Cairnstores Ltd v Aktiebolaget Hassle (Application for Revocation)
| Jurisdiction | England & Wales |
| Judgment Date | 22 October 2002 |
| Neutral Citation | [2002] EWCA Civ 1504 |
| Docket Number | Case No: A3/2002/0650 |
| Court | Court of Appeal (Civil Division) |
| Date | 22 October 2002 |
[2002] EWCA Civ 1504
IN THE SUPREME COURT OF JUDICATURE
COURT OF APPEAL (CIVIL DIVISION)
ON APPEAL FROM CHANCERY DIVISION
MR JUSTICE LADDIE
Royal Courts of Justice
Strand, London, WC2A 2LL
Lord Justice Aldous
Lord Justice Tuckey and
Lord Justice Longmore
Case No: A3/2002/0650
Mr Simon Thorley QC and Mr Colin Birss (instructed by Simmons and Simmons) for the Appellant/Defendant
Mr Christopher Floyd QC and Mr Michael Tappin (instructed by S.J. Berwin) for the Respondent/Claimant Cairnstores
Mr Christopher Floyd QC and Mr Adrian Speck (instructed by Taylor Wessing) for the Respondent/Claimant Generics (UK) Ltd
This is the judgment of the Court.
On 6th March 2002, Laddie J handed down his judgment in the conjoined actions for revocation of Aktiebolaget Hässles' (Hässle) European Patents (UK) Numbers 0247983 and 0496437. The claimants seeking revocation were Cairnstores Ltd and Generics (UK) Limited.
The judge held both patents obvious and therefore invalid. Against that conclusion Hässle appeal. In their notice of appeal their main ground of appeal was based on their view of the way the judge behaved during the trial. They asserted that the conduct of the judge during the trial and in particular during the cross-examination of their expert, Dr Rees, was such as to create an appearance of bias. In effect he descended into the arena on the side of the claimants. The result was that the judge's conduct during the cross-examination of Dr Rees deprived him of the advantage of a calm and dispassionate observation of the demeanour of the witness. They also claimed that the judge's conduct had meant that they had not had a fair trial. We will come later to those grounds of appeal, but must first deal with the background, the patents and the judgment.
The background – The patents are concerned with formulation of an oral preparation for the administration of a drug known as omeprazole. It is a potent inhibitor of the secretion of acid in the stomach. It has been widely marketed under the name "Losec" for the treatment of gastric ulcers and other gastro-intestinal diseases. The patents for omeprazole were applied for in the 1970's. They have expired, but they were covered by supplementary protection certificates that expired in April 2002.
Omeprazole is taken orally in the form of a tablet. It has to pass through the stomach and into the intestines of the patient to be absorbed into the patient's bloodstream so as to the reach the sites in the body which control secretion of gastric juices.
Omeprazole is acid labile, that is to say it is very sensitive to and can be degraded by acid. The contents of the stomach are acid and therefore the active ingredient needs to reach the intestines without suffering significant degradation. It therefore has to be in a form which protects it during its passage through the stomach to the intestines. The inventions, the subject of the patents, provide a form of oral administration of the drug which is resistant to stomach acid but which is biodegradable in the intestines.
There are differences between the patents, but they were not significant to the issues the judge had to decide. Therefore the parties and the judge considered only the 983 patent. The position is the same on appeal.
The 983 Patent – The patent claims priority of 30th April 1986. It is entitled "New Pharmaceutical Preparation for Oral Use". The specification starts by stating that the present invention relates to a new stable pharmaceutical preparation containing omeprazole for oral use and to a method for the manufacture of such a preparation.
The specification then records that omeprazole was a substance known to be a potent inhibitor of gastric secretion useful for the treatment of gastric and duodenal ulcers. It continues at page 3 line 8:
"Omeprazole is however susceptible to degradation/transformation in acid reacting and neutral media. The half-life of omeprazole in water solutions at pH-values less than four is shorter than ten minutes. Also at neutral pH-values the degradation reaction proceeds rapidly, e.g. at pH = 7 the half-life of omeprazole is about 14 hours, while at higher pH-values the stability in solution is much better (Pilbrant and Cederberg, Scand. J. Gastroenterology 1985; 20 (suppl. 108) p. 113–120). The stability profile is similar in solid phase. The degradation of omeprazole is catalyzed by acidic reacting compounds and is stabilized in mixtures with alkaline reacting compounds. The stability of omeprazole is also affected by moisture and organic solvents.
From what is said about the stability properties of omeprazole, it is obvious that an oral dosage form of omeprazole must be protected from contact with the acid reacting gastric juice in order to reach the small intestine without degradation.
In human pharmacological studies it was found that the rate of release of omeprazole from a pharmaceutical dosage form can influence the total extent of absorption of omeprazole to the general circulation (Pilbrant and Cederberg, Scand. J. Gastroenterology 1985; 20 (suppl. 108) p. 113–120). A fully bioavailable dosage form of omeprazole must release the active drug rapidly in the proximal part of the gastrointestinal canal.
In order to obtain a pharmaceutical dosage form of omeprazole which prevents omeprazole from contact with acidic gastric juice, the cores must be enteric coated."
The specification goes on to point out that ordinary enteric coatings are made of acidic compounds and that, if omeprazole is covered with a conventional enteric coating, it rapidly decomposes by direct or indirect contact with the result that the preparations become badly discoloured and lose omeprazole content with the passage of time.
The specification states that in order to enhance the storage stability of cores which contain omeprazole, they must also contain alkaline reacting constituents. The specification continues at page 3 line 30:
"When such an alkaline core is enteric coated with an amount of a conventional coating polymer such as for example, cellulose acetate phthalate, that permits the dissolution of the coating and the active drug contained in the cores in the proximal part of the small intestine, it also will allow some diffusion of water of gastric juice through the enteric coating into the cores, during the time the dosage form resides in the stomach before it is emptied into the small intestine. The diffused water of gastric juice will dissolve parts of the core in the close proximity of enteric coating layer and there form an alkaline solution inside the coated dosage form. The alkaline solution will interfere with the enteric coating and eventually dissolve it."
The article by Pilbrant and Cederberg is then referred to. It is said to describe a conventional enteric coated dosage form of omeprazole which had an acceptable storage stability for clinical studies. However, the specification points out that it was later found that the stability of this dosage form was insufficient during long-term storage required for a marketed pharmaceutical dosage form.
The specification then sets out at page 3 line 43 the problem that the patentees faced.
"If a conventional formulation of omeprazole is made, the stability is not satisfactory, particularly in resistance to humidity, and special moisture-proof packing has been adopted to minimise the troubles. However, this provides no satisfactory solution to the problems in today's drug distribution system, and also leads to increased costs. Under the circumstances, there has been a demand for the development of new enteric preparations of omeprazole with better stability."
The object of the invention is stated in these terms:
"The object of the present invention is to provide an enteric coated dosage form of omeprazole, which is stable to discolouration and which is resistant to dissolution in acid media and which dissolves rapidly in neutral to alkaline media and which has a good stability during long-term storage."
There follows a description of the invention which in essence sets out claim 1 which is in this form:
"An oral, pharmaceutical preparation stable to discolouration containing omeprazole as the active ingredient characterized in that it is composed of core material in the form of small beads or tablets containing omeprazole together with an alkaline reacting compound, or an alkaline salt of omeprazole optionally together with an alkaline reacting compound, and on said core material one or more inert reacting subcoating layers comprising tablet excipients which are soluble or rapidly disintegrating in water, or polymeric, water soluble, filmforming compounds, optionally containing pH-buffering, alkaline compounds between the alkaline reacting core and an outer layer, which is an enteric coating."
The solution as claimed in claim 1 is the protection of the acidic enteric coating from reaction with the omeprazole core by keeping them apart by use of a separating layer which breaks down in the intestines. To do this it must be either water soluble or dispersible.
The judgment – Having reviewed the patent, the judge came to consider the witnesses. He concluded that Dr Rue, the claimants' expert witness, was "an impressive and reliable witness". He rejected the submission that because he did not have direct experience of enteric coatings, he was not qualified to give evidence upon the issues in this case.
As to Dr Rees, he said:
"23. The other witness was Dr Rees. He clearly is highly...
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