of Harris was going to put any rational person off investigating oral finasteride for the treatment of MPB, did it not put Merck off doing so?
- In that context, he refers to another Merck confidential document (CX4 in the trial bundle) explaining Mercks' own rationale in doing what it did and which resulted in the discovery. In relation to that, I do, of course, bear in mind Mr Watson's submissions about the unhelpfulness of evidence about the rationale for the steps taken by the inventor which may well not assist in explaining whether or not the steps were obvious: see in particular Laddie J in Hoeschst Celanese v BP Chemicals [1997] FSR 547 at p565. In the document to which I have just referred, the authors go back to Imperato-McGinley and, reciting the history of the development of knowledge, state what had for a long time been assumed to be the case, namely that the same enzyme was thought to be present in all tissues. They then say that, more recently, the presence of two forms had been shown to be present in man. A table of tissue distribution shows type 1 as being present in, and type 2 absent from, scalp skin (with a footnote that there is some evidence that scalp skin expressed type 2 especially in early life). There is then further reference to Imperato-McGinley, with the observation that it "suggests the importance of the type 2 isozyme and the contribution of circulating DHT in this clinical condition [MPB]". It is then remarked – and this was surely common general knowledge – that DHT is the androgen necessary for the development of androgenic alopecia.
- Building on that, the rationale for the use of finasteride for the treatment of MPB is therefore based on (1) the biology and pathophysiology of scalp hair follicles (2) the ability of finasteride to suppress serum DHT (3) the absence of baldness in males castrated prior to puberty (4) the absence of baldness in subjects born with an inherited deficiency of 5α-reductase, who lack DHT but have normal or elevated levels of testosterone (5) the prevention of hair loss in a primate model of MPB (stumptail macaque) treated with oral finasteride or topical 4-MA and (6) the excellent safety profile of finasteride. I note that all of this material can be found in the papers which I have already mentioned and was all in the public domain.
- As to that, Mr Watson first adopts Professor Russell's comments in cross-examination. First, the author might be rationalising in reverse. Secondly, the rationale relies in part on information which was not published. Thirdly, the writer already knew the idea worked and "is basically outlining all the positives here and none of the negative". Fourthly, Merck (as opposed to another organisation) had a particular incentive to trial finasteride for MPB. I am not clear what unpublished material is here being referred to. What I observe is clear is that Harris and Thigpen are referred to.
- In any case, Mr Watson says that asking whether the acts were rational (as Professor Russell accepted that they were) is simply the wrong question. What should have been asked is whether Merck's acts (free of non published information) were obvious.
Conclusions
- In my judgment, it would not have been obvious to the skilled team in October 1993 to embark upon trials of oral finasteride as a treatment for MPB. I reach this conclusion for the following reasons.
- Prior to the discovery, or confirmation of the hypothesis, that there was more than one enzyme, it was thought that 5α-reductase had some function in respect to MPB. Once it had become known that there were two isozymes, there was evidence which would have made people think that it was type 2 which was important in this respect because of its association with male pseudohermaphrodism. Prior to Harris and Thigpen, there would have been a case for the further investigation of finasteride following the teaching of Sudduth in particular in the light of Diani. Professor Russell is no doubt correct in sounding the notes of caution which he does. But, so it seems to me, one obvious way forward for a team interested in treating androgenic alopecia and having as a member the scientist interested in 5α-reductase, would, for the reasons given by Mr Thorley, be to trial finasteride. There would have been an expectation of success at dosages well within dosages which would have given no cause for concerns on the grounds of safety. In particular, trialling at 5mg day would have been an obvious course (and that would have led to trialling at lower doses and would have revealed the invention). The reasons for reaching this conclusion are very much the same, therefore, as the rationale which is expressed in the Merck confidential document (CX4 in the trial bundle).
- However, by October 1993, Harris and Thigpen revealed, to put it at its lowest, that the scalp appeared to contain type 1 and that type 2 had not been found in the scalp. Harris and Thigpen cannot be taken as ruling out the possibility of type 2 being found in the scalp, nor as ruling out that type 2 might have some part to play in MPB. The results of the studies indicate that a single inhibitor may not be suitable given the differences in the enzymes. It seems to me to be clear that the message being conveyed (whether or not it is a correct message) is that type 1 is found in the scalp and that therefore a type 2 inhibitor may not be suitable. In other words, Harris and Thigpen assumes that, to the extent that DHT suppression might be a treatment for MPB, it is type 1 which needs to be suppressed.
- The conclusion which I draw from Harris and Thigpen, therefore, is that the authors of those papers considered that, because type 1 is present in the scalp, a type 1 inhibitor is necessary if there is to be an effective treatment of MPB. It may be that a type 2 inhibitor (such as finasteride) has a part to play in such treatment since it may be that type 2 is also present in a relevant way in the scalp. But two things are important to note: first, the perception of the authors was that it was DHT in the scalp which was the problem to be dealt with; and secondly, that Mr Watson must be correct when he says that Mr Thorley's argument fails adequately to deal with the need to inhibit type 1 even if there is also a need to inhibit type 2. In other words, it was not obvious to trial oral finasteride by itself at all let alone in a dose of 5mg per day. It has not been suggested that there was any obvious course for developing a dual inhibitor (ie something which would inhibit both type 1 and type 2). It is not, therefore, possible to argue successfully that the (obvious) trial of a dual inhibitor would have involved the (obvious) trial of finasteride by itself.
- Further, the conclusion which I draw on the totality of the evidence, is that the assumption on which Harris and Thigpen proceeded was generally accepted, namely that it was the presence of DHT in the scalp which had a connection with MPB. Although Dr Thornton explains that she herself had reservations about the results of those papers on the grounds which I have already explained, she did not express the most important of those reservations in any published paper before the priority date or indeed for a considerable time thereafter; in other words, she never put forward the theory on which Mr Thorley bases his argument, namely the importance of the enzyme distribution in the hair follicle rather than the scalp in general and her concerns that DHT levels in the scalp might not be indicative of levels in the hair follicle. Nor did any other paper before the priority date express similar concerns. Harris and Thigpen thus gave rise at least to a very serious doubt that a type 2 inhibitor could be an effective treatment for MPB. I do not consider that Itami was enough to displace that very serious doubt and to make "obvious to try" something which otherwise would not be expected to succeed. I accept that finasteride was a weak inhibitor of type 1. At very large doses it might have been effective against MPB but there is no suggestion that anyone would have thought it worth trying at these large doses which fell so far outside any acceptable treatment dose.
- Although, of course, papers which post-date the priority date cannot form part of the common general knowledge at that date, it is, I think (and in agreement with Mr Watson's submission) relevant that no published papers in the period immediately after the priority date focussed on the importance of the enzyme type to be found other than in the scalp. That is not, of course, conclusive and, in any event, what is common general knowledge might have changed since the priority date. But one would have expected researchers in the field to have mentioned in their published papers the importance of this reservation if they had perceived it to be of importance.
- Further, I agree with Mr Watson when he says that Diani would not have been perceived as inconsistent with the conclusion that a type 1 inhibitor was required. Although Diani, in isolation, might be seen as supporting Actavis' case providing that the non-responsive monkey was ignored, Diani would need to be re-assessed in the light of Harris and Thigpen. It could then be seen that it is in fact inappropriate to ignore the non-responsive monkey: if it is not ignored, the Diani results are statistically insignificant and there is no inconsistency which needs to be explained.
- I do not, however, accept Mr Watson's arguments concerning the preference of trialling topical finasteride over oral finasteride. Nor do I accept his suggestion that a trial of oral finasteride would have had to be carried out at such a high dose as, in effect, to rule out the trial. If it was obvious to trial oral finasteride, it would have been obvious to do so at dosages of 5mg per day and less without the need to trial at the higher dosages of 10mg per day, let alone at 70mg per day.
- I do not consider that Mercks' own rationale for pursuing trials on oral finasteride as a treatment for MPB shows that the course adopted was obvious. I am persuaded by Professor Russell's comments (other than the fourth of them, which carries little weight) that it is unsafe to rely on that rationale as showing obviousness, in contrast with rationality or reasonableness, especially bearing in mind the caution with which an inventor's reasons for reaching the invention must be approached.
- Harris was a Merck paper, and its results were known to Merck well before publication in November 1992. It was in August that the results were communicated for publication and must have been known to Merck some time before that. I do not know, however, whether the decision to start trials had been made before the results were known. But even if they were known before a decision had been made, I do not find it surprising that trials were pursued nonetheless. There could have been many reasons why Merck – which it must be remembered held the Patent on finasteride which had some time to run – would have seen it as logical and rational to investigate its use in the treatment of MPB without it being obvious to do so. Mr Thorley's question "Why did they continue" is not, I think, a lion-killer.
- In summary, Actavis succeeds in its case concerning second medical use but fails in its case on obviousness. The overall position, therefore, is that Actavis succeeds in its claim for revocation of the Patent.
ANNEX
Papers referred to in the Judgment
- Rittmaster demonstrated the effects of finasteride on serum androgens and androgen conjugates in 12 healthy men. Doses of 10, 20, 50 and 100 mg finasteride were given two weeks apart. The results showed that serum DHT levels in normal men were significantly reduced on administration of a 5α-reductase inhibitor. The authors noted that "If 5α-reductase inhibitors are to be used to treat DHT-dependant diseases, it will be important to ensure that tissue DHT levels are suppressed".
- McConnell showed that the amount of DHT in the prostate is ten times higher than the amount of testosterone, which is in contrast to levels of these two androgens in the plasma where testosterone is typically ten times more abundant than DHT. McConnell further showed that administration of finasteride reversed the intra-prostatic testosterone to DHT ratio, driving levels of testosterone to ten times those of DHT.
- Anderssonwas a paper from Professor Russell's laboratory. It shows the existence of at least two 5α-reductases in man. Professor Russell explains that at this point in the early 1990s, it was not known which was the major isozyme in the skin.
- Jenkins reports work carried out at the same time as that reported in Andersson. However, Andersson was published very quickly and Jenkins took longer to appear. Jenkins provides evidence for more than one human 5α-reductase through a series of molecular and genetic studies, without the complete proof shown in the Nature paper. Jenkins notes that it is unknown whether humans are unique in having more than one 5α-reductase and questions what the function of a second enzyme might be.
- Itami demonstrates that the 5α-reductase present in dermal papilla cells from androgen dependent beard follicles was similar to that found in the prostate but dissimilar to that present in dermal papilla cells from non-androgen dependent occipital scalp follicles.
Papers put to Dr Thornton in cross-examination and
Merck's conclusions on them
Frye: 6-Azasteroids: Potent Dual Inhibitors of Human Type 1 and 2 Steroid 5α-reductase
Frye (1993) was a Glaxo paper which cited Thigpen. Dr Thornton accepted that the authors had no problem in concluding from Thigpen that it was type 1 5α-reductase in the skin. Dr Thornton made the point that they did not say that this was the case with the hair follicle in particular: the distinction was not drawn but, as she pointed out, this was because the paper was about the skin, not the hair follicle. Frye appeared in 1993, and although received for publication on 1 October was not published until after the priority date.
Hirsch: LY191704 A selective, nonsteroidal inhibitor of human steroid 5α-reductase type 1
Hirsch (June 1993) is a paper from Eli Lilly. Mr Watson refers to the concluding paragraph, which states:
"…Of particular interest is the treatment of androgenic alopecia (male pattern baldness), which is known to be associated with an increase in DHT production in the scalp…Preliminary immuno-chemical results have indicated that in man, 5α-reductase type 1 is the predominant isozyme in scalp [references to Itami and 'unpublished observations']. If these studies can be confirmed, and if the retention of hair in balding macaques treated with 5α-reductase inhibitors is due to inhibition of this enzyme [references are made to Rittmaster and Diani], then selective type 1 inhibitors such as LY191704 may be useful as therapeutic agents for treatment of male pattern baldness as well as prostatic hyperplasia."
Dr Thornton accepted that the paper is saying that the predominant isozyme in the scalp was type 1 but made the point that Thigpen and Harris had looked at the scalp in its entirety; 5α-reductase is the predominant enzyme in the scalp whole tissue but that does not mean it is the predominant one in the hair follicle.
Rhodes: The Effects of Finasteride (Proscar) on Hair Growth, Hair Cycle State, and Serum Testosterone and Dihydrotestosterone in Adult Male and Female Stumptail Macacques
Rhodes (May/June 1994) is a post-priority document describing the effect of high dose finasteride in the balding macaque. It cited Harris without criticism, and accepted that the scalp tissue in general contained type 1. Mr Watson says, correctly, that Dr Thornton agreed that Rhodes did not take any point that the dermal papilla might be different from the rest of the scalp tissue. She did, however, say that she thought the authors had been very careful to refer to the tissue, scalp skin and not the hair follicle.
Dr Eve was cross examined on Rhodes. He pointed out that Merck was conducting these studies in parallel with the human studies. He was, I consider, correct in this respect for reasons given by Mr Thorley at paragraph 55 of the Closing Submissions on behalf of Actavis.
Neubauer: LY191704 Inhibits Type 1 Steroid 5α-reductasein Human Scalp
Neubauer (1996) is another Eli Lilly paper. Again, Harris and Thigpen were cited without criticism as Dr Thornton accepted. She also accepted that the "best knowledge" available to the authors indicated that a type 1 inhibitor might be useful for treating androgenic disorders in the scalp, and that further studies using such an inhibitor would be worth pursuing. No point was taken by the authors of this paper on the role of the hair follicle.
Ellsworth MK386: a Potent, Selective Inhibitor of the Human Type 1 5α-reductase
Ellsworth (1996) quoted the conclusions in Harris and Thigpen that "The type 1 enzyme is localised in the scalp skin and liver whereas type 2 enzyme is present in the prostrate, epididymis, seminal vesicles and liver". Dr Thornton raised her concern that the paper was not specific as to the site of the scalp samples used in the study. Her concern was that the authors were assuming that everywhere on the scalp is the same.
Schwartz: MK-386, an Inhibitor of 5α-reductaseType 1, Reduces Dihyrotestosterone Concentrations in Serum and Sebum without Affecting Dihydrotestosterone Concentrations in Semen
Schwartz dated from the end of 1996/beginning of 1997. It is a paper coming from Merck. Harris is again quoted without criticism. Dr Thornton agreed that these authors were of the opinion, in 1997, that inhibiting type 1 would be the answer to androgenic alopecia. In response to Mr Watson's point that the authors were still working on the basis that it is the type 1 isozyme which is responsible for androgenic activity such as androgenic alopecia, she drew attention to the fact that the authors had included acne in this; by 1997, it was clear that the sebaceous gland produced type 1; and that the authors had grouped it all together as an androgenic response, whereas the sebaceous gland is a different organ from the hair follicle.
Rushton: Topical 0.05% finasteride significantly reduced serum DHT concentrations, but had no effect in preventing the expression of genetic hair loss in men
Rushton (1996) was given at a symposium attended by Dr Thornton, and later appeared in a book edited by her colleague Valerie Randall. This was the first paper to draw attention to the role of 5α-reductase in the hair follicle itself. The studies in point were carried out using topical finasteride. Dr Thornton was taken to the conclusion of the paper where it was stated:
"With the development of finasteride it was hoped that a specific treatment for genetic hair loss might at last be available. However it now transpires that the enzyme 5α-reductase exists as isozymes, with a type 1 found in the scalp hair follicles and the type 2 form being present in prostrate. Since finasteride was developed as a 5α-reductase inhibitor for BPH, the efficacy of a type 2 inhibitor in genetic hair loss would therefore depend upon the presence of this isozyme (type 2) within scalp hair follicles (to date frequency distributions for the isozymes have yet to be published).
……….
These findings suggest that in individuals in whom hair follicles have little or no type 2 5α-reductase activity, topically applied inhibitors like finasteride are unlikely to be effective. Oral Proscar (5mg finasteride) is also unlikely to be effective unless metabolites with different specificity to 5α-reductase isozymes are produced. We therefore eagerly await the arrival of a type 1 or mixed 5α-reductase inhibitor."
It is not at all clear to me what can be drawn from this paper. Mr Watson points out that the authors of the paper were writing in the context of trying to cure baldness (something Dr Thornton accepted). They seem to assume, in the first paragraph of the conclusion above, that it is type 1 which is found in scalp hair follicles. Whilst it is no doubt true (as is shown by Itami) that this is correct in relation to some scalp hair follicles (the occipital scalp) there is no literature concerning which isozyme is present in the hair follicles of the balding scalp. However, it seems to me that they assume this to be the case, otherwise their conclusions do not make sense (unless they have been carrying out their studies in relation to the occipital scalp, something which seems highly unlikely). And yet, as Dr Thornton points out, it is odd that the authors should be testing finasteride on the balding scalp if it was believed that it was type 1 which was present in the hair follicles found there. Nonetheless, the message one gets from this paper is, I think, that finasteride, whether applied topically or taken orally (at 5mg) is unlikely to be effective in the treatment of generic hair loss; and the reason for this is because type 1 is believed to be present in the relevant target hair follicles.
Iehlé: Human Prostatic Steroid 5α-reductase Isoforms – A Comparative Study of Selective Inhibitors
Iehlé (1995) was a pan-European collaboration. The authors reference Thigpen for the proposition that the skin contains the type 1 isozyme. Mr Watson correctly says that no distinction is made between different parts of the scalp or about the role of the follicles in particular. However, it should be noted that, as Dr Thornton observed, the gist of the paper is that the authors are not interested in the hair follicles; they are looking at the prostate, the skin and possibly also the liver as separate tissues.
Spera: 5α-reductases and Their Inhibitors
Spera appeared in 1995. One of its references was Thigpen. The conclusion of the paper suggests the use of a type 1 inhibitor for MPB. Dr Thornton accepted that that was what was written in the conclusion, but suggested that it contradicted what they had said earlier in the paper where they state that finasteride was used clinically in the treatment of MPB, citing Diani and Rittmaster. I do not think that, by referring to those two papers as they did, that the authors of Spera were expressing a conclusion or view contradictory to the clear view later expressed. Their conclusion is that type 1 inhibitors would be the best way forward in the treatment of MPB.
