Pharmacia Corporation v Merck & Company Inc.
| Jurisdiction | England & Wales |
| Judge | LORD JUSTICE ALDOUS,LORD JUSTICE SEDLEY,LADY JUSTICE ARDEN |
| Judgment Date | 14 December 2001 |
| Neutral Citation | [2001] EWCA Civ 1957,[2001] EWCA Civ 1610 |
| Docket Number | A3/2001/0422,Case No: A3/2000/0422 |
| Court | Court of Appeal (Civil Division) |
| Date | 14 December 2001 |
[2001] EWCA Civ 1610
Lord Justice Aldous
Lord Justice Sedley and
Lady Justice Arden
Case No: A3/2000/0422
IN THE SUPREME COURT OF JUDICATURE
COURT OF APPEAL (CIVIL DIVISION)
ON APPEAL FROM CHANCERY DIVISION
MR JUSTICE PUMFREY
Royal Courts of Justice
Strand,
London, WC2A 2LL
Mr. David Kitchin QC and Mr Richard Meade (instructed by Bristows for the Appellants)
Mr David Young QC, Mr Justin Turner and Mr Thomas Hinchliffe (instructed by Lovells for the Respondents)
The appellants G.D. Searle & Co, the Pharmacia Corporation and Pfizer Inc. are the proprietors of European Patent (UK) 0 679 157. I will refer to them as the patentees. They alleged that that patent had been infringed by Merck & Co Inc. and Merck Sharp & Dohme Limited by amongst other acts the manufacture and sale of a non-steriodal anti-inflammatory (NSAID) sold under the trademark Vioxx, but referred to by Merck as MK-966.
Merck accepted that they had carried out the allegedly infringing acts, but denied infringement and submitted that the patent was invalid upon a number of grounds. Pumfrey J upheld those submissions. His decision is challenged by the patentees in this appeal.
The appeal involves issues which require knowledge of a difficult area of chemistry. I am indebted to the judge for his full and clear exposition of the chemistry, the issues involved and his reasons for coming to the conclusions that he did. It has lightened the considerable burden involved in this appeal.
The Patent
The background — The patent was published on 2nd November 1995 and claims priority from a U.S application filed on 15th January 1993. It is entitled "Novel 3,4-Diaryl Thiophenes and Analogs Thereof Having Use as Antiinflammatory Agents". Such compounds would be recognised by the addressee of the specification as NSAIDs. They are well known drugs which include aspirin, paracetamol and ibuprofen. As is commonly known they can cause gastro-intestinal ulceration. Research in 1971 suggested these drugs had the ability to inhibit synthesis of a prostaglandin produced by the body during inflammation. This is because known NSAIDs directly inhibited what is called COX. The addressee of the specification would have been appraised of the common general knowledge of those working in that field. The judge summarised that knowledge in these passages of his judgment.
"5. 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.
6. 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.
…
10. 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.
…
15. 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 A)
Figure A: 2,3 diaryl compounds
16. 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.
17. 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."
There was a dispute before the judge as to whether the skilled addressee's common general knowledge would include knowledge of the existence of the isozymes COX 1 and COX 2 and that one of the isozymes was inducible and was a target for NSAID research. His conclusion was not challenged during the appeal. He said:
"24. 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."
The Specification – The specification starts with a general description of the invention. It states that the invention is in the field of anti-inflammatory pharmaceutical agents and relates to compounds and methods for treating inflammation and inflammation-related disorders. It says: "More specifically this invention relates to selected effective and safe compounds having anti-inflammatory and/or analgesic activity without erosion of the stomach." It continues with a short explanation of the background:
"Prostaglandins play a major role in the inflammation process, and the inhibition of prostaglandin production, especially production of PGG2, PGH2 and PGE2, has been a common target of anti-inflammatory drug discoveries. However, common non-steriodal anti-inflammatory drugs (NSAIDs) that are active in reducing prostaglandin-induced pain and swelling associated with the inflammation process, are also active in affecting other prostaglandin-regulated processes not associated with the...
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