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England and Wales Court of Appeal (Civil Division) Decisions

You are here: BAILII >> Databases >> England and Wales Court of Appeal (Civil Division) Decisions >> American Home Products Corp & Anor v Novartis Pharmaceuticals UK Ltd & Anor [2000] EWCA Civ 231 (27 July 2000)
Cite as: [2000] EWCA Civ 231, [2001] RPC 159, [2000] IP & T 1308

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Case No: A2/1999/1278

Royal Courts of Justice
Strand, London, WC2A 2LL
Date: 27th July 2000

B e f o r e :

(1) American Home Products Corporation
(2) Professor Roy Calne

(1) Novartis Pharmaceuticals UK Limited
(2) Novartis Pharma AG

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(Transcript of the Handed Down Judgment of
Smith Bernal Reporting Limited, 190 Fleet Street
London EC4A 2AG
Tel No: 020 7421 4040, Fax No: 020 7831 8838
Official Shorthand Writers to the Court)
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Henry Carr QC and Piers Acland (instructed by Bristows for the Defendant/Appellants)
John Baldwin QC and Michael Tappin (instructed by Linklaters for the Claimants/Respondents)
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As Approved by the Court
Crown Copyright ©

1. The appellants, Novartis Pharmaceuticals UK Limited and Novartis Pharma AG, are defendants in a patent action. There is no need to differentiate between them and I will refer to them as Novartis. They are also claimants in an action for a declaration of non-infringement.
2. The respondents are Professor Sir Roy Calne and American Home Products Corporation. Professor Sir Roy Calne is the patentee of European Patent (UK) 0401747, the patent in issue, and American Home Products Corporation are the exclusive licensees which work the invention the subject of that patent. Again there is no need to differentiate between them and I will refer to them as the patentees.
3. The parties to the action agreed that the issues of infringement and insufficiency should be tried first and the remaining attacks upon validity and the issue of whether both the Novartis companies infringed should be stood over to be heard at a later date. That course was acceptable to the Court and therefore those issues came on for trial before Laddie J. In his judgment ([2000] RPC 547) he held the patent infringed and that the allegation of insufficiency failed. He therefore refused to make the declaration of non-infringement that was sought.
4. The patent is based upon the discovery by Professor Sir Roy Calne that a product, produced by the bacterium streptomyces hygroscopicus, called rapamycin, was useful to suppress transplant rejection. Rapamycin was at the priority date of the patent, 6th June 1989, known to have antifungal and antitumour properties.
5. Because rapamycin was a known product at the priority date, it could not be patented: neither could its use as a treatment, because that would offend section 4(2) of the Patents Act 1977. For those reasons the main claims of the patent followed the form known as "Swiss type" which is used to claim an invention for a second medical use. Claim 1 therefore claims as inventive:
"1. Use of rapamycin for the preparation of a medicament for inhibiting organ or tissue transplant rejection in a mammal in need thereof."
6. The basic issue raised in this appeal revolves around the alleged infringement. Novartis have produced an immunosuppressant which is referred to as SDZ RAD. It is a derivative of rapamycin. The judge upheld the patentees contention that it fell within the ambit of claim 1. Novartis contend that he was wrong and that the claims of the patent do not cover a derivative such as SDZ RAD. If they do, then the patent is invalid as "the specification of the patent does not disclose the invention clearly enough and completely enough for it to be performed by a person skilled in the art" (section 72(1)(c)). In essence they contend that if the claims were to be construed as the patentees contend, the specification would be insufficient as there is no disclosure in the specification of how to make or select derivatives of rapamycin to prepare a medicament "suitable for inhibiting organ or tissue transplant rejection in a mammal" as required by claim 1.
7. The technical background to the invention and the technical information needed to understand the dispute were set out by the judge with clarity. I gratefully adopt them in full.
"Technical background
(a) Transplant rejection
2. The patent and this case are concerned with medicaments which are or may be of use in the treatment of patients who have undergone surgical transplants. Save for the case of identical twins, each of us has a genetic make up which is different from everyone else. If living tissue, such as a heart or kidney, is taken from one person and is transplanted into another, the recipient's immune system is likely to recognise the transplant as foreign. It will automatically try to attack and exclude or kill the intruder. If this happens the transplant is said to be rejected. This problem can be reduced to some extent by selecting a donor whose genetic makeup is very similar to that of the recipient. For example close relatives may have very similar tissues. If this is done the transplant will look only a little bit foreign to the recipient's immune system and the rejection may not be so severe. However, even if this is done, the immune system in the recipient is still likely to try to reject the graft. For this reason it is currently necessary to use drugs which weaken the immune response of the recipient. Such drugs are called immunosuppressants.
3. Although a number of immunosuppressants are known and used they vary in efficacy and, to a greater or lesser degree, cause undesirable side-effects in the recipient. It is common to use a cocktail of such immunosuppressants. At the date of the patent in suit three types of immunosuppressant in particular were used, frequently together. They are azathioprine, a group of chemicals known as corticosteroids and cyclosporin. Cyclosporin is the most powerful of these but it is nephrotoxic, that is to say it is capable of poisoning kidney tissue. It is not in dispute that scientists have been searching for additional and preferably better drugs to use as transplant rejection inhibitors.
(b) Biological activity
4. Living organisms contain numerous complicated molecules. A molecule is made up of number of different atoms, such as carbon, hydrogen and oxygen connected together in a particular arrangement. It is convenient and conventional to draw a molecule's structure by showing a flat plan of the atoms connected together. For example, benzene, which is made up of a ring of 6 interconnected carbon atoms (C) each of which is connected to one hydrogen atom (H) can be depicted as follows:
Illustration 1:
Click here for Picture

5. This is highly stylised and merely indicates which atoms are connected to which, rather like the map of the London Underground system. In fact, just like the stations in the London Underground, the atoms are usually not all in one plane. Most large organic molecules take up a complicated three-dimensional form. This is referred to as the molecule's tertiary structure or conformation. It is the nature of the atoms in the molecule and the forces which exist between them which twists the molecules into their sometimes complicated three-dimensional shapes. There are numerous molecules which have very specific biological activities. Examples are antibiotics, enzymes and antibodies. It has become recognised over time that in many cases the biological activity of these molecules is largely dependent upon the molecule's shape. It is the ability of a molecule to fit onto another molecule - for example on the surface of a living cell - which allows it to perform or causes its biological function. For example enzymes are large molecules, only particular parts of which, because of their spatial relationship to one another, help to promote particular chemical reactions. If the molecule is modified so as to alter significantly the shape of that part of the molecule which is responsible for its biological action, it may lose all or most of that activity. Although all analogies break down at some point, the importance of the shape of a biologically active molecule can be explained as follows. The molecule can be likened to a key. The complicated shape of part of it (equivalent to the wards on the key) enables it to fit into a complementary location (equivalent to the wards in the lock) on another molecule: for example, on the surface of a cell. The interaction allows the molecule to perform its biological function, just as the interfit between the key and lock allows the former to operate the latter. If the part of the molecule which has the important shape is modified, it may lose its ability to interact with the other molecule. In much the same way, modification of the shape of the `business end' of a key may make it incapable of fitting into or operating the lock. On the other hand, altering a part of the molecule which has little effect on the shape of the interfitting parts has little effect on biological activity. In much the same way, modification of the shape of the shank or handle of a key is much less likely to stop it opening the lock.
6. Unlike the key and lock analogy, the interfit between a biologically active molecule and its target is `soft'. Whereas a key either does or does not operate a lock, in the case of biologically active molecules, the better the fit the more active the molecule is.
7. A molecule may have more than one biological activity. Part may render it poisonous, another part may make it an effective enzyme, a third may give it hormonal properties and so on. Furthermore a molecule which through evolution has developed to perform one particular biological function may happen to have a shape which enables it to perform another, and unintended, function. For example a molecule taken from one living system may have an entirely different and unexpected effect on another living system, the shape of the molecule bestowing on it activity which it either did not need or did not have in the system from which it is derived. Once again, using the analogy of keys and locks, it is as if a piece of shaped metal designed, say, as a paper-clip is found by chance to have the necessary shape to fit and operate a lock.
8. A chemical discipline has grown up, called medicinal chemistry. The expertise of a medicinal chemist was discussed by Professor Bycroft, himself a medicinal chemist and Head of the Pharmacy School and of the School of Pharmaceutical Sciences at the University of Nottingham, who gave evidence on behalf of the claimants. He said that a medicinal chemist is typically an organic chemist who has experience of synthesising organic molecules and is involved in the study of structure-activity relationships of pharmacologically active compounds i.e. the use of organic compounds (synthetic or natural) as drug agents. The medicinal chemist has to have not only a knowledge of the molecular chemistry of the compounds with which he is concerned but also a `feel' for the biological effects, including the possible effects of modifications. The medicinal chemist, by his experience and training, will accordingly have and need to have a working knowledge of the various disciplines which surround the strict organic chemistry concerned. A medicinal chemist will also develop expertise in looking at the shape of molecules. As the evidence in this trial showed, he would be expected to know in many cases how the atoms within a molecule interact with each other spatially. For example, he will know that some types of atom-to-atom bonds will twist or modify the shape of the molecule in which they are located. Thus he may know that a particular atom-to-atom bond in a particular location will make it difficult for those atoms, and therefore the parts of the molecule immediately adjacent to them, to twist or rotate in relation to each other as compared to a different pairing of atoms at the same position in an otherwise identical molecule.
10. In fact the molecule known as rapamycin was not discovered by Professor Calne. It is produced naturally in a particular strain of bacterium called Streptomyces hygroscopicus. It is a large molecule the structure of which is depicted in two dimensions and schematically as follows:
Illustration 2:
Click here for Picture

11. The numbers 1 to 40, with the exception of 7, all represent carbon atoms while 7 represents a nitrogen atom. Hydrogen atoms (H) bonded directly to carbon atoms are not shown but it is readily apparent where they are, since it is known that carbon has a valency of 4. Thus the carbon at position 12 has two of its bonds occupied (by single bond connections to the carbon atoms at 11 and 13). It therefore has two free bonds. Each bond is capable of connecting to a single hydrogen atom so there are two hydrogen atoms at this location. On the other hand the carbon at 18 has three of its bonds shown as occupied. Therefore there is a single remaining bond connected to a single hydrogen atom. If one starts with the carbon atom indicated by 1, it will be seen that there is a string of interconnected atoms all the way round to carbon 34. This is then connected to carbon at 1 by an oxygen (O) atom. This therefore is a loop of interconnected atoms. It is referred to as the macrolide ring. To it is attached a side chain consisting of the part of the molecule containing carbons 35 to 40. The macrolide ring is therefore:
Illustration 3:
Click here for Picture

The defendants' product
13. The defendants have also produced an immunosuppressant containing a macrolide ring. It is referred to as SDZ RAD. It has the following structure:
Illustration 4:
Click here for Picture

14. It is made by a two-step process in which the hydroxyl (OH) unit connected to the carbon atom at position 40 on the side ring of rapamycin is O-alkylated with a 2-hydroxyethyl group. Save in this respect, it has a chemical composition which is identical to rapamycin. The proper chemical name for SDZ RAD is 40-O-(2-hydroxyethyl)-rapamycin."
The judge also made these findings of fact:
"37. I do not think that there was much dispute between the parties and I find as a fact that on reading the patent a skilled addressee would have understood the following as a result of the content of the patent and common knowledge in the art in the late 1980's:
(a) At that time it was very likely that the immunosuppressive effect discovered by Professor Calne, like the biological activity in other known large molecules, was dependent on the shape of the rapamycin molecule or a part of it.
(b) The immune response is a multi-stage process, details of which were not then (and even now are not) known. It was likely that rapamycin acted in the second half of the process but where precisely and how was not known and would be likely to take a long time to find out.
(c) The mechanism by which rapamycin worked was not known. That is to say, it was not known what part or parts of the molecule gave it its efficacy nor was the shape or location of the receptor sites in the molecules to which it attached itself known.
(d) There was a strong probability that other molecules derived from rapamycin would exhibit similar conformation in those areas which made rapamycin efficacious and would also exhibit similar immunosuppressant activity. Put the other way round, it was most unlikely that rapamycin was the only molecule of similar shape which exhibited such efficacy although it was not possible to be certain that this was so. As a corollary it was unlikely that Professor Calne had happened to hit upon the only molecule within the large number of molecules with similar composition and shape which happened to work.
(e) Similarly, it was unlikely that Professor Calne had struck upon the most efficacious molecule.
(f) Whether any particular molecule derived from rapamycin would work at all was impossible to predict with certainty.
(g) The number of possible derivatives of rapamycin is vast. It is almost certain that many of them would not exhibit immunosuppresant activity: just as it would not be possible to predict with certainty which derivatives have immunosuppressant activity, it would not be possible to predict how many would have such activity.
(h) It was likely, but not known, that the important part or parts of the shape of the rapamycin molecule was or were to be found on the macrolide ring.
(i) It was at the time possible to make changes to rapamycin which would be expected to produce little or no change to the shape of the macrolide ring and others which would be expected to produce large changes to the shape of that ring.
(j) Those derivatives of rapamycin which were most likely to work were those which involved small changes to the side chain rather than changes to the macrolide ring.
(k) A skilled addressee team would be able to make up a list of possible derivatives with those most likely to exhibit immunosuppressive activity at the top and those least likely to work at the bottom. Finding derivatives which work would involve a systematic and progressive iterative process in which different derivatives were made by modifying different parts of the rapamycin molecule. That process would not be rapid or guaranteed of success.
(l) Even if a rapamycin derivative were produced which had immunosuppressant activities, it would be impossible to be certain that it did not exhibit unpredictable defects, such as toxicity, low rates of absorption and so on which would render it unsuitable for clinical use. Discovering whether such defects exist would involve testing, some of it in vivo, and would take a long time."
8. The judge also held that "no-one in 1989 was able to set down on a piece of paper with certainty what other derivatives work": even among the experts, predicting which derivatives were most likely to work would produce different lists of candidate molecules. Also, testing rapamycin, which included in vitro and in vivo tests, was a lengthy and, no doubt, costly process. Doing the same for a number of derivatives would be commensurably longer and more costly.
The Patent
9. The patent is entitled "Use of rapamycin and derivatives and prodrugs thereof in the manufacture of a medicament for inhibiting transplant rejection in mammals". At the outset the specification states that the invention relates to the use of rapamycin for the preparation of a medicament for inhibiting organ or tissue transplant rejection in mammals. It goes on to explain what the judge set out in paragraph 3 of his judgment (see above). It then states, page 3 lines 19 to 21, that:
"It would be extremely useful to discover a compound having immunosuppressive activity which could be employed to increase transplant acceptance in a recipient but without causing serious toxic side effects typically associated with conventional immunosuppressant therapy, such as discussed above."
10. The patent continues with a review of what was known about rapamycin and then comes to the object of the inventor which was to discover a compound having increased immunosuppressant activity with low toxicity. There follows on page 3 lines 43 to 47 this description of what the inventor discovered.
"The present inventor has discovered that rapamycin can be used for the preparation of a medicament for inhibiting organ or tissue transplant rejection in a mammal in need thereof.
The present inventor has also discovered a pharmaceutical composition comprising (a) rapamycin in combination with (b) one or more other chemotherapeutic agents for inhibiting transplant rejection selected from the group consisting of azathioprine, corticosteroids, cyclosporin and FK-506."
11. The specification continues with two paragraphs relied on by the patentees to support their submission that the word "rapamycin", when used in claim 1, includes derivatives of rapamycin.
"Rapamycin is an antifungal antibiotic which is extractable from a streptomycete, e.g. Streptomyces hygroscopicus. Methods for the preparation of rapamycin are disclosed in Sehgal et al., US Patent Nos 3,929,992 and 3,993,749. In addition monoacyl and diacyl derivatives of rapamycin and methods for their preparation are disclosed by Rakhit US Patent No. 4,316,885. Furthermore, Stella et al., US Patent No. 4,650,803 disclose water soluble prodrugs of rapamycin i.e. rapamycin derivatives including the following rapamycin prodrugs: glycinate prodrugs, propionate prodrugs and the pyrrolidino butyrate prodrugs.
The present invention includes the use of natural and synthetic rapamycin, genetically engineered rapamycin and all derivatives and prodrugs of rapamycin, such as described in the aforementioned US patents, US Patent Nos 3,929,992: 3,993,749: 4,316,885: and 4,650.803."
12. The specification goes on to explain that the inventor had noted the efficacy of rapamycin in inhibiting transplant rejection e.g. by depressing the immune system in mammals without the attendant toxic side-effects associated with other conventional immunosuppressive agents. It also explains how rapamycin can be used in combination with other drugs. To illustrate the invention the specification sets out the results of studies that were conducted using rapamycin on rats and pigs.
13. The specification ends with this conclusion:
"In conclusion, rapamycin is a very effective immunosuppressive agent which can be employed to inhibit allograft transplantation rejection in mammalian subjects."
14. There follows 11 claims of which only claim 1, 5 and 11 are relevant.
"1. Use of rapamycin for the preparation of a medicament for inhibiting organ or tissue transplant rejection in a mammal in need thereof."
5. Use of rapamycin according to any one of claims 1 to 4, wherein said medicament is formulated for administration of rapamycin to said mammal in an amount of from 1 to 5 mg/kg/day.
11. A pharmaceutical composition for use as a medicament comprising a combination of (a) rapamycin and (b) one or more chemotherapeutic agents from the group consisting of azathioprine, corticosteroids, cyclosporin and FK-506."
Infringement - the appeal
15. The main issues on the appeal depend upon the construction of claim 1. The primary issue concerns the meaning of the word "rapamycin" in claim 1. In particular, whether SDZ RAD, being a derivative of rapamycin, falls within the claim.
16. Mr Baldwin QC, counsel for the patentees, submitted that claim 1 should be read as meaning "rapamycin itself and derivatives thereof which exhibit the same type of inhibition to organ rejection as rapamycin and which are suitable for the preparation of a medicament for inhibiting organ or tissue transplant rejection in a mammal." The judge, I think, construed claim 1 differently. He construed the word "rapamycin" as including derivatives with the result that the functional words in the claim limited it to rapamycin and its derivatives which were suitable for preparation of a medicament which was suitable for treating organ transplant rejection. He said in paragraph 46 of his judgment:
"46. .... Notwithstanding the wording used in the claims, I have come to the conclusion that the scope of protection afforded by the patent includes derivatives of rapamycin. It does not, however, cover all derivatives. The claims refer to the use of rapamycin in the preparation of "a medicament for inhibiting organ or tissue transplant rejection". All the derivatives covered by the claims must have similar utility. It follows that the scope of the patent includes such derivatives of rapamycin as exhibit the same type of inhibition to organ rejection as rapamycin itself does."
17. Novartis submitted that the claim when properly construed was limited to use of rapamycin. They went on to submit that if its ambit was widened to include derivatives, or rapamycin-like derivatives, the patent was invalid because there was no sufficient disclosure to enable performance. I will come to the submissions on insufficiency, but first I will construe claim 1.
18. This Court has explained in a number of cases the correct approach to construction. The most recent is the explanation in paragraphs 18 to 26 of my judgment in Wheatley v Drillsafe Limited C.A. 5th July 2000. I shall adopt that approach.
19. In the present case, both parties put forward distinguished experts in the field of chemistry, transplant medicine and toxicology. Some of them expressed their views as to how the word "rapamycin" would be understood by them in the context of claim 1. Not surprisingly there was a difference of opinion. There is no need to resolve which opinion was right as they are irrelevant. The task of the Court, once educated as to technical words, is to interpret the claim as a claim, in the context of the specification, according to the principles laid down in the Protocol. None of the witnesses were qualified to do that and did not purport to do so.
20. The judge considered how the word "rapamycin" had been used in the specification. He held that "all the description in the specification is directed at a single known chemical." I agree. Throughout the specification the word "rapamycin" is used to denote the molecule rapamycin. In a passage, I have quoted the specification states that "the present inventor has discovered that rapamycin can be used for preparation of a medicament ...." for treating transplant rejection. That must be read as meaning rapamycin itself. The specification four lines later states that "the present invention provides the use of rapamycin for the preparation of a medicament for inhibiting organ or tissue transplant rejection ...". A similar statement is made in the concluding paragraph of the specification. That amounts to a clear statement that the invention was the use of rapamycin itself, not a derivative. That is not surprising as no derivative had at that time been produced and tried and as the judge found "finding other similar molecules (to rapamycin) with similar activities would have been a long and laborious job." The only references to derivatives are in the title and in the passage on page 3 line 54 to page 4 line 3. That passage draws the distinction between rapamycin and derivatives, but the specification does not itself identify a single derivative which had been shown to work.
21. Against that background I turn to consider the question of infringement with the aid of the questions, called in Wheatley "the Protocol questions".
22. Question 1 - Does the variant have a material effect upon the way that the invention worked?
It is important to have in mind that the invention is the discovery of a second medical use for rapamycin. The variation is the class of compounds called derivatives of rapamycin. The actual variant in issue is SDZ RAD.
23. Mr Baldwin relied upon the functional parts of the claim. He submitted that as the claim only covered variants which were suitable for producing a medicament which had to be suitable for inhibiting rejection, the variants could not have a material effect upon the way that the invention worked. Further the functional limitation meant that the second question would be answered in the affirmative as it would be obvious that the variant would work in the same way.
24. That submission, as Mr Carr QC, who appeared for Novartis pointed out, meant that the first two Protocol questions had to be answered in a patentee's favour if a claim was limited to variants which would work and obviously work. The fallacy involved in that approach can be demonstrated by taking SDZ RAD, the derivative in question, as the variant. The invention is the second medical use of rapamycin. Thus the first question can be stated as - Does the variant, the derivative of rapamycin called SDZ RAD, have a material effect upon the way that the invention worked, namely the way rapamycin worked as a medicament for inhibiting rejection? So stated it is clear that the variant is the derivative and the invention to be considered is the second medical use contained in the functional requirements of the claim.
25. I think Mr Baldwin realised that there could be difficulty in relying upon the functional part of the claim to answer the first two questions. It was for that reason that he submitted that the variants, the derivatives, should be limited to those that had rapamycin-like activity. If that was the definition, then the first two questions would be answered in the affirmative. The conclusion is logically right, but it is a hopeless submission. As the judge held, the specification used the word "rapamycin" as denoting the molecule rapamycin. Derivatives are referred to in the passage bridging pages 3 and 4 and in the heading. The word "derivative" is never qualified: to the contrary the passage at the top of page 4 states in terms "The present invention includes use of natural and synthetic rapamycin, genetically engineered rapamycin and all [my emphasis] derivatives and prodrugs of rapamycin ...". There is no basis in the specification to enable the skilled person to decide whether a particular derivative had rapamycin-like effect other than the requirement of the functional part of the claim. Some test or standard would be needed before such a limitation could be read into the claim, particularly as the mechanism by which rapamycin worked was not known nor was it described in the specification (see above in paragraph 37(c) of the judge's judgment). Thus such a claim would never have been allowed by the European Patent Office and would be invalid for insufficiency.
26. It is sufficient, for the purpose of answering the first question, to take SDZ RAD as the variant. Although the judge did not make any explicit finding as to the equivalence of SDZ RAD to rapamycin, there was evidence that use of SDZ RAD would not materially affect the way the invention worked. I will therefore assume that question 1 should be answered in favour of the patentee, namely in the affirmative.

27. Question 2 - Would it have been obvious to a skilled person that the variant would not have a material effect upon the way the invention worked?
I have already rejected the primary submission of the patentees that the answer should be in the affirmative because the variant was a derivative which had rapamycin-like effect or was a derivative which complied with the functional limitation in the claim. The variant is either all derivatives of rapamycin or the particular derivative SDZ RAD.
28. Upon the findings of fact by the judge, this question has to be answered "No". As the judge held, there was, at the date of the patent, a strong probability that other derivatives would work, but it was impossible to predict with certainty whether any particular one would. It may be that SDZ RAD was a good candidate to try, but it was not obvious that it would work as an immunosuppressant. To find out, the product would have to be made and tested. A similar conclusion would be reached for other derivatives. At most it was likely that one or more derivatives would work, but which would require research.
29. Mr Baldwin, relying upon a sentence in my judgment in Wheatley, submitted that this question should be modified so that an affirmative answer would be obtained if the skilled person would have expected that the variant would not produce a material effect. That submission fails for two reasons. First the judge did not find that the skilled person would have had that expectation. Second, the modification of the question is inconsistent with the settled law and I believe with the aim of the Protocol. As I pointed out in Wheatley, it is fair to the patentee to include within the claim immaterial variants and to exclude material variants: thus question 1. However third parties have to be taken into account. Question 2 is designed for that purpose in that it excludes variants unless third parties should have realised they were immaterial. For there to be reasonable certainty, those are the variants which are obviously or clearly immaterial.
30. Mr Baldwin reminded us that the patentees had disclosed that rapamycin was a good immunosuppressant. He submitted that that disclosure had given to the world, not only the second medical use of rapamycin, but also the knowledge that derivatives of rapamycin would work as immunosuppressants. It followed that the technical contribution of the patent extended beyond the second medical use of rapamycin and included derivatives which had the same effect. That submission fails upon the facts found by the judge. The skilled person, who read the specification, would not be able to predict how many derivatives would have the appropriate effect nor be able to predict with any certainty whether any would or which would. The inventor, as stated in the specification, had only discovered and described the second medical use of rapamycin. It was left to others to find out which derivatives, if any, worked. Also, concentration on what was the technical contribution does not reflect the true task of the court which is construction of the claim according to the Protocol. As pointed out in Wheatley, it is unfair to a patentee to construe his claim in a way not intended. To ignore a limitation could render a patent invalid contrary to the wishes of the patentee. In any case it would be unfair to third parties to construe a claim in a way that the patentee had indicated by language that it should not be construed. That of course is the purpose of the third question which does not arise in this case as I have answered question 2 in the negative. However I will go on to consider question 3 upon the assumption that question 2 was answered in the affirmative.
31. Question 3 - Would the skilled person have understood from the language of the claim that the patentee intended that strict compliance with the primary meaning was an essential requirement of the invention?
In my view the answer must be "Yes". As I have explained the specification throughout uses the word "rapamycin" as denoting the molecule rapamycin. Derivatives are referred to as such. It would therefore be surprising if a different nomenclature was used in the claims. Second the specification sets out on page 3 line 43 to 47 what the inventor discovered, namely that rapamycin was a useful immunosuppressant either by itself or in combination with other drugs. It would therefore be surprising to find in the claim that the word "rapamycin" was used in a different sense as meaning compounds extending outside the discovery. The suggestion that all derivatives were included could not be right as the skilled person would not believe that they would all work. Third, claim 1 is not a claim which contains words which are difficult to construe. The word "rapamycin" prima facie has the same meaning in the claim as it does in the specification. If the patentee had intended to cover derivatives, he could easily have done so. Fourth, a claim to rapamycin and rapamycin derivatives or rapamycin-like derivatives would not have been allowed by the European Patent Office as it would have lacked support and would have been speculative. This forms the basis of the insufficiency dispute to which I turn. To do that I shall assume that claim 1 should be construed as suggested by the patentees despite the conclusion reached that Novartis are right on construction.
32. Section 72(1)(c) of the Patents Act 1977 provides that a patent may be revoked on the ground that "the specification of the patent does not disclose the invention clearly enough and completely enough for it to be performed by a person skilled in the art."
33. Having regard to the findings of fact made by the judge, there is no dispute as to what is the disclosure in the specification. But there are two differences of substance between the parties. The first requires a decision as to whether the disclosure has to be sufficient for the full ambit of the claim to be performed and the second, what particularity of disclosure is necessary.
34. The first was settled in principle by the House of Lords in Biogen Inc v Medeva Plc [1997] RPC 1. The reasons for the conclusion reached were given by Lord Hoffmann. In the relevant passages of his speech he also indicated, in general terms, the answer to the second. At page 53 he pointed out that his reasons for deciding that the Biogen patent was not entitled to the earliest priority date applied to consideration of whether the claims were sufficient. That reasoning appears at pages 47 to 49. The parts relevant to section 72 are as follows:
" The concept of an enabling disclosure is central to the law of patents. For present purposes, it touches the matters in issue at three different points. First, as we have seen, it forms part of the requirement of "support" in section 5(2)(a). Secondly, it is one of the requirements of a valid application in section 14. And thirdly, it is essential to one of the grounds for the revocation of a patent in section 72. I shall start with section 14. Subsection (3) says:
"The specification of an application shall disclose the invention in a manner which is clear enough and complete enough for the invention to be performed by a person skilled in the art."
This is plainly a requirement of an "enabling disclosure". In addition, subsection (5)(c) says that the claim or claims shall be "supported by the description". It was by reference to subsection (3) that Lord Oliver of Aylmerton, who gave the leading speech in Asahi, reasoned at page 536 that a description would not "support" the claims for the purpose of subsection (5)(c) unless it contained sufficient material to enable the specification to constitute the enabling disclosure which subsection (3) required: "the Act can hardly have contemplated a complete application for a patent lacking some of the material necessary to sustain the claims made". By parity of reasoning, he said that "support" must have the same meaning in section 5(2)(a).
The absence of an enabling disclosure is likewise one of the grounds for the revocation of a patent specified in section 72(1). Paragraph (c) says that one such ground is that -
"the specification of the patent does not disclose the invention clearly enough and completely enough for it to be performed by a person skilled in the art."
This is entirely in accordance with what one would expect. The requirement of an enabling disclosure in a patent application is a matter of substance and not form. Its absence should therefore be a ground not only for refusal of the application but also for revocation of the patent after grant. Similarly, the same concept is involved in the question of whether the patent is entitled to priority from an earlier application. This is not to say that the question in each case is the same. The purposes for which the question is being asked are different. But the underlying concept is the same.
The need for an enabling disclosure to satisfy the requirements of support under section 5(2)(a), valid application under section 14 and sufficiency under section 72(1)(c) has, I think, been plain and undisputed since the decision in Asahi. What has been less clear is what the concept of an enabling disclosure means. Part of the difficulty has been caused by a misinterpretation of what the Technical Board of Appeal of the E.P.O. said in Genentech I/Polypeptide expression (T 292/85) [1989] O.J. E.P.O. 275. This was a patent for a plasmid suitable for transforming a bacterial host which included an expression control sequence or "regulon" which could enable the expression of foreign DNA as a recoverable polypeptide. The Examining Division was willing to grant a patent only in respect of the plasmids, bacteria and polypeptides known at the date of application. The Technical Board of Appeal allowed the appeal, saying that the Examining Division had taken too narrow a view of the requirement of enabling disclosure:
"What is also important in the present case is the irrelevancy of the particular choice of a variant within the functional terms ´bacteria', ´regulon' or ´plasmid'. It is not just that some result within the range of polypeptides is obtained in each case but it is the same polypeptide which is expressed, independent of the choice of these means. ... Unless variants of components are also embraced in the claims, which are, now or later on, equally suitable to achieve the same effect in a manner which could not have been envisaged without the invention, the protection provided by the patent would be ineffectual ... The character of the invention this time is one of general methodology which is fully applicable with any starting material, and is, as it was already stated, also independent from the known, trivial, or inventive character of the end-products." [paras. 3.1.3, 3.1.5, 3.3.2]
In other words, the applicants had invented a general principle for enabling plasmids to control the expression of polypeptides in bacteria and there was no reason to believe that it would not work equally well with any plasmid, bacterium or polypeptide. The patent was therefore granted in general terms.
In Mölnlycke AB v. Procter & Gamble Ltd [1992] F.S.R. 549, however, Morritt J. interpreted this decision to mean that it was a general rule of European patent law that an invention was sufficiently disclosed if the skilled man could make a single embodiment. This interpretation was followed by Aldous J. in Chiron Corporation v. Organon Teknika Ltd [1994] F.S.R. 202, although I think I detect in his judgment some surprise that the E.P.O. should have adopted such a mechanistic and impoverished approach to the concept of enabling disclosure. As we shall see, he applied the same rule in the present case.
In fact the Board in Genentech I/Polypeptide expression was doing no more than apply a principle of patent law which has long been established in the United Kingdom, namely, that the specification must enable the invention to be performed to the full extent of the monopoly claimed. If the invention discloses a principle capable of general application, the claims may be in correspondingly general terms. The patentee need not show that he has proved its application in every individual instance. On the other hand, if the claims include a number of discrete methods or products, the patentee must enable the invention to be performed in respect of each of them.
Thus if the patentee has hit upon a new product which has a beneficial effect but cannot demonstrate that there is a common principle by which that effect will be shared by other products of the same class, he will be entitled to a patent for that product but not for the class, even though some may subsequently turn out to have the same beneficial effect: see May & Baker Ltd. v. Boots Pure Drug Co. Ltd. (1950) 67 R.P.C. 23, 50. On the other hand, if he has disclosed a beneficial property which is common to the class, he will be entitled to a patent for all products of that class (assuming them to be new) even though he has not himself made more than one or two of them.
I think that in concentrating upon the question of whether Professor Murray's invention could, so to speak, deliver the goods across the full width of the patent or priority document, the courts and the E.P.O. allowed their attention to be diverted from what seems to me in this particular case the critical issue. It is not whether the claimed invention could deliver the goods, but whether the claims cover other ways in which they might be delivered: ways which owe nothing to the teaching of the patent or any principle which it disclosed.
It will be remembered that in Genentech I/Polypeptide expression the Technical Board spoke of the need for the patent to give protection against other ways of achieving the same effect "in a manner which could not have been envisaged without the invention". This shows that there is more than one way in which the breadth of a claim may exceed the technical contribution to the art embodied in the invention. The patent may claim results which it does not enable, such as making a wide class of products when it enables only one of those products and discloses no principle which would enable others to be made. Or it may claim every way of achieving a result when it enables only one way and it is possible to envisage other ways of achieving that result which make no use of the invention."
35. Mr Baldwin submitted that the inventor had disclosed in the specification a beneficial property of a class of products, namely that rapamcyin and derivatives with rapamycin-effect had immunosuppressant qualities. I disagree.
36. As the judge held, Professor Calne hit upon a new use for rapamycin. The specification contains an enabling disclosure of that product. Whether any particular molecule derived from rapamycin would work at all was impossible to predict with certainty nor how many would have immunosuppressant activity. Even if a rapamycin derivative were produced which had immunosuppressant activity, it would be impossible to be certain that it did not exhibit unpredictable defects. Discovering those defects would need in vivo tests which would take a long time. As the judge described the claim, it covered all the molecules which would work, but left it uncertain as to which ones do and how many of them there are. Such a claim does not reflect a class with a unifying characteristic. It is a claim to a number of compounds with the number and identity being left to the skilled person to find out.
37. Professor Calne had not discovered nor had he disclosed in his patent a class or a beneficial property of a class of compounds. Rapamycin had before the priority date been reported as inhibiting two experimental immunopathies (see page 3 line 25 of the specification). But the reports did not, according to the specification, teach its use for transplant rejection in mammals nor did they disclose the discovered beneficial effect on toxicity. The invention as described was the discovery that rapamycin had those advantages. Some derivatives would be expected to have similar advantages, but the skilled person would not be able to predict which ones would have that actuality and, even if the right one was selected, it would take prolonged tests to find out whether it had the appropriate qualities. It follows that, as Lord Hoffmann pointed out in Biogen, the patent, to be sufficient, must provide an enabling disclosure across the breadth of the claim.
38. General guidance was given by this Court in Mentor Corporation v Hollister Inc [1993] RPC 7 on what was required to establish an enabling disclosure, or to put it another way, what standard of disclosure was needed for a patent to be sufficient as required by section 72(1)(c). At page 10 Lloyd LJ said:
"But if a working definition is required then one cannot do better than that proposed by Buckley LJ in giving the judgment of the Court of Appeal in Valensi v. British Radio Corporation [1973] R.P.C. 337. After referring to a number of earlier authorities, including Edison & Swan v. Holland, he said:
"We think that the effect of these cases as a whole is to show that the hypothetical addressee is not a person of exceptional skill and knowledge, that he is not to be expected to exercise any invention nor any prolonged research, inquiry or experiment. He must, however, be prepared to display a reasonable degree of skill and common knowledge of the art in making trials and to correct obvious errors in the specification if a means of correcting them can readily be found."
Then a little later:
"Further, we are of the opinion that it is not only inventive steps that cannot be required of the addressee. While the addressee must be taken as a person with a will to make the instructions work, he is not to be called upon to make a prolonged study of matters which present some initial difficulty: and, in particular, if there are actual errors in the specification - if the apparatus really will not work without departing from what is described - then, unless both the existence of the error and the way to correct it can quickly be discovered by an addressee of the degree of skill and knowledge which we envisage, the description is insufficient."
In that case there was a mistake in the specification. But Buckley LJ's language is equally apt to cover an omission. Aldous J held that the Valensi test is as apposite under the 1977 Act as it was under the 1949 Act. I agree."
39. It is also right to bear in mind what I said in that case, cited by Lloyd LJ at page 11. He said:
"It is dangerous to generalise. Aldous J made the point well in his judgment in the present case (at page 19B to D):
"Even where patents relate to articles, the inventions disclosed in different specifications can be different in kind. For example, the invention disclosed may relate to an article which will perform a particular function or an article which is cheaper to make than similar articles. In the latter case, it is the very essence of the invention disclosed in the specification that the article can be made more cheaply and therefore to perform the invention, the person skilled in the art must be able to make the article cheaply as described in the specification. In the former case, the person skilled in the art must be able to produce the article which will perform the function, as that is the invention disclosed".
Then a little later he said:
"In each case, it is a question of fact, depending on the nature of the invention, as to whether the steps needed to perform the invention are ordinary steps of trial and error which a skilled man would realise would be necessary and normal to produce a practical result."
40. There is a difference between on the one hand a specification which requires the skilled person to use his skill and application to perform the invention and, on the other, a specification which requires the skilled person to go to the expense and labour of trying to ascertain whether some product has the required properties. When carrying out the former the skilled person is trying to perform the invention, whereas the latter requires him to go further and to carry out research to ascertain how the invention is to be performed. If the latter is required the specification would appear to be insufficient.
41. The patentees wish to construe claim 1 to include derivatives of rapamycin which exhibit inhibition to organ rejection like rapamycin itself. Thus upon the patentees' construction, the specification must teach how to perform the invention with such derivatives of rapamycin. Upon the judge's findings of fact, the specification does not contain that teaching and therefore the patent would be insufficient, if that were the correct construction of claim 1.
42. The judge held that the number of possible derivatives was vast and whether any particular molecule derived from rapamycin would work at all was impossible to predict with certainty. Many derivatives would not exhibit immunosuppressant activity. Those which involved small changes to the side chain would be the most likely to work. Thus the skilled person could make up a list of possibles, with those believed to be the most likely at the top of the list. Even so, finding appropriate derivatives, if they existed, would involve a systematic and iterative process. Further, when a derivative which had appropriate activity had been identified, it would be impossible to be certain that it did not exhibit unpredictable defects. To discover whether it did would require further tests which would take a long time.
43. The very uncertainty and unpredictability found by the judge meant that the skilled person was being required to carry out research. The duty upon the patentee is to provide a description which enables the skilled person to perform the invention, in this case across the breadth of the claim; not to supply a starting point for a research programme. If the claim includes derivatives of rapamycin, an enabling description of such derivatives is needed so that the products of the claim can be ascertained.
44. The judge concluded in paragraph 65 of his judgment that the "amount of work involved in finding useful derivatives of rapamycin does not impose an undue burden on those working in the field and this argument of insufficiency fails." However the specification has to be sufficient to enable the invention to be performed. There is a difference between research to find out which derivatives work and the application of the teaching in the specification with appropriate skill and tenacity. In this case the specification tells the skilled man where to start but, upon the construction of claim 1 sought by the patentees, it leaves him to ascertain by research what will work. Once it is appreciated that a claim which encompasses derivatives has to be sufficient across its breadth, the extent of the research task becomes apparent. The number of derivatives is vast and the task of ascertaining which will satisfy the functional part of the claim will also be vast and correspondingly burdensome.

45. The judge appears to have been influenced by his view as to the needs of a patentee, such as Professor Sir Roy Calne, who has discovered a second medical use of one molecule, to obtain a monopoly covering more than the particular molecule in a case where the skilled person would realise that some derivatives were likely to work. This can be illustrated from these paragraphs in his judgment:
"44. I do not believe that any reasonable and objective person skilled in the art would read this patent as indicating that the inventive contribution was limited to rapamycin alone or that Professor Calne intended to restrict his monopoly simply to the use of that single chemical. ... To do that would have rendered the patent virtually valueless. It would have left out of its scope, for example, those closely similar molecules which could be derived by standard chemistry from rapamycin and which probably would have included many which those in the art would have expected to have equivalent or even better immunosuppressant properties. It would have disclosed to the art the novel seam of interrelated molecules but have claimed only one of them. In practice it was inevitable that the discovery of the activity of rapamycin would lead workers in the art to look for similar molecules derived from rapamycin which would have a better profile of properties. That is inherent in the evidence of Professor Acheson, another of the defendants' expert witnesses. He said:
"I have been informed by Novartis that the aim of the SDZ RAD program within Novartis was to develop new and improved rapamycin derivatives. Such a project was clearly justifiable. There is no reason why a natural product, such as rapamycin, should be the best drug for treating a particular medical condition. There are known examples of synthetic derivatives, developed from a natural product, which show improved or advantageous functions and properties over the natural product itself. The production and screening of potentially useful derivatives is a huge task but vital. Because there is no sure way of predicting which derivatives of complex biological molecules, if any, will possess new and improved properties, it is, however, a high risk venture."
64. ... Furthermore, even if Professor Calne had been lucky and sufficiently funded enough to have a large team of technicians working with him so that he had been able to put into his patent application not only the good news about rapamycin but also the same good news about one or two derivatives, Mr. Carr's argument would have applied with exactly the same force to all the other derivatives which had not been tried by the Professor and his team. In addition Mr. Carr's argument would apply with equal force whether the scope of the patent is as I have held it to be here, namely applying to rapamycin and working derivatives, or had been limited to an arbitrary list of identified derivatives. In each case the same process of synthesis and testing would be needed. It would follow that the only safe course in this field would be to limit one's patents to those molecules you have tried and tested. Again, that would make patents in relation to pharmaceuticals more or less valueless. As a practical matter it is likely that full testing even of one molecule such as rapamycin itself is not possible before a patent is applied for."
46. For my part I do not agree that a patent limited to the second use of rapamycin is virtually valueless. The patent protects the second medical use and the long and expensive work that has been carried out to obtain regulatory approval. Thus a person who wishes to market a derivative has to make the derivative and then carry out the long and expensive work needed to get it on the market. Without the patent, other manufacturers could use the work of the patentees. In any case, I do not believe that the patent system should be used to enable a person to monopolise more than that which he has described in sufficient detail to amount to an enabling disclosure. If it was, it would in this case stifle research to find a derivative of rapamycin which was a substantially better immunosuppressant than rapamycin itself. This statement by Lord Hoffmann in respect of the work done by Professor Murray, the inventor of the Biogen patent is, I believe, apt:
"It is said that what Professor Murray showed by his invention was that it could be done. HBV antigens could be produced by expressing Dane particle DNA in a host cell. Those who followed, even by different routes, could have greater confidence by reason of his success. I do not think that this is enough to justify a monopoly of the whole field. I suppose it could be said that Samuel Morse had shown that electric telegraphy could be done. The Wright Brothers showed that heavier-than-air flight was possible, but that did not entitle them to a monopoly of heavier-than-air flying machines. It is inevitable in a young science, like electricity in the early nineteenth century or flying at the turn of the last century or recombinant DNA technology in the 1970s, that dramatically new things will be done for the first time. The technical contribution made in such cases deserved to be recognised. But care is needed not to stifle further research and healthy competition by allowing the first person who has found a way of achieving an obviously desirable goal to monopolise every other way of doing so. (See Merges and Nelson, On the Complex Economics of Patent Scope (1990) 90 Columbia Law Review 839.)"
47. I conclude that if claim 1 were to be construed in the way suggested by the patentees, it would be invalid.
Respondents' Notice
48. The patentees contended in this Court that infringement had been established even if claim 1 was restricted to the use of rapamycin itself. The judge did not have to deal with those contentions and did not do so.
49. First the patentees submitted that Novartis had infringed because they had done an act falling within section 60(1)(c) of the 1977 Act. That provides that a person infringes if:
"Where the invention is a process, he disposes of, offers to dispose of, uses or imports any product obtained directly by means of that process, or keeps any such product whether for disposal or otherwise."
50. The patentees submitted that claim 1 was a process claim. Novartis had manufactured SDZ using rapamycin as the starting material. The first step was to alkylate the C40 hydroxyl. The second step was to hydrolyse off the silyl group to give SDZ RAD. Thus Novartis had imported a product (SDZ RAD) obtained by means of the process of claim 1 in that they had used rapamycin for the preparation of a medicament (SDZ RAD) which was suitable for inhibiting transplant rejection.
51. The simplicity of the patentees' submission hides the difficulties. As Mr Carr pointed out, the submission involves reading the word "medicament" as covering any medicament which will inhibit transplant rejection. If so, the only connection that the medicament would have with rapamycin would be that it was the starting material or a starting material used in what might be a complex manufacturing process. Such a construction would result in the claim being hopelessly invalid on the ground of insufficiency because there is no enabling disclosure of any medicament other than rapamycin.
52. The claim has to be construed in context. It is a Swiss-type claim to an invention for a the second medical use of rapamycin. As the specification makes clear, the medicament that provides the inhibition is rapamycin. There is no disclosure of any other medicament. It would be unfair to the patentee to construe the word "medicament" as meaning any product whether or not it contained rapamycin as that would render the patent invalid. SDZ RAD is not a medicament within the meaning of that word in claim 1. As I have pointed out the claim is not a claim to a class or principle and therefore it has to be sufficient across its width. It follows that the claim, to be construed as suggested would be invalid unless there was an enabling disclosure of medicaments which might not have any rapamycin present and their method of manufacture. There are none. I did not understand that Mr Baldwin wished the claim to be construed in a way that would make it invalid. It follows that the word "medicament" must be construed as referring to the product rapamycin which is the product described in the specification as having been discovered by the inventor to have the beneficial immunosuppressant properties.
53. The second submission was that Novartis had imported a product made by the process of claim 1 which had the essential characteristics of rapamycin. In effect the relevant identity of rapamycin was present in SDZ RAD. That submission cannot be accepted for the same reasons. It is in essence a reformulation of previous submissions made by the patentees.
54. SDZ RAD is a derivative of rapamycin. Chemically it retains a substantial part of the molecule rapamycin. For it to come within the ambit of claim 1, the word "rapamycin" must be construed as covering derivatives of rapamycin which retain the essential characteristics of rapamycin. For the reasons I have given that is not a possible construction. If it was, the patent would have been invalid for insufficiency.
55. The third submission relies upon the fact that up to 0.8% of SDZ RAD is rapamycin. It is there as an impurity due to the fact that it is the starting material for the manufacturing process of SDZ RAD. I am prepared to accept that the therapeutic effect of the rapamycin will be in proportion to its amount. Even so, the claim is not infringed. To construe claim 1 as covering a medicament which only contains 0.8% rapamycin would be contrary to all rules of construction. The technical contribution of the inventor was the discovery of the second medical use of rapamycin. He did not discover that medicaments which only contained 0.8% rapamycin had any therapeutic effect and there is no enabling disclosure of how to make such a medicament. As Lord Hoffmann pointed out in Biogen, the concept of an enabling disclosure is central to the law of patents. It is only necessary to contemplate answering the Protocol questions in respect to a variant where the medicament included only 0.8% rapamycin to see that the claim must be construed as meaning that the medicament has to be essentially rapamycin.
56. The patentees also relied upon claim 11. This claim must also be construed in context. For the reasons already given this claim is not infringed.
57. Finally I draw attention to the decision of the District Court of the Hague Case No.99/1435 March 2000 which dealt with the corresponding Dutch patent. I note that that court came to the same conclusion as I have. However I have not relied upon the reasons given as we were told it was to be appealed and was decided upon different evidence.
58. For the reasons given, I have come to the conclusion that SDZ RAD does not infringe any claim of the patent. If so, the patent is sufficient. I would therefore allow the appeal and make an order to that effect.

59. I agree.
60. I also agree.
1. The Appeal is allowed.
2. The Respondent's notice is dismissed.
3. The Order of Laddie J made on 6th December 1999 is set aside.
4. The Respondent's claim of infringement of European Patent UK No 401747 ("the Patent") is dismissed.
5. (i) Novartis' costs of this Appeal and Respondents Notice, and (save as specified below) Novartis' costs at first instance be paid by the Respondents and each on them on the standard basis and subject to detailed assessment if not agreed.
(ii) Novartis' costs relating to the Counterclaim in Claim HC 1999 No. 03633 in respect of lack of novelty and lack of inventive stop be reserved to the judge at first instance at the trial of those issues.
(iii) Novartis have permission to apply for a payment on account of their costs pursuant to CPR Part 44.3(8)
6. And it is declared that the making, disposing of, offering to dispose of, using, importing, or keeping SDZ RAD in the United Kingdom does not infringe any claim of the Patent.
7. Permission to appeal to the House of Lords refused.
(Order does not form part of the approved judgment.)

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