Tercica Inc v (1) Avecia Ltd. Insmed Inc Genentech Inc

Mr Justice Mann Approved judgment Neutral Citation Number: [2005] EWHC 984 (Ch) IN THE HIGH COURT OF JUSTICE CHANCERY DIVISION Tercica v Avecia & Ors Case No: HC04C03940 HC05C00415 Royal Courts of Justice Strand, London, WC2A 2LL Date: 20/05/2005 Between: Between: Before : MR. JUSTICE MANN - - - - - - - - - - - - - - - - - - - - - TERCICA INC - and - (1) AVECIA LIMITED (2) INSMED INC (3) GENENTECH INC - and - (1) (2) AVECIA LIMITED INSMED INC - and - GENENTECH INC Claimant Defendants Claimants Defendant - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - MR. ANDREW WAUGH Q. C. and DR. JUSTIN TURNER (instructed by Messrs Howrey LLP) for Avecia and Insmed. MR. DAVID KITCHIN Q. C. and MR. MICHAEL TAPPIN (instructed by Messrs. Marks & Clerk Solicitors) for Tercica and (by Messrs. Wragge & Co.) for Genentech. Hearing dates: 10th, 11th and 12th May 2005 - - - - - - - - - - - - - - - - - - - - - Judgment Mr Justice Mann Approved judgment Mr Justice Mann : Introduction Tercica v Avecia & Ors 1. These are applications for summary judgment in two linked patent actions. In the first action Tercica Inc, a licencee under the patent in suit, sues Avecia Ltd and Insmed Inc for infringement. In the second those two defendants, this time as claimants, seek revocation of the patent and sue Genentech Inc, the patentee, to that end. In these two applications Avecia Ltd and Insmed Inc seek summary judgment on their claim for revocation in their own action on the grounds that Genentech has no reasonable prospects of successfully defending the claim, and striking out in Tercica’s action on the footing that the claim is bound to fail because the patent is bad. The attack on the patent is under a number of heads, but in the application before me the applicants concentrated on limited aspects of want of novelty and an averment that it discloses a method of treatment of the human body within section 4(2) of the Patents Act 1977. It is said that whatever debates there may be about other areas of the attack on the patent, there can be no serious debate about those and the patent should be revoked. If it is revoked then the infringement claim must necessarily fail. Summary judgment – the principles 2. As will appear, the applications in this case would require me to form a view as to the disputed construction of both the patent in suit and some of the prior art. Both sides were at one as to the principles to be applied in an application for summary judgment such as this. The approach was summarised by the Vice Chancellor in Celador Productions v Melville [2004] EWHC 2362 at para 7 as follows: “(a) it is for the applicant for summary judgment to demonstrate that the respondent has no real prospect of success in his claim or defence as the case may be; (b) a “real” prospect of success is one which is more than fanciful or merely arguable; (c) if it is clear beyond question that the respondent will not be able at trial to establish the facts on which he relies then his prospects of success are not real; but (d) the court is not entitled on an application for summary judgment to conduct a trial on documents without disclosure or cross-examination.” 3. In addition, and since the exercise before me requires construing the patent, Mr Kitchin QC, who appeared for the respondents, drew my attention to what was said by the Court of Appeal in Monsanto v Merck [2000] RPC 77 at pp 89-90: Mr Justice Mann Approved judgment Tercica v Avecia & Ors “Although construction of the claim was for the court, it had to be carried out according to section 125 of the Act and that required application of the Protocol on Interpretation. That task could, in this case, only be accomplished after the court had adopted the mantle of a skilled man in the art, which could not be done at this stage. The correct approach was that advocated by the Court of Appeal in Strix Ltd. v. Otter Controls Ltd. [1991] FSR 354 [in which Dillon L. J. said at 357-358]: “The difficulty that arises where it is sought to strike out a patent action on the ground that there is no arguable case of infringement arises because the construction of a patent, though a question of law for the court, is not a mere question of the judge reading the patent with the assistance of the legal arguments of counsel; it is a much more sophisticated exercise for two reasons. First the language of the patent is deemed to have been addressed by the inventor not to a panel of equity draftsmen but to ‘the man skilled in the art’, and consequently the court has to consider what the language of the patent would mean not to lawyers, but to the man skilled in the art with his knowledge of the art. Secondly it has long been established that a person does not avoid infringing a patent if he departs from the strict requirements of the claims by what the man skilled in the art would recognise as an ‘obviously immaterial variant’…” At p.92 Aldous LJ said: “…it would not be right, at this stage of the action, to come to any concluded view as to the ambit of claim 20. The patent must be construed as a whole and the claims interpreted according to the Protocol on Interpretation. The subject of this specification is complicated. To come to a concluded view, the mantle of a man skilled in the art must be adopted. That will require the aid of expert evidence. The words of Dillon L. J. in Strix Ltd. v. Otter Controls Ltd. which I have quoted, are in my view just as apt today after the Civil Court Procedure Rules came into force as they were when the Rules of the Supreme Court were applicable.” 4. 5. Mr Kitchin says that the same considerations apply where I have to construe the prior art, and I agree with him. Nevertheless some summary judgment applications are capable of throwing up disputes of construction which can be seen to be clearly determinable on the basis of the evidence before the court at the summary judgment stage. Mr Waugh QC, who appeared for the applicants, submits that this case is one of them. He pointed out that in Monsanto v Merck there was no expert evidence which would have assisted the judge in donning the mantle of the skilled man, whereas I have the assistance of written expert evidence (which is true), and he submitted that that evidence, even taking it all at its highest against his client, gives me the clothing I need at this stage, and that thus clothed I can and should decide the case in his favour. I must therefore Mr Justice Mann Approved judgment Tercica v Avecia & Ors consider whether he is right about that or not. I do so being fully aware of the fact that matters which are not clear to a summary judgment tribunal at the outset can be rendered sufficiently clear by the exposition and elaboration of evidence so that that which appeared difficult and obscure at the beginning can be seen at the end of the summary judgment day to be capable of resolution and sufficiently clear of difficulty once everything has been explained. I was not short of patient explanation in this case, and I have to consider whether that patient explanation has produced a case from which it is clear that the applicants must win in “Celador” terms. The patent in suit 6. The Patent relates to a medicament for improving or promoting growth in mammals. I shall come back to its detailed terms when I consider questions of its construction, and for the moment a generalised description will suffice. IGF’s (“insulin-like growth factors”) are medium-sized proteins produced by the liver and a wide variety of other tissues. Two human IGF’s have been identified - IGF-I and IGF-2. They are mediators of growth hormone action. Growth hormone, produced by the pituitary, is secreted into the circulation where it stimulates production of IGF-I, which in turn stimulates statural growth by acting at the growth plates, which are located at the ends of the long bones. By themselves IGFs are rapidly cleared from the system, having a half-life measured in minutes. However, they normally circulate in serum complexed to one of a number of binding proteins (IGFBPs), which prolongs this half-life from minutes to 12-18 hours. 6 of those IGFBPs are now known, but at the priority date of this patent (12th February 1991) only 3 were known (though others were suspected); the major IGFBP in the circulation was known to be one known as IGFBP-3 (I shall call it “BP-3” in this judgment). After binding with a molecule of IGF, the IGF-BP3 complex forms a ternary complex with the acid labile subunit. Although some studies had suggested that some IGFBPs enhanced IGF action, their prime role was seen as inhibitory. The skilled addressee would know that studies had demonstrated inhibitory effects, but would not know the detailed content of those studies. Clinical studies had shown that one of the inhibiting effects was to reduce the hypoglycaemic effect that administering IGF by itself had been shown to have. According to Professor Rosenfeld (who provided expert evidence for the respondents) as at the priority date it was reasonable to speculate that IGF could, by itself, stimulate growth, but the issue was whether one required local production of IGF-I at the growth plate or whether systemic IGF-I was sufficient to stimulate growth. 7. The case of the respondents is that the patent contains the discovery that the right combination of IGF-I and BP-3, administered by a subcutaneous bolus injection and within certain molar ratios, would promote growth. The actual wording used is “anabolic state”, and it is about those words that a question of construction arises, and I will deal with that in due course. Claim 1 claims: “1. The use of a combination of IGFBP-3 and IGF-I in a molar ratio of 0.5:1 to 3:1 in the manufacture of a medicament for producing an anabolic state in a Mr Justice Mann Approved judgment Tercica v Avecia & Ors mammal, said medicament being intended for subcutaneous bolus injection.” Claim 4 is: “4. The use of claim 1 wherein the mammal is human”. It is claimed that the administration of these two products together promotes a greater anabolic effect than using the same amount of IGF-I, administered by the same protocol, regimen and route but without the co-administration of BP-3. This is claimed to be substantiated by experimental data from rats. The patent provides three examples of experimentation on rats which are said to show: “Significant anabolic properties of IGF-I are observed only when free IGF-I is delivered by slow infusion. Multiple injections of IGF-I, for example, given twice a day, are relatively ineffective at inducing anabolic responses. Co- administration of IGF-I and IGFBP-3 as a sc [subcutaneous] infusion did not improve the efficacy of the IGF-I. It was only when IGF-I and IGFBP-3 were given as a bolus sc injection that an enhancement of the growth promoting activity of IGF-I was observed. It is seen that IGFBP-3 inhibits the hypoglycaemia induced by a large dose of IGF-I. Thus IGF-I delivered by bolus sc injections coupled to IGFBP-3 would allow less frequent injections to be given with a broader therapeutic index as short-term metabolic responses (hypoglycaemia) would be minimized.” The substance of the attacks on the patent 8. It is said by the applicants that the patent fails for want of novelty on the basis of three pieces of prior art: i) European Patent Application 0 369 943 – “Binkert” (priority date 11th November 1988; date of publication 22nd May 1990). ii) PCT Application WO/90/06950 – “Spencer II” (priority date 22nd December 1988; date of publication 28th June 1990). iii) Material made available at the 2nd International Symposium on Insulin-Like Growth Factors/Somatomedins (San Francisco, 12th-16th January, 1991), namely a short paper by Christopher A Maack entitled “Insulin-like Growth Factor Binding Protein-3 potentiates the effects of IGF-I in rat and pig wound healing models” – “Maack”. 9. The third of those in particular involves considering a question of construction of the patent in order to see the extent to which it does or does not anticipate. I will deal with it first. Mr Justice Mann Approved judgment Tercica v Avecia & Ors The construction of the patent and anticipation by Maack 10. Maack is a short paper (less than one side). It recites how “IGF-I and its binding proteins are expected to play a major role in wound healing”, and it describes how samples of IGF-I, BP-3 and “the IGF-I/IGFBP-3 complex” were injected into wound cylinders placed in rats. It describes how the complex had the maximum effect on wound healing increasing parameters by 110% to 180% over control values. Other useful effects were discovered by topical application on pigs. The conclusion was that: “These data clearly demonstrate that IGFBP-3 can be used in conjunction with IGF-I to facilitate wound healing in two very different animal wound healing models.” This is said by the applicants to anticipate because it describes an anabolic state to which the patent relates. 11. This is a patent of the so-called “Swiss-type”. Thus the essential inventive element of it is said to be not the invention of the drug (or combination) itself but the use to which it is put. Accordingly, of central importance is the expression “for producing an anabolic state” in Claim 1. Maack is said to anticipate this use because wound healing is said to be within the expression “anabolic state”. The respondents say that, properly construed, the patent uses “anabolic state” in a different manner which is not the same as, and does not include, wound healing. I will therefore address this issue. I should record that in doing so I am not devoid of assistance as to how the skilled man would read the patent, because I have the evidence of experts from each side directed to that issue – Professor Peter Sonksen for the applicants and Professor Ron G Rosenfeld for the respondents. They each provide evidence as to the knowledge available to the skilled man of the time, and indeed they each go on to express a view as to how the patent should be construed even though it is common ground that that decision is mine and not theirs. 12. The question for me is whether the applicants have successfully demonstrated that on its true construction the patent uses “anabolic state” in such a way as describes the wound healing disclosed in Maack. The applicants say it does. Their case is that that the wording should be taken to signify a general meaning of “anabolism”, which is said to be the process of building up complex substances for body tissues or, to quote the Penguin Dictionary of Biology: “Anabolism is the enzymatic synthesis (build up) of more complex molecules from more simple ones.” The respondents say that the patent does not use the expression in that general sense; it is narrower or more particular. They say that the patent uses the expression to mean increased statural growth, or increasing total body weight, which is not the Mr Justice Mann Approved judgment Tercica v Avecia & Ors 13. 14. 15. same as wound healing (or indeed other processes that might otherwise be said to be part a general description of anabolism). The applicants describe this as a “short point of construction”, doubtless with an eye on the fact that this is a summary judgment application on which non-short points of construction are not such promising material for success. In arriving at their suggested conclusion they start from the general meaning of anabolism, rely on a fairly close textual analysis of the patent, and place that in the context of what they say the experts have demonstrated to be the knowledge of the skilled man (agreed to be a person interested in the endocrinology of growth and/or growth disorders). They conclude that the broad meaning is intended. The background material to this point covers a very significant number of pages of the expert evidence, and the attention required to be given to the wording of the patent is detailed. Whether this justifies the adjective “short” is a matter of debate, but I suppose that if at the end of the day it is all sufficiently convincing then I can reach a conclusion in the applicants’ favour. However, having considered this matter carefully I have concluded that I cannot reach that conclusion. Since it is not necessary for me to reach a final decision on construction, I will not set out in detail the various factors pointing one way or another, and will merely outline the main arguments of the parties and the short reasons why I do not think that the questions of construction are sufficiently clearly determinable in the applicants’ favour to entitle them to succeed on the point at this stage. Mr Kitchin correctly pointed out that the applicants’ starting point is a definition of “anabolism” which refers to its operation at a molecular level. Since it is a dictionary definition it is not necessarily the right definition for a patent, and it may or may not be a useful starting point. Lord Hoffman adverted to this in Kirin-Amgen Inc v Hoechst Marion Roussel Ltd [2005] RPC 169 at para 32. The context is all- important. What is even more important is any actual definition in the patent itself, and there is one in the present case. At col 6 line 53, under the heading “Definitions”, the following appears: “As used herein, the words “producing an anabolic state” refer to promoting total body weight gain as well as the dynamics of statural growth experienced by an individual during infancy, childhood and adolescence as depicted by a normal growth curve, i.e. growth of linear-producing bone plate driven by chondrocytes, as well as growth of osteoblast cells, derived from a different part of the bone. Restoration of normal growth patterns would allow the patient to approach a more satisfactory growth curve. Examples of patients that are relatively resistant to GH [growth hormone] but require treatment to produce an anabolic effect include those with Turner’s Syndrome, GH- deficient children who grow poorly in response to GH treatment, children who experience a slowing or retardation in their normal growth curve about 2-3 years before their growth plate closes, so that GH administered alone would no longer increase growth of the children, so-called short normal children and Mr Justice Mann Approved judgment Tercica v Avecia & Ors patients where the IGF-1 response to GH has been blocked chemically (i.e. by glucocorticoid treatment) or by a natural condition such as in adult patients where the IGF-1 response to GH is naturally reduced. In addition, the method herein is useful for treating pregnant women who are in a catabolic state and/or experience loss of bone mass, for treating women with osteoporosis, and for repairing bone.” 16. That definition is clearly the proper starting point. Mr Kitchin emphasises the first sentence, which limits the meaning of the expression to a particular type of growth – promoting total body weight gain and statural growth. According to Professor Rosenfeld, the general concept of anabolism includes different processes, and he gives as examples statural growth, osteoporosis, bone repair, weight gain and wound healing. The biology of, for example, wound healing is very different to that of overall growth of a human or mammalian subject or the overall whole body anabolic effect in an adult of increasing whole body lean mass. This provides some justification for using a more limited meaning, as in the opening words of the definition. 17. In response to this Mr Waugh drew attention to various parts of the patent which indicated that the expression “anabolic effect” or similar expressions had a wider meaning. Thus he relied on the opening paragraph of the Description: “This invention relates to a medicament for producing an anabolic or growth promoting state in a mammal. More specifically, this invention is directed to the use of a complex of IGF-1 and one of its binding proteins to produce an anabolic state, including enhancing whole body and bone growth.” and said that the word “including” with the words following it showed that the words “produce an anabolic effect” were general words with one specific example. At col 5 there is the following sentence: The fact that the data show a general anabolic effect in the whole mammal, including whole body weight gain and an increase in organ weight, implies that an anabolic effect would be observed in other situations, e.g., in states of nutritional stress.” Again, Mr Waugh relied on the words “including” and following as demonstrating the same thing – the overall effect relied on by the respondents was one example of an overall whole, and it was the overall whole that the patent was referring to. 18. Mr Waugh had other examples of the same sort of thing, which he said built up to an overall picture and supported his starting point of what the usual meaning of “anabolism” is. He included the words at the end of the paragraph containing the definition (appearing above), saying that they demonstrated that the expression must be taken to have the wider meaning. He had about 10 examples. Mr Kitchin Mr Justice Mann Approved judgment Tercica v Avecia & Ors 19. 20. produced about the same number of counter-examples which he said pointed the other way. The state of the argument, against the background of the admissible evidence of the experts, is such that I cannot at this stage determine the point in favour of Mr Waugh. Indeed, my view is that if I had to decide it I would be more likely to decide it in favour of Mr Kitchin and the respondents. The evidence of Professor Rosenfeld is that anabolism incorporates many effects, and that the processes involved in each of them are not necessarily the same. The Definition section of the patent is a more appropriate starting point for the debate than a dictionary definition, and combined with Professor Rosenfeld’s evidence it points towards a narrower, rather than a broader (molecular), meaning. The wording at the end of the paragraph strikes me as probably not broadening the initial definition, but describing potential applications which the patentee considers as coming within the definition. If they do broaden, it does not follow that they broaden to the extent relied on by the applicants. While some of Mr Waugh’s other examples might be said to introduce a degree of equivocation, they do not strike me as introducing enough to turn the apparently narrow definition into a wide concept. However, I do not need to go further. No-one has sought the determination of the construction of the patent as a preliminary question, so if I cannot decide it in favour of the applicants (and I cannot) then I do not need to decide it at all. I may be right in my present leanings, or I may be wrong. It is inappropriate for me to go further on an application for summary judgment, and I shall therefore say no more about it. The point will be finally determined at the trial, at which the experts can elaborate as may be necessary (and admissible) on the skilled man’s perceptions as to the constituents or manifestations of anabolism and their similarities and differences. This conclusion means that Maack as an anticipating disclosure is not made out (at this stage). Maack discloses the effects of the combination of IGF-I and BP-3 as promoting wound healing. Professor Sonksen says clearly that wound healing is an anabolic state. That is not inconsistent with Professor Rosenfeld, who refers to a number of aspects of anabolism, of which wound healing is one. However, it is not the point that arises on this patent in the context of Maack. The right question in that context is whether wound healing is within the expression “promoting an anabolic state” as that expression is used in claim 1. If wound healing is not within the concept of “producing an anabolic state” within the meaning of the patent then Maack does not anticipate. While it might be capable of being within that concept in some contexts, it is not established sufficiently clearly that it is within the use of that expression in the relevant parts of the patent in suit. Since I have not concluded that it is within that concept so used, it follows that I cannot say at this stage that Maack anticipates. In the light of that conclusion is it not necessary, at this stage, to consider the other arguments raised in relation to Maack. Mr Justice Mann Approved judgment Binkert Tercica v Avecia & Ors 21. This patent application was concerned with the production of one of the binding proteins – in fact IGFBP-2, not IGFBP-3. It is said by the applicants that in the course of setting out the basis of or background to the invention this application teaches the combination of (inter alia) IGF-I and BP-3 to produce the effect relied on by the respondents in their patent (stimulating growth). In order to deal with this submission I need to set out parts of that application and refer to some of the law relied on by the parties. 22. The application refers to, deals with or contains the following relevant material: i) It identifies IGFs as existing, and identifies the two different ones then known as being IGF-I and IGF-II. IGF-I is referred to as mediating the growth promoting effect of growth hormone in chondrogenesis and bone formation. In addition to their “primary effect on skeletal tissues they also assume growth-stimulating functions on other tissues.” ii) It refers to the fact that IGFs have hypoglycaemic properties, which are prevented by a regulatory mechanism which involves carrier proteins present in the blood and able to form complexes with IGFs. Through this association, binding to the IGF’s cell surface receptors is inhibited. iii) “In accordance with the foregoing, IGFs may be useful in vivo to stimulate (a) the growth of animals and humans with growth hormone deficiency; (b) tissue regeneration, such as erythropoiesis and chondrogenesis; (c) wound healing and (d) the functions of various organs, e.g. liver or kidney. As a result of their chondrogenesis stimulating activity, IGFs are of particularly suitable use for bone formation, e.g. in the treatment of osteoporosis. IGFs for use in the above- referred treatments are advantageously administered to a subject in association with at least one IGF-binding protein. Administration of this combination rather than IGF alone has beneficial effects including the prevention of hypoglycemia and possible mitogenic effects at injection sites and the prolongation of IGF half- life. Further, it has now been found that binding proteins are also useful for potentiating the erythropoietin like-effect of IGF-1.” This is an important passage in the context of this application. iv) It refers to the fact that in recent years “at least two major species of IGF-binding proteins, different in size, have been detected in the serum of rodents and humans”, and it then identifies a larger and smaller one. The larger one, thus identified, cannot be BP3 (according to Professor Rosenfeld, whose evidence is to be accepted for present purposes), and the smaller one might be BP2, but it is not identified as such. Mr Justice Mann Approved judgment Tercica v Avecia & Ors v) Other IGF-binding proteins had been identified in human tissue extracts and cell culture media. They are not identified either, though again one of the references might be to BP-2 and one might be to BP-3, though that is not made clear. 23. It is the applicants’ case, supported by Professor Sonksen, that this application anticipates the combination and the use which is the subject of the patent in suit. In short, they say that Binkert is teaching the administration of IGFBPs, with IGF, for the purpose of stimulating growth, which is the purpose or use relied on in the patent (even on the respondents’ construction). Although the patent’s particular combination (IGF-I and BP-3) is not explicitly taught, since IGF-I is explicitly referred to as being one of the two known IGF’s, and BP-3 is within the binding proteins referred to (and was known at the patent’s priority date as being one of the identified binding proteins) then it must be teaching that combination. This, they say, is sufficiently clear to entitle them to summary judgment on the question of want of novelty. 24. The respondents’ answer to this is, in short, as follows: i) One has to read this document with the background knowledge of the skilled man in mind. Professor Rosenfeld has dealt with this, and the most important factors are those which I have set out above in this judgment. In addition, he says that it was known that different binding proteins were likely to have different biological effects, both when administered by themselves and when administered with IGFs. ii) Particularly bearing this in mind, this application does not teach the relevant matter with sufficient (or probably any) clarity. It is at most suggesting something that might happen, or that might be a fruitful source of investigation, or something like that. It is speculative. It does not give clear instructions to combine the two specific products (IGF-I and BP-3); or to combine them in the specified (or any) ratio; or to manufacture in a form suitable for subcutaneous bolus injection. iii) Professor Rosenfeld has expressed the view that insofar as Binkert is seeking to extrapolate from other binding proteins to BP-3 specifically, then that exercise is not justified. Prior to the studies referred to in the patent in suit, the skilled addressee would have no data to indicate what effect, if any, IGFBP would have on any particular activity of IGF-I other than prolonging its half life and inhibiting its hypoglycaemic effect. 25. The arguments advanced by the respondents seem to me to be good arguments, though again I do not have to express a concluded view. It is sufficient for me to say that I am not satisfied that the applicants are correct on the material that I have before me. I have reached that conclusion for the following reasons. 26. Once again it must be borne in mind that the patent in suit has a Swiss-style claim. Its central point is the use to which the drugs are put; they are said to be new uses. Any Mr Justice Mann Approved judgment Tercica v Avecia & Ors anticipating disclosure must disclose that use. In the words of General Tire v Firestone Tyre & Rubber Co [1972] RPC 457: “To anticipate the patentee’s claim the prior publication must contain clear and unmistakeable directions to do that which the patentee claims to have invented…. A signpost, however clear, upon the road to the patentee’s invention will not suffice. The prior inventor must be clearly shown to have planted his flag at the precise destination before the patentee.” 27. As was said in Hills v Evans (1862) 31 LJ Ch 457 at 463: “…the antecedent statement must be such that a person of ordinary knowledge of the subject would at once perceive, understand and be able practically to apply the discovery without the necessity for making further experiments and gaining further information before the invention can be made useful. If something remains to be ascertained which is necessary for the useful application of the discovery, that affords sufficient room for another valid patent.” 28. There is no material dispute between the parties as to the applicability of those principles, though they argue for differing results when they are applied. Mr Kitchin says that Binkert is no more than a signpost; Mr Waugh says it is a flag. In my view there is still a strong argument in favour of signposts. The critical passage is that quoted above, but it is significant that it follows hard on a reference to the inhibitory effects of binding proteins. The critical passage starts with the uses of IGFs by themselves. In fact it is a qualified statement, (“may be useful”), but for present purposes I shall assume that it is a firmer pointer than that. It then lists some effects, at least one of which is stimulating the growth of animals and humans. But there is nothing so far about the potentiating effects of combining with binding proteins. That comes next. It is said that IGFs are “advantageously administered … in association with at least one IGF-binding protein”. The effects are then set out – the first two are inhibitory effects, and do not indicate an improvement in anabolic effect (of any kind). The third (prolongation of half-life) is not inhibitory, but is still not a reference to promoting the anabolic effect. The fourth is potentiating – the increased erythropoietin-like effect. This may cross-reference to the second of the four listed useful effects of IGF-I, but that is all (and it is not clear to me that even that is the case). Unless it is clear as a matter of construction that any anabolic effect is within the claims of the patent in suit (which it is not), then thus far the link between improving the effect of IGFs as promoting relevant anabolic effects and the co- administration of BP3 is not made out. 29. Next is the failure to identify explicitly any particular combination. It is true that no particular combination is explicitly identified, but Mr Waugh said that did not matter. He said the application identified two IGFs of which IGF-1 was one, and binding proteins, of which BP-3 was one. There was a limited number of combinations of IGFs and binding proteins, and all were disclosed – certainly the IGF-I/BP-3 Mr Justice Mann Approved judgment Tercica v Avecia & Ors combination was disclosed. In this respect he relied on Norton Healthcare Ltd v Beecham Group plc (Jacob J, unreported, 31st July 1995). In the relevant part of his judgment in that case Jacob J considered an allegation of want of novelty over the disclosure in a previous patent. The question was whether a given combination was disclosed in that earlier patent. At pages 6 to 7 of his judgment he demonstrates the disclosure and shows how it moves from disclosing a broad range of matters and becomes more specific, and at page 7 he says: “So ‘977 first suggests a combination of one of a large class (clavanulates) with one of another large class (penicillins or cephalosporins). It also specifically suggests the sodium or potassium salt with amoxycillin or ampicillin trihydrate – four possible combinations only. I regard this as a disclosure of each of these combinations. The skilled man needs no experimentation to put any of these together. It was not suggested before me that any of these four combinations would not have practical utility.” Mr Waugh invites me to approach Binkert on the same footing. It discloses, he says, a number of combinations, of which a combination of IGF-I and BP-3 is one. I do not think that this case assists Mr Waugh very much. It is ultimately a decision on the facts. In that case the judge held, in the light of a very differently drafted patent, that four specific combinations were in fact disclosed (of which one was material). The case merely shows that that exercise can be done if the facts justify it. The question is whether it can be done in the present case. Mr Waugh has not satisfied me that it can. On the one side of the combination the two IGFs are disclosed. However, on the other only BP-2 is reasonably clearly disclosed, and even that is debatable at points of the document. One of the references to “the large binding protein” may well be a reference to the ternary complex involving IGF-I and BP-3 and referred to above, but that is not necessarily a reference to BP-3 alone. All in all, this document seems to me to be very differently structured from the document before Jacob J, and it does not readily permit the process required by Mr Waugh’s approach. I am not satisfied at present that it in fact does. In order for the applicants to establish this point one has to do rather more teasing out and detective work than was necessary in Norton v Beecham. The extent to which that is appropriate is for the experts to assist on. Professor Rosenfeld does not in terms deal with this approach in his reports; that may be because it was not foreshadowed in anything he had before he wrote it. Be that as it may, that strengthens my view that it would not be appropriate for me to find in favour of the applicants on this approach on this application. 30. 31. Next is the question of the strength of the direction given by Binkert. The respondents’ case is that the skilled man would consider the suggested combination to be nothing more than speculation. Speculation is not the firm flag-planting required by General Tire. In particular, they rely on the absence of data. The skilled reader comes to this document knowing of the uncertainties in the field, to which I have referred above. With that background, he receives what amounts to suggestions from Binkert. The absence of data is not conclusive, but bearing in mind that this Mr Justice Mann Approved judgment Tercica v Avecia & Ors application concerns the making of BP-2 and the relevant passage is there by way of background, it is or may be significant in determining whether what is written is speculation or suggestion on the one hand (signposts) or firm teaching on the other (flags). There is no indication of any prior experimentation, and it is arguable that the reader is required to make his own experiments to find out whether any particular, and if so which, combination has the effects contended for. Mr Waugh referred me to C van der Lely NV v Bamfords Ltd [1963] RPC 61 in which Lord Reid made observations to the effect that the need to make practical “trial and error” experiments involving no inventive step to put a disclosure into effect did not necessarily mean that a prior disclosure was not sufficiently enabling. I accept that, of course, but it seems to me to be clearly arguable that any experimentation which would be required in order to implement such disclosure as there is in Binkert goes rather beyond that. Yet again it is important to bear in mind the Swiss nature of this claim, so that it is the effect, and not merely the fact, of the combination that is important. Professor Rosenfeld refers to the impossibility of making a reliable prediction as to the effects of a different binding protein in a combination, and I can see why he says that without necessarily having to agree with him at this stage. 32. Accordingly, I find that it has not been sufficiently clearly shown that Binkert discloses the combination referred to in the patent in suit as having the effect referred to there. I am unable to find, on this application, that the patent is not novel over Binkert. This conclusion makes it unnecessary to consider the additional elements disclosed by the patent in suit and said not to be anticipated by Binkert, namely the molar ratio and the method of administration (subcutaneous injection). Spencer II 33. This is another patent application. The prime focus of this application is (it is common ground) a method of production of BP-3 using recombinant DNA. It is a long and difficult document, whose lack of clarity at points is such that for a time it confused even Professor Rosenfeld in its use of terminology – he had to file a separate report to indicate a change of appreciation as to how it was deploying its terms. The meat of the applicants’ point on this is that the combination of IGF-I and BP-3, having the use referred to in the patent in suit, is disclosed in the following passages of Spencer II: (at page 21) “SM could be delivered to target tissues in a safe, effective physiologic manner and their half-life significantly prolonged by complexing them to the carrier protein subunits of the invention. The SM in a SM-carrier protein subunit complex would not be mitogenic at injection sites or hypoglycemic. This complex could be formulated to provide controlled, long- term absorption. After transport to target tissues, dissociation would release SM. Thus, therapy would mimic the physiologic delivery system. Successful therapeutic and animal husbandry use of SM-C, IGF-II and other somatomedin-like polypeptides are permitted by a composition of at least one human somatomedin-like polypeptide and at least one carrier protein subunit. Mr Justice Mann Approved judgment Tercica v Avecia & Ors Compositions comprising one or more carrier protein subunit and one or more SMs would also be useful for treatment of diseases such as postmenopausal osteoporosis, other forms of osteoporosis, and human GH deficiency, as well as for healing wounds and increasing animal growth. Such composition would be used to deliver SM to bony tissues and stimulate the growth of bone. Dissociation of the SM from the carrier protein subunit-SM complex should stimulate osteoblasts to increase bone formation in postmenopausal osteoporosis, invade the porous matrix of a prosthetic joint thereby stabilising the prosthesis, and to promote healing of un-united fractures. “Therapeutic compositions comprising an effective amount of at least one carrier protein subunit capable of binding somatomedin-like polypeptides, or pharmacologically acceptable salts thereof, and a pharmacologically acceptable carrier and therapeutic processes using such compositions may also be useful in treating injuries or diseases in which the natural healing mechanism or response involves the presence of regulated levels of biologically active somatomedins. For example, such compositions may be useful in wound healing, where the natural physiological response involves the presence of endogenous SMs at the site of the wound. An effective amount of carrier protein subunit is an amount sufficient to prolong the half-life of the endogenous biologically active somatomedins.” (at page 29) “The invention is also embodied in a composition having at least one such carrier protein-like polypeptide described above substantially complexed with at least one somatomedin-like polypeptide. Such compositions may be used in a therapeutic composition for treating osteoporosis in humans, for stimulating the growth of bone, for stimulating animal growth, for stimulating the healing of human and animal wounds, or for stimulating the growth of patients with growth hormone deficiency, comprising an effective amount of such a composition. Such compositions may also be used in a method for treating such conditions comprising administering an effective amount of such a composition.” 34. These passages are said to teach the combination of IGF-1 and BP-3 for the purposes of the patent. They do not use the same terminology as the patent, and in order to understand what it is saying some translation is required. The translation is provided by definitions in the application but they have to be supplemented, to an extent, by the experts (and in particular Professor Rosenfeld). The important terms and concepts for present purposes are as follows: i) “SM” means somatomedins. IGF’s are somatomedins. ii) “Carrier protein” is thought by Professor Rosenfeld to be the same concept as the ternary complex referred to above. He changed his mind about this, at one stage Mr Justice Mann Approved judgment Tercica v Avecia & Ors 35. 36. thinking it referred to BP-3 (as opposed to the complex of which BP-3 formed part). Professor Sonksen does not necessarily agree with this. iii) “Carrier protein sub-unit” is thought by Professor Rosenfeld to refer to fragments of glycosylated BP-3, and not necessarily intact BP-3 itself. He reaches this conclusion (which has an air of the tentative about it) by a process of inference and deduction from definitions in the document and from other extracts, including drawing conclusions from ranges of specified molecular weights. iv) The term “carrier protein-like polypeptide” refers to BP-3 and variations of BP-3. v) The term “somatomedin-like polypeptide” means a polypeptide displaying the biological activities of one of the human SMs or insulin-like growth factors, including but not limited to SM-C, SM-A, IGF-I and IGF-II. SM-C and IGF-I are the same. Those definitions are sufficient to make sense (for present purposes) of the passages relied on by the applicants, but it should not be thought that they are easily won. Some (such as that at (v)) are definitions extracted from the definition section of the application, but others have to be worked at and arrived at by deduction and inference by the experts. In his evidence provided to support this application Professor Sonksen refers to the first of the above two quoted passages only, with some of the passages leading up to it. He says that the passages discuss “the use of SM’s (including in particular SM-C) complexed with the carrier proteins of the invention” and concludes that “it is abundantly clear that Spencer II is teaching that BP-3 can be administered with IGF-I to produce an anabolic state”. Professor Rosenfeld disagrees. He says that to say that a composition is “potentially useful” in therapy does not teach that any particular combination will have a particular effect, and he relies on the absence of data to substantiate any claim that a composition will have any of the anabolic effects (and particular growth-promotion) referred to. The suggestions are, he says, speculation only. He also points out that this passage does not explicitly identify the combination of IGF-I and BP-3. It teaches (he says) only the use of an IGF with one of a number of possible binding proteins. In relation to this last point, Mr Waugh relied on Norton v Beecham again, and sought to say that the application disclosed only a limited number of combinations, particularly bearing in mind that only two IGFs were known at the time, and that this combination was one of them in the same way as the crucial combination was disclosed in Norton v Beecham. 37. Once again I do not think that Mr Waugh has made out his case sufficiently to entitle him to judgment on this passage. He has carried out a careful analysis of this complicated application, and sought to show that if one translates the actual wording used into the language of the patent then one can identify IGFs on one hand and IGFBPs on the other, and thus find the teaching of a combination of each variant, including a combination of IGF-I and BP-3. This faces difficulties on both fronts. It Mr Justice Mann Approved judgment Tercica v Avecia & Ors is not clear that the first passage (at page 21) does identify a group of binding proteins as such. The evidence showed that the use of the words “carrier protein subunit” may not be an entirely apt way of describing BP-3 since it may be intended to connote a fragment or the whole of a BP-3 molecule. If that is right then it is not sufficiently clear that BP-3 as such is identified here at all. Furthermore, so far as the strength of the teaching is concerned, one has to consider how the matter would appear to the skilled man, and place the wording of this application in that context. Professor Sonksen provides evidence on this point that is little more than assertion as to what its effect is, and he does not really address any of the real difficulties. Professor Rosenfeld does embark on a little more of the background (though not a lot), and points out that the physiological role of BP-3 on the activity of IGF-I was not known at the time, and reaches a contrary conclusion as to what a skilled addressee would conclude from this part of the application. I cannot say that Professor Rosenfeld is wrong about this. All in all, I consider that significant additional assistance would be afforded by fuller evidence from the experts and cross-examination where appropriate. 38. In relation to the second of the cited passages (at page 29) Mr Waugh’s submissions were in substance the same as in relation to the earlier passage – the later passage is said to disclose a number of combinations of IGFs and binding proteins which are said to have a relevant anabolic effect, and one of those combinations is IGF-I and BP-3. The answer, at this stage, is also the same – the applicants’ case is not sufficiently made out on the evidence. Professor Rosenfeld’s evidence is the same in relation to this passage. The points are that the particular elements of the suggested construction are not identified, and the claims made for it could be viewed by the skilled addressee as speculative in the absence of data and predicted results. This seems to me to be clearly arguable. The position in relation to this complex application will be helpfully clarified by the assistance of expert evidence at a trial. 39. For the sake of completeness, I should add that Mr Waugh relied on other parts of this application, but the most important aspects are those that I have identified, and those other parts do not firm up the teaching of this patent (in disputed areas) to any significant extent. I will therefore not lengthen this judgment by dealing with them. The prior art – an additional point 40. That is sufficient to deal with this piece of prior art because it means that the prior art does not sufficiently clearly disclose the combination and effect that lie at the heart of this Swiss-type claim. However, I should record an additional area of dispute between the parties which applies to Spencer II and to Binkert as well. So far I have focused on what the prior art teaches in relation to a particular combination and its effect in anabolic terms. Mr Kitchin took a further point. He pointed out that neither Spencer II nor Binkert disclosed the molar ratios identified in Claim 1 of the patent in suit; nor did they disclose the fact that it was only when the combination was administered by subcutaneous bolus injection (and not by infusion or any other Mr Justice Mann Approved judgment Tercica v Avecia & Ors method of administration) that the proper effect could be achieved. Therefore, he said, the prior art did not anticipate. 41. Mr Waugh’s answer to this was to say that those two matters do not confer novelty for the purposes of a Swiss-type claim, because all that such claims did was to allow a second medical use to confer novelty and those features were not part of the use. In addition, so far as the patentee seeks to rely on them as the technical contribution of this patent then it is seeking to rely on a method of treatment within the meaning of section 4(2) of the Patents Act 1977: “4(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. 4(3) Subsection (2) above shall not prevent a product consisting of a substance of composition being treated as capable of industrial application merely because it is invented for use in any such method.” 42. In support of this submission he relied on Bristol-Myers Squibb v Baker Norton [2001] RPC 1. In that case the Court of Appeal considered a patent which was ostensibly in Swiss form but held it was not, on its facts, a claim for a second therapeutic use, and was actually (on the facts) a method of treatment within section 4(2). The case concerned the administration of a known drug to treat cancer, for which purpose it was already known. The only inventive step was found to be the discovery that administering it over 3 hours, as opposed to a longer infusion, achieved less neutropenia. In addition to striking down the patent on the grounds of obviousness, the Court of Appeal held that this was not a new therapeutic purpose for the purposes of a Swiss-type claim. It was merely a discovery about an old use (per Aldous LJ at para 46; per Buxton LJ at para 88); that it did not demonstrate a new therapeutic use (the therapeutic use being already established and the reduction of neutropenia not being such a use) (Holman J at para 111); and that in addition it was a method of treatment (per Aldous LJ at para 63; per Buxton LJ at para 93; and per Holman J at para 107). Mr Waugh submitted that the same reasoning applied in the present case. On the footing that the use of the combination of molecules was disclosed for the purpose stated, all that was new was dosage and method of administration. These were not a second use (or indeed any relevant use) for the purposes of a Swiss-style claim, so there was no relevant novelty; and the dosage and subcutaneous administration requirement made the only new element a method of treatment. Mr Waugh also relied on Merck & Co Inc’s Patent [2003] FSR 498, approved on this point at [2004] FSR 330 at para 59, as establishing that a new method of administration of a known drug for a known disease was a method of treatment within section 4(2), so that a patent claim relying on it would fail. 43. Mr Kitchin sought to refute this. I do not need to set out all the details of his argument, but he claimed that the ability to couch a claim in a Swiss-style format overcame problems that might otherwise exist in both novelty and method of Mr Justice Mann Approved judgment Tercica v Avecia & Ors 44. treatment terms. He took me to various TBA decisions (some of which were apparently cited without comment in Bristol Myers) in which that body seemed to accept that a different method of delivery of the same substance used to treat the same condition was allowed as a Swiss-type claim, albeit apparently without any explicit consideration of the method of treatment point. But at the end his case, as I understood it, was that the patent’s dosing or combination range and its method of delivery were all part of the new use which the patent claimed – the production of highly improved effectiveness of IGF-I. Swiss-style claims were allowed and recognised by the Enlarged Board of Appeal in Re Eisai Co Ltd, Decision Gr 05/83 [1985] OJ EPO 064. They were acknowledged as permissible in England & Wales in John Wyeth & Brother Ltd’s Application [1985] RPC 545 (Whitford and Falconer JJ sitting en banc). This device allows a claim to be formulated as one describing the manufacture of a known product for the treatment of a new condition or for a new use (that is to say, a condition or use for which it had not hitherto been considered as being useful). The new use is what protects against want of novelty arguments. It is less clear what the interface is with the method of treatment exception. Mr Kitchin was minded to submit that Swiss-type claims, couched in the manner in which they are, overcome that point as well, but that does not sit easily with the Merck case or with the analysis of Aldous LJ in Bristol Myers at para 63 where he looked at the substance of what was claimed rather than the form. What I was asked to consider (among other things) was a concept which Jacob J has called the “artificial construct of a Swiss form claim” (see Merck & Co Inc’s Patents [2003] FSR 498 at para 80), and in particular what is meant by “new use” where part of that new use involves a particular method of administration, and the interface with the method of treatment point. One of the questions which might arise is: just how far can the artificiality be pushed before reality forces its way in? These are not subjects which are particularly happily determined on applications for summary judgment, even when those applications are argued as well and as fully as the one before me was. For that reason, and since my decision on the other attacks of Mr Waugh mean that I do not have to decide the sort of points arising under this head, I do not propose to express a view on those matters. Conclusion 45. In the circumstances I shall dismiss the applications before me.