England and Wales High Court (Patents Court) Decisions
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Cite as: [2000] EWHC Patents 154, [2000] RPC 709
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BAILII Citation Number: [2000] EWHC Patents 154
Case No. CH 1998 M 1421
IN THE HIGH COURT OF JUSTICE
CHANCERY DIVISION
PATENTS COURT
Date: 4 February 2000
Mr Justice Pumfrey
BETWEEN
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(1) MONSANTO COMPANY |
Claimant |
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– and – |
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(1) MERCK & CO INC |
Defendant |
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David Kitchin QC, Richard Meade and Charlotte May instructed
by Bristows for the Claimants
David Young QC, Justin Turner and Thomas Hinchliffe instructed
by Lovell White Durrant for the Defendant
Hearing date(s): 4-8, 11-15, 18-22 October 1999
JUDGMENT
I direct that no official shorthand note shall be taken of this judgment and that copies of this version as handed down may be treated as authentic.
DATED 4 February 2000
Introduction
- This is an action for infringement of European Patent (UK) 0 697 157 which stands in the name of the Claimants. The patent is said to relate to a potentially important new class of non-steroidal anti-inflammatory drugs, or NSAID’s. The defendants’ own name for the infringing material was MK-966 and this is how it was referred to during the action and how I shall refer to it. It is sold under the trade mark Vioxx, and its generic name is rofecoxib. Infringement of the patent is denied, and its validity challenged on the grounds of anticipation, obviousness, insufficiency and added matter. In order to meet some aspects of the challenge to validity the claimants apply to amend the patent in suit to limit the size of the class of compounds claimed. The allowability of this amendment is challenged on the ground that it also adds to the disclosure, and results in a patent open to all the objections levelled at the unamended patent.
- The claimants have a compound at the stage of obtaining approval in Europe which will compete with MK-966. It is called Celebrex (its generic name is celecoxib) and it is not suggested that it falls within the claims of the patent in suit. Their properties apart, there is no relationship between the claimants’ and defendants’ respective products.
- The hearing occupied some fifteen days, and much of the evidence was inevitably highly complex. The parties prepared a primer which was of great assistance but was to some extent overtaken when the experts and witnesses as to fact came to explain their views in detail. I shall not repeat what is set out in the primer in the judgment except when it is necessary to do so.
- NSAID’s have a long history. There are a large number of different families of compounds, and some of the drugs are household remedies. Aspirin, paracetamol, phenacetin and ibuprofen are all NSAID’s. These drugs, and certain more powerful compounds such as piroxicam are important because they are used for the treatment of pain and inflammation in chronic diseases such as arthritis. It is fairly generally known that they can cause irritation of the gastro-intestinal tract, and if administered over a prolonged period can cause bleeding and ulceration. For a very long time there has been a need for NSAID’s which do not possess this side effect. Indeed, included in the large number of literature references used at trial was an article suggesting that the discovery of aspirin (acetylsalicylic acid) at the end of the last century was the result of an attempt to find a drug less irritating to the stomach than sodium salicylate, the original NSAID. The term used during the trial was for this desirable property was "gastric sparing".
- I take the following account of the development of the understanding of the action of NSAID’s from Professor Flower’s evidence, which was unchallenged on this issue. There are two major classes of anti-inflammatory compounds, the steroids and the NSAID’s. In 1971, Sir John Vane and his colleagues discovered that aspirin, indomethacin and sodium salicylate had the ability to inhibit the synthesis of prostaglandins, and suggested that this was the major mode of operation of these drugs. Prostaglandins are chemicals which play a part in inflammation. There are a number of prostaglandins, and they are responsible for many of the body’s regulatory functions. The ones in which Vane was interested were those which were produced by the body during inflammation. They are synthesised in the body from arachidonic acid and other fatty acids via an enzyme then called prostaglandin H synthase, then fatty acid cyclooxygenase, and finally COX. Vane showed that NSAID’s directly inhibited COX in cell-free tissue extracts in vitro. This discovery explained the tendency of the NSAID’s, to cause stomach irritation and ulceration. The drugs cause the irritation because they inhibit the synthesis of the prostaglandin which is responsible for regulating the secretion of acid in the stomach and the secretion of the mucus which protects the lining of the stomach against being digested.
- This elucidation of the action of NSAID’s led immediately to a method of screening potential drugs for aspirin-like activity without having to perform in vivo experiments. Provided that a source of COX was available, the enzyme could be exposed to the drug, and its ability to synthesise prostaglandin from arachidonic acid could be measured. If the drug successfully inhibited COX, little arachidonic acid would be used to synthesise prostaglandin and the amount produced could be measured. At this time, all the enzyme available had to be derived from animal tissue; so there was dog spleen COX, rabbit brain COX, and so on.
- At this point I should explain a little about enzymes. Enzymes are proteins (polypeptides) and there are a vast number of them. The function of enzymes is to catalyse the chemical reactions upon which the functioning of the organism depends. Some enzymes are highly specific, catalysing one particular reaction. Others are much more general in their abilities. For example, some enzymes are capable of decomposing a variety of different proteins into their component amino acids. Enzymes are large molecules, and the way in which they work is subtle. In outline, every enzyme has one or more active sites. These active sites are designed to receive the molecule or molecules upon which the enzyme is to operate (called the substrate(s)) precisely orientated in such a way that certain of the groups of atoms in the molecule of enzyme exercise a particular chemical influence on the target groups of atoms in the substrate(s). As the catalysed reaction proceeds, chemical bonds are formed between the atoms of the substrate(s) and of the enzyme and are broken, so that the desired chemical reaction takes place.
- It is possible to fool an enzyme. Enzymes are sensitive to inhibition by chemicals which interfere with the binding of the substrate at the active site or with conversion of the enzyme-substrate combination into products. A chemical which has this effect is called an inhibitor, and the enzyme to which it is bound is said to be inhibited. Such inhibition may be permanent, in that unbreakable covalent bonds are formed, and the inhibition is irreversible. The body has to make new enzyme. Or the inhibitor may bind to the enzyme reversibly. If one were intending to design a molecule to inhibit a particular enzyme, it might be thought that the best approach would be to synthesise an inert molecule generally similar in shape and distribution of chemical groups to the enzyme’s intended substrate. But apparent similarity in shape is not necessary for a successful inhibitor. For example, arachidonic acid, the substrate of COX, has the structure shown in the following diagram of the start and end points of the synthesis of prostaglandins (Figure A)
- Successful inhibitors act in different ways, and may not appear to the unskilled eye to have a shape like the substrate (Figure B)
- Once the discovery of COX had been made, those responsible for the development of NSAID’s, having available an assay for the activity of a compound, were in a position easily to investigate both new NSAID’s and existing drugs.
- The evidence is that such development is carried out by a team of scientists representing three basic skills. The skills in question are those of the medical chemist, the pharmacologist and the biologist. The stages of the development of a drug are in vitro investigation; in vivo investigation in animals, and clinical trials. The medical chemist synthesises the compounds and is responsible for putting together the results gained from their investigation in vivo and in vitro. The biologist or enzymologist is responsible for designing and performing the necessary assays to assess the activity of the compound. The biologist is thus responsible for the design of assays which provide as good an insight as possible into the performance of the compound in vivo, first in animals and subsequently in humans. A pharmacologist is responsible for designing the dosage form of the drug and for investigating efficacy, toxicity and the pharmacokinetic properties of the drug in humans. Obviously, the early investigation of a class of compounds will be primarily the function of the medical chemist and of the biologist, who will refine the assays as the investigation proceeds.
- I heard evidence from representatives of all three components of the team. As is not uncommon in patent actions, the eminence and ability of the witnesses greatly exceeded the abilities which it would be fair to expect of the addressee of the specification, the person or persons who, in Lord Diplock’s phrase, have a practical interest in the subject matter of the invention. Thus for the claimants I heard evidence from Professor Sir Jack Baldwin FRS, presently head of the Dyson Perrins Laboratory in Oxford and a very eminent organic chemist. His counterparts on the defendants’ side were Professor Anthony Kirby FRS, the Professor of Bioorganic Chemistry at Cambridge and Professor Raymond Baker FRS, who is presently the Chief Executive of the Biotechnology and Biological Sciences Research Council after a career in industry and academia, having been both Professor of Organic Chemistry at Southampton and Executive Director of Medicinal Chemistry at the second defendant’s Neuroscience Research Centre. These were the principal experts on the chemical aspects of the case. On the pharmacological considerations the claimants called Professor Roderick Flower, a well known pharmacologist with long experience of NSAID’s. His counterpart was Professor Derek Willoughby. Professor Flower and Professor Willoughby both come from the William Harvey Research Institute, and both have a long-term interest in inflammatory diseases. The claimants called no expert on the subject of in vitro assays, but the defendants called Dr Percival, an in-house expert enzymologist. Expert evidence was also given by Dr Baillie on behalf of the defendants on the issue of metabolism. The employment of such a large number of experts in a patent action is to be discouraged, but in this case, I accept that there were three relevant areas of expertise so far as the addressee is concerned, and I permitted Dr Baillie to give expert evidence having regard to the way in which the contentions on metabolism of the alleged infringement came into the case. I was greatly assisted by counsel and by the manner in which the experts’ reports had been prepared by the parties’ solicitors who kept the overlap between the various experts to the minimum. All the experts and the witnesses of fact gave their evidence frankly and as helpfully as possible, and I have no criticism to make of any of them. Where I am asked to approach their evidence with caution it is because they simply knew far too much (Professor Baldwin, Professor Flower, Professor Kirby, Professor Willoughby) or because their expertise, though great, was not in the area of NSAID’s (Professor Baker). I shall deal with these criticisms as it is necessary to do so.
- It is clear that the skills of the medicinal chemist are central to the
task of developing a new drug. Professor Baker described the role of the
medical chemist in the development of a modern drug as follows, in a part
of his evidence which was not challenged.
The starting point for a drug discovery programme is to identify a pharmacological effect or an important feature of pharmacology which allows the establishment of an in vitro or in vivo assay. The assay will be dependent on the identification of an active site on an enzyme or target receptor which will be responsible for controlling a biological response. The basis of drug therapy, in its broadest terms, is the use of discrete chemical compounds to bind to the target thereby blocking the normal action of the enzyme or receptor. Once a target has been identified and, notwithstanding that the target would be associated with many different aspects of pharmacology, the fundamental aspects of medicinal chemistry programmes would follow similar lines. It is particularly important that a suitable in vitro assay is developed so that it can be used for assessing the biological activity of candidate compounds.
Once one or more lead compounds have been identified, it is normal procedure for a patent and literature search to be undertaken to find out what was known about such compounds including how they can be synthesised and what other similar compounds might have been investigated. It would be then necessary to identify the key features of the lead compounds which determine their ability to bind to the enzyme or receptor target.
To identify the key features of a lead compound it is common practice to synthesise and screen a number of structurally closely analogous compounds, which could be isomers or compounds differing by say one functional group at a time. In such a screening programme one would expect such closely analogous compounds to possess similar biological properties to the lead compound albeit that there will be differences in potency and/or specificity. The medicinal chemist would be particularly seeking molecules which would have good bioavailability and would also have in mind the question of toxicity. Some types of molecules are known to be associated with toxicity and the programme would be directed in such a way to avoid potential problems. The overall aim is, as far as possible, to develop a perfect compound with good activity, selective action, good in vivo properties, and a lack of any adverse effects in patients.
- The skills of the biologist or enzymologist lie in the design of suitable biochemical assays to test the compounds under consideration for useful activity. One such assay is carried out semi-automatically, by a method called ELISA which stands for Enzyme-Linked Immuno-Sorbent Assay. This assay method is used in two of the assays described in the patent. Such an assay must, if it is to give useful results, be optimised. I shall discuss the ELISA used by the claimants and the defendants when I consider the experimental evidence in the case.
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Figure A: Arachidonic acid/prostaglandin pathway
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Figure B: COX inhibitors
The process described by Professor Baker as the identification of the key features of the lead compounds which determine their ability to bind to the enzyme or receptor target is called producing an SAR or structure activity relationship. Elsewhere in his report Professor Baker says that it is standard practice for the medicinal chemist to generate an SAR.
Developments up to the priority date
- By the mid-1980’s a number of companies (including the defendants) had run their investigation of novel NSAID’s down. During the later 1970’s and the 1980’s it appears that at least two groups were working on the activity of NSAID’s in the inhibition of the COX enzyme. At DuPont, a long investigation into the properties of existing compounds had started in 1979/80, as Dr Galbraith described. This work consisted at that time of screening the compounds in vivo and the principal area of concentration was diaryl heterocycles. Such compounds are the subject of the two Haber patents relied on by the defendants in these proceedings as rendering the patent invalid. The diaryl heterocycles were (as far as the evidence went) 2,3 diaryl materials (Figure C)
- Among the results of this work was a compound called DuP 697, a description of which was published in 1989 in a patent applied for in 1984 relied on by the defendants ("Haber 2"). This compound is also the subject of a paper also relied on by the defendants to support their allegation of invalidity by Gans and others. DuP 697 was reported as having low gastric irritancy but good anti-inflammatory characteristics. The authors of this Gans paper hypothesised that its good gastric characteristics were due to tissue selectivity and its lack of an acid functional group in the molecule, a group possessed by the largest class of NSAID’s.
- During the 1980’s, other work was being carried out in relation to the prostaglandins and inflammation, particularly by Dr Needleman’s group both before and after he joined the claimants in 1989. By 1989, it had been demonstrated that some COX enzyme was manufactured by the body in response to inflammatory stimuli. This means that the COX responsible for the inflammatory response was not a purely constitutive enzyme (i.e. present all the time in the body). In 1988 Dr Needleman had hypothesised that there might be two different COX enzymes. Then in 1991 it was reported by a number of groups that there was in fact not one but two COX enzymes. The paper of one of these groups (Xie) is relied on by the defendants. In 1992 Dr Needleman’s group confirmed that there was a second COX enzyme which came to be called COX-2. The gene for this enzyme was cloned by late 1992, so making available supplies of recombinant COX-2 to all those who had access to the cloned gene.
- Finally, it is necessary to mention that Dr Galbraith delivered a paper at the Winter Prostaglandin Conference at Keystone, Colorado, in January 1992 in which he suggested that DuP 697 might be a selective COX inhibitor, and that such a mode of activity might explain its previously reported gastric-sparing qualities. This paper is an important plank in the defendants’ case and I shall consider its disclosure in detail below. DuP 697 was never commercialised by DuPont as it turned out to be eliminated very slowly from the body.
- So far as the claimants are concerned, Dr Galbraith’s disclosure led directly to an investigation of DuP 697. I shall deal with the details of this investigation when I come to consider obviousness. Dr Bertenshaw, the inventor of the patent in suit, was a member of the group which evolved out of the investigation of DuP 697. The most successful compound identified by the claimants and falling within the patent in suit was eventually dropped as a candidate compound because of poor bioavailability. The defendants on the other hand did not react to the Winter Prostaglandin conference because the person attending it had not sent her report of the proceedings to the right people in the company. They did, however, react to the Summer conference in the same year, when a compound called NS 398 was disclosed by Futaki. NS 398 is referred to in the patent in suit at page 3 lines 26 to 28. A literature search then led the defendants to DuP 697. Starting from DuP 697 the defendants also synthesised certain 3,4 disubstituted products within the claims during this investigation, and again I shall consider the significance of what they did when I come to consider obviousness.
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Figure C: 2,3 diaryl compounds
The Common General Knowledge
- In any patent action it is the task of the court to place itself in the
position of the addressee at the priority date, so as to see the world through
his eyes. To ascertain the common general knowledge to be attributed to
the addressee is an essential part of this process. The Court of Appeal
in General Tire v Firestone [1972] RPC 457 at 482 described the common
general knowledge in terms which have been substantially reproduced in the
more recent case of Beloit v Valmet [1997] RPC 489 at 494. It is,
in essence, the knowledge which the addressee of the specification can be
expected to have as part of his ordinary professional knowledge. This is
a case in which it is clear that the total of scientific knowledge relating
to COX was increasing rapidly at the priority date, and it is necessary
to be particularly cautious. Aldous LJ put it this way in Beloit:
It has never been easy to differentiate between common general knowledge and that which is known by some. It has become particularly difficult with the modern ability to circulate and retrieve information. Employees of some companies, with the use of libraries and patent departments, will become aware of information soon after it is published in a whole variety of documents; whereas others, without such advantages, may never do so until that information is accepted generally and put into practice. The notional skilled addressee is the ordinary man who may not have the advantages that some employees of large companies may have. The information in a patent specification is addressed to such a man and must contain sufficient details for him to understand and apply the invention. It will only lack an inventive step if it is obvious to such a man.
- The common general knowledge of the team of investigators to which I have referred at the claimed priority date of 15 January 1993 plainly included knowledge of how NSAID’s were thought to work, that is, by preventing the production of prostaglandin by inhibiting an enzyme in the arachidonic acid/prostaglandin pathway called COX. Sir John Vane’s explanation of the action of the NSAID’s was universally accepted as a good basis for further action. There is no doubt that the team would be aware of the properties of existing NSAID’s, including their tendency to irritate the stomach or cause ulcers. There is no doubt that the team could carry out the assays mentioned in the patent in suit, including the cloning of the gene responsible for human or murine COX.
- Where the dispute comes in the present case is whether the skilled man would know, as a matter of common general knowledge, about either the existence of the isozymes Cox I and Cox II or that one of the isozymes was inducible and was a target for NSAID research.
- As I have indicated, there were a number of groups who were steadily working
away at NSAID research and at research into prostaglandins. Dr Needleman
ran such a group. Dr Galbraith was a member of such a group. Professor Flower
was well acquainted with the work as it progressed. There must also have
been groups in Japan, Professor Flower identifies three other groups and
says this in his witness statement:
Needleman's group confirmed the role of a second Cox isozyme in inflammation in a 1992 publication . They reported data indicating the existence of a constitutive Cox enzyme, which is normally present in most tissue and is unaffected by steroids, and an inducible Cox which is expressed only in the context of inflammation and which is under steroid regulation. Referring to Simmons’ and Herschmann’s work they concluded that it was possible that the inducible Cox observed in the inflammation studies, and detected by polyclonal antibodies, might represent the expression of a second Cox gene product. Although I recall having heard Needleman's hypothesis before this publication I distinctly remember the impact that this paper made upon those working in the inflammation field when it appeared in 1992. Identification of this inducible isoform of Cox created a new focus of interest in prostaglandin biochemistry, pharmacology and therapeutics.
3. I think that it is clear that those working at the forefront of NSAID research were in all probability aware of the existence of Cox II and of its importance. Indeed, it appeared from Dr Galbraith’s evidence under cross-examination that all the information with which I am concerned was discussed at that conference by himself and the other speakers. The list of those attending survives, and although it represents a good cross-section of well-known chemical companies I cannot say that the attendees are representative of every company who might be interested in the subject matter of the patent. But a year elapsed from the Winter Prostaglandin conference to the priority date of the patent in suit, and another year until the application resulting in the patent in suit. By the application date for the patent in suit, I have no doubt that the Cox I/Cox II relationship, its importance and the fact that Cox II was a target for NSAID development was common general knowledge. On the whole of the evidence, and paying attention to that of Professor Flower, I think that it was also part of the knowledge of the skilled man, as a good basis for further action, at the claimed priority date.
Obviously this statement of principle has to be applied to the facts of the particular case. If the specification plainly makes assumptions about the level of skill of the addressee and the information available to him, it is always open to a defendant to choose whether to rely upon that assumption in support of the allegation of obviousness or to allege that the specification is insufficient. There are fields of industry in which the basic level of attainment is extremely high. The field with which I am concerned in this case is one such, and one would expect the addressee to have a number of years’ post-doctoral experience.
2. Professor Flower’s statement that the publication of the second COX enzyme made an impact "on those working in the inflammation field" clearly indicates the importance to be attached to this event. Dr Galbraith’s expectation was that at the Winter Prostaglandin conference in 1992 he would be told by Herschmann that the gene for Cox II had been cloned. Professor Flower was himself offered a sample of cells which could manufacture Cox II ("transfected with the cDNA coding for Cox II") by Dr Herschmann in 1992. Dr Isakson and Dr Prasit also gave evidence as to the impact of the availability of cell lines for Cox I and Cox II which confirms what Professor Flower said.
The patent in suit
- The patent is entitled ‘Novel 3,4-diaryl thiophenes and analogs thereof having use as anti-inflammatory agents". The opening words of the specification say that the invention relates to compounds, compositions and methods for treating inflammation and inflammation-associated disorders such as arthritis. Having identified the general nature of the compounds (3,4 diaryl substituted thiophene, furan and pyrrole derivatives and analogues thereof), it is said that the invention more particularly relates to selected effective and safe compounds having anti-inflammatory and/or analgesic activity without erosion of the stomach.
- The scientific context of the invention is described
in the four opening paragraphs of the section of the patent entitled "Background
to the invention". This section begins with a discussion of the role
of prostaglandins in the inflammation process. It points out that the common
NSAID’s which are effective in reducing the prostaglandin-induced pain and
swelling associated with inflammation are also active in affecting prostaglandin-regulated
processes not associated with inflammation. The specification continues:
Previous NSAID’s have been found to prevent the production of prostaglandins by inhibiting enzymes in the human arachidonic acid/prostaglandin pathway, including the enzyme cyclooxygenase (COX). Recently, the sequence of another heretofore unknown enzyme in the human arachidonic acid/prostaglandin pathway has been reported by T. Hia and K. Nielson, Proc. Natl. Acad, Sci, USA, 89, 7384 (1992) and named "cyclooxygenase II (COX II)" or "prostaglandin G/H synthase II". The discovery of an inducible enzyme associated with inflammation provides a viable target of inhibition which more effectively reduces inflammation and produces fewer and less drastic side effects. Cyclooxygenase II is inducible by cytokines or endotoxins and such induction is inhibited by glucocortoids (J. Masferrer et al, Proc. Natl. Acad. Sci. USA, 89, 3917 (1992)). The 6-methoxy-2-naphthylacetic acid metabolite of nabumetone has been found by E. Meade et al to selectively inhibit the COX II enzyme (J. Biol. Chem. 268, 6610 (1993)). In addition, Futaki et al (Gen. Pharmac., 24, 105 (1993)) has reported that N-(2-cyclohexyloxy-4-nitrophenyl)methanesulphonamide is anti-inflammatory and lacks gastric side effects.
- There follows a specific remark upon a limited class of compounds, the thiophenes, which are the compounds of claim 1 in which the heteroatom Y is sulphur.
4. After an acknowledgement of the prior art, the specification points out that the documents referred to show continuing efforts to find a safe and effective anti-inflammatory agent. After setting out the claim, the specification sets out the indications for which the claimed compounds would be useful, and concludes the list by saying that
9. The specification proceeds to list preferred and more preferred classes of compounds. The more preferred class corresponds to claim 7. This class also, on the claimants’ analysis, embraces the alleged infringement. It appears that it also covers a class of compounds not within claim 1 (see paragraph 146). A class of compounds of particular interest is identified in which X is hydrogen or a halogen. A "family" of specific compounds of particular interest is identified with each member of the family being individually set out. There are 122 or so members of this family, but the only one which I need to notice is at page 7 line 37, 4-[3-(4-methoxyphenyl)-2-bromo-fur-4-yl]benzenesulphonamide. This is compound 68 in the defendants’ Notice of Experiments.
10. Formula II on page 8 of the specification represents a "subclass of compounds of high interest" within formula I. These compounds correspond to claim 9. This claim is not alleged to be infringed. Various subclasses are stated to be preferred within this class on page 8. A list of compounds said to be of particular interest within Formula II is also given. After setting out a long passage of definitions of chemical terms used in the claims and elsewhere, the term "pharmaceutically acceptable salt" is defined, which I consider in detail in paragraph 224.
11. The synthetic procedures which are described do not call for special comment. There was a challenge to the sufficiency of the specification in relation to certain prescribed compounds, but that objection is not pressed. It should be noted that in a number of cases a compound is said to be within the claim (compound 11 in scheme III for example), and is also an intermediate to another compound within the claim (see schemes V and VIII). Schemes IX and X provide further examples.
12. The text may be picked up at page 31, where the biological evaluation of the compounds are described. Two in vivo and two in vitro tests are described. The in vivo tests are well established tests carried out on rats to evaluate NSAID’s, and form part of the common general knowledge. It should be noted that such evaluations are performed only in respect of those compounds which have already demonstrated promise in vitro. In summary, the carrageenan foot pad oedema test is to determine whether the compound reduces the inflammation-induced swelling induced in a rat’s paw caused by injection of a compound (carrageenan). The carrageenan-induced analgesia test consists of inflaming the paw, again by injection of carrageenan, and seeing whether the compound increases the time which it takes for the rat to remove its paw from a source of pain. A number of these evaluations were carried out for the purpose of this action. The results reported in the specification were in respect of 5 compounds only, and as will be apparent from Table I on page 32 of the specification not all 5 compounds were assayed on both tests. Example 1 is shown as analgesic but not as anti-inflammatory. Examples 2, 13 and 14, which are within the claim, are shown as having an anti-inflammatory effect, while the comparison example 4 shows comparable anti-inflammatory characteristics. It should be noted that Example 4 is said to be a comparison example. The compound is 3,4-bis (4-methoxyphenyl) thiophene. This compound does not fall within claim 1 because neither of the substituent aryl groups is itself substituted with methylsulphonyl or sulphamyl.
13. A very large amount of evidence was provoked by the in vitro tests which the specification now describes. The tests as described depend upon having available the gene for either human or mouse Cox I and Cox II.
15. The identification of the gene coding for human or murine COX had been identified by the claimed priority date. Professor Flower’s evidence was that Needleman’s hypothesis of the existence of the two isozymes was accepted by 1992 and the cloning of the human gene had been achieved in 1992. This passage of the specification reinforces my view that Professor Flower’s evidence as to what was generally known is correct, and that the genes were available.
16. The assay for Cox I and Cox II activity which is described in the specification is in fact that which was used by the claimants at the relevant time in assessing Cox I/Cox II activity. The basic idea of the assay is that the enzyme is pre-incubated with the compound under test. During the period of incubation, the enzyme will be inhibited if the compound is a COX inhibitor. The enzyme is then exposed to its substrate, arachidonic acid, and the amount of prostaglandin synthesised by the enzyme in a fixed period is measured. A good inhibitor will mean less prostaglandin. The compound is tested at a number of concentrations and the final figure which is used for comparison purposed between different compounds is the concentration of compound which is needed to produce 50% inhibition, the so-called ID50 or IC50. Table II of the patent on page 33 shows the results of such tests. Fourteen compounds of the patent are shown as having been tested, mainly by reference to mouse Cox I and Cox II, although one of the results (Example 1) relates to human COX. The specification does not provide any interpretation of these results. The only guide to their interpretation is the passages to which I have already referred. There is no comparison with, for example, an established NSAID such as indomethacin which is used, incidentally, to stop the synthesis of prostaglandin during the assay. It seems to follow that this test is essentially a comparative test which is intended to reveal differences in Cox I and Cox II activity.
17. The final test to which the patent relates is the whole blood assay for thromboxane B2 activity. This is an assay for Cox I inhibition. Professor Flower describes it as follows. This experiment tests for eicosanoid (i.e. prostaglandin derivative) synthesis as a consequence of blood platelet (red blood cell) aggregation. Briefly, blood is taken from a healthy volunteer. A sample is measured out together with the test compound and the blood is allowed to clot naturally in a 37°C water bath. During the clotting process, platelets are activated and arachidonic acid is released. Large amounts of prostanoids (that is, prostaglandin derivatives) will be produced by the platelets, as a result of Cox I acting on the arachidonic acid substrate. These prostanoids can be recovered (mainly in the form of thromboxane B2 or TXB2) in the serum. The presence in the blood of Cox inhibitors will reduce the TXB2 formation. This is a very convenient way of assessing the activity of potential inhibitors in man and precise IC50 values can be obtained.
18. Thus, the idea is that the thromboxane B2 assay is that it provides a way of detecting Cox I inhibition alone. Professor Flower emphasises, and all the witnesses agreed, that it is not possible directly to compare the results of the thromboxane B2 assay with that of the Cox I/Cox II comparative assay. The specification says nothing about the interpretation of the thromboxane B2 assays that are set out. In general terms, however, it may be seen that the higher the IC50 , the more of the compound is needed to achieve a 50% reduction in prostanoid synthesis, and thus the less effective is the compound as a Cox I inhibitor. Seen in the context of the passage in the specification to which I have referred in paragraph 26 above, this test enables the skilled man to identify those compounds included within the claim which do not significantly inhibit one or more "other arachidonic pathway steps, such as thromboxane B2 production." Two preferable ranges for IC50 in the thromboxane B2 assay are indicated at page 5 line 5: greater than 1.5µM and greater than 10µM. Table III thus shows three groups of compounds: 1, 13 and 14, which show IC50’s comfortably in excess of 10µM; compounds 10 and 11, which show IC50’s in excess of 1.5µM, and compounds 2, 4 and 7 which are potent inhibitors of Cox I with very low IC50’s.
19. This table may be compared with Table II, which shows relative Cox I/Cox II activity in that assay. Example 1 is highly Cox II selective over Cox I. Example 13 is also highly Cox II selective over Cox I. Example 14 is Cox II selective, as are compounds 10, 11 and 13. Example 4, the comparison example, shows little or no Cox II selectivity. If there is Cox II selectivity in example 7, it is obscured because in this assay example 7 is a potent inhibitor both of Cox II and of Cox I. The specification draws no conclusions from these results, which are merely presented to the reader. They may be related to the preferred ranges of selectivity set out on page 4 at line 9: Examples 1, 10 and 11 are certainly over 100, and example 14 may be: it is certainly over 50. Examples 3 and 13 show a selectivity of 50 or above. The remainder are Cox II selective, with the exception of example 4 (where they are comparable) and example 7, where no conclusions can be drawn.
20. There was a fundamental dispute between the parties as to what the invention actually provided. The claimants’ case as opened to me was that the classes of compounds claimed were classes of compounds all of which could reasonably be expected to have anti-inflammatory properties, which they possessed by reason of being COX inhibitors. The claimants contended, however, that the specification did not suggest that the claimed class of compounds had gastric sparing qualities; and, regardless of whether selectivity of Cox II over Cox I provided gastric sparing qualities or not, did not suggest that the claimed classes were Cox II selective. Their contention was that among the compounds which were members of the novel classes there were compounds which would be gastric sparing or Cox II/Cox I selective, and that the specification provided sufficient material (in the form of the comparative assay and the well-established thromboxane B2 assay) to enable the skilled team to identify such desirable compounds from among the broad class, by synthesis and test.
21. In advancing this construction of the patent specification, the claimants based themselves both on a textual analysis and upon the flavour of the specification. Mr Kitchin relied on the passage bridging pages 4 and 5 of the specification following the list of indications that I have quoted in paragraph 26. He emphasised the words "the present invention also includes compounds which selectively inhibit cyclooxygenase I over cyclooxygenase II" and said that this was a clear indication of the wider scope of the claimed class, a contention which he reinforced by a reference to the preferred ranges for Cox II/Cox I selectivity of 50 and 100. Pointing out that the words "such preferred selectivity may indicate an ability to reduce the incidence of common NSAID-induced side-effects, such as ulcers" he said that the teaching of the specification in relation to the gastric sparing quality and its relationship to Cox II/Cox I selectivity was tentative, and that it plainly left open the possibility that other factors might influence the ability of the compound to act as an anti-inflammatory while sparing the stomach. The only fair reading of the specification was therefore that a class of anti-inflammatories was disclosed among which would be found compounds which were either Cox II/Cox I selective or gastric sparing for some other reason. The claimants also contended that the addressee of the specification would know, from his common general knowledge, that it was most likely that gastric irritancy is caused by the carboxylic acid moiety present in many well-known NSAID’s, and that the addressee for this reason also would not attribute an ability to spare the stomach merely to Cox II selectivity.
22. This last point was the subject of some debate, and can conveniently be disposed of here. First, as I explain in paragraph 146, claim 7 of the patent in suit includes within its ambit compounds possessing a carboxyl substitution for X. Second, it is not disputed that claim 1 does cover acids, including the carbamyl acids, which possess a carboxylic group. Third, it was not in dispute that not all existing NSAID’s are carboxylic acids or acids at all. Professor Baldwin was aware of existing non-acid and non-carboxylic acid NSAID’s, but was unaware of their effect on the gastric mucosa. It was established that piroxicam (non-carboxylic and weakly acid) was an irritant, but I think that it was certainly established that there was a perception in the art (rightly or wrongly) that the acid group would contribute to irritancy if present. But for present purposes this does not matter, because the claims cover acids. The specification is describing the properties of the classes in general, and those classes include acids. The skilled man could not have associated the lack of irritancy to the lack of carboxylic acid groups, or to a non-acidic nature.
23. On the other hand the defendants contended that the invention of the specification was a class of compounds substantially all of which were both anti-inflammatory and had significantly less harmful side effects than the existing NSAID’s. They further said that the specification taught only two mechanisms for reducing harmful side effects: to provide Cox II selectivity, and further to provide Cox I inactivity. They submitted that while gastric-sparing qualities might arise from other causes, so far as the specification was concerned the teaching was such that the addressee would understand that the inventor’s contribution lay in a class of compounds which possessed Cox II/Cox I selectivity at least when assayed in the manner described in the specification. However, apart from a specific teaching in respect of the thiophenes at page 3 line 29 (see paragraph 27 above) the patent neither identifies the members of the claimed class which possess Cox II selectivity nor those which do not inhibit Cox I. The defendants contend that accordingly the teaching of the patent is that all the claimed classes, or at least all the thiophenes, possess Cox II selectivity, and moreover produce a reduced amount of side effects. This question as to the teaching of the specification is fundamental to the dispute between the parties. It goes to the priority date of the patent. Further, the defendants contend that they have demonstrated that a number of compounds falling within claim 1 are not Cox II selective, and that in fact the majority of the claim 1 compounds will not be Cox II selective. Basing themselves on the decision of the House of Lords in Biogen v Medeva [1997] RPC 1 they say that the specification is insufficient for this reason, but they say also that the specification is insufficient even if the classes claimed are anti-inflammatory only.
24. The defendants also base their submissions on both a textual analysis of the specification and upon an appeal to the broader flavour of the teaching. Mr Young submits that it is quite clear from its opening words that the specification is presenting an invention which is an anti-inflammatory which produces fewer and less drastic side effects. The common general knowledge of the skilled man at the priority date and at the filing date included, as I have found, that Cox II was a promising basis as a target for NSAID development because it was an inducible enzyme responsible for synthesising the prostaglandins responsible for the inflammatory response. It must, so the defendants contend, have been absolutely clear to the addressee of the specification at the priority date and at the application date that the significantly reduced gastric side effects were in all probability due to selective Cox II inhibition, and the patent provides no other explanation. It accompanies its own explanation of Cox II selectivity with an assay for making the comparison. Indeed, the evidence showed that it was only after the application date that further investigation by various research groups suggested that Cox II selectivity and Cox I inactivity were not the whole story so far as gastric-sparing qualities were concerned.
25. A certain amount of evidence was adduced on this point. So Professor Baldwin said in his report:
27. Professor Flower was rather more definite than this. Rather than refer to "useful biological activity" he said this:
33. I have come to the conclusion that the defendants’ contention is correct. The class is presented as a class of compounds which have anti-inflammatory and/or analgesic activity with fewer and less drastic side effects, the reduction in side effects being due to Cox II selectivity. Of the particular passages in the specification on which the claimants relied, I consider that the passage bridging pages 4 and 5 of the patent supports the construction which I think is the right one. As a matter of language, it says that all the compounds of the present invention selectively inhibit Cox II over Cox I, and some of them also do not inhibit one or more other arachidonic pathway steps (i.e. Cox I). The experimental results and the manner in which they are presented are also consistent with this view. All the compounds tested in vivo show either anti-inflammatory or analgesic qualities. The comparison compound 4 does not exhibit Cox II selectivity, but those within the claim do, with the exception of example 7 where the result is not determinate. Those compounds tested with a high degree of Cox II selectivity also have poor Cox I activity in the thromboxane B2 assay. So apart from example 7, which is equivocal, the experimental results demonstrate that the compounds tested within the claim are Cox II selective. The preferred ratios for Cox II over Cox I activity do not throw any light on the problem, since they leave open the question whether the class includes compounds which exhibit no Cox II selectivity at all. The diffident statement that "Such preferred selectivity may indicate an ability to reduce the incidence of common NSAID-induced side effects, such as ulcers" again does not indicate that the class includes compounds which are not Cox II selective, and must be read in the context of the clear statement in respect of the thiophenes to which I have already referred and the general statement that the compounds have fewer and less drastic side effects. The whole thrust of the specification is towards Cox II selectivity.
The substituted thiophene compounds disclosed herein selectively inhibit cyclooxygenase II over cyclooxygenase I and relieve the effects of inflammation. These compounds, in addition, do not display substantial inhibition of cyclooxygenase I and produce a reduced amount of side effects.
5. The compounds are useful as anti-inflammatory agents, such as for the treatment of arthritis, with the additional benefit of having significantly less harmful side effects.
6. The present invention also includes compounds which selectively inhibit cyclooxygenase II over cyclooxygenase I and do not significantly inhibit one or more other arachidonic pathway steps, such as thromboxane B2 (TXB2) production. Importantly, thromboxanes cause blood platelet aggregation and have vasoconstriction properties. Thus a lack of effect in the regulation of non-inflammation related thromboxane production is further evidence of the beneficial selectivity of the present compounds.
7. Preferably the compounds of the present invention have a thromboxane B2 inhibition lC50 of greater than about 1.5 µM, as determined by a whole cell assay and preferably over 10 µM. The inhibition of the production of TXB2 by a whole cell assay is a better indicator of potential in vivo behavior as the assay also incorporates such factors as cell transport.
8. More preferably the compounds also have a selectivity ratio of cyclooxygenase II inhibition over cyclooxygenase I inhibition of at least 50 and preferably of at least 100. Such preferred selectivity may indicate an ability to reduce the incidence of common NSAID-induced side effects, such as ulcers.
14. A 2.0 kb fragment containing the coding region of either human or murine COX-I or human or murine COX-II was cloned into a BamHI site of the baculovirus transfer vector pVL1393 to generate the baculovirus transfer vector. Recombinant baculoviruses were isolated by transfecting 4µg of baculovirus transfer vector DNA into SF9 cells (2 x 10e8) along with 200 ng of linearized baculovirus plasmid DNA by the calcium phosphate method. Recombinant viruses were purified by three rounds of plaque purification and high titer (10E7 - 10E8 pfu/mI) stocks of virus were prepared. For large scale production SF9 insect cells were infected in 10 liter fermentors (Bioprocess group) (0.5 x 106/mI) with the recombinant baculovirus stock such that the multiplicity of infection was 0.1. After 72 hours the cells were centrifuged and the cell pellet homogenized in Tris/Sucrose (50 mM: 25%, pH 8.0) containing 1% CHAPS. The homogenate was centrifuged at 10,000xG for 30 minutes, and the resultant supernatant was stored at -80ºC before being assayed for COX activity.
26. The compounds of the Amended Patent are described as having useful biological activity. Among the compounds there will be those with properties which permit the development of a commercially successful drug. The process of pharmaceutical development and clinical evaluation will be necessary to identify the successful candidate. I would expect the compounds to exhibit a spectrum of activity. Some will be potent anti-inflammatories with less harmful side effects. Some will be less effective. Some compounds may not be absorbed by the body as well as others, some compounds will be more stable than others in the body. Indeed, different compounds may need to be administered by different means in order to maximise their effectiveness since some may not be very soluble in aqueous solution. Similarly, some of the compounds will be easier to synthesise than others. In short, the Amended Patent identifies a class of compounds worthy of further development as potential commercially successful compounds.
28. I understand the invention of the Patent to relate to compounds with anti-inflammatory and/or analgesic activity with reduced gastric side-effects. Such compounds will include compounds that are Cox II selective. However, there may be biological mechanisms other than inhibition of Cox by which compounds exert an anti-inflammatory/analgesic effect and such compounds may also have reduced gastric side effects.
30. Q. Therefore, I thought your opinion was therefore the compounds the subject of the patent were not necessarily COX-2 selective. That was your view, as you have just expressed it. A. I think what I am trying to get at is that there are other ways that you can get gastric tolerance without being a selective COX-2 inhibitor.
31. Q. In so far as this patent is concerned, this document that we are looking at, it says, does it not, that the way that you determine, or at least the skilled man would realise the way you are going to determine, whether something had reduced side-effects or not was by reference to the COX-1 and COX-2 assay. A. That is one assay, but it says such .... I am not disputing that such compounds will include compounds that are COX-2 selective, but does it mean they all have to be COX-2 selective? I did not read it in that way.
32. This passage, although relied on by the claimants, seems to me to be unhelpful. Professor Flower was basing himself, it turned out, on a reading of the bridging passage between pages 4 and 5 of the specification that I do not accept for reasons which I give below. This was not a matter for the expert witness, but a matter of construction. I accept, however, the thrust of his evidence and that of Professor Baldwin that nobody would expect that all the compounds falling within the claim would have similar degrees of Cox II selectivity. It does not follow that the compounds must not present some substantial degree of Cox II selectivity, and must not (for example) be Cox I selective, or both Cox I and Cox II inactive.
The claim
- Claim 1 of the unamended patent is as follows. I have added labels to the features for ease of reference. This subdivision of the features was given to me by the claimants without dissent from the defendants. I have also underlined those features of the claim which are relied on for the allegation of infringement.
.png)
A compound of Formula I
wherein Y is selected from S, O and NR1;
wherein R1 is selected from hydrido and C1-C6 alkyl;
wherein X is one or more substituents selected from
a)
(i) hydrido(b) S(O)nR5, wherein R5 is C1-C6 alkyl optionally substituted at a substitutable position with fluoro, and n is 0, 1 or 2,
(ii) halo
(iii) cyano
(iv) nitro
(v) hydroxy
(vi) acyl
(vii) lower alkyl substituted at a substitutable position with a substituent selected from halo, hydroxyl,
mino, acylamino, lower alkylamino, lower alkyl(acyl)amino, acyl, aryl optionally substituted with hydroxyl, a heterocyclic group, hydroxyimine and lower alkoxyimine,
(viii) lower alkonyl optionally substituted at a substitutable position with cyano,
(ix) amino optionally substituted at a substitutable position with a radical selected from acyl and lower alkylsulfonyl,
(x) sulfo,
(xi) sulfamoyl optionally substituted with a substituent selected from the group consisting of lower alkyl, halo(lower)alkyl, aryl, hydroxyl, lower alkylamino(lower)alkyl, a heterocyclic group and (esterified carboxy)lower alkyl,
(xii) N-containing heterocyclicsulfonyl,
(xiii) a heterocyclic group optionally substituted at a substitutable position with a substituent selected from the group consisting of hydroxyl, oxo, amino and lower alkylamino, provided that when Y is O or NR1 then X cannot be hydroxyalkyl,
c) C(R6)(OR8)(R7) wherein R6 and R7 independently are selected from CF3, CF2H, CFCl2, CF2Cl, CClFH, CCl2F, CF3CF2 and C1-C2 alkyl, and wherein R8 is selected from hydrido, C1 -C4 alkyl, (C1-C3 alkyl)C(O) and CO2R9 wherein R9 is C1-C4 alkyl,
d) C(O)ZR4, wherein Z is O, N, or S, and R4 is selected from hydrido, C1-C5 alkyl and aryl, and when Z is N then R4 is independently taken twice, and
e) C(R9) (NHR11) (R10), wherein R9 and R10 are independently selected from CF3, CF2H, CFCl2, CF2Cl, CClFH, CCl2F, and R11 is selected from hydrido and C1-C3 alkyl, and
wherein R2 and R3 are independently selected from aryl or heteroaryl, wherein the aryl or heteroaryl radical is optionally substituted at a substitutable position with a radical selected from halo, lower alkyl lower alkoxy, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, nitro, amide, amino, lower akylamino, sulfamyl and lower alkylsulfonylamino, provided that at least one of R2 and R3 is substituted with methylsulfonyl or sulfamyl;
or a pharmaceutically acceptable salt thereof.
The amendment
- So far as claim 1 is concerned, the claimants seek to amend to limit the scope of the claim to compounds in which there is only one X substituent in the heterocycle; in which the substituents at the 3 and 4 positions in the heterocycle are both phenyl groups one of which is optionally substituted and the other of which is substituted with the 4–methylsulphonyl group. The amendment to claim 9 limits that claim to 3,4 substituted thiophenes, removing pyrroles and furans from its ambit.
- The question of the existence of discretionary grounds for refusing the amendment has by agreement been left over, and I am asked at this stage to decide the question of allowability in law only. In summary, the defendants contend that the patent as amended is still open to all the objections pleaded against it in its unamended form, but that the effect of the amendment is that the patent discloses a new class of compounds for the first time, a class defined by features which make it, in substance, a new class, the existence of which cannot be derived from the specification prior to amendment. The result is that the specification discloses additional matter, and the amendment is unallowable.
- I consider the objection of added matter against the patent as granted below. I do not think that the amendment itself adds to the disclosure: it seems to me to be a straightforward limitation to a class contained wholly within a class already disclosed, and this is not the case with the patent as granted when contrasted with the application. In a case such as the present, it is necessary to exercise caution, since amendment to disclaim would otherwise always amount to a new disclosure, and that is neither desirable not the law. There is a question of degree here: but it seems to me that the nature of this amendment (which is to exclude certain substituents altogether and require the mandatory 4- substitution) creates a legitimate sub-class, and I would not refuse the amendment on the ground that it results in the specification disclosing additional matter. For the reasons which I give below, the patent as proposed to be amended still discloses matter not in disclosed in the application as filed and is invalid for this reason.
Experimental results
- The experimental results were examined in detail during the trial. They form an important plank in the defendants’ case on priority date, insufficiency and added matter. I shall summarise the pleadings to which they are relevant and their results here.
- First, priority date. As I explain in the section of this judgment on this issue, part of the defendants’ case is that the priority document fails to teach which (if any) of the classes of 3,4 diaryl thiophenes, furans and pyrroles referred to in the priority document are Cox II selective, exhibit anti-inflammatory activity, or exhibit reduced gastric side effects. Nor does the priority document contain a teaching enabling such classes to be identified. The defendants say that this teaching cannot support a claim to a class of compounds the common feature of which is said to be precisely these qualities. It is necessarily a part of this contention that the classes of compounds of the priority document do not all possess the required qualities.
- Second, insufficiency. The plea of insufficiency is directed to the patent both before and after amendment. Members of the classes disclosed and claimed are alleged not to have the required characteristics.
- So far as the priority document is concerned, the defendants identified
the following classes of compounds as not possessing Cox II selectivity
and as not exhibiting reduced gastric side effects:
(a) Compounds in which R2 is not either 4-methylsulphonylphenyl or 4-sulphamylphenyl;
(b) Compounds in which the aryl or heteroaryl group in the R3 group is substituted by an alkoxy, alkylthio, alkylsulphynyl, alkyl or alkylamino group wherein the alkyl is larger than an ethyl group or by any alkylsulphonyl, sulphonyl or alkylsulphonylamino group;
(c) compounds in which R3 is a phenyl group di-substituted at the 2 and 6 positions by anything larger than fluorine or R3 is a non-phenyl aryl group substituted at the 2 position by anything larger than fluorine.
(d) compounds in which the thiophene, furan or pyrrole ring is substituted at the carbon atom adjacent to the 4-methylsulphonylphenyl or 4-sulphamyl group with a bromine group or any group that occupies a space as large as or larger than a bromine group;
(e) Compounds in which the thiophene, furan or pyrrole ring is substituted at the carbon atom opposite to the 4-methylsulphonylphenyl group of 4-sulphamylphenyl group by a bulky group such as acyl, substituted alkyl, aryl, heteroaryl, optionally substituted sulphonylamino or optionally substituted alkylsulphonyl group;
(f) Compounds in which the thiophene or furan ring is substituted at the position opposite to the 4-methylsulphonylphenyl or 4-sulphamylphenyl group by a bromine group or any group that occupies a space as large as or larger than a bromine group and the aryl or heteroaryl group in R3 is substituted in the 2 position by a group that occupies a space as large as or larger than a bromine group;
…
- The plea of insufficiency relies on (a), (b) and (d) to (f). For the purpose of this plea, the defendants add to these classes compounds in which R3 is a phenyl group substituted in the 2 position by an alkyl group and substituted in the 6 position by any group occupying a space larger than fluorine and compounds in which R3 is a non-phenyl aryl group substituted in the 2 position by any group occupying a space larger than fluorine. Such compounds, they say, are compounds claimed in the patent which are not Cox II selective and do not exhibit reduced gastric side effects.
- In opening, the claimants produced a table relating the facts to be proved by the defendants’ Notice of Experiments to the pleading of lack of support and insufficiency and the classes of compounds set out in exhibit RB7 to Professor Baker’s evidence. In summary, four classes of compounds (B, C, D and E) relate to the essential nature of the 4-methylsulphonylphenyl or 4-sulphamylphenyl group (particulars paragraph (a)). Class (F) relates to paragraphs (b) and (c) (R3 substituted with bulky groups). Class G relates to paragraph (e) (bulky X substituents). Class H relates to paragraph (d) (bulky groups at X adjacent the methylsulphonylphenyl or sulphamyl group).
- The defendants carried out both in vitro and in vivo experiments. The in vitro work consisted of performing an assay for Cox II activity and selectivity similar to that described in the patent. Some of the compounds examined are covered by the patent, the application for the patent and by the priority document; others by the patent as sought to be amended, yet others by the patent and the application alone. In many cases, the claimants had themselves carried out routine experimental work on the compounds selected by the defendants, and sought to rely on the results of this work to challenge the defendants’ results. The claimants also wanted to rely on their internal results in respect of some compounds which fell within the defendants classes but which had not been experimented on by the defendants to show that the defendants had not identified the classes of non-working compounds correctly. The resulting dispute was complicated, but the whole of the in vitro work was summarised in a single exhibit RJF-25 to Professor Flower’s evidence. I was also supplied, by the hard work of the claimants’ solicitors, with a copy of RJF-25 to which the great majority of the evidence references had been added. This proved to be very helpful, and I am grateful for it. The in vivo work was (rightly) not very extensive, but in vivo tests are the only way to look at gastric irritancy, as opposed to predicting it on the basis of Cox II selectivity and Cox I inactivity.
- The defendants contended that their experiments showed that certain of the compounds which they had tested were inactive. Before turning to the significance of the results as they appear in RJF 25, it is necessary to consider the criteria for inactivity adopted by the defendants. They tested their selected compounds using an assay similar to that described in the patent. The correctness of their assay technique in principle was not challenged, but two things were said about their results. The assay depends upon the compound in question being dissolved when the enzyme is added to it. The compounds claimed are generally very insoluble in water, and at the repetition of the defendants’ experiments both Professor Flower and Ms Koboldt observed precipitation in the wells of the ELISA plates used. The question of precipitation was said by the claimants to throw serious doubts on all the ELISA work carried out by the defendants. The other issue, which in my judgment was far more important, was whether the defendants’ criterion for inactivity was correct. The contentions on precipitation are dealt with in paragraph 84. My conclusion is that having regard to the nature of the compounds tested, the defendants’ technique was acceptable. The second issue calls for a legal analysis of the objection of insufficiency.
Summary of the experiments
Insufficiency — what is an inactive compound?
- This question is one of the questions central to the action. A claim to a class of chemical compounds characterised, like the compounds in the present case, by the presence of particular functional groups in the compounds, confers a monopoly on the patentee in respect of those compounds. There are many millions of compounds covered by the claim. It is clear that the skilled man equipped with experimental techniques which are either described in the specification or available as a matter of his ordinary general knowledge will be enabled to identify those compounds which are Cox II selective and Cox I inactive, and moreover to identify those which exhibit diminished side effects. Can a specification which gives the skilled man a novel field, and provides him with the tools to identify which parts of the field are promising for further exploitation, properly be described as insufficient?
- It is a generally recognised principle of patent law that the patentee is not entitled to protection wider than the contribution which he has made to the art. It goes without saying that the patentee’s claim should not cover that which is old or obvious. If it were otherwise, the patentee would be able to prevent others from doing what was old or obvious at the priority date, and this is intuitively wrong. Of course, this principle must be qualified. Merrell Dow v Norton [1996] RPC 76 establishes that it applies only to matters rendered old or obvious by information disclosed before the priority date. Other forms of protection (rather than invalidity) are provided by the statute for those who have used the invention before the priority date but in a manner which conveys nothing.
- When one turns to the extent of the patentee’s contribution to the art, the problem becomes more difficult. The essential underlying concept is that of the enabling disclosure. The patentee may not obtain a monopoly for matter which he has not told the public about and enabled them to do for themselves on the basis of what he has disclosed in the specification. This concept is manifested in two substantive requirements for the specification and claims. Subsection 14(3) of the Act requires that the specification of the application shall disclose the invention in a manner clear enough and complete enough for it to be performed by a person skilled in the art. Subsection 14(5) of the Act, mirroring Article 84 EPC, requires that the claim be supported by the description. It has never been the law that the claim must be co-extensive with the embodiments specifically disclosed by the patentee in his specification. Protection limited in this way would in all probability be illusory. When the patentee makes an invention, he may not appreciate its ramifications, and, when he files an application, he has in effect a year in which to develop and refine his invention before describing it in a further application which will result in the patent. The process of development and refinement may result in further applications along the way, but the application which will result in the patent must be made within a year. If, and only if, the claim is supported by the matter disclosed in the earliest application will it be entitled to priority from that application; and the intervening applications may form the bases of other claims to priority. The claims of the patent itself must be supported by the description given in the application for the patent, and the patentee may not add further to the disclosure of the application during the process of prosecution. As Lord Hoffmann explained in Biogen v Medeva [1997] RPC 1 at page 46, when the Act provides in section 72 for revocation of the patent 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 man skilled in the art, it gives effect not merely to the substantive requirement of subsection 14(3) but to that of subsection 14(5)(c) as well.
- In Biogen, Lord Hoffmann examined the consequences of this general principle when considering the priority date of the claims under section 5 of the 1977 Act and the objection of insufficiency. In the section of his speech entitled "Priority date" Lord Hoffmann prefaces his analysis of section 5 of the 1977 Act with a consideration of the wider concept of "enabling disclosure".
- In considering what is meant by "enabling" in the phrase "enabling disclosure" Lord Hoffmann said this:
35. This passage was of course written in a case in which the issue before their Lordships was whether the invention of the amended specification was substantially larger than, or substantially different from, the invention of the unamended specification. Thus the nature of the invention of the unamended specification had to be ascertained, and, as both Lord Simonds and Lord Macdermott indicate, it consisted not merely of the class of compounds specified by the claim but of their unifying characteristic. What is the consequence if the unifying characteristic turns out not to have been possessed by all the members of the class? There are two possibilities. The first is that the claim is to be read as covering only those members of the class possessing the desired characteristic. But if that is the answer, the only contribution which the patentee has made to the art is a family of compounds which may or may not possess some desirable characteristic. There is no longer any common property possessed by the claimed class. They have neither been made nor tested. In such a case, the EPO has suggested, in T 939/92 Triazoles/AGREVO, that a class of novel chemical compounds lacking any technically useful properties may not amount to an invention, and may moreover be intrinsically obvious. A second approach is given by the decision in Biogen.
- Biogen itself was a case in which the claim was effectively a claim to any recombinant method of making antigens possessed by the hepatitis B virus. There were two antigens, called the core and surface antigens. When he comes to consider the question of support for the claims, Lord Hoffmann starts by considering the extent to which the priority document (‘Biogen I’) was enabling. Lord Hoffmann accepted Aldous J’s finding of fact that both core and surface antigens (HBcAg and HBsAg) could be made by the skilled man on the basis of the disclosure of Biogen I, which was accordingly enabling for both materials. There follows a key passage:
- BUSM v Simon Collier was a case of a claim to automaticity however achieved in a particular industrial step. Such cases are sometimes called "known desideratum" cases. The end result is obvious or known, and the opportunity for invention lies in the route to the obvious end result (in Biogen, hepatitis B virus antigen by recombinant techniques for use in a vaccine). Thus the claim is too broad, and is unsupported by the disclosure of Biogen I. Having lost its date, it was invalid. Lord Hoffmann also considers the sufficiency of the patent:
41. This seems to me to be a clear statement that the applicable principle is that the claim must equiparate (to use Graham J’s phrase in Olin Mathieson v Biorex [1970] RPC 157) with the invention, and, if it does not do so, the claim will not be enabled across its full width, because it will cover matter which owes nothing to the invention disclosed. It follows that if the claim covers compounds which do not satisfy the representations made about them in the specification, it is likely to be invalid, because, again, the claim will be covering compounds which owe nothing to the teaching of the specification. This is not to say that when the claim reflects a new feature uniting the class as a class, and relating the desirable quality of the compounds to this feature, it is bad if a few members of the class do not possess the desirable quality or possess it in an attenuated form. But the qualities of the class must be related to the features of the claim. If compounds having the features of the claim may or may not possess the qualities which the patent says unify the class, it cannot be said that the claim reflects a true class at all. It is just a generalised description of a large number of chemical compounds. Such a claim is not analogous to a claim to a new principle, since the patentee has given no information, such as a structure/activity relationship, which enables the reader of the specification to draw any conclusions as to the properties of any particular compound without further experiment. All he has done is to describe the scope of the claim with spurious precision.
42. It is always necessary to bear in mind the constraints placed on patentees by the mundane factors associated with applying for a patent. It takes time to elucidate a structure/activity relationship, and the amount of time available to the patentee to make his application is strictly limited. Once he has made his first application, to all intents and purposes he has a further year in which he can file an application claiming priority from his first application. Thereafter, he cannot add matter to his application. I do not think that this can be a justification for seeking claims which might be characterised as speculative or, more accurately, as claims covering compounds for the properties of which no well-founded prediction may be made.
43. In the present case, the patentee claims a vast number of different compounds. As a matter of construction, I have found that the representation that is made for these compounds is that they possess Cox II selectivity and that they possess fewer and less drastic side effects than existing NSAID’s. These characteristics are not a feature of claim 1. It seems to me that the defendant must, if it is to establish an objection under section 72(1)(c), be in a position to demonstrate that a substantial number of the class in question does not possess the unifying characteristic on the specification’s own terms. The contrary view, which I reject, was best expressed by Professor Flower himself:
45. Where the class in question is large, as it is here, the defendant cannot test all (or even a measurable percentage) of the compounds covered by the claim. What it must do, therefore, is to show that some compounds do not possess the desired characteristics, and that as a matter of reasonable prediction a substantial number of those which it has not proved possible to test will not possess those properties either. The extent of the burden placed on a defendant will be dictated by the disclosure of the specification. In the present case, some 14 compounds are described, some only of which are tested. No structure-activity relationship other than that which can be ascertained by the skilled man in reading the claim is provided.
46. I can turn to the details of the experiments. The ELISA plates are made of translucent plastics material and contain 96 "wells" in which reagents are successively added to the compound under test. This is a standard technique which utilises an antibody which can bind specifically to PGE2. It results in a colour change which can be measured using a spectrophotometer and is inversely proportional to the amount of PGE2 present. The ELISA used is based on a proprietary kit produced by Cayman Chemicals. There are a number of prescribed concentrations of compound, expressed as micro moles or µM, which enables the results of the assay on different compounds to be compared. If a compound is insufficiently soluble to pass into solution, the results are said to be valueless because not all the compound is in solution and the nominal concentration is not achieved.
47. The concentrations selected by the defendants were 0.0064µM, 0.032µM, 0.16µM, 0.8µM, 4µM, 20µM, 100µM and 1000µM. Each successive concentration is five times the preceding one (except, obviously, between 100 and 1000µM). There was precipitation in all of the defendants’ experiments at 1000µM. There is some dispute as to the extent to which there was precipitation in the others.
48. So far as the patent in suit is concerned, it can be inferred from the results quoted that the assays used stopped either at 10µM or 100µM. Since the assay is intended to operate in a region in which the concentration is similar to that in which the drug would appear in the body, it was suggested that 1000µM was a very high concentration. One reaction which appeared unforced was that of Dr Percival, who said in relation to activity at the 1000m M point that he had never before been asked to look at such inactive compounds. On the other hand, Professor Flower pointed out that certain well known NSAID’s such as aspirin reached concentrations of that order in blood. The selection of any particular cutoff is to some extent arbitrary, and dictated by the purpose for which the assay is being carried out. The criterion which I should adopt is, I think, the normal criterion for insufficiency. The skilled man is to be taken to be seeking to put the invention into effect without undue experimentation. The criterion which he adopts is therefore one which is appropriate to this purpose; and the best evidence is the criterion adopted by both the claimants and the defendants in their investigations. The invention consists of a family of compounds which have the desirable characteristics which I have identified. This is not, therefore, an investigation in which no lead has been given, and in which any trace of activity is of interest. The investigation which the skilled man is undertaking is an investigation of compounds where leads have already been identified by the specification itself. Dr Percival’s evidence was that the cut-off of 100m M was appropriate for a case in which there was no potent lead compound and one was searching for new chemical leads.
49. The defendants advance a number of further justifications for the selection of a 100m M cut-off. The first is that a 100m M cut-off affords a margin which would enable compounds to be identified which according to the patentee’s own internal criteria would be suitable for taking forward to the next stage, which is testing for anti-inflammatory characteristics, which is probably an IC50 against Cox II of less than 0.5m M. This is consistent with Dr Percival’s evidence.
- Second, an IC50 cut-off greater than 100m M is said to be related to the need for there to be a relationship between in vitro and in vivo potency. This is said to be established by Example 5 (Compound B64 in RJF 25). This compound was inactive in vivo altogether. It showed an IC40 but did not, taking the results as a whole, ever show an IC50, while most results were consistent with IC50 in excess of 100m M. In my judgment, while it may well be true that a high IC50 is poorly related, if at all, to significant in vivo activity, one example is insufficient to show it.
50. The defendants also relied on the lead compounds with which those of the patented compounds which were tested were compared, DuP 697 and NS 398. These have IC50 values for Cox II of 0.1m M and 0.01m M respectively. Thus, the defendants say, their cut-off point rejects compounds more than 1000 times less potent than these compounds, and that is, they say, reasonable. This argument is attractive, but it is capable only of supporting a criterion adopted according to objective criteria available at the priority date. Such objective criteria are in my judgment to be found in the assay itself. Dr Percival gave evidence, and it does not seem to have been disputed, that in an enzyme assay of the kind described in the patent use of too high a concentration of compound will increase the chance of inhibition resulting from non-specific interactions rather than specific interactions involving binding to the active site of the enzyme of interest.
51. All the compounds of the patent in suit are sparingly soluble. Indeed, the fact of precipitation in aqueous solution is one of the claimants’ criticisms of the defendants’ experimental technique, which I consider below. The defendants say that with sparingly soluble compounds a cut-off above which all the tested compounds showed precipitation was reasonable. The criticism of this approach came from Professor Flower, summarised in the passage which I have already quoted. A "spurious negative" may possibly conceal a successful drug but it was not contended that it was likely to do so: quite the opposite. In my judgment, it is not the function of the specification to invite further experimentation on compounds which show no activity in the assay described in the specification at the point at which they are in saturated solution, and it is reasonable to say that inactivity has been demonstrated according to the specification’s own criteria if the compound precipitates at 1000m M and does not show an IC50 less than 100m M. Accordingly it was reasonable and in accordance with the common general knowledge to adopt this cut-off.
‘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.’
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.
In May & Baker, Lord Simonds said of the invention that "the inventor claims that the whole range of benzene sulphonamido derivatives which fall within the consistory clause is his invention, not indeed in the sense that he discovered that they could be made or how to make them, but in the sense that he discovered that, one and all, they had therapeutic value". In the passage referred to by Lord Hoffmann, Lord Macdermott says this:
34. Before proceeding to consider the original specification and the nature of the invention it claims it will be appropriate to mention two matters which, while this particular art remains in an empirical state, appear to me to be necessary consequences of that characteristic. In the first place an invention in this chemo-therapeutic field must be in respect of a substance which has actually been produced. There cannot be an empirical discovery in respect of a bare formula. And secondly, the discovery of each new compound having a therapeutic value is a separate invention. If the inventor is bound to say–"I have made a new substance which I find has therapeutic value, but I cannot be certain that any other substance, no matter how similar its molecular structure, will have such a value until I make and test it" then, as it seems to me, the inventive step he has taken must attach to the single substance he has made and to it alone. And if he has made and proved several such substances the position must, I think, remain the same for, while the art retains its empirical nature, the worth of each new substance is a new discovery. But when the inventor can say that his inventive step is such that each of the various new products which manifest it must have therapeutic value, and that although some of them have never been made, then, as I see the matter, the state of the art will have changed. It will have lost its empirical nature, at least to some extent, and the chemist will have found some law or principle by which he may predicate therapeutic effect m advance.
36. But the fact that the skilled man following the teaching of Biogen 1 would have been able to make HBCAg and HBsAg in bacterial cells, or indeed in any cells, does not conclude the matter. 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.
37. Professor Murray had used a particular technique to introduce the DNA coding for the particular polypeptide into a host cell in which the DNA had been expressed. It had been held by the judge that Professor Murray’s technique was not obvious at the date. But the actual end result, which was synthetic HB virus antigen, was an obvious thing to try to make. So, Lord Hoffmann’s conclusion is that the claim was too broad:
38. A similar English case is British United Shoe Machinery Co. Ltd. v. Simon Collier Ltd. (1908) 26 R.P.C. 21. The patentee invented a piece of machinery for automatically trimming the soles of boots and shoes by means of a cam. One of the claims was in general terms for automatic means of trimming soles. Parker J. said, at pages 49-50:
"[T]he problem was simply how to do automatically what could already be done by the skill of the workman. On the other hand, the principle which the inventor applies for the solution of the problem is the capacity of a cam to vary the relative positions of two parts of a machine while the machine is running. Assuming this principle to be new, it might be possible for the inventor, having shown one method of applying it to the solution of the problem, to protect himself during the life of his patent from any other method of applying it for the same purpose, but I do not think that the novelty of the principle applied would enable him to make a valid claim for all means of solving the problem whether the same or a different principle were applied to its solution."
39. I return therefore to consider the technical contribution to the art which Professor Murray made in 1978 and disclosed in Biogen 1. As it seems to me, it consisted in showing that despite the uncertainties which then existed over the DNA of the Dane particle - in particular, whether it included the antigen genes and whether it had introns - known recombinant techniques could nevertheless be used to make the antigens in a prokaryotic host cell. As I have said, I accept the judge's findings that the method was shown to be capable of making both antigens and I am willing to accept that it would work in any otherwise suitable host cell. Does this contribution justify a claim to a monopoly of any recombinant method of making the antigens? In my view it does not. The claimed invention is too broad. Its excessive breadth is due, not to the inability of the teaching to produce all the promised results, but to the fact that the same results could be produced by different means. Professor Murray had won a brilliant Napoleonic victory in cutting through the uncertainties which existed in his day to achieve the desired result. But his success did not in my view establish any new principle which his successors had to follow if they were to achieve the same results. The inventive step, as I have said, was the idea of trying to express unsequenced eukaryotic DNA in a prokaryotic host. Biogen 1 discloses that the way to do it is to choose the restriction enzymes likely to cleave the Dane particle DNA into the largest fragments. This, if anything, was the original element in what Professor Murray did. But once the DNA had been sequenced, no one would choose restriction enzymes on this basis. They would choose those which digested the sites closest to the relevant gene or the part of the gene which expressed an antigenic fragment of the polypeptide. The metaphor used by one of the witnesses was that before the genome had been sequenced everyone was working in the dark. Professor Murray invented a way of working with the genome in the dark. But he did not switch on the light and once the light was on his method was no longer needed. Nor, once they could use vectors for mammalian cells, would they be concerned with the same problem of introns which had so exercised those skilled in the art in 1978. Of course there might be other problems, but Biogen 1 did not teach how to solve them. The respondents Medeva, who use restriction enzymes based on knowledge of the HBV genome and mammalian host cells, owe nothing to Professor Murray's invention.
…the reasoning by which I have come to the conclusion that the patent was not entitled to the earlier priority also, in my view, leads to the conclusion it was insufficient.
…whatever date one chooses, the patent did not disclose any method for making the antigens other than that disclosed in Biogen I. It therefore remained insufficient for the purposes of sustaining a claim to every recombinant DNA method.
…
40. Section 72(1)(c) of the 1977 is not only intended to ensure that the public can work the invention after expiration of the monopoly. It is also intended to give the court in revocation proceedings a jurisdiction which mirrors that of the Patent Office under section 14(3) or the E.P.O. under article 83 of the EPC, namely, to hold a patent invalid on the substantive ground that, as the E.P.O. said in Exxon/Fuel Oils (T 409/91) [1994] O.J. E.P.O. 653, paragraph 3.3, the extent of the monopoly claimed exceeds the technical contribution to the art made by the invention as described in the specification. In the 1949 Act, this function was performed by another ground for revocation, namely that the claim was not "fairly based on the matter disclosed in the specification" (section 32(1)(i)). The requirement of sufficiency was therefore regarded as serving a narrower purpose. But the disappearance of "lack of fair basis" as an express ground for revocation does not in my view mean that general principle which it expressed has been abandoned. The jurisprudence of the E.P.O. shows that it is still in full vigour and embodied in articles 83 and 84 of the EPC, of which the equivalents in the 1977 Act are section 14(3) and (5) and section 72(1)(c).
"This is in fact one of my key points really. If you try a series of drugs in one assay and get no result and it is such an important point, as this one, that I think you have to take into account the fact that you might try them in other assays under other conditions to see whether in fact that assay was in fact really a negative or whether it was a spurious negative. It is an unfortunate fact with these assays that whilst positives are always positive, if you have a negative you have to think twice about it, especially if there is evidence of solubility problems and this really is my key point. If you have a series of compounds which may have solubility compounds and you get a null result, how do you know that that result is a genuine negative and that if you tried it in a different assay or a different system it would not produce a positive effect? That is really the crux of the matter."
44. I should add to this that Professor Flower was emphatic that it was possible to detect a dose-related response, which means that inhibition increased with increased dose, in the case of many of the compounds which had not achieved 50% inhibition in the experiments. He said that these compounds could not be rejected as inactive. Rather, resort should be had to other assays, and to other methods of solubilising the compounds, in the hope of investigating their behaviour at higher concentrations. In my judgment, the criterion must be that provided by the specification itself. In the present case, the criterion is Cox II selectivity by use of the assay provided by the specification. I accept that once Cox II selectivity is shown so far as the specification is concerned, and the evidence showed, that it was a reasonable inference that the compound under test would have fewer and less drastic side effects.
Other criticisms of the defendants’ in vitro experiments
- The other criticisms are as follows. First, the defendants selected the compounds with a view to making the position look as bad as possible on the basis of their own undisclosed work. Second, the defendants did not optimise the assay. Finally, the defendants did not accurately record those compounds which showed precipitation at concentrations less than 1000m M (the defendants accepted that all the compounds which they tested showed precipitation at this concentration). I can take these criticisms in turn.
- Selection of the compounds tested. Professor Baker gave evidence that he had considered the selection of compounds made by the defendants and considered the selection reasonable for the purpose of demonstrating a structure/activity relationship of the compounds according to the patent in suit. It was suggested that the experiments had been designed for failure. A particular point was made of compound 68 (compound B97 in RJF 25) which it is accepted, I think, was both a gastric irritant and Cox I selective. It was shown to have all the undesirable features which the invention of the patent in suit was intended to overcome. It was said by the claimants that this was a clear example of the defendants "putting together all the features which the defendants had identified by extensive SAR work as being likely to promote Cox I inhibition over Cox II." Dr Prasit of the defendants was cross-examined on the work he had done on the SAR of DuP 697, and it was put to him that compound 68 possessed all three of the features which he had identified as likely to potentiate Cox I over Cox II, a proposition to which he gave qualified assent. Compound 68 is a furan. There were photographs of the gastric lesions which it caused. It plainly was a gastric irritant, comparable with, if not quite as bad as, indomethacin, and it was Cox I selective. The compound is shown in Figure D.
- Compound 68 is, however, a preferred compound of the patent in suit prior to amendment, being 4-[3-(4-methoxyphenyl)-2-bromo-fur-4-yl]benzenesulphonamide, expressly listed at page 7 line 37 of the patent. It is not covered by the claim as proposed to be amended (it does not have the 4-methylsulphonylphenyl substitution). Compounds 65 and 66 are close analogues (and not covered by the amended claim) which also showed Cox I selectivity.
- In fact compound 68 does go to confirm one aspect of the SAR of these compounds. Compound 66, an identically substituted thiophene, and compound 65, which is identical to compound 66 save that the oxygen is replaced by a sulphur, are both Cox I selective.
- I am not persuaded by the claimants’ criticism that these compounds were carefully selected. The fact is that the claim covers compounds, both preferred compounds and others which are either inactive or are Cox I selective, and the experiments broadly demonstrate this. It would be necessary to show positively that these compounds are exceptional.
- Optimisation of the assay. The chemical reaction which takes place between an inhibitor and the enzyme is complex. Professor Flower explained that there are basically two types of interaction between inhibitor and enzyme. These may be termed reversible and irreversible inhibition. Aspirin is an example of an irreversible inhibitor. Once the enzyme molecule has reacted with a molecule of aspirin it will never function again. On the other hand, other inhibitors are reversible; and others exhibit behaviour which is a combination of the two. Such inhibitors may, for example, be sensitive to substrate concentration. The relevant variables are the time for which the enzyme is exposed to the inhibitor (the pre-incubation time); the substrate concentration, and the time for which the substrate is exposed to the enzyme after pre-incubation. All the values used by the defendants were in accordance with those of the patent. Professor Flowers’ criticism is that the conditions should have been worked on again, and not blindly copied from somebody else. It was never established that any failure to optimise the assays was responsible for any substantial error in the results. The main criticism was of the failure to take into account the precipitation of the compounds.
- Precipitation. The question of precipitation underpinned the claimants’ criticisms of the defendants’ experiments. When they performed their experiments, the defendants noted that all the compounds tested showed precipitation at 1000µM concentration. At the repeats, Professor Flower and Ms Koboldt, who are both experienced in this class of assays, considered that they had seen precipitation in some of the compounds at lower concentrations. Precipitation is an indication that the compound is in saturated solution in the assay. The position in the human body may be quite different. Professor Flower said that the body was a genius at dissolving things. Thus, the criticism is that it is not fair to the compound to rule it out because of inactivity in the assay if it is not active at 100µM, or even 1000µM and at those concentrations it is in saturated solution. In the body, a higher concentration of the dissolved compound may be achievable, and at those concentrations the compound may have activity. A number of the graphs recording the activity of the compounds against their concentration were examined with the experts. The curves showed a "plateau" in activity. An example looks like this. It is the compound of Example 5 of the patent.
- The claimants say that the defendants took no steps to solubilize the compounds. There was a criticism of M. Ouellet, who had carried out the dissolution of the compounds, that he was insufficiently careful to dissolve the compounds initially, but this criticism failed. He was performing the assay as he always did. In the experiment, the test compound is in solution in a very powerful solvent, dimethyl sulphoxide (DMSO) before the addition of the enzyme, pre-incubation and addition of the substrate. The two latter are in aqueous solution and it is at the stage of addition of either the former or the latter that precipitation may take place. Professor Flower said that once precipitation was observed it would be appropriate to ring the changes on the solvents to see if there was one which would be better with these compounds than DMSO. I accept that to carry out such an investigation would be appropriate, but there was no evidence that any other solvent (Professor Flower suggested ethanol or dimethylformamide) would in fact be any more successful and DMSO is known to be an extremely powerful solvent.
- The defendants say that there are two answers to the criticism made of their reliance on results where precipitation took place. The first is that when all the results were examined it could be seen that there was no relationship between those compounds which Professor Flower and Ms Koboldt said precipitated and the compounds which showed a lack of activity in the sense of not possessing an IC50 at a concentration below 100µM. They say that the lack of activity might just as well be due to a kinetic effect, that is, to the compound possessing only weakly inhibiting qualities. Professor Flower was specifically taken to a substantial number of compounds in cross-examination, and he accepted this contention as a possibility. Of the example above, he said this:
52. The defendants’ second answer is that in fact the precipitation reported by Professor Flower and Ms Koboldt was incorrectly identified. They point to the fact that Professor Willoughby and Dr Percival, who produced a joint observation, recorded different results from Professor Flower and Ms Koboldt who differed among themselves. Thus they say that the only reliable observations are those which they accept, which are precipitation at 1000µM in every case observed by all. There is no doubt that the observation of precipitation in the very small wells of the plates in question was subjective, and there is no doubt scope for differences of genuinely held opinions. My view is that had the point been one of real importance, it would have justified an experiment in reply using the defendants’ compounds, enzymes and stock solutions. The lack of any identifiable correlation between the compounds that showed precipitation in the eyes of Professor Flower and Ms Koboldt and the compounds showing poor activity in the assays justifies me in not analysing the detailed observations. Any solubility-related effect was irrelevant to the conclusions drawn from their experiments by the defendants.
53. In my judgment, the criticisms of the defendants’ techniques have no substance, given that they performed the tests which the patent itself describes as having been used to identify the examples which it describes. The insolubility of the compounds was not shown to vitiate the conclusions which the defendants drew from their experiments.
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Figure D: Compound 68
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Figure E: Compounds 65 and 66
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Sometimes, the plateau was in excess of 50% inhibition, in which case the concentration corresponding to the point at which the curve crossed the 50% line represented the IC50. Such a compound would be described as active by the defendants if the IC50 was below a concentration of 100µM. Other compounds reached a plateau like the one above, at about 40% or less. The claimants’ criticism was that if the curve hit a plateau at say 40% inhibition, and if the compound was precipitating at that point, all that the experiment showed was that the limit of solubility in the assay had been reached. It said nothing about the activity of the compound.
Q. The lack of activity or lack of getting to an IC50 or ID50 may be due to one of two things; it could be solubility or it could be some other cause like kinetics.
A. Yes. In fact in my report I only speculate it could be solubility and I am quite happy to, as I said in my evidence there are other possibilities. Whatever they are it is worrying, is it not, that you can call that compound inactive if there are very good reasons why it never hits 100%, whatever they are? There is a clear difference between the profile of this compound and, for example, the base line traces we see with some of the other ones that I also pointed out. For example, if you turn over the page to page 39, the bottom graph, there must be a difference surely, must there not, between the sorts of responses we are getting here and the sort of responses we are getting there where it is just going on the base line with no effect at all? I am happy to embrace your kinetic argument but I think it makes it even more worrying in a way that you could still miss what may be perfectly good inhibitors because they happen to come in under 40%.
He returned to this example later:
Q. This one shows in this case a plateauing out at the 40% inhibition level and it has no IC50 clearly. So far as the observed precipitation on this one was concerned you observed a precipitation at 100 micromolar and Dr. Koboldt at 1,000. The plateauing effect is not due to the precipitation; it is again a question of its lesser activity than the previous two ones we have looked at.
A. Perhaps we are on a slightly different wavelength here. I am not saying that the lack of activity in compounds is due to the fact it is precipitated. What I am saying is that the precipitation is a symptom of the fact that the compound is basically insoluble and, therefore, these concentrations may or may not be absolutely correct. It is very difficult to tell either way. That is my point.
The results of the experiments.
- In paragraph 54 I set out the classes of compounds identified by the defendants in their pleaded case as being inactive. It is not an entirely straightforward task to relate these classes to the pleaded case. So far as Professor Baker’s RB7 and Professor Flower’s RJF 25 are concerned, experimental class A is the class of compounds which work. The remainder of the results can be classified as follows:
- Experimental classes B, C, D and E correspond to paragraph (a), which is concerned with the proposition that R2 must be substituted with either 4-methylsulphonyl or 4-sulphamyl if it is to be active;
- Experimental class F appears to cover paragraphs (b) and (c) of the pleading;
- Class H corresponds to paragraph (d);
- Class G corresponds to paragraph (e); and
- Class F (two compounds only) corresponds to paragraph (f).
- Most of the remaining results which are relied on are contained in Exhibit RJF 25. This exhibit is derived from one prepared by Professor Baker (RB 7) in which every compound which was either the subject of an experiment performed for these proceedings or had been tested by the claimants in the normal course of research was give a B number by Professor Baker. Professor Flower included compounds tested by the defendants in the ordinary course of research, giving them C numbers.
- The class A compounds, which included the compounds of examples 1,2, 6, 7 10, 11, 12, 13, 14 and 15 all showed Cox II selectivity and Cox II activity. Some of the compounds showed Cox I activity. There are 22 compounds in this class.
- Class B consists of compounds B23 - B37 (15 compounds). These compounds were said to lack Cox II selectivity. These compounds do lack Cox II selectivity and several lack Cox II activity. One possible exception is B34 which shows some evidence of Cox II selectivity but at a level of activity which in one of the claimants’ assays and at least two of the defendants’ assays showed inactivity.
- One further compound which fell within this class (ie a compound in which neither R3 nor R2 is substituted at the 4 position with either methylsulphonyl or sulphamyl) was a compound which is known only by the number it was given internally by the defendants, L-745 278. This compound appears to be Cox II selective to some extent. It emerged during the cross-examination of Dr Prasit. It was examined during the defendants’ screening programme, but was of no interest to them. His evidence was:
- On the basis of this example, and B34, Mr Kitchin submits that the defendants can no longer support the sweeping proposition that a compound in which neither R3 nor R2 is substituted at the 4 position with either methylsulphonyl or sulphamyl will not be Cox II selective. I do not accept this proposition. B34 does not show clear evidence of activity at all. L-745 278 possibly does but the evidence is inconclusive. It was clear from the Notice of Experiments served in January 1999 that this contention was to be an important part of the defendants’ case, and had there been available any counterexamples of which the claimants were aware they would have produced them. I conclude that L-745 278 is not enough to displace the strong impression created by the 15 examples in the experiment, and that substitution at the 4 position of R2 or R3 by a methylsulphonyl or sulphamyl group is essential to Cox II selectivity.
- Class C contains compounds in which the methylsulphonyl or sulphamyl group are present but not on a phenyl ring. Four examples (all of which were 3,4 diaryl thiophenes) were eventually relied on, one of which was the subject of an experiment included in the Notice. In these compounds the substituted ring (R2 or R3) is a 6-membered heteroaryl ring (pyridine) or 5 membered (thiophene) ring. Compound C1 was relied on as a counterexample, showing Cox II selectivity, and this is accepted. Accordingly there are four examples of compounds which possess a methylsulphonyl substitution at the 4 position in non-phenyl rings and are inactive. There is one example of such a substitution in which the compound is both active and Cox II selective. I think the only conclusion which one can draw from these five examples is that it is beginning to look as though activity will be rather more likely if R2 is a phenyl ring.
- Class D is intended to show that substitution at the 4 position in R2 is essential, a move to either the 2 or 3 positions resulting in an inactive molecule. This the experiments did show: there were no counterexamples. The claimants say that the result is to be explained by insolubility, and those otherwise analogous compounds in class A which did work are to be explained by the fact that sufficient got into solution to work. In fact, a check of the results show that these compounds showed no activity at any concentration whether there was precipitation or not. This experiment establishes that a compound in which the methylsulphonyl or sulphamyl group is not at the 4 position will be inactive.
- Class E is a class of compounds with disubsituted phenyl ring R2. There were three examples. Compounds B47 and B48 (one a thiophene and the other a furan) were said to be inactive. The only criticism which was made of the result in relation to B48 was that it was insoluble. B47 was said to be active, on the basis of a result obtained by the defendants using a so-called TMPD assay. There is no doubt that it was inactive in the assay carried out for the purpose of these proceedings. The evidence was that in an assay using cells from Chinese Hamster Ovaries (CHO) for Cox II the compound had some activity and may have showed a dose related effect. In an assay called TMPD_NODET (that is, without detergent) it was equally considered to be inactive. In an assay called TMPD_DET (that is, with detergent) there was some activity. In yet another microsomal assay, it is not shown as having an IC50, that is, it was considered to be inactive. Dr Percival gave evidence that the TMPD assay was used by the defendants and that it produced a good dose response curve. He said, however, that he was leery of the assay and that in the version with detergent its results correlated poorly with the CHO assay. In its version without detergent the correlation was better, but there were still outliers (compounds for which it correlated poorly). Dr Percival could not, unsurprisingly, remember all the compounds where the correlation was poor, but he said there was a large number of them. I see no reason to reject this evidence, and it follows, it seems to me, that these results may indicate a degree of activity in these assays. However, I consider that the investigation of the nature and quality of the TMPD assay was irrelevant. The patent provides its own criteria, and in the assay of the patent there is no doubt that B47 was inactive.
- Class F was a somewhat miscellaneous class, intended to show that various bulky groups on the aryl ring not substituted at the 4 position with methylsulphonyl or sulphamyl would prevent inhibitory activity. The claimants complain, with some justification, that Class F represented a moving target. There were three classes of compounds. The Notice of Experiments states that the fact to be proved is
58. Classes G and H related to the X substituent in the heterocycle. Again many of these compounds were inactive, but some showed some degree of activity. Certain compounds in class G (or which were placed in class G by Professor Flower, such as B19) showed an IC50 at a concentration of less than 100µM. C14, C15 and C18 are examples, but there is doubt as to the bulkiness of the iodine molecule in C18.
59. I think that it is possible to draw a number of conclusions from the very extensive evidence which was available in respect of classes F, G and H. The first is that it is quite clear that it is not possible to predict the degree of activity of the compounds in general. The second is that it is likely that the defendants have identified classes of compounds within the claims in which activity is very unlikely. In particular, it seems clear that large substituents at X will be inactive, and this is more likely if there are two X substituents, as the claim permits. Since X may be acyl, a substantially unbounded class of substituents, and aryl, a very large class also, and since both on Professor Baker’s unchallenged evidence include substituents equal in size to or bigger than the whole of the rest of the molecule, I am satisfied that what can loosely be called the bulky group point is established. From classes B, C and D I am satisfied that unless there is a 4-methylsulphonylphenyl or 4-sulphamylphenyl substitution at either the 3 or 4 position of the heterocycle, it is very much more likely than not that the compound will be on the patent’s own terms inactive. Finally, Class E does establish that disubstitution of the 4-substituted phenyl ring will substantially reduce the prospects of finding an active compound.
I do not propose further to consider paragraph (f), which depends on two members only of class F. I do not see how it is possible to draw the conclusion that paragraph (f) of the pleading is supported by so few examples.
Q. This does not seem to indicate activity against COX-1 or if it does it is at a much lower level. A. It is very hard to say with 3 or 4 point, but the compound was not of interest to us.
…compounds in which the aryl or heteroaryl group R3 is substituted with a bulky group, or are disubstituted, are inactive as measured by either h-Cox I or h-Cox II inhibition in vitro (see for example compounds 27 - 34 and 37).
54. In his report, Professor Baker relied not only upon this experiment but upon three other compounds. Thus his class F in its entirety consists of compounds B50 to B63 inclusive. In support of the fact, however, Professor Baker also relied on a number of compounds in Class A (which, it will be remembered, the defendants considered to be active and Cox II selective). His evidence was this:
55. Section F of the Table contains a list of compounds that differ from selective COX-2 molecules only in that they have a large group on the other aryl group (R3). Comparison of Sections A and F indicates that, whilst there is some space around the second aryl group, such that fluoro (B1), methyl (B6), methoxy (B3), thiomethyl (B13) and amino (B14) can be tolerated, anything significantly larger cannot be accommodated in the enzyme.
56. The examples which he gives of the effect of such substitutions is complicated, and he summarises them in his report thus:
(a) A second 4-methylsulphonylphenyl or sulphamylphenyl group is not tolerated by either COX-1 or COX-2 (see compounds B50 & B51). Further, a 4-methylsulphinylphenyl group is not tolerated (B58);
(b) Even relatively small groups are not tolerated in the 2-position (see B52, B55 and B56). This effect may be aggravated if there is a substituent in the X position opposite the 4-methylsulphonylphenyl because this may cause the twisting of the aromatic ring (see B62).
(c) Whilst there appears to be more space around the 4-position, moderately large alkyl or alkylamine groups in these positions result in inactive compounds against either form of the enzyme (see B53 and B54).
(d) The 2, 6 or 3,5 di-substituted compounds for example in which R3 is 2, 6-dichlorophenyl and 3,5-difluorophenyl are inactive (see B60 and B61).
57. Professor Flower introduced a number of additional compounds into the discussion, with the result that RJF 25 contains 30 compounds in class F. It should be recalled that the compounds found by Professor Flower in the defendants’ documents have a number beginning C and it is not suggested that Professor Baker was aware of these compounds when he wrote his report. With his C compounds, Professor Flower produces counter-examples to each of these propositions of Professor Baker’s. In fact, there is a clear counter-example to (a) in compound C13 as Professor Baker accepted in cross-examination. Professor Baker himself qualified paragraph (b) in the light of compound C9. His evidence was that the results collected in RJF 25 represented an attempt at an SAR for these molecules, which would necessarily require refinement, but this is not one of the facts that the Notice of Experiments was put forward to show. There is no doubt that many of the compounds in question were inactive; others less so. The claimants pointed to C3, C5, C6, C10, C11 and C12 as compounds where there was activity below but close to 50% at 100µM or 1000µM. On the other hand, some compounds were plainly inactive, among which B55 is to be included. The same goes for paragraph (d). The evidence was thin, but the compounds disubstituted at the 2,6 and 3,5 positions actually tested were inactive.
The in vivo experiments
- The in vivo tests were carried out on rats. They consisted of three tests well established in the investigation of NSAID’s and a direct investigation of the capacity of the compound under test to irritate the stomach. The tests are the rat paw oedema test, the adjuvant arthritis test, the test for gastric irritancy and a test for analgesic effects. The protocols used gave rise to no dispute, but there are two aspects of the experiments which need to be considered. The first is the weighing error made by the defendants, and the second is the use by the claimants of DMSO as a solvent. In summary the tests were as follows:
- Carrageenan-induced Paw Oedema Assay. This assay measures the ability of a compound to reduce acute inflammation which has been induced in a rat paw by carrageenan. The compound is tested relative to a control, in order to measure the relative anti-inflammatory effect and ensure that any such effect is attributable to the compound and not the test vehicle. Results are given in terms of % inhibition which indicates the % reduction in swelling relative to the control.
- Gastric Irritancy Assay. This assay measures the degree of gastric irritancy of the compound under test relative to a control compound. Irritation is measured by counting the number of lesions visible on the stomach wall. The greater the number of lesions, the more irritant the compound. It is a well known assay that has been in use in the field for about 20 years.
- Adjuvant Arthritis Assay. This assay measures the ability of the compound under test to reduce chronic inflammation, caused by an autoimmune response. Arthritis is an autoimmune disease. The immune reaction is induced in the rat by injecting a heat-killed bacterium contained in oil. Reduction in inflammation is measured relative to a control, thereby ensuring that any effect is attributable to the compound under test.
- Carrageenan-induced Analgesia Assay. This assay indicates the ability of the compound under test to reduce sensitivity to pain. It measures the time it takes for a rat to remove its inflamed paw (the inflammation being induced by an injection of carrageenan) from a heat source. The longer it takes the rat to withdraw its paw relative to a control, the more analgesic the compound. Results are given in terms of % inhibition which indicates % of pain suppressed relative to the control.
- The claimants carried out experiments on the compound of Example 1 of the patent only. The defendants tested the compounds of examples 1, 2, 5, 11 and 15 in various of the assays. As in the case of the in vitro tests both parties referred to the corresponding tests which had been carried out by them in the ordinary course of research, and there was again more experimental evidence than the Notice of Experiments would suggest. Three issues arise. The first relates only to the tests carried out by the claimants both in-house and in their Notice of Experiments and concerns their use of DMSO as a solvent. The second relates to the question of cut-off, just as in the case of the in vitro tests. Finally, an error was made in weighing by the defendants at the first set of repetitions of their in vivo experiments, which the claimants said threw doubt on all the in vivo experiments recorded in the Notice. I reject this. The cross-examination of the experimentalist concerned (Mr Gordon) who was very experienced in performing this experiment satisfied me that the mistake was made because he was harassed on a particular occasion, and that it was very unlikely that he would have made the same mistake at any other time.
- The DMSO issue. If an in vivo test is to be performed, it goes without saying that steps must be taken to ensure that the compound is absorbed into the body. The claimants used DMSO when they carried out their experiment on Example 1 of the patent, but the defendants did not use it at all. Its use on the compounds of the patent in suit for improving bioavailability is not referred to in that document, which refers to the use of methyl cellulose as a carrier. The compounds are sparingly soluble, and Professor Flower said that he would immediately think of using DMSO to improve solubility (I should add that it can only be used in animal experiments. It cannot be used for administration to humans). DMSO is a remarkable compound. It passes through the membranes of the body with ease. There was a real dispute between the experts as to the significance or otherwise of using DMSO. Professor Willoughby regarded it as a very controversial carrier. No doubt it would have been better had it not been used, but the defendants failed to show that its use was affecting results in a significant way. But the reverse is also true. The claimants failed to show that the results achieved by the defendants were achieved because they did not use DMSO.
- The cut-off issue. Again, the defendants adopted a criterion for anti-inflammatory activity of 30% inhibition at a dose of 30mg active compound per kilogram body weight (mg/kg). This was a criterion admittedly suitable for selecting a compound for carrying forward, but both Professor Flower and Professor Willoughby were reluctant to adopt any hard and fast criterion. The two controls used by the defendants do provide some guidance: they used the established NSAID indomethacin and the prior art 2,3 diaryl substituted thiophene DuP 697. But such controls cannot serve to provide a criterion for inactivity as an anti-inflammatory compound, and the criterion which should be adopted is whether or not the compound shows an anti-inflammatory effect not statistically significantly different from zero.
- Example 1 There is no doubt that this compound exhibited poor bioavailability. The in vivo results showed wide variability, but there is no doubt that in the rat paw oedema test the tendency of the results was in favour of this compound demonstrating an anti-inflammatory effect. It was not tested in the adjuvant arthritis assay or in the analgesia assay, and it did not cause stomach erosion.
- Example 2. This compound also demonstrated an anti-inflammatory effect in the rat paw oedema test. The results are again variable, and the compound is probably poorly bioavailable. It showed no activity in the adjuvant arthritis test. It is not clear that it has analgesic properties. This was because a known analgesic, DuP 697, also returned a null result in this assay.
- Example 5. Example 5 was plainly inactive in the rat paw oedema test. It was not tested in the adjuvant arthritis test.
- Example 7. This was tested for analgesia only.
- Example 11 and 15. These compounds are in the same position as the compound of Example 5.
- Professor Flower was at pains to emphasise that use of DMSO with these examples, might have improved the position. Once a null result is shown, the evidential burden shifts to the patentee, and, if the patentee is in a position to do any necessary experiment in reply and does not do it, it seems to me that I am justified in accepting the result which is in evidence unless there are other reasons for doubting it. I was not persuaded that there were good reasons for doubting the result, and I was not satisfied from the claimants’ results using DMSO that its use would have made any difference. Examples 5, 11 and 15 did not exhibit any anti-inflammatory effect. I am not satisfied that any of the null results in the analgesia test were probative because of the null result with DuP 697, a known analgesic.
- Compound 68. Compound 68 was conclusively shown to be a bad gastric irritant in the in vivo tests.
After these assays the rats are killed. Necessarily a number of rats are used in each assay, so that results which are statistically significant are obtained.
Summary of the in vivo tests.
- The in vivo tests did demonstrate that there were three examples of the patent in suit which failed to demonstrate any anti-inflammatory effect, and a preferred compound (compound 68) which was a gastric irritant. They did not demonstrate that example 1 of the patent in suit was inactive as an anti-inflammatory, but did show that it was certainly not attractive.
Insufficiency—findings
- Until a comparatively late stage, the defendants contended that it was not possible to make a number of compounds falling within the claim. This allegation was abandoned, and it is now not in dispute that all the compounds falling within the claim are in principle capable of being made by the addressee of the specification. I have already discussed the defendants’ assays and the conclusions which it is possible to draw from them. There was a suggestion that the defendants had gone out of their way to select compounds having undesirable characteristics, and that the compounds selected were all examples of the kind of occasional failure to exhibit desirable qualities, or the exhibition of those qualities in an attenuated form, which should not affect the validity of the claim. The defendants said that their selection of compounds was, in fact, the sort of selection that a medicinal chemist seeking to construct an SAR would make.
- The pleaded case of insufficiency is set out in the Particulars of Objections
as follows:
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. In particular
(a) the specification of the patent fails to identify which (if any) compounds among those classes of 3,4 diaryl thiophenes, furans and pyrroles claimed:
In coming to a conclusion on the question of the right criterion to apply in deciding whether or not a compound exhibits activity in the in vitro tests, I have gone over a great amount of the ground covered by the objection of insufficiency. I am satisfied that the experimental evidence shows that the specification provides the skilled man with a class comprising many compounds which may or may not be Cox II selective with diminished side effects. The effect of the experiments taken as a whole is to demonstrate that the class in question is unpredictable in its qualities and contains a substantial number of compounds which do not have one or other or both of these qualities. It is not possible to point to any characteristic which underpins success, and avoids failure. As I have indicated, the feature which immediately distinguishes the compounds of claim 1 from those constituting the state of the art is (subject to the disclosure of Brown) the 3,4 disubstitution of the heterocycle as opposed to the 2,3 disubstitution displayed in, for example, DuP 697. But it is clear that this does not give success on its own; and I am satisfied on the evidence that it has not proved possible to provide a general description of a class having the desired characteristics. As will be apparent when I consider the history of the claimants’ development, I do not consider that the work they had done by the priority date nor the later work which they did justify any suggestion that it was a reasonable prediction that the class of claim 1 either as granted or as amended would possess anti-inflammatory properties.
The invention of claim 13 must be considered separately. Claim 13 covers "a pharmaceutical composition comprising a therapeutically-effective amount of an anti-inflammatory compound, said compound selected from a compound of Claim 1, or a pharmaceutically-acceptable salt thereof". This is a claim, in effect, to any compound of claim 1 which works. Necessarily, the specification is open to the same objections in respect of the invention specified by this claim as it is in respect of that of claim 1. Claim 20 stands or falls with claim 1 so far as this objection is concerned. I conclude that the unamended specification is insufficient in respect of the invention of claims 1, 13 and 20.
So far as the amended specification is concerned, the position is to some extent different. The amendment to claim 1 restricts that claim to compounds in which one of R2 or R3 is a 4-methylsulphonylphenyl group and the other a substituted phenyl group, and in which there is only one substituent X. The experimentally demonstrated fact that it is likely that substitution by a methylsulphonyl or sulphamyl group at the 4 position of a phenyl ring is essential to activity is accordingly accommodated by the amendment. The excessive range of possible X substituents, which includes substituents larger than the rest of the molecule and is unbounded in number is not catered for. As I have found that on the balance of probabilities a large number of these compounds will also be inactive, the specification is still insufficient in respect of the invention specified by the amended claim 1, and so also in relation to that of claims 13 and 20.
The patent claims priority from US 4822, an application made in the United States on 15 January 1993. This application is entitled "Novel 3.4-diaryl thiophenes and analogs thereof having use as anti-inflammatory agents". The general description of the invention is as follows:
Formula I is a much narrower preferred class (Figure F) of 40 or so compounds.
The priority document concentrates on 3-(4-methylsulphonylphenyl)-4-(4-fluorophenyl) thiophene and derivatives. This compound is as Formula I in which X is hydrogen, and Y is sulphur. All the preparations illustrated are of it or its pyrrole (Y=NH) and furan (Y=O) analogues. It is also example 1 of the patent in suit. It is the only compound for which any biological result is reported in the priority document. This result, which is a rat paw oedema assay at various dosages using for comparison indomethacin, shows a dosage-related anti-inflammatory effect. Any statement concerning erosion of the stomach in the priority document is assertion only, so far as the teaching of that document is concerned. It is of interest to note that the claimants thought that it was a reasonable assertion to make because, as Dr Isakson said,
The methylsulphonyl group on one of R2 or R3 is a feature of claim 1. There is a disclosure of this substitution in the priority document as one of the optional lower alkylsulphonyl group substituents for R2 and/or R3. One gets to this disclosure from the statement in the priority document that the lower alkyl moiety in the term "lower alkylsulphonyl" is preferably methyl or ethyl. There is no disclosure in relation to the general formula I 2 that at least one of R2 and R3 be substituted with a methylsulphonyl group. It is optional. So far as Formula I is concerned, there is a disclosure of a 4–methylsulphonyl substitution in a phenyl group; but this disclosure is in the context only of a 4–fluorophenyl group and a bromo group as the other substituents in the heterocycle. The defendants submit that to make the methylsulphonyl group an essential feature of the combination (and a fortiori the 4–methylsulphonyl substitution) is an addition to the disclosure of the priority document at which it does not even hint.
The defendants submit that this is a clear case of a selection from the wider class disclosed in the specification in suit without any basis having been disclosed for the selection. Professor Baldwin said that there was no way of predicting which compounds comprised within Formula I 2 would be both anti-inflammatory or analgesic and gastric erosion free. The defendants also submit that Formula I could not be relied as support for the wide claim 1 of the patent in suit because that is a disclosure limited to a combination with the 4–fluorophenyl substitution, and to remove it from that context would be to add to the disclosure, in effect saying that it has now been discovered that the 4–methylsulphonylphenyl substitution is essential even in the absence of the 4–fluorophenyl substitution in the other position on the heterocycle.
In order to argue that the claim was supported by the disclosure of the priority document, the claimants relied on the evidence of Professor Baldwin that it was possible to discern in claim 1 three functional elements, or modules. The first was the 5-membered heterocycle, optionally substituted with the same X’s both in the priority document and the patent. The second module was the optionally substituted phenyl group at the 3 position, and the third module the optionally substituted phenyl group at the 4 position. When one came to the disclosure of Formula I (Figure G) Professor Baldwin said that the same three functional elements were disclosed by Formula I (ignoring the sulphamyl group in R2 or R3).
This evidence was vigorously attacked by the defendants, who point to three principal facts which, they say, go to show that the view expressed is either tainted by hindsight or is based on a degree of insight not possessed by the hypothetical addressee. The three considerations may be summarised as follows.
- The DuPont work. Central to this case is the work done at DuPont before the priority date. This work, carried out over a long period of time, culminated in DuP 697, which is 5-bromo-2-(4-fluorophenyl)-3-(4-methylsulphonylphenyl)-thiophene. One at least of the patents originating with the DuPont group responsible for DuP 697 is the patent called Haber 2, which is for a small number of 2,3 substituted diaryl thiophenes in which one of the substituents is the 4-fluorophenyl group. This shows, say the defendants, that DuPont thought that the 4-fluorophenyl group was as important as (for example) the 4-methylsulphonylpheny group, at least in a 2,3 substitution as opposed to a 3,4 substitution.
- The Monsanto work. The defendants say that the claimants’ disclosure in this case goes to confirm that the 4-fluorophenyl substitution was seen by the claimants themselves to be either important or essential. They start with the slides from a presentation which was apparently intended to show a proposed way forward from the disclosure of DuP 697 and the compound called NS 398. This latter compound had come into the picture because on 29 July 1992 Dr Seibert, Dr Needleman and Dr Isakson saw the structure of a novel NSAID NS-398 on a poster presented by Taisho at a Montreal conference. The structure of NS-398 was distinct from DuP697 and indeed all the other potential Cox-2 selective inhibitors identified by August 1992. It was related to a commercially available NSAID developed by 3M, Nimesulide, and was in a class known as the methanesulphonilides. The structure of NS-398 is shown below (Figure H).
NS-398 exhibited all the anti-inflammatory properties of DuP 697 but had better data regarding gastrointestinal, renal and platelet side effects. Having confirmed that NS-398 was indeed a Cox-2 selective inhibitor it seems that Monsanto began synthesising and screening analogues of NS-398 for Cox-2 inhibition. The slide presentation starts with DuP 697 and NS 398 and finishes, under the heading Summary and Plans, with the statement bis-4-methoxyphenyl thiophenes are selective Cox I inhibitors; 4-fluorophenyl 4'-methylsulphonylphenyl thiophene derivatives are selective Cox II inhibitors; one 4-flurophenyl 4'methylsulphonylphenyl pyridine derivative is a Cox II inhibitor. The plans are to prepare bis-4-methylsulphonylphenyl thiophene derivatives; Enhance Cox II activity of pyridine analogues, and make Cox II selective methanesulphonamides. The date of the slide show appears to be late 1992, so demonstrating, say the defendants, that the 4-fluorophenyl group in DuP 697 was seen by the claimants as an important part of the molecule, not to be disregarded.
The same goes for other slide shows, in which (for example) the summary is that application of the p-fluorophenyl and p-methylsulphonylphenyl motif to other heterocycles enhances Cox II activity, but then in mid 1993 one of the slide shows reports that "the para-fluoro substituent may be replaced without effecting [sic] the Cox II potency". Two further documents may be referred to. The first is undated, and headed "Anti-inflammatory Cyclooxygenase Inhibitors". It concludes with the following paragraph:
Well, say the defendants, if the addressee would have immediately recognised the para-fluorophenyl substitution as irrelevant or of minor importance, then why is this fact reported as a discovery well after the priority date? This was put to Dr Isakson in cross-examination. Dr Isakson pointed out that the preparation of the compound had taken a long time, and they had a large quantity of the 4-fluorophenyl substituent to test. He was emphatic that the 4-fluorophenyl substitution had been considered to be relatively unimportant.
Whatever the exact perception at Monsanto, it seems to me that the only disclosure of the priority document is of the 4-methylsulphonylphenyl substitution of the heterocycle in combination with the 4-fluorophenyl substitution. The law relating to support for a claim is clear, and is stated by Aldous J in Schering Biotech Corporation's Application [1993] RPC 249. This was an appeal from the Patent Office which had objected that the claim of an application was not supported by the disclosure of the specification, as section 14(5)(c) of the 1977 Act requires. The test is the same for support of the claim by the priority document: see Beloit v Valmet [1995] RPC 705 (Jacob J) and (implicitly) Biogen v Medeva [1997] RPC 1 at 47-8 (Lord Hoffmann). Aldous J said:
So far as the disclosure of Formula I 2 of the priority document is concerned, either methylsulphonyl or sulphamyl substitutions in R2 or R3 are disclosed as optional features of the invention. The aryl component may be, but does not have to be, phenyl. It may be naphthyl, or phenyl substituted with lower alkyl, "and the like". The invention of Formula I is of a comparatively narrow class, all of whose members have both a 4-methylsulphonylphenyl and 4-fluorophenyl substitutions in the heterocycle and do not include many of the X substitutions called for by claim 1 of the patent in suit, including hydroxy. This distinction is reflected in the claims of the priority document. The disclosure of claims 2, 3, 4 and 5 is a disclosure of a 4-methylsulphonyl group at R2 and a 4-fluoro group at R3, both R2 and R3 being phenyl. The disclosure of the priority document cannot be affected by the relative importance which the skilled man would attach to the two substituents in Formula I. This is not an express part of the disclosure, and it is not something which is necessarily implied by the disclosure.
So far as the unamended patent in suit is concerned, on the other hand, at least one methylsulphonyl or sulphamyl substitution, not necessarily on a phenyl ring but on an aryl ring (which includes naphthyl, phenyl substituted with a lower alkyl, and also other two-membered rings, three-membered rings and heteroaryl rings) is a defining feature of the claim. In my judgment, claim 1 of the patent in suit is not entitled to priority for three reasons. First, because there is no disclosure of a sulphamyl substitution in R2 or R3 in the priority document other than in the list of Formula I 2, and certainly no disclosure of it as a defining feature of the invention. Second, there is no disclosure of a methylsulphonyl substitution in R2 or R3 as a defining feature of the invention, but only as defining a preferred subclass in combination with a 4-fluorophenyl substitution, a subclass which does not include a hydroxy substitution at X. Third, a monopoly defined by one or other of these substitutions as an invariant feature across the whole width of the claim cannot be fairly based on a disclosure which does not hint at their materiality either textually or as a matter of necessary implication but only, at best, as a result of well-informed assessment of probabilities.
The amended claim is no longer open to objection on the ground either that it covers a sulphamyl substituent at R2 or R3, or that it covers R2 or R3 substituted with methylsulphonyl other than as 4-methylsulphonylphenyl. The objection that there is no disclosure in the priority document of such a substitution otherwise than in the combination I have already described, and the consequence is the same.
As I have indicated above in considering the experimental evidence, Mr Young based a distinct argument on priority date on the contention that the patent in suit represents that the common feature of the compounds of claim 1 (or amended claim 1) is that they possess anti-inflammatory activity with a reduced amount of side effects, a contention with which I agree. The argument is that if the teaching of the priority document does not provide support for a claim to a class of compounds having these features because not all the compounds of the priority document do in fact have these qualities, then it cannot provide support for a claim to a class said to possess these qualities, the more so since the priority document contains neither the teaching in relation to Cox II selectivity to be found in the patent in suit nor the latter’s disclosure of a suitable assay.
To deal adequately with Mr Young’s argument I must first revisit the question of the invention of the patent in suit. I have found that the invention of the patent lies in the provision of a class of compounds which are not merely anti-inflammatory but which have fewer and less drastic side effects, the reduction in side effects being due to Cox II selectivity. I have no doubt that the disclosure of the priority document does not support such a claim. Not only are the classes which it discloses not the same as those of the patent, but there is no teaching of the priority document which enables the addressee to identify such a class. It is now accepted that the priority document is enabling in the sense that the addressee can make the compounds (all of them) encompassed by the claim. This being so, it is in principle possible for each of these compounds to be tested for its anti-inflammatory effects and its gastric sparing qualities on animals in vivo. Suitable tests were part of the common general knowledge at the priority date and provide the nearest thing to a gold standard, as Professor Willoughby emphasised. It is not suggested that such tests could not be used on the compounds of the priority document. However, Dr Isakson accepted that the first fifteen compounds in exhibit RB 14, which are compounds within the disclosure of the priority document were inactive in the Cox I/Cox II assay and that some of the others were actually Cox I selective. Such a disclosure cannot enable, and does not support, an invention consisting of compounds which owe their gastric sparing qualities to Cox II selectivity. For this reason also, the claim is not entitled to claim priority from the application date.
I should add a footnote to the foregoing discussion. I ordered the claimants to serve a Statement of Case in relation to two issues. The first was whether they were claiming that all or substantially all the compounds disclosed in the patent and the priority document were Cox II selective and, if not, which were said not to possess such selectivity; and second, whether they were drawing a distinction between Cox II selectivity on the one hand and an absence of gastric side effects on the other. In paragraph 1 of their Statement of Case the claimants contended that the invention of the patent in suit relates more particularly to compounds having anti-inflammatory and/or analgesic activity with reduced gastric side effects compared with NSAID’s available at the priority date, such as indomethacin. In paragraph 2, they say that it is a reasonable prediction that all, or substantially all, of the compounds falling within the claims of the patent will exhibit the activity described in the patent, namely anti-inflammatory and/or analgesic activity with reduced gastric side effects. In paragraph 7 of the statement of case, they say that the priority document relates to 2,3 diaryl substituted thiophene, furan or pyrrole derivatives and analogues thereof having anti-inflammatory and/or analgesic activity with reduced gastric side effects. Their contentions at trial were not consistent with these contentions, and in my judgment could not be, once it was established that compounds disclosed in the priority document did not have substantial activity in the assays set out in the patent in suit, since it was not possible to demonstrate that the classes of compounds disclosed in the priority document were in fact gastric sparing.
(i) are Cox II selective or enable the skilled addressee of the patent to predict which compounds are Cox II selective;
(ii) exhibit anti-inflammatory activity or enabled the skilled addressee of the patent to predict which compounds exhibit anti-inflammatory activity;
(iii) exhibit reduced gastric side effects when administered to patients or enable the skilled addressee of the patent to predict which compounds will exhibit reduced gastric side effects.
(b) the specification of the patent fails to teach the skilled addressee how to synthesise the substituted pyrrole and furan derivatives of the invention and in particular the hydroxyfurans of the invention.
60. In the premises the claims of the Patent extend beyond the technical contribution to the art (if any) of the specification of the Patent.
The allegation of paragraph (b) was persisted in only in respect of the hydroxyfurans, the compounds exhibiting tautomerism that I discuss in detail below when considering the scope of the claim and infringement. Put shortly, the allegation is that many, or all, of the hydroxyfurans covered by the claim will generally be present in negligible quantities in tautomeric equilibrium with the corresponding furanones, which are not covered by the claim, and if the skilled man sets out to make the hydroxyfuran he will be disappointed, getting nothing but furanone for his pains.
Priority date
This invention relates to 3,4-diaryl substituted thiophene, furan and or pyrrol derivatives and/or analogs thereof, pharmaceutical compositions containing them and methods of using them to treat inflammation and/or pain in mammals. More particularly, this invention relates to selected 3,4 diaryl thiophenes and analogs thereof having antiinflammatory and/or analgesic activity without erosion of the stomach and therefore more effective and safe.
There is no mention of Cox II selectivity, and no mention of Cox I inactivity. Nor is there any further reference to the gastric sparing qualities of the compounds. Two general formulae, I 2 and I, are disclosed. Formula I 2 denotes a wide class of 3,4-diaryl compounds. Formula I 2 has the same general three-ring structure consisting of a 3,4 diaryl substitution in the heterocycle, but the classes of permitted substituents are wider than those of the patent and there is no overall requirement that at least one of R2 and R3 be substituted with methylsulphonyl or sulphamyl. That, synthetic schemes apart, is the extent of the teaching of the priority document.
.png)
Figure F (Formula I of priority document)
In Formula I (Figure F) Y is S, O, NR1 wherein R1 is hydrogen or lower alkyl of from one to six carbons, preferably where Y is S;
X is hydrogen, fluoro, chloro or bromo, preferably wherein X is hydrogen and more preferably wherein X is bromo.
"We had in vitro data that showed that it favoured COX-2 over COX-1. There was published data using both NS 398 and the Du Pont compound [i.e. DuP 697] showing that they had an absence or a reduced gastrointestinal side-effects profile, so the conclusion was that from that lack of COX-1 activity might in fact be beneficial. It was certainly not proven at that time. That was still very much a hypothesis."
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Professor Baldwin’s evidence was that the addressee of the specification would immediately realise that the 4-methylsulphonylphenyl substitution was more important than the 4-fluoro substitution in the binding activity of the molecule. The argument was as follows. Formula I is a preferred subclass of Formula I 2. Y may be S, O or NR', and therefore has no effect on whether or not the subclass is preferred. Although X is limited to H, F, Cl and Br in Formula I, the reader would understand from Formula I 2 that other substitutions will still be biologically active. The result is that the "preferredness" of Formula I 2 must depend upon the 4'-methylsulphonylphenyl and 4'-fluorophenyl groups. Of these, it is far more likely that the methylsulphonylphenyl group will be the one which matters. Chemically it was a large polar group, and much more likely than the fluorine group to matter when the interaction of the molecule and the active site(s) of Cox II was considered. Fluorine was a small group (not much bigger than hydrogen) and likely not to differ substantially from hydrogen in its binding effects at an enzyme site.
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Figure H: NS 398
To summarize this initial phase of the research project, the following were the most important observations: 1. The aromatic rings of the diaryl heterocycle had to be on adjacent positions for cyclooxygenase activity. 2. The para-methylsulphonyl moiety had to be present for mCOX-2 activity. 3. Substituents other than para-fluoro on the other benzene ring gave similar cyclooxygenase activity. The absence of the para-methylsulphonyl results in molecules capable of inhibiting both mcox-1 and mCOX-2 or mCOX-1 selectively.
The second is the "Semiannual report in Medicinal Chemistry June 1993". This document says that the specificity of diarylheterocyclic derivatives of COX-1 versus COX-2 has been found to be exquisitely sensitive to the nature of the substituents on the aryl rings.
Modification of diarylheterocycles by incorporation of a para-methylsufonyl and para-fluorophenyl substituent has lead [sic] to the formation of selective COX-2 inhibitors. Almost without exception, incorporation of this structural motif resulted in production of selective inhibitor candidates. To date we have prepared more than thirty molecules that possess very selective COX-2 inhibitory activity, ie IC50’s < 0.1µM, almost all of which possess the para-fluorophenyl and para-methylsulphonylphenyl structural feature.
The words "supported by the description" were new in the 1977 Act. The 1949 Act contained the requirement that the claims had to be fairly based on the matter disclosed in the specification. I am not sure whether the change in wording between the 1949 Act and the 1977 Act means that there has been a practical change. I have therefore not felt it right to rely upon the cases decided under the 1949 Act.
In my view the correct approach under the 1977 Act is to consider the description and claims in the specification through the eyes of the skilled man in the art. Under section 125(1) the invention is that specified in the claims. Thus to decide whether the claims are supported by the description it is necessary to ascertain what is the invention which is specified in the claims and then compare that with the invention which has been described in the specification. Thereafter the court's task is to decide whether the invention in the claims is supported by the description. I do not believe that the mere mention in the specification of features appearing in the claim will necessarily be a sufficient support. The word "support" means more than that and requires the description to be the base which can fairly entitle the patentee to a monopoly of the width claimed. This approach is I believe consistent with the decision of the European Patent Office's Technical Board of Appeals in the Biogen case T301/87 of 16 February 1989. They said: "The scope of protection in the claims must be fair having regard to the way in which the invention is described and having regard to the information which the skilled person has been given in the description as to how the invention can be carried out".
The test is one of comparison of the invention called for by the claims, properly construed, and the invention disclosed to the addressee by the priority document. The disclosure is, as always, that which is disclosed either expressly or as a matter of necessary implication. The relative importance which the skilled man would ascribe to the various substitutions disclosed is irrelevant, unless it is something that would necessarily be communicated to him by the disclosure. In this respect, the law as stated by Aldous J is much the same as that applied by the European Patent Office: see Case T 73/88 Snackfood/HOWARD. In the present case, the view of the disclosure of the priority document taken by Professor Baldwin can be no more than an assessment of the likely importance of the 4-methylsulphonyl as opposed to the 4-fluorophenyl group, and as Professor Baldwin said, no conclusions could be drawn without experiment. I conclude, therefore, that there is no disclosure in the priority document of any class of compounds in which a 4-methylsulphonyl substituent in R2 or R3 is an essential component other than that of Formula I.
Added matter
- Having regard to the conclusions that I have reached on the remainder of the case, it is not necessary to deal with this objection, but the matter was argued and I should give my conclusions. The objection of added matter is pleaded against the patent as granted and as proposed to be amended. The objection may be shortly stated: the class of claim 1 as granted is nowhere described in the application as filed. The only class described in the application in which a methylsulfonyl (or 4-methylsulphonyl) substituent on either R2 or R3 is mandatory is the class covered by claim 14 of the application as filed, which is otherwise a different, much narrower class than that of claim 1 as granted. There is no disclosure of the presence of such a substitution in combination with all the other substituents of claim 1 as applied for. Accordingly it is said that the new claim represents a generalisation of claim 14 as applied for with added elements of claim 1 as applied for; and such a class, being nowhere described, must have been added to the disclosure of the application as filed. The other changes in the scope of claim 1 relied on by the defendants (narrowing the range of X substituents and narrowing the choice of R2 and R3 groups) seem to me not to affect the disclosure at all. In Bonzel v Intervention (No. 3) [1991] RPC 553 at 574, Aldous J formulated the test as follows:
- It seems to me that there is an addition to the disclosure in the respect which I have indicated. There is no disclosure in the application as filed of the importance, or necessity, of the methylsulphonyl group in combination with the whole of the list of other substituents from claim 1 as filed restricted as it is in claim 1 as granted. In this respect, Professor Baldwin’s evidence, which seeks to consider the group in isolation from the context in which it is disclosed, does not, it seems to me, proceed upon a correct legal basis. This is not a case in which the same invention is described in a different way, and it is not a pure disclaimer. Accordingly the patent as granted is bad for added matter, and the same must go for the amended patent, for the same reason.
The decision as to whether there was an extension of disclosure must be made on a comparison of the two documents (application as filed, patent as granted) read through the eyes of a skilled addressee. The task of the Court is threefold:
(a) to ascertain through the eyes of a skilled addressee what is disclosed, both explicitly and implicitly in the application;
(b) to do the same in respect of the patent as granted
(c) to compare the two disclosures and decide whether any subject matter relevant to the invention has been added whether by deletion or addition. The comparison is strict in the sense that subject matter will be added unless such matter is clearly and unambiguously disclosed in the application either explicitly or implicitly.
Anticipation and obviousness
- Before turning to the specific documents pleaded, I should set out my understanding of the law. For a claim to be anticipated by a prior disclosure, the prior disclosure must contain a clear description of, or clear instructions to do or make, something that would infringe the patentee’s claim if carried out after the grant of the patentee’s patent. If, on the other hand, the prior publication contains a direction which is capable of being carried out in a manner which would infringe the patentee’s claim, but would be at least as likely to be carried out in a way which would not do so, the patentee’s claim will not have been anticipated, although it may fail on the grounds of obviousness. 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. These propositions are established by the judgment of the Court of Appeal in General Tire & Rubber Company v Firestone Tyre and Rubber Company Limited [1972] RPC 457 at 484, and represent the modern law as to anticipation by prior disclosure. The objection of obviousness assumes that there is no anticipation of the claim, but that nonetheless there has been no inventive activity on the part of the patentee which justifies the grant of a patent. Obviousness is a question of fact, and the factual analysis is habitually approached in the manner described by Oliver LJ in Windsurfing International v Tabur Marine [1985] RPC 59 at 73.
- The inventive concept of the patent in suit can be stated compendiously as follows. It is a class of compounds having the structure specified by claim 1 and which possess anti-inflammatory and/or analgesic activity without erosion of the stomach, or with reduced side effects, by reason of their ability selectively to inhibit Cox II.
There are, we think, four steps which require to be taken in answering the jury question. The first is to identify the inventive concept embodied in the patent in suit. Thereafter, the court has to assume the mantle of the normally skilled but unimaginative addressee in the art at the priority date and to impute to him what was, at that date, common general knowledge in the art in question. The third step is to identify what, if any, differences exist between the matter cited as [forming part of the state of the art] and the alleged invention. Finally, the court has to ask itself whether, viewed without any knowledge of the alleged invention, those differences constitute steps which would have been obvious to the skilled man or whether they require any degree of invention.
There are a number of arguments which are frequently advanced to fend off an attack of obviousness which need to be considered with care. The first (and perhaps the commonest) is that where there is a number of possible courses of action for the skilled man to pursue in the light of a particular disclosure, no particular course is obvious. This is wrong: all of the courses of action which present themselves without the exercise of invention are obvious (see Brugger v Medicaid [1996] rpc 635). The second is that the test in such a case is whether the skilled man could, rather than would, adopt the course of action which would bring him within the claim. A test formulated in this way almost invites the tribunal to consider irrelevant considerations, such as commercial attractiveness (Hallen v Brabantia [1991] RPC 195). In each case, the only question is whether something within the claim was technically obvious to the skilled man in the light of the disclosure relied on. Evidence of what was actually done in the art at the relevant time can be of assistance, but what people actually did may be explicable on many grounds having nothing to do with technical obviousness. For this reason it has been said that such evidence has to be kept in its place and it is necessarily valueless unless the persons whose activities are under examination can be shown both to be aware of the prior art and possessed of the common general knowledge (see Molnlycke v Procter & Gamble [1994] RPC 49 and Hoechst Celanese v BP [1997] FSR 547).
Validity in the light of Brown
- Novelty is attacked on the basis of the disclosure of US Patent 3,743,656 (Brown). In summary, Brown discloses a substantial subclass of the compounds of claim 1 either as granted or as proposed to be amended, and the claim is invalid for this reason.
- There is also an attack of obviousness based on Brown. The point is very narrow: given a disclosure of a methylsulphonylphenyl substitution, but no disclosure of a 4-methylsulphonylphenyl substitution, is the latter obvious? I conclude that it is: a general disclosure of such a substitution renders obvious the easiest way to do it. My detailed reasoning is as follows.
- Brown is said (column 1 line 22) to relate to novel heterocyclic aromatic compounds and to processes for preparing them. The compounds are furans, thiophenes and pyrroles substituted by two aryl groups and an aliphatic acid group containing from two to six carbon atoms or a derivative thereof. The compounds of the invention are said to be pharmacologically efficacious as anti-inflammatory agents. The class of compounds with which Brown is concerned is again huge, but it is to be noted that all the members of the class must have an aliphatic acid group as a substituent on the furan, thiophene or pyrrole ring. The compounds disclosed as having pharmacological activity can only anticipate any claim of the patent in suit if the claim of the latter is capable of covering such compounds. The case on anticipation by Brown is put in two distinct ways. First it is said that distinct classes of the pharmacologically active anti-inflammatory compounds which it discloses fall within the product claims of the patent in suit, and, being disclosed as anti-inflammatories, also anticipate claim 13 and claim 20, at least. Second, it is said that certain classes of intermediates proposed by Brown for the making of the compounds also fall within the product claim 1 of the patent in suit. Necessarily, the disclosure of compounds as intermediates cannot anticipate claims to pharmaceutical compositions but will anticipate the use claims as they have been construed by the Court of Appeal.
- The first question is accordingly one of construction of the patent in suit. Does the claim allow X to be an aliphatic acid? The argument proceeds in stages. First, the claim expressly contemplates that one of the substituents (or the substituent, so far as the amended claim is concerned) may be an acyl group (feature a(vi) of the claim as I have labelled them) or may be a "lower alkyl group substituted … with a substituent selected from … acylamino, … lower alkyl(acyl)amino, acyl …" (feature a(vii) of the claim). The terms "acyl" and "acylamino" are normally well defined. The primer gives the necessary structural diagrams.
- At page 9 line 56 of the specification, the term "acyl" is given
an extended meaning:
The term "acyl", whether used alone, or within a term such as "acylamino", denotes a radical provided by the residue after removal of a hydroxyl ion from an organic acid. Suitable "acyl" and acyl moiety in the terms "acylamino" and "lower alkyl(acyl)amino" may be carboxy,…"
Such acids are called carbamic acids, as Professor Baldwin pointed out. Are such acids aliphatic? The answer is that they are not, because of the nitrogen atom in the chain. But Mr Young points out that the "more preferred" class of compounds described in the patent in suit at page 5 line 28 is stated to fall within formula I and undoubtedly expressly contemplates substitution of a lower alkyl itself substituted with carboxy (lines 29-31). This passage corresponds to claim 7 of the patent in suit, which is to a class of compounds "of claim 1" and which therefore on the face of it fall within claim 1. He submits that one way or another X=(lower alkyl substituted with carboxy) and hence X=aliphatic acid is contemplated by claim 1. Mr Kitchin acknowledged the difficulty, saying that there is a clear inconsistency between claim 1 and claim 7 in this respect, and that claim 7 covers at least one class of compounds which do not fall within claim 1.
Professor Kirby acutely observed that the list of X substituents in claim 1 (and I should add the part of the explanatory text relating to the term "acyl") bear a remarkable similarity to corresponding passages in Fujisawa (WO 91/19708) which was published on 26 December 1991. The claimants did not rise to this suggestion. It is as well to bear in mind that a list of the kind I am considering is drafted so as to achieve as wide a protection as the draftsman thinks the invention will support, wherever he gets his text from. Carelessness (or just complexity) can result in anomalies and inconsistencies, and it is not reasonable to expect that examiners will detect them all. When one comes to put a meaning on the claims, this sort of problem has to be approached robustly, and in my judgment it does less violence to the express lists of substituents on pages 8, 9 and 10 of the specification if I accept Mr Kitchin’s submission and say that claim 7 does cover the aliphatic acid substituent, whereas claim 1 does not do so.
It follows that while claim 7 is anticipated, claim 1 is not anticipated by this disclosure of Brown.
I turn to the intermediates disclosed by Brown. Brown discloses a number of ways of synthesising the compounds of his invention. Before considering the intermediates with which I am concerned, it is necessary to consider the classes of compounds which Brown discloses. He starts of with a general formula (I):
The substituent Z is expressly exemplified as hydrogen (ie no substituent Z). The substituents Ar and Ar1 are aryl groups: specifically exemplified (column 1 line 63) are unsubstituted phenyl; phenyl substituted by fluorine; and phenyl substituted by the methylsulphonyl group. The aryl groups are specifically described as being in the 2– and 4– positions, the 2– and 4– positions, the 3– and 4– positions, the 3– and 5– positions and the 2– and 5– positions. No position of the substituents on the phenyl groups are exemplified, and the disclosure is thus indifferent as to the position of the substituents on the Ar substituents. Thus amongst the specific disclosures we have this:
Mr Young submits that the disclosure of the intermediate compounds of Formula 3 goes hand in hand with the disclosure of the final products, and thus there is a specific disclosure of an intermediate without the R group corresponding to Formula 2 above, which would have a structure plainly falling within unamended claim 1 of the patent in suit:
The argument does not stop there, because other classes of substituents in the phenyl rings apart from the methylsulphonyl group are also expressly disclosed by Brown and claimed as substituents in the phenyl groups by the patent in suit. The list of claimed classes in the patent is
There is a substantial overlap between the classes claimed and those disclosed by Brown, and in each case the class disclosed by Brown falls within the class called for by the claim. Thus, it is said, the disclosure of the intermediates anticipates the product claims of the patent in suit, and since the compounds are disclosed as intermediates for the purpose of making a pharmacologically active compound for treating inflammation also anticipates claim 20.
Against this, the claimants submit that the disclosure is a disclosure of a less-preferred method. This is, of course, irrelevant. It cannot matter if the disclosure is less preferred, since we are here concerned with a description of the compounds themselves, not with determining whether there are clear and unambiguous directions to do or make something within the claim. Second, they submit that there is no disclosure of the 4– substitution of the methylsulphonyl group. This is correct. I do not think that the 4– substitution is expressly disclosed, but it is plainly obvious, since any person wishing to substitute one of the Ar rings of Brown with a methylsulphonyl group in accordance with Brown’s specific teaching will, on Professor Baldwin’s evidence, go for the easiest substitution, which is at the 4 position. It is not suggested that Brown does not give sufficient directions for the intermediates to be prepared.
I conclude that claims 1 and 20 of the unamended specification are anticipated by Brown disclosure of intermediates, and that claims 1 and 20 of the amended specification are obvious in the light of Brown.
In summary, Brown anticipates unamended claims 1, 7 and 20, and renders obvious amended claims 1 and 20.
The acyl group is shown thus (R is an alkyl group, that is, what is left after removing a single hydrogen atom from a hydrocarbon).
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The acylamino group is shown thus (R1 is an alkyl group, R2 is an alkyl group or hydrogen):
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At page 10 line 6, the specification continues
The terms "carboxy" or "carboxyl", whether used alone or with other terms, such as "carboxyalkyl", denotes –CO2H.
Taken together, these two passages may be summarised as saying that acyl equals an acid without its -OH; but in the term "lower alkyl(acyl)amino" it may mean carboxy, that is, an acid which has not had its -OH removed. It therefore includes acid substituents of this general type:
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Formula 1
This discloses a 5-membered heterocycle with four substituents. The hetero atom X may be sulphur (making the compound a thiophene), oxygen (a furan) or –NY– (a pyrrole).
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The first, preferred method of synthesis is described at column 2 line 26. Among the classes of compounds specifically disclosed as being made by this preferred method is a 3–, 4– substituted class (formula VId). The preferred method is to prepare a precursor of which the R (aliphatic acid group) forms part (column 2 lines 29 – 46). However, a less preferred method consists of making a molecule in which the position in the precursor molecule which would be occupied by the aliphatic acid is instead occupied merely by a hydrogen atom. The compound which will be produced looks like this:
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The compound of the invention is then produced by introducing the aliphatic acid moiety into the thiophene, furan or pyrrole ring in the manner described at column 5 lines 23–56.
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Moreover, he submits that the 4– substitution of the methylsulphonyl group is obvious, or the simplest and most straightforward to think of (as Professor Baldwin acknowledged).
(a) halo (disclosed by Brown at column 1 line 64),
(b) lower alkyl, which means from one to about 10 carbon atoms, disclosed by Brown at column 1 line 65, with examples of methyl, ethyl, propyl or butyl (ie 1 to 4 carbon atoms);
(c) lower alkoxy, which is –OR where R is lower alkyl, one to six atoms, disclosed Brown at column 1 line 66;
(d) lower alkylthio, a single example of which (methylthio) is disclosed by Brown at column 1 line 70;
(e) lower alkylsulphinyl, not disclosed by Brown;
(f) lower alkylsulphonyl, a single example of which (methylsulphonyl) is disclosed by Brown at column 1 line 70;
(g) nitro, disclosed by Brown at column 1 line 67;
(h) amide, not disclosed by Brown;
(i) lower alkylamino, disclosed by Brown at column 1 line 67 to 69;
(j) sulphamyl and lower alkylsulphonylamino, not disclosed by Brown.
Obviousness in the light of DuP 697
- The substantial allegation of obviousness is based on disclosures of DuP 697 and its properties. A comparison with Example 2 of the patent in suit shows why:
- DuP 697 is disclosed in three publications, to which I shall refer as Gans, Haber II and at the conference presentation at the Winter Prostaglandin Conference at Keystone by Dr Galbraith to which I have already referred.
- Gans. Gans is a 1990 paper which describes the anti-inflammatory activity of DuP 697 in rats. It points out that there is a need for NSAID’s which are safer than existing drugs, and states that DuP 697 does not produce either intestinal or gastric ulcers in rats at single doses of up to 400 mg/kg. This apparent gastric safety is attributed to its distinct chemical structure as a non-acidic thiophene, and also to the possibility that it may be tissue selective, that is, it may inhibit prostaglandin synthesis only in certain tissues and not in gastrointestinal tissue. This paper shows, therefore, that at 1990 DuP 697 was an interesting compound, but that the possibility that there might be two isoforms of COX had not been appreciated, and there is nothing, therefore, about Cox II selectivity. The claimants contend that the evidence is that the lack of irritancy of DuP 697 is attributed in the paper to its lack of a carboxylic acid moiety: this is certainly one reason advanced, but tissue selectivity is advanced as an alternative, or additional, reason.
- Haber II. This is a DuPont patent. DuP 697 is example 2 of the patent, which relates to four 2,3 substituted bromothiophenes. DuP 697 is shown to have a better IC50 than indomethacin in an assay for COX inhibition, and a marked anti-inflammatory capability in the adjuvant arthritis test.
- The Winter Prostaglandin Conference at Keystone. The pleaded disclosure is an oral disclosure by Dr Galbraith, who gave evidence before me. I draw the following conclusions from his evidence. At the meeting, which was attended by a substantial number of NSAID researchers, there had already been a paper from Dr Herschman and from others on the existence of PGH Synthase 1 and 2, i.e. Cox I and Cox II. Dr Galbraith’s paper was entitled "DuP 697 As An Agent Which May Be A Selective Cyclooxygenase Inhibitor". Much of the data which he presented was also in Gans, which, it will be recalled, said nothing about possible Cox isoforms, but speculated about tissue selectivity. I am satisfied that the type of selectivity which was being suggested by Dr Galbraith at Keystone was Cox selectivity. He refused to advance Cox II selectivity as the reason for DuP 697’s qualities, since he had not been able to obtain the cloned genes for Cox I and Cox II, but he believed that it was in fact the reason. He considered that the existence of the Cox I and Cox II isoforms was an explanation for the tissue selectivity which he was satisfied was exhibited by DuP 697. He mentioned this as a possibility in his address, and it is explicit on the final slide of the presentation which reads as follows:
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DuP 697 is the 2,3 isomer of Example 2 of the patent in suit. The Defendant’s case is simple. They say that if one wishes to produce an SAR of DuP 697, then it is obvious to make its 3,4 isomer, which falls within the claim. Routine investigation would also traverse a great number of compounds within the claim.
DuP 697 Summary
- Active as an anti-inflammatory, antipyretic and in models of inflammatory pain.
- Evidence of selective inhibition of cyclooxygenase in cellular and enzymatic assays.
- Lack of platelet activity and safety profile may reflect in vivo results of selective CO inhibition.
-
May be a useful tool to understand role of cyclooxygenases 1 and 2.
Dr Galbraith impressed me as a careful witness, and I am satisfied that his discussion of DuP 697 at the Winter Prostaglandin Conference did explicitly make the connection between the properties of DuP 697 and selective Cox inhibition. I believe that any skilled person who attended the conference would have been given every incentive to investigate the reasons for DuP 697’s activity.
- That is not, of itself, any reason for supposing that the skilled man would investigate 3,4 substitutions as opposed to the 2,3 substitution on the heterocycle which is DuP 697. Of course, for this purpose it is not legitimate to pray Brown in aid. There is no reason to suppose that the skilled man would be aware of the teaching of Brown in the context at all. He might find it on a search: but it is not clear that he would, and it is even less clear that he would act on an inference from Brown. The real question is what the skilled person would have done, either to establish a structure-activity relationship, or for any other reason, given this disclosure in relation to DuP 697.
- Professor Baker agreed with Professor Baldwin that the skilled man would investigate the effect of different substitutions on the periphery of the molecule. He was not impressed by the various reasons which were suggested to him as reasons why the skilled man would be deterred from going further and making the change from 2,3 to 3,4 substitution. Professor Baldwin, on the other hand, considered that the change from 2,3 to 3,4 effected a change in the shape of the molecules relative to their axis of symmetry, and would therefore create a different relationship with the active site on the enzyme which it was sought to inhibit. It was generally agreed that the methylsulphonyl group seemed, on inspection, to be the most significant feature of the molecule from the point of view of binding to the active site, and, of course, the change from DuP 697 to (for example) Example 2 of the patent does not affect this relationship. I conclude that there is no reason to draw a sharp distinction between the 2,3 and 3,4 substituted compounds on this basis.
- Professor Baldwin’s view of medicinal chemists working in industry was that they basically try to copy. When they get a lead, he suggested that they mounted "some sort of chemical war" on the molecule to make something better. Generally, I think his view was that they take the line of least resistance: that is, they go first for the things that are easy to make. The evidence was that the 2,3 compounds were easier to synthesise than the 3,4 compounds. I do not think that I misrepresent his evidence if I say that his view was that invention might lie in departing from the line of least resistance. I have no doubt that he may be correct. His view was that the change from 2,3 to 3,4 substitution was sufficiently radical that it would not immediately commend itself to a skilled team seeking to make more anti-inflammatory compounds having reduced side effects.
- Both claimants and defendants were well aware of DuP 697. DuPont themselves had been investigating the diaryl heterocycles for many years. They had concentrated on the 2,3 substitutions. Both claimants and defendants were aware of DuP 697 before the priority date. Their stories are interesting, and I set them out here in rather more detail than has been necessary hitherto.
- The defendants had been represented at the Winter Prostaglandin Conference at Keystone, but I understand that the note of what had been said was lost in the bureaucracy. As Dr Prasit said, it was sent upwards rather than downwards. They only became interested at the following Summer conference in June in Montreal, where a poster showing the properties of NS 398, the compound prepared by Dr Futaki of Taisho, was displayed, explicitly drawing attention to its capacity to inhibit Cox II. This seems to have stimulated a research program which started almost immediately. The first step which Merck took was to develop assays for Cox I/Cox II selective inhibition. This was done by August 1992, and, NS 398 having been shown to be Cox II selective but unpatentable, the search for other compounds started in September. The literature was examined, and DuP 697 was established as a lead compound, along with members of other, unrelated, families of NSAID’s. Two structural families were proceeded with: the sulides (NS398, flosulide and nimesulide) and DuP 697. The investigation was into the structure/activity relationship of these compounds, and on the DuP 697 side Merck started by investigating the 2,3 compounds. By December, on the suggestion of Dr Gauthier, they had started with the 3,4 compounds, the first of which is the same as example 1 of the patent in suit. It is Cox II selective, but not bioavailable. The general conclusions which were drawn are summarised by Dr Prasit. He says that it was established that the position of the substituents on the thiophene ring was not crucial, but that methyl sulphonyl substitution at the 4 position on the phenyl ring was essential. To confirm this, a DuP analogue at the 4,5 position was tested as well. Rings other than a thiophene could be used, but there was no general principle relating structure to bioavailability, since by February DuP 697 was the only 2,3 compound tested to have good bioavailability. The allegedly infringing compound was developed from a furanone intermediate developed in the other (sulide) program which was passed to Dr Prasit because it was a tricyclic compound in which he was known to be interested. Dr Prasit considered that it might be useful as a prodrug, and incorporated the 4-methylsulphonyl substitution. After optimisation by removal of a 4-fluoro substitution on the other phenyl ring, he had MK-966.
- The claimants’ research was not much different. They too had DuP 697 as a lead compound, but earlier than the defendants because they had apparently acted on the disclosure of the Keystone conference. DuP 697 was synthesised and had been shown to be Cox II selective by April 1992. Various analogues of DuP 697 in which the 5-bromo substitution is replaced by various groups were synthesised and tested (this is consistent with Professor Baldwin’s view as to the first stage, which is to experiment with the peripheral groups). The project appears from Dr Isakson’s evidence to have started definitively in August 1992, and Dr Bertenshaw, an inventor of the patent in suit, was immediately assigned to 3,4 diaryl thiophenes. His notebook says this, on the first page:
- Dr Bertenshaw’s work on the 3,4 analogues of DuP 697 appears from an internal paper which he wrote in August 1992 to have been done "to ascertain the ideal disposition of the two aryl moieties", that is, as part of the investigation of the SAR. In another internal paper in October of which Dr Bertenshaw is a co-author, this is said:
- It would be idle to pretend that an important influence on this work was not a desire to obtain a novel, as well as effective, compound. It is clear from the evidence in this case that the requirement of novelty for the grant of a patent provides a powerful driving force to investigations of this kind. Thus in another internal paper from the claimants, which is undated but which appears to be reviewing the work which went into the patent in suit, the following is said under the heading "Thiophene derivatives"
I note in passing that these conclusions are consistent with the experimental results in this case. To return to the history, Example 1 was synthesised in October 1992, and tested in vitro. It had good activity. Example 2 was made and tested before the priority document was filed. There was no possible basis for suggesting that the class encompassed either by Formula I or Formula I 2 in the priority document could be reasonably predicted to have anti-inflammatory effect. The best which could have been said was that it was possible. Only 34 compounds were ever synthesised which fell within the claim after the priority date. There was one furan, and no pyrrole. In the end, the series of 3,4 disubstituted thiophenes was dropped by the claimants for the same reason as the defendants identified: very poor bioavailability.
Structurally, there is a clear similarity between DuP 697 and its close 3,4 disubstituted analogues. It is a matter of reasonable prediction that they will have similar activity. I think that a medical chemist wishing to investigate the structure/activity relationship of DuP 697 would think of making its 3,4-diaryl analogues, with a view to seeing whether they are active. I also think that confronted with DuP 697 and required to develop a novel compound of similar activity, the 3,4-diaryl substitution is one of the first things which would occur to the medical chemist. The claimants point to DuPont. Why, they say, if it was so obvious to use the 3,4-diaryl substitution, did not DuPont do so. The answer to this is, I think, threefold. First of all, DuP 697 was a good compound: it was not commercialised not because it had poor bioavailability but because it has too long a lifetime in the body. Second, it was comparatively straightforward to synthesise. Third, Dr Galbraith’s evidence suggests that there was a degree of inertia in this field, which was only dissipated with the discovery of the inducible Cox II enzyme. All the evidence gave me the clear picture that the 3,4 diaryl compounds were obvious to try for any skilled person knowing of DuP 697, and the ones which were most obvious to try (Examples 1 and 2 of the specification) are both Cox II selective, anti-inflammatory, and gastric sparing. It follows that in my judgment claim 1 both as granted and as sought to be amended is obvious in the light of Dr Galbraith’s disclosure, which provides the impulse to test for Cox II selectivity. Given also that the existence of the inducible isoform of the COX enzyme was in my view common general knowledge at the priority date, it was obvious to investigate the compound of Gans, which was said to be gastric sparing, to see why.
I am more doubtful about Haber 2, since standing on its own it only suggests that DuP 697 is another NSAID among many. On the whole, I think that what finally renders the claim obvious is the disclosure that DuP 697 is gastric sparing. The claim is not obvious in the light of Haber 2.
The position of the amended claim is the same. All the analogues of DuP 697 which I have discussed are within the amended claim.
Proposal: the proposed compounds should exhibit either cyclooxygenase or lypooxygenase inhibition. They should exhibit antiinflammatory activity with minimal or no toxicity to the kidney and little or not lesion forming activity to GI.
The structure which he gives is a 3,4 substituted thiophene, furan or pyrrole. By December 1992, he had identified a wide class of 3,4 disubstituted thiophenes which he considered would be anti-inflammatory but would have toxic and gastrointestinal side effects, and that the best selective Cox II inhibitors may have 4-methylsulphonyl and 4-fluoro substitutions in the phenyl rings.
During the previous two months we have been busy preparing compounds that will provide answers to certain SAR questions. A very large body of anti-inflammatory 2,3-diaryl thiophenes derivatives have been described in the patent literature. Surprisingly, we can find no mention of the evaluation of 3,4-diaryl thiophene derivatives as cyclooxygenase inhibitors. We speculated that an appropriately substituted 3,4-diaryl thiophene derivative might serve as a cyclooxygenase inhibitor.
After describing the 2,3 and 3,4 diaryl thiophenes synthesised, the paper notes that the 2,3 and 3,4 diaryl thiophenes showed strikingly similar inhibitory activity, and, on the basis of work done on the 2,3 compounds says that "we are hopeful that the appropriately substituted 3,4-diaryl analogue will possess selective Cox II activity".
The other pharmacophore that possessed the ability to selectively inhibit COX-2 was embodied in DuP-697. The initial approach taken was to learn the precise structural requirements for biological activity in vitro. It was known from Len Lee’s work on DuP-697 that the isomeric analogue 1[this is 2-(4-methylsulphonylphenyl)-3-(4-fluorophenyl)-5-bromothiophene] possessed nearly identical in vitro activity….The presence of a bromine contributed a small amount to the in vitro potency…. but had a detrimental effect on the selectivity for the inducible enzyme. With these data then, a synthesis effort was initiated to identify a novel, proprietary [my emphasis] anti-inflammatory COX-2 selective inhibitor.
As mentioned earlier, the precise 2,3 arrangement of aromatic rings about the thiophene was not an absolute requirement for in vitro potency. We wonder what effect a translocation of the aromatic ring in the 2-position to the 4-position would have on in vitro potency. …
Then, after discussing the initial results, the document continues:
To summarise this initial phase of the research project, the following were the most important observations: 1. The aromatic rings of the diaryl heterocycle had to be on adjacent positions for cyclooxygenase activity. 2. The para-methylsulfonyl moiety had to be present for mCOX-2 activity. 3. Substituents other than para-fluoro on the other benzene ring gave similar cyclooxygenase activity. The absence of the para-methylsulfonyl results in molecules capable of inhibiting both mCOX-1 and mCOX-2 or mCOX-1 selectively.
INFRINGEMENT
The allegation of infringement
- The compound sold by Merck as the active ingredient of Vioxx is 3-phenyl-4-(4-methylsulphonylphenyl)-2-(5H) furanone. It is referred to as MK-966 (Figure I).
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Figure I: MK-966
It is common ground that this compound is not among those explicitly listed in claim 1. In aqueous conditions, however, MK-966 undergoes a chemical process called tautomerisation, and it is from this fact that the allegation of infringement really springs. Before turning to the details of the allegation of infringement, I should first describe tautomerism.
Tautomerism
- An undergraduate chemist knows that certain classes of compounds are capable of tautomerising, that is to say, spontaneously transforming themselves into another compound and back again. A particular form of tautomerism, called keto-enol tautomerism, is at issue in this case. I take the basic description from Professor Baldwin’s report. Organic molecules are composed of atoms joined by chemical bonds. Acetone, which is a common solvent, contains carbon hydrogen and oxygen atoms joined together by chemical bonds (Figure J).
- Enols are acids, and will themselves tend to dissociate into anions and protons (Figure L).
- There is no doubt that the enol and the keto species are different chemical species. I was given a number of examples, of which the commonest is again acetone. For example, the halogenation of acetone proceeds via the enol: the keto form does not react directly.
- The evidence which went to show that tautomerism was a familiar phenomenon, and part of the common general knowledge of any graduate chemist, was really overwhelming. Professor Baldwin and Professor Kirby referred to a number of textbooks. Professor Baldwin said, and I accept, that in systems exhibiting tautomerism the properties of the system reflect the presence of all the tautomers. Professor Kirby agreed, but was anxious to emphasise that the reference to keto and enol "forms" of a compound should not suggest to the unskilled reader that these were different physical versions of the same molecule but were different chemical species, and that the properties of tautomeric substances reflect the relative amounts of the tautomers present. Both these propositions I also accept. I am satisfied that these matters would be known to a competent undergraduate chemist, and a fortiori to the addressee of this specification.
- The same is true of tautomerism in aromatic molecules. Returning to the defendants’ compound MK-966, this undergoes tautomerisation in aqueous solution. Its tautomeric companion is 3-phenyl-4-(4-methylsulphonylphenyl)-2-hydroxyfuran (Figure M).
- Tautomerism in heterocycles is widely described in the textbooks relating to heterocycles. Joule and Smith, a standard textbook, contains the following passage which caused some discussion at trial:
- Finally, Professor Baldwin said that not all substituted furanones would be capable in principle of tautomerising to the enol form: it depended upon the substituent at the 5– position (this is why the Joule & Smith extract refers to the 3H and 5H furanones, so specifying the availability of a hydrogen atom at the 3 or 5 positions). On the other hand, other substituents at the 5 position (Professor Baldwin suggested a nitro group) would tend to favour the enol, and make it stable. It all depended on the nature of the substituent at the 5 position. Whilst in some cases the enol might be comparatively stable and present in comparatively large quantities, in the case of MK-966 this would not, as I understand it, be expected. Professor Kirby agreed with this. I think that it is established as a matter of common general knowledge that in general it would be expected that a hydroxyfuran species is unlikely to exist in quantities likely to be significant, but that with certain other substituents in the furan ring, such as (for example, a nitro substitution at the 5 position) it might be stable and present in more than negligible quantities.
- As in the simple case of acetone referred to above the 2(5H)–furanone and the 2-hydroxyfuran are different chemical species. Furanones are not aromatic. Hydroxyfurans are aromatic and therefore exhibit the characteristics of aromatic molecules. In this respect, Professor Baldwin considered there to be a distinct difference between the two.
- The hydroxyfuran is an acid, and will dissociate to some extent into an anion (a negatively charged ion) and a hydrogen ion (or proton).
- There is no dispute between the parties that at any moment the quantity of enol and enolate present in the human body after administration of MK-966 is likely to be extremely small in comparison with the quantity of keto compound. In neutral solution, the ratio lies between 10-9 and 10-10, on any view a small quantity. There is thus a real issue as to whether the enol/enolate is likely to play any direct role in the activity of MK-966, in the sense that it actually has anti-inflammatory activity or inhibits the COX enzymes selectively or at all. For this reason the Claimants widened the allegation of infringement to include a suggestion that the enol/enolate plays a significant role in the metabolism of the drug in the human body. In effect, they contend that even if MK-966 does not have a direct pharmaceutical action it at least contributes to the metabolism of the active ingredient. I consider this issue under the heading "Metabolism" below.
- One other fact needs to be borne in mind. Whilst the enol species is present in neutral solution at any one time in one billionth the quantity of the keto species, the nature of a dynamic equilibrium means that there is a finite probability that any keto molecule will transform itself into an enol molecule within, say, a second. Over a period of time, most of the keto molecules will transform into an enol molecule, and almost certainly change back again within a short time. The claimants conducted an elegant experiment, which it is not necessary to describe, which showed that over a period of 20 hours or so about 50% of the keto molecules in neutral solution will have transformed into the enol, the vast majority changing back again. A convenient way of appreciating this phenomenon is to consider the "half-life" of the molecules concerned (the half-life of a molecule is the time for half of the molecules present to have been transformed). The half-life of a keto molecule is about 20 hours in neutral solution, but that of the enol molecule is a few microseconds only. Professor Kirby gave the following unchallenged evidence for the relative amounts of keto, enol and enolate present at pH 7.4, which is close to the average physiological pH of a human being:
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Figure J: acetone
The carbon-oxygen double bond is called a carbonyl group, or a ketone group. It is a double bond because two electrons are involved, not just one as is the case in a single bond. When the compound tautomerises, one of the hydrogen atoms in one of the methyl (-CH3) groups moves to the oxygen atom to form a hydroxyl (-OH) group and the double bond forms between two carbons (Figure K).
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Figure K: tautomerism of acetone
The compound on the right is called an enol. The en- part of its name says that a double bond is associated with the carbon atom and a hydroxy (-ol) group is attached to the molecule. The two half-arrows are used to show that the process is happening constantly and that an equilibrium will be established in which the ratio of keto to enol will be constant as the molecules continuously tautomerise.
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Figure L: the enolate ion
The negatively charged ion (the anion) is called the enolate ion. As the conditions become more basic (that is more alkali) the equilibrium favours the enolate ion, and more enol will dissociate. The keto/enol balance will be maintained, but there will necessarily be less of the keto form as more enol goes to form enolate. That is the nature of equilibria. The amount of enolate will increase by a factor of 10 for every unit increase in the pH of the solution.
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Figure M: tautomerism of MK-966
"If 2-hydroxyfuran exists at all, it is only at an undetectably low concentration in a tautomeric equilibrium involving a 2(5H)-furanone and a 2(3H)-furanone….The chemistry of the 2-oxyfurans, then, is essentially that of unsaturated lactones and has no special relevance to furan chemistry."
The 2-oxyfurans are the furanones, and MK-966 is a 2(5H)–furanone. This passage is suggesting that the chemistry of the furanones are largely their own, and unaffected by the presence of the enol. Professor Baldwin considered that this is a textbook which one would expect to be consulted by any skilled man seeking to synthesise substituted heterocycles, Other textbooks make the same, or a similar, point: Gilchrist says that hydroxyfurans exist in the keto tautomeric forms, as ³-lactones, thus suggesting that the hydroxyfurans do not exist as such. Newkome & Paudler, a widely used textbook, says that while considerable confusion has existed in the literature with regard to both the 2– and 3–"hydroxy" furans it has finally been established that the oxo forms (i.e. the furanones) are the lone tautomers in this series. So these books suggest either that the hydroxyfurans do not exist at all, or only in very small quantities.
.png)
Figure N: formation of enolate
The charges are shown by the plus and minus signs. The negatively charged ion is the enolate ion.
|
MK966 (furanone) |
Enol |
Enolate |
|
6.3´ 1010 |
1 |
16 |
Construction issues raised by contentions on infringement
- The allegation of infringement has three aspects. The first allegation is that the keto compound falls squarely within claim 1. This raises the first issue of construction, which can be simply stated: when the specification and claim refer to the hydroxyl substituent in the furan ring is the keto compound also disclosed and claimed? The second allegation is that if the claim does not cover the keto compound, in any event both the enol and enolate are within the claim, and the defendants are liable for infringement by virtue of subsection 60(2) of the Patents Act 1977 since these compounds are produced when the drug is administered to a patient, and the enol form plays a part in the metabolism of the drug. The third allegation is that the enol compound or the enolate are present during manufacture, and the defendants infringe claim 20 at least by importing a substance (VIOXX containing only the keto compound) directly obtained by the use of an infringing process, the process infringing by virtue of the presence of the enol/enolate in the aqueous phase during its manufacture. The allegation in respect of claim 20 raises a second issue of construction, viz. what is the process which is the subject of that claim. The enolate is said to be within the claim because it is a "pharmaceutically acceptable salt" of the enol.
Does the claim cover the keto compound?
- I have already set out the claim and I have underlined the words which mean that it covers the hydroxyfuran tautomer of MK-966. I must now consider in more detail the compounds which are covered by the claim.
- Some of the substituents are single groups (e.g. hydrido, which means hydrogen, or hydroxy, which means –OH). Others are physically comparatively small (halo, which means substituted with a fluorine, chlorine, bromine or iodine atom). Others are large, and yet others very large. The full explanation and definition of all the terms used in claim 1 covers slightly less than two full pages of the specification in a single paragraph, a passage which is, in essence, the dictionary of the words of the claim. I was told that the claim covers millions of compounds. Comparatively few of these compounds are expressly disclosed and still fewer described; the coverage of the claim is ascertained by working out all the possible permutations of the features called for by the claim. What the permutations have in common is the 5-membered heterocyclic ring, the aryl or heteroaryl substituents (single, two or three-ring compounds) at the 3- and 4- positions on the heterocyclic ring; and the substitution of a methylsulphonyl or sulphamyl group on one or other of the substituent rings. Each possible substituent, and in particular the substituent(s) X on the heterocycle, are exhaustively classified in the passage to which I have referred. Nowhere is there any reference to tautomerism, or to tautomeric versions of the compounds in which X is a hydroxy group, in the cases in which such compounds can exist as the enol member of a keto-enol tautomeric pair. No hydroxyfuran is disclosed or described. One furanone only is disclosed and is described as an intermediate in Scheme IV for the synthesis of compounds of the invention (see page 14 lines 40–43). The specification does not suggest that this material would itself be a compound of the invention, although as a 3,4 diaryl substituted 2(5H)–furanone it would be capable of tautomerising to a hydroxyfuran within the claim, and, if the claimants are right on the question of construction, would itself fall within the claim.
- It may be helpful to set out my understanding of the principles of law applicable to this question. The starting point is the speech of Lord Diplock in Catnic v Hill & Smith [1982] RPC 183 at 242. In this case, the right approach to construction is to read the patent specification through the eyes of the man skilled in the art and, in cases in which the alleged infringement represents a variant upon the words of the claim narrowly construed, to give the claim a purposive construction with a view to determining whether the feature or features in question encompass variants on the strict meaning of the words used, the variants having no effect upon the way the invention worked and that fact being obvious to the skilled man at the date of the patent.
- In formulating his three tests in Improver v Remington [1990] FSR 181, which have been approved by the Court of Appeal and provide the approach to construction of claims which is habitually adopted, Hoffmann J restated Lord Diplock’s approach as a sequence of three questions to be asked whenever the alleged infringement fell outside the "primary, literal or acontextual meaning" of the word or phrase in question:
- In his formulation of the "nutshell" question, Lord Diplock may be thought to suggest that reasons extraneous to the specification are capable of providing the answer to the third question, summarising the considerations by asking, in effect, "what plausible reason could there be for the patentee choosing to limit himself in this way?" Hoffmann LJ identified this question as one of construction of the specification alone in Improver, and returned to this subject in Société Technique de Pulverisation STEP v Emson Europe Limited [1993] RPC 513:
The principles articulated in these cases require me to approach the question of the meaning of the claim simply as what it conveys to the skilled man. The claimants’ contention is that if the skilled man would assume that when the enol is referred to the keto tautomer is embraced as well, then the keto tautomer falls within the claim. In the present case, there is no doubt that the alleged infringement (the furanone MK-966) acts in the same way as that in which the specification suggests that the compounds to which it does expressly refer, including the hydroxyfuran, would act. I will assume that this would have been apparent to the skilled man at the date of the patent, at least if he were permitted to perform the tests set out in the patent. But whether or not this is the case, the skilled man knows that tautomers are indivisible: where there is one in aqueous solution, there also will be the other, whether it is present as an ineffective or even undetectable trace or as the predominant species. He would know also that in this case the claim specifies what is likely to be the improbable tautomer, that is, the tautomer which from his general knowledge the addressee would expect to be present in very small, or undetectable, quantities compared with the other.
Professor Baldwin’s evidence in chief was that he read the patent and its claims as referring to the keto tautomer as well as the expressly mentioned enol, at least after he had been asked specifically about the hydroxy substituent. He accepted, I think, that a mention of the 2-hydroxyfuran as a specific compound would mean that compound to the exclusion of its tautomer, but that such an approach was inappropriate when one was considering a generalised formula.
If I am to find that the claim covers the furanone, I am not merely saying that it covers a variant on the claimed compounds which contain a hydroxy group. Linguistically, it is the addition of a number of compounds (of which the infringement is only one) to the list by adding a further class of substituents. The further substituents which are added are compounds in which there is one double bond in the heterocycle (not two) and X is oxo. Oxo substitutions are only mentioned in the claim in feature (a)(xiii), which is talking about heterocyclic rings which are themselves substituents in the principal heterocyclic ring at X. Alternatively, it is the addition of the words "and their keto tautomers, as appropriate" after the word hydroxy in feature (a)(v) or at the end of the claim. This is not the process of finding out what the term "hydroxy" means to the skilled man. The meaning of "hydroxy" is clear and unambiguous. It means a hydroxyl substitution, and the skilled man knows that the compound with the hydroxyl substitution is a different chemical species from its keto tautomer. It can best be viewed, I suppose, as what the claim to a hydroxyl substitution necessarily implies to the skilled man when he considers the other species which must also be present to some extent.
In my judgment, the right conclusion to draw must be a conclusion which is good for all the claimed hydroxy-substituted heterocycles: not just the hydroxyfurans likely to be unobservable but any other heterocyclic ring contemplated by the claim. It must be satisfactory whether or not there are also present electron-withdrawing groups which might tend to stabilise the enol tautomer. It is important not to be influenced by the fact that in the case with which I am dealing substantially the only compound present is the furanone. The fact that some of the enols are so unstable that they are unlikely to be detectable is irrelevant. It is generally true that the preparation of the claimed half of a tautomeric pair will inevitably (at least in aqueous conditions) involve the production of the other tautomer, which will in part be responsible for the properties of the mixture produced. The skilled man would know this as a matter of his common general knowledge, and, given that it is part of the common general knowledge, the natural conclusion to draw when one species is mentioned to the exclusion of the other is that the species not mentioned is not intended to be covered. It is not for the skilled man to speculate why this should be so, as Step v Emson points out. After a great deal of doubt, I have come to the conclusion that the correct answer should be that the claim does not cover the keto tautomers of the explicitly claimed enols.
The passages in Improver and Catnic which I have set out above do not provide me with a licence to employ a Humpty Dumpty construction in which words mean what I want them to mean, neither more nor less. It is not open to me to say that as a matter of the meaning of words "hydroxy" also means an additional H and a %PO at different places in the heterocycle. As I have indicated, I am not concerned with a "variant on some descriptive word or phrase". Nor is the word "hydroxy" being used as a figure for some wider class. It is perhaps a difficulty with Improver and Catnic that they were both mechanical cases. The term in issue in the first case ("vertically") is a word which has a wide penumbra of meaning. It does no violence to the primary meaning of "vertically" to say that within its contemplation are degrees of verticality distinct from the strictly vertical, particularly since the presence of the word in the claim is explicable only if it is to refer to the load bearing capacity of the lintel. Looked at another way, the word "strictly" in the phrase "strictly vertically" is neither redundant nor surprising. It is there to eliminate the penumbra which the word "vertically" otherwise possesses. In Improver the phrase "helical spring" is necessarily of narrow import, and since in the process of construction it must retain its primary meaning the problem is to find a class which is describable by those words and covers both a helical string in the strict sense and "bendy slitty rod". Since the skilled man would not have identified such a class the words were not capable of covering it. The same goes for the parts of the device which had to be present in a particular relationship in STEP v Emson. It is not altogether easy to apply the principles of construction articulated in these cases to a claim in which every term is unambiguous and devoid of any question of degree (except as to the number of carbons embraced by the phrase "lower alkyl" and similar matters) but which would nonetheless be read as necessarily involving the presence of other species which are not mentioned but which would play a role in the chemical properties of the compound claimed. The third Improver question also presents a difficulty. It is in the nature of class claims that not every member of every class will be exemplified and described. If there is no description of a hydroxy-substituted compound, there will be nothing in the specification likely to help to decide whether the patentee intended as a matter of words to exclude the tautomer, but, since the presence of the tautomer is a matter of common general knowledge the fact that there is no reference to suggests a deliberate exclusion.
I must be satisfied that the construction which I place on the claim satisfies the requirements of the Protocol by providing fair protection for the patentee and a reasonable degree of certainty for third parties. Were the claim to be construed so as not to cover a compound which is necessarily present with a compound expressly claimed, and which would be prepared with that compound, I think that there is no offence against this principle. I believe that it is helpful to consider the phrase used by Fox LJ which is quoted by Hoffmann J in Improver, "within the ambit of the language". My conclusion is that the words used in the claim have a clear and unambiguous meaning which does not admit of variants, and that the words are not used figuratively so that the correct conclusion is that the claim does not cover the furanone tautomer of the 2-hydroxyfuran expressly claimed.
"Where it is not obvious, in the light of then-existing knowledge, the reader is entitled to assume that the patentee thought at the time of the specification that he had good reason for limiting his monopoly so strictly and had intended to do so, even though subsequent work by him or others in the field of the invention might show the limitation to have been unnecessary. It is to be answered in the negative only when it would be apparent to any reader skilled in the art that a particular descriptive word or phrase used in a claim cannot have been intended by a patentee, who was also skilled in the art, to exclude minor variants which, to the knowledge of both him and the readers to whom the patent was addressed, could have no material effect upon the way in which the invention worked.
…Put in a nutshell the question to be answered is: Would the specification make it obvious to a builder familiar with ordinary building operations that the description of a lintel in the form of a weight-bearing box girder of which the back plate was referred to as "extending vertically" from one of the two horizontal plates to join the other, could not have been intended to exclude lintels in which the back plate although not positioned at precisely 90° to both horizontal plates was close enough to 90° to make no material difference to the way the lintel worked when used in building operations? No plausible reason has been advanced why any rational patentee should want to place so narrow a limitation on his invention. On the contrary, to do so would render his monopoly for practical purposes worthless, since any imitator could avoid it and take all the benefit of the invention by the simple expedient of positioning the back plate a degree or two from the exact vertical.
(1) Does the variant have a material effect upon the way the invention works? If yes, the variant is outside the claim. If no—
(2) Would this (i.e. that the variant had no material effect) have been obvious at the date of publication of the patent to a reader skilled in the art? If no, the variant is outside the claim. If yes—
(3) Would the reader skilled in the art nevertheless 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? If yes, the variant is outside the claim.
Hoffmann J concentrated on the manner in which the words of narrow meaning are being used in the claim:
"On the other hand, a negative answer to the last question would lead to the conclusion that the patentee was intending the word or phrase to have not a literal but a figurative meaning (the figure being a form of synecdoche or metonymy) denoting a class of things which included the variant and the literal meaning, the latter being perhaps the most perfect, best-known or striking example of the class.
Thus in Catnic itself the claim of a patent for a lintel of box construction required that the upper plate be supported upon the lower plate by two rigid supports, one in the front and the other "extending vertically" from the one plate to the other at the rear. The defendant’s lintel had a rear support which was inclined 6° or 8° from the vertical. The House of Lords decided that this variation had no material effect upon the load-bearing capacity of the lintel or the way it worked and that this would have been obvious to the skilled builder at the date of publication of the patent. It also decided that the skilled reader would not have understood from the language of the claim that the patentee was insisting upon precisely 90° as an essential requirement of his invention. The conclusion was that "extending vertically" meant "extending with the range of angles which give substantially the maximum load-bearing capacity and of which 90° is the perfect example."
In the end, therefore, the question is always whether the alleged infringement is covered by the language of the claim. This, I think, is what Lord Diplock meant in Catnic when he said that there was no dichotomy between "textual infringement" and infringement of the "pith and marrow" of the patent and why I respectfully think that Fox L.J. put the question with great precision in Anchor Building Products Ltd. v. Redland Roof Tiles Ltd. when he said the question was whether the absence of a feature mentioned in the claim was "an immaterial variant which a person skilled in the trade would have regarded as being within the ambit of the language" (My emphasis). It is worth noticing that Lord Diplock’s first two questions, although they cannot sensibly be answered without reference to the patent, do not primarily involve questions of construction: whether the variant would make a material difference to the way the invention worked and whether this would have been obvious to the skilled reader are questions of fact. The answers are used to provide the factual background against which the specification must be construed. It is the third question which raises the question of construction and Lord Diplock’s formulation makes it clear that on this question the answers to the first two questions are not conclusive. Even a purposive construction of the language of the patent may lead to the conclusion that although the variant made no material difference and this would have been obvious at the time, the patentee for some reason was confining his claim to the primary meaning and excluding the variant. If this were not the case, there would be no point in asking the third question at all.
Catnic was a decision on the Patents Act 1949. Section 125 of the Patents Act 1977, which is declared by section 139(7) to be framed to have as nearly as practicable the same effect as Article 69 of the European Patent Convention, says that the invention shall be taken to be that specified in a claim, as interpreted by the description and drawings. Section 125(3) applies to English patents the Protocol on the Interpretation of Article 69 which, if I may paraphrase, says that Article 69 and section 125(1) mean what they say: the scope of the invention must be found in the language of the claims. Extrinsic material such as the description can be used to interpret those claims but cannot provide independent support for a cause of action which the language of the claim, literally or figuratively construed, simply cannot bear. On the other hand, the claims should not be interpreted literally but in a way which "combines a fair protection for the patentee with a reasonable degree of certainty for third parties."
The judge [held] that a bore through a solid block forming the bottom of the cylinder, the top of which formed the bottom of the pump chamber, was arguably "conduit means extending upwards within the cylinder to define therewith a pump chamber." In other words, nothing needed to extend upwards into the pump chamber part of the cylinder at all. [Counsel] did not support this construction and I do not think it is legitimate. The well known principle that patent claims are given a purposive construction does not mean that an integer can be treated as struck out if it does not appear to make any difference to the inventive concept. It may have some other purpose buried in the prior art and even if this is not discernible, the patentee may have had some reason of his own for introducing it.
Hoffmann LJ is talking here about the omission of features of the claim (integers), but it is difficult to see why the principle is not equally applicable to variants upon features which are clearly defined. (This is a different problem from ascertaining the scope of words of degree, such as "thin and flexible"). To ascertain whether a particular term is being used figuratively or literally is a task which cannot be achieved by analysis of many patent specifications, and often tends to be answered by reference to the other Improver questions. The temptation is to approach the question in this way: if the invention works in the same way with the defined feature as with the variant, and there is no obvious reason appearing from the specification why the patentee did not intend to cover the variant, it follows the word or phrase must be being used figuratively.
Q. But would you not have expected, if what you are saying is correct, that there would have been .... If they had intended to include furanones, there would have been some reference, even if not to furanones within the purview of this, it could have been said the tautomers of the hydroxy furans? A. I do not agree with that.
Q. Why not? A. Because in heterocyclic chemistry, if you go to a book on heterocyclic chemistry, which theses things are, you will find many, many structures of heterocycles where nobody actually knows what the actual equilibria are. Yet they made these compounds and written them down as either the hydroxy form or the keto form without specification and writing only one structure.
Q. But it would be right, would it not, that, normally speaking, or in fact traditionally, if you write down, taking your tautomer argument, the minor tautomer, you would expect to be considering that minor tautomer because there would be no other reason for focusing on that minor tautomer? A. Or if you were given a specific compound, an individual compound, as opposed to a general formula, I agree with that, but not if you were writing a general formula to embrace a large number of different heterocycles with different X groups or substituent groups. I do not agree with that.
Q. Take, for example, your reference to phenol at paragraph 50 of your report. If one had simply referred in some paper to the keto form of that, without reference, that is, to the phenol at all, one would have assumed, would one not, that the person who was referring to that keto tautomer would indeed have been referring to that rather than the phenol itself? A. Yes, and this is another specific case of an individual compound. It does not relate to a general formula for all phenols or all ketones of that type; it is a specific case. I think, in the specific case, if the person who was writing the formula knew what the equilibrium position was, unless they had some other reason, they would write it down. You cannot compare this figure 12 with Formula I because Formula I is an attempt by somebody to embrace a huge number of molecular structures.
Q. But that works both ways, does it not, professor? The huge number, which does not include a particular class, which is the furanones, would indicate that that was not intended to be included. Would that not be right? A. No, I do not agree with that.
Q. Why not? A. Because of the reason that you do not know in the a priori what the equilibrium position of all these things are. We do not even know in that formula X where if we had a sulphur there would be appreciable amounts of hydroxy versus keto form. We have had nitrogen the same. I would assume that in a formula like that, you cannot extract the information that says that is the major isomer or the major tautomer. You are just say that we have made compounds with that connectivity of atoms. We do not know where the proton is in the tautomeric equilibrium, and we claim those compounds.
Q. Furanones are a distinct class, is this correct, to furans? You would agree with that. A. I do not know what you mean by "distinct class".
Q. Can I put it this way, that, in the literature, they are treated separately. We will look at some literature in a moment, but is that correct? A. No, I do not think so. I think that the literature, depending on the level of the literature, will treat furanones as separate entities. If somebody said, for example, he had this compound, a natural product that was a furanone, he would describe it probably as a five-membered ring lactone. That is a general class of compounds. If you were to think about a question of tautomerism of furanones, you could not just separate them off as though they have no connection with hydroxy furans or enolates.
I think that the right conclusion to draw from this is Professor Baldwin thinks that if an author specifies a long list of compounds by the use of a formula identifying the hydroxyfurans, then the skilled reader, who knows that the furanones are associated with the hydroxyfurans, would assume that both tautomers were in contemplation because he could not know which was the minor and which the major tautomer. More importantly, perhaps, if he set out to make one, he would either get both or would get negligible quantities of the one he set out to make, and nearly exclusively the other. Professor Kirby acknowledged this:
Q. If, in any one case, one made the enol form it would be through the process of tautomerisation that you would get in your solution the keto form. A. If you specifically set out to make the enol form, the hydroxy form, in most cases that would work and you would end up with the keto form; yes, that is right.
Q. The keto would then be existing in equilibrium with the enol and the enolate? A. To a greater or lesser extent depending on the system, yes.
Q. To a greater or lesser extent depending on the system and that such tautomerism is exactly what one would expect. A. Yes.
Q. In solution it is accordingly right, is it not, that these keto, or if you make the enol form, exist as components of a system in which both parts -- by both parts I mean the tautomers -- may be important? A. Yes. That is more or less the same as saying there is equilibrium. You cannot be in equilibrium unless both parts are important.
This fact gave rise to an allegation of insufficiency with which it is not necessary to deal separately: it was not possible to prepare the 2-hydroxyfurans, since to all intents and purposes they could not be made in aqueous solution, because they would immediately tautomerise to the furanone.
Conclusions on the primary argument for infringement
- It follows from my conclusions that claim 1 is not infringed by the importation and sale of MK-966. Claim 13 is not infringed by the importation and sale of pharmaceutical preparations containing it.
- I must now deal with the claimants’ contention that if the claim does not cover the keto tautomer, there is nonetheless infringement. There are a number of complex issues of fact which need to be resolved. These are, first, is there any evidence that the enol tautomer does any work as a drug; second, does it play any part in metabolism; and third (relevant to claim 20) what is the role which it plays in the manufacture of MK-966.
Infringement 2—Which tautomer does the work
- The starting point for this discussion is the indisputable fact that the ratio of keto:enol at any time is 10-10 or thereabouts. On the face of it, the enol is unlikely to play any significant role in the anti-inflammatory activity of MK-966. On administration to a patient, the ratios will be those which I have set out in paragraph 185. Even if the enol and enolate compete with the furanone directly in binding to the active site of the enzyme, it is very unlikely that they would play any significant part in the activity of the drug, and in particular in its binding to the COX-2 enzyme. This was the evidence of both Professor Baldwin and Professor Kirby. Professor Kirby pointed out that if the enol/enolate was binding to the COX-2 enzyme as effectively as the furanone, the binding would be 109 times stronger than that of the furanone, and this would be both extraordinary and irreversible, which is not what is observed. It is known that the binding of MK-966 to COX-2 is reversible. Professor Baldwin suggested that it was possible that local conditions at the binding site(s) on the enzyme might be strongly basic, so encouraging or stabilising the enolate. There was no evidence that this was happening, and there was no evidence that the enol/enolate was acting as a "gateway" through which the furanone passed before it bound to the enzyme.
- Given that this is the position, I think that it is an abuse of language to say that the enolate is a "pharmaceutically acceptable" salt of MK-966. Whether or not it is acceptable (a question to which I return below), if I am wrong on the principal issue of construction, it cannot be regarded as a pharmaceutical. It does nothing.
- A further indication which should not be overlooked that it is the furanone which is the active material within the body is the performance of compound 67 in the defendants’ Notice of Experiments. This was a similar compound to MK-966 save that there is no hydrogen at the 5 position but two methyl groups instead (Figure O). The absence of an available hydrogen prevents tautomerisation, so there is no enol form of compound 67.
- Compound 67 was comparable with MK-966 in the COX-2 assay described in the patent and this supports the view that the furanone MK-966 is the active compound. This example is suggestive rather than conclusive, but in the end there was no concrete evidence at all that the enol or enolate were making any contribution to the pharmaceutical activity of MK-966, and the simplest and most obvious explanation for this lack of evidence is that the furanone is the active ingredient, as I find. Perhaps I can summarise by saying that the defendants make and sell a compound which is the active ingredient of the drug which is administered to patients and it is this compound which possesses the pharmacological activity to the exclusion of all others.
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Infringement 2—Metabolism
- The contentions on metabolism were not clearly pleaded. At the beginning
of the trial, I permitted the patentees further to amend their Statement
of Case on infringement by adding thereto clearer contentions. Rather than
summarise them, it is easier to set the contentions out.
1. It is the Claimants' case that MK-966 is altered upon administration to patients, in the said patients' bodies, so as to fall within the claims of the Patent. First, the Keto Form, Enol Form and Enolate are in dynamic equilibrium in the body. Thus at least half of the MK-966 molecules will exist as the Enol Form and/or Enolate over the lifetime of the drug in the body. Second, MK-966 metabolises, in substantial part, via the Enol Form and/or Enolate. Two such metabolic routes are shown in Figures l and 2. The removal of MK-966 from the body via these routes will result in the generation of additional Enol Form and/or Enolate from the Keto Form owing to the dynamic equilibrium between the species.
2. It is also the Claimants’ case that the presence of the Enol Form and/or Enolate in patients’ bodies affects the pharmaceutical properties of MK-966. The Enol Form and Enolate are present when MK-966 binds to the Cox-2 enzyme. Further, the pharmaceutical properties of an inhibitor are not limited to its interaction with its target molecule, but include its ability to be transported throughout the body and be metabolised appropriately. Accordingly, the pharmaceutical properties of MK-966 are in part dependent on the metabolism of MK-966 via the Enol Form and/or Enolate. If MK-966 could not be metabolised in this way the drug would have different pharmaceutical properties as a result of it being in the body for a different length of time and/or producing different metabolites.
- Annexed to the pleading to which I have referred are two schemes for metabolic pathways for MK-966. The first was described during the hearing as a reductive pathway, since the overall chemical process which is relied on is called reduction. Reduction can be viewed as the addition of a hydrogen atom or the removal of an oxygen atom. The second pathway was called the oxidative pathway as the overall chemical process is called an oxidation, which can be viewed as the addition of an oxygen atom or the removal of a hydrogen. The pathways were proposed by Professor Baldwin on the basis of certain documents incidentally in discovery, and in particular one known as the "Slaughter document". It seems that the Slaughter document is a speculation on the possible metabolic pathways of MK-966 on the basis of two pieces of evidence: an analysis of the urine of humans, dogs, rats and monkeys, and upon an in vitro study of the effects of incubating MK-966 with human liver cytosol, that is, an extract of the cellular contents of the human liver, which can be expected to contain all enzymes relevant to metabolism in the liver. In order to deal with this allegation, the defendants relied in their evidence in answer on parts of their submission made to the Food and Drug Administration in the United States for the purpose of seeking approval of Vioxx. I ordered disclosure of the whole collection of documents forming this part of the submission and the facts and experimental results recorded or referred to in these documents formed the basis of the views expressed by the experts before me. The claimants themselves performed no experiments, and as I have indicated their contentions on metabolism are only found clearly in their evidence in chief. However, since the defendants did not seek an adjournment and did not seek to have the allegation struck out, I must deal with it.
- The claimants’ case is that both the oxidative and the reductive pathways for the metabolism of MK-966 were proposed by the defendants, and form the defendants’ best opinion as to what happens to MK-966 in the body. Their contention, supported by the evidence of Professor Baldwin, is that both oxidative and reductive pathways involve the enol. The defendants submit that on the material available it is overwhelmingly likely that the enol plays no part in the oxidative pathway, and that the evidence is insufficiently strong for me to come to any conclusion in respect of the reductive pathway. My conclusion is that I am not satisfied on the balance of probabilities on the evidence available that the enol does play a part in the metabolism of MK-966 by the reductive pathway, although I suspect that it does so. I am satisfied that there is no evidence supporting its participation in the oxidative pathway. My reasons are as follows.
- Taking the oxidative pathway first, the reaction concerned is the oxidation of MK-966 to a compound referred to as L 755,190. This is a compound like MK-966 save that one of the hydrogens at the 5 in the heterocyclic ring is replaced by an -OH group, a process called hydroxylation. The product is occasionally referred to in the documents as 5-hydroxy MK-966 but I shall call it L 755,190.
- One of the proposed oxidative pathways is via a general purpose oxidative enzyme present in the liver called cytochrome P450. This enzyme can oxidise many substrates. The defendants say that the reaction is a direct hydroxylation: the claimants say it proceeds via the enol. For the enzyme to oxidise MK-966 via the enol, the enol would have to bind preferentially to cytochrome P450 relative to MK-966 itself. Professor Baldwin proposed a route in which the MK-966 bound to the enzyme and was then converted into enol/enolate which was stabilised by the enzyme. He described this as "chemically equally viable" to a direct oxidation of the furanone, and pointed out that a number of enzyme catalysed reactions are thought to proceed by way of enzyme stabilised enolates. He accepted, however, that the examples which he gave were all specific enzymes binding to specific substrates. I think that the mechanisms which Professor Baldwin proposed were essentially speculative. That is not to say that they may not be shown to be right, or even, given their source, that they are very likely to be shown to be right, but they are speculations. In cross-examination he accepted, on the basis of an extract from Woolf, Handbook of Drug Metabolism, that hydroxylation adjacent a heteroatom or a À-bond (as this hydroxylation would be) is highly favoured by cytochrome P450 owing to the weaker bond strengths of the relevant C–H bonds. Given that Professor Baldwin accepts this mechanism as a possibility, and given that there is no direct evidence of the presence of the enol in the reactions, it is in my judgment impossible to say on the balance of probabilities that the enol is involved in this version of the oxidative pathway.
- I should add that Dr Baillie, who gave evidence for the defendants on the issue of metabolic pathways, considered that the cytochrome P450 route was unlikely to involve the enol for another reason. This was that if the enol was involved, it would be oxidised to an epoxide, which would react directly with the proteins present forming adducts. No such adducts are observed, and thus the enol is not involved. Professor Baldwin did not accept this analysis. He said that he thought that Dr Baillie’s proposed mechanism was incorrect, and that an epoxide bond would break in a manner which would give L755190 directly, affording no opportunity for the forming of adducts with the proteins present. Dr Baillie agreed this was a reasonable hypothesis, but not the only one, and that his remained a possibility. From this it followed that absence of the adducts suggested that the enol was not involved at all. Professor Kirby considered that either Dr Baillie’s or Professor Baldwin’s route was a possibility. These considerations suggest that it is less, rather than more, likely that the enol is involved in this pathway. Unless I can be satisfied that Professor Baldwin’s proposed mechanism is correct to the exclusion of Dr Baillie’s, which I cannot do on the evidence, there should be evidence of adducts if the enol is involved at all. But there is no such evidence.
- There was some cross-examination on a non-cytochrome P450 mediated oxidation of MK-966, but I do not understand the claimants now to rely on this pathway.
- In conclusion, I am not satisfied on the evidence that the enol tautomer of MK-966 plays any role in the oxidative metabolism of MK-966 in humans or animals.
- So far as the reductive route is concerned, the Slaughter document describes various metabolites found in urine (in particular those called the cis- and trans-dihydrohydroxyacids or DHHA’s), and describes the results of the in vitro work. It states the first hypothesis which was advanced as to the correct metabolic pathway:
The defendants had identified the M+18 metabolite by a classic experiment. They incubated MK-966 with liver cytosol, in the absence of a chemical (NADPH) which is essential for complete reduction by the enzymes present in the cytosol. The reaction product was the M+18 metabolite. The argument is thus that the M+18 metabolite is a stage through which the metabolic reaction proceeds, and that the NADPH is necessary for its next stage. The existence of the M+18 metabolite forms an important feature of the proposed route as it is set out in the papers which the defendants assembled for their submission to the FDA. Before me, they emphasised that the presence of the M+18 metabolite as an actual stage in the reductive pathway had never been conclusively demonstrated, since its presence in vivo had never been shown. Therefore, it should be regarded as a good hypothesis, but not as a fact.
The defendants had thus thought of two possible metabolic routes. The first was via the so-called dihydrolactone to the DHHA. This was called the six o’clock route, since it proceeds vertically on the reaction scheme (Figure P).
The defendants appear from the Slaughter document to have rejected the six o’clock route, and come down in favour of the route shown on the right hand side of Figure P. This proceeds via the enol to the M+18 metabolite, which then reduced to the DHHA via a ring-opening step.
Professor Baldwin accepted that the defendants’ experimentalists had found the presence of cis– and trans– dihydrolactones in analysis of the urine samples, and while lactones would be expected if the six o’clock route was the right one, he could not see that the proposed reaction would produce both cis- and trans- forms, that is, a racemic mixture. He took the view that it was more likely that the dihydrolactones were produced not during metabolism but during the "work-up" of the material for the experiment, a view supported by other experimental results. He also pointed out that the fact that both cis- and trans- forms were present was anyway more consistent with the M+18 pathway than with a direct reduction of MK-966 to the dihydrolactones. He thought that a direct reduction, which would be mediated by an enzyme, would be stereospecific, producing either the cis- or trans- isomer, but not both. On the other hand, the presence of a mixture of cis- and trans- forms might reasonably be expected if the second hypothesis as to the metabolic pathway was accepted. Professor Kirby described this as an acute comment. Dr Baillie said it was a good point, but that examination of some of the experimental results recorded by Dr Slaughter suggested that the material had originally been produced as one stereoisomer and had subsequently racemised, that is, the cis– and trans– forms had interconverted in aqueous solution. Moreover, he said that general-purpose enzymes were not very stereospecific. I do not believe that Dr Baillie was cross-examined on this issue.
There is experimental support for the existence of the M+18 metabolite. Given that it seems to be the defendants’ view that the in vitro experiments accurately model the in vivo system, I find that it is more likely than not that the M+18 metabolite does play a role in the reductive metabolic pathway. On the other hand, the dihydrolactone has not been detected in vivo or in vitro. Accordingly, I find that it is more likely than not the dihydrolactone does not play a part in the metabolic pathway.
The question is how the M+18 metabolite is formed. The defendants’ hypothesis set out in Figure P is that it proceeds via the enol directly in aqueous conditions. Their hypothesis was that the enol was hydrated directly. Professor Baldwin thought that the reaction did not proceed in this way, but via an intermediate, the 3H keto tautomer, which he recognises as being in equilibrium with the enol. Professor Kirby also rejected direct hydration, which he considered was more likely to produce the 4-hydroxy compound rather than M+18, which is a 5-hydroxy compound. Professor Kirby’s first suggestion for a route, set out in paragraph 12 of his second report, was criticised by Professor Baldwin, and Professor Kirby accepted the criticism. A rather similar scheme to that rejected by Professor Kirby was proposed by Dr Baillie. Professor Kirby accepted that Dr Baillie’s scheme was unlikely, since the various equilibria would be likely to favour MK-966 rather than the hoped-for metabolites. Mr Kitchin submitted that Professor Baldwin’s scheme, as elaborated in his supplementary witness statement, was the only acceptable hypothesis as to what was going on.
Professor Kirby had objections to the second hypothesis as to the metabolic path, and considered the six o’clock route, which appears to be rejected in the Slaughter document, to be reasonable. In chief it was his evidence that the direct reduction of MK-966 to the cis- and trans-dihydrolactones was reasonable, and he emphasised that the evidence was equivocal and inconclusive. He thought that the possible metabolic pathways of the drug were presently speculative.
While it is clear that the presence of the various metabolites (including the presence in the liver of the hemiacetal M+18 material) was a fact, I was left with the distinct impression that the actual mechanism of metabolism of MK-966 was far from completely elucidated. I have no doubt that it is a reasonable possibility that the enol/enolate forms part of the pathway, but I have also no doubt that it is a reasonable possibility that it does not do so. The allegation in relation to metabolism was raised late in the trial. In spite of Mr Kitchin’s protests, I am quite satisfied that it was not raised clearly in the Statement of Case on infringement which I ordered. It is clear that when that document says that MK-966 "is altered upon administration to patients, in the said patients’ bodies, so as to fall within the said claims of the patent" it is talking about the formation of the enol tautomer by reason of the aqueous environment. It is not talking about metabolic pathways. This is made clear by paragraph 9 of the Statement of Case. I do not think that I have enough material to enable me to come to a proper decision to prefer the views of one eminent chemist to that of the other, and I have to say that I consider that the question has not yet been scientifically answered. Accordingly, while I suspect that Professor Baldwin’s explanation is the correct one, I cannot conclude that it is established as the correct reductive metabolic pathway on the balance of probabilities.
It was assumed that the overall transformation involved reduction of MK-966 to the dihydrolactones followed by hydrolysis.
This is illustrated in the figure attached to the document. Having described an experiment in which a possible intermediate, called the M+18 metabolite (for mass 18 units higher than MK-966) was identified, it says this in rejecting the first hypothesis:
Thus it is proposed that the dihydroxyacids form by hydration of the enolic form of MK-966 followed by spontaneous ring opening of the resulting hemiacetal [the M+18 metabolite is a hemiacetal] and NAPDH dependent aldehyde reduction.
In other words, the metabolism of the drug happens via the enol/enolate. This pathway also is illustrated in the figure in the pleadings and in the Slaughter document.
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Infringement 3 — manufacture
- This allegation of infringement is based on the proposition that during manufacture, which takes place in solution, substantial quantities of the MK-966 will have passed into the enol/enolate form and back again. So, it is said, the enol or enolate is used to prepare MK-966, and this is sufficient to infringe claim 20, which has been construed by the Court of Appeal as a process claim relating to the whole of the process of manufacture of the medicament. The claim is as follows:
- The reaction medium is diisopropylamine. At any one time MK-966 will be present at about 0.03% enolate, the same minute quantity of enol as in physiological conditions, and >99.95% furanone. During the synthesis, the greater part of the MK-966 will have spent some time as the enolate.
- A salt is conventionally regarded as consisting of two components, an anion and a cation. The cation is positively charged, and the anion is negatively charged. The enolate ion is an anion. The cation of the salt of which the enolate is the anion has not been identified, as it must be if there is to be infringement. It must be emphasised the enolate is an ion, not a neutral compound. The presence of enolate can only be relevant to infringement if it is the cation of a "pharmaceutically acceptable salt".
- Pharmaceutically acceptable salt. This term was said by the claimants to embrace a physiological solution containing any anion derived from a compound within the claim by removal of a proton. This was said to be a pharmaceutically acceptable salt on the footing that all the cations present in the solution would necessarily be pharmaceutically acceptable and there would be a charge balance. Therefore this was a solution of a pharmaceutically acceptable salt. Thus, when MK-966 was administered to a patient, a solution of a pharmaceutically acceptable salt of MK-966 was formed. In my judgment, the phrase is plainly intended to relate to the material as administered to the patient. This is the natural meaning of the words, and it is reinforced by the passage at page 10 line 57 to page 11 line 14. Accordingly, it means a salt produced where the various substituents have free acid or base groups. It does not include a solution which contains enolate produced in basic conditions by subtracting a proton from the furanone.
- Professor Kirby’s evidence was that the enolate was not an intermediate in the manufacture of MK-966 but was just there: it was produced as the MK-966 was produced during the synthesis in very small quantities in dynamic equilibrium with the MK-966 and when the solution is acidified to precipitate the MK-966 it vanishes. The enol tautomer is present in even smaller quantities. Both vanish when the MK-966 is dried, and reappear when it is dissolved.
- The evidence was that the enolate is a very strong base. Professor Kirby said it was comparable in strength to caustic soda, and that no salt would be stable in a normal atmosphere. He said it had been made, but was stable only in the absence of moisture.
- Thus, the enol is present in vanishingly small quantities during manufacture, which does not last for long enough for a substantial proportion of the MK-966 present to have spent some time as the enol. Enolate salts are not pharmaceutically acceptable, and the presence of the enolate in pharmaceutically acceptable solution upon administration to the patient is irrelevant. On the assumption that I am wrong in my construction of claim 1, claim 20 is not infringed.
Use of a compound of claim 1 for preparing a medicament for treating inflammation or an inflammation-associated disorder.
I struck this allegation of infringement out on the basis that the claim related to the making of a medicament for the specified indication in which the "compound of claim 1" was the active ingredient, but the Court of Appeal have said that this approach to this claim is wrong. It is therefore necessary to consider the facts, on which extensive discovery was given.
CONCLUSIONS
- The patent is invalid in its amended and unamended form, and must be revoked. The proposed amendments are not objectionable in themselves. None of the claims have been infringed by the defendants.
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