Cairnstores Ltd v Aktiebolaget Hassle (Application for Revocation)
| Jurisdiction | England & Wales |
| Judge | Mr Justice Laddie |
| Judgment Date | 06 March 2002 |
| Neutral Citation | [2002] EWHC 309 (Ch) |
| Docket Number | Claim No: HC01C05083 |
| Court | Chancery Division |
| Date | 06 March 2002 |
[2002] EWHC 309 (Ch)
IN THE HIGH COURT OF JUSTICE
CHANCERY DIVISION
PATENTS COURT
Royal Courts of Justice
Strand, London, WC2A 2LL
The Honourable Mr Justice Laddie
Claim No: HC01C05083
Claim No: HC0005802
Mr Christopher Floyd QC and Mr Michael Tappin (instructed by SJ Berwin & Co for Cairnstores Ltd)
Mr Christopher Floyd QC and Mr Adrian Speck (instructed by Taylor Joynson Garrett for Generics (UK) Ltd)
Mr Simon Thorley QC and Mr Colin Birss (instructed by Simmons & Simmons for the Defendant)
Hearing dates: 6–8, 11, 12 February 2002
APPROVED JUDGMENT
| I direct that pursuant to CPR PD 39A para 6.1 no official shorthand note shall be taken of this judgment and that copies of this version as handed down may be treated as authentic. |
Mr Justice Laddie
This is the judgment in two conjoined actions for revocation of two patents, European Patent (UK) No. 0 247 983B1 ("'983") and European Patent (UK) No. 0 496 437 B1. The claimants are Cairnstores Limited and Generics (UK) Limited. The defendant proprietor of both patents is Aktiebolaget Hässle ("Hässle"). Although there are small differences between the patents, none of them are of any significance to the issues I have to decide and I will adopt the course adopted by the parties at the trial, namely consider only '983.
'983 is concerned with a formulation of an oral preparation containing a drug known as omeprazole. Omeprazole is a potent inhibitor of the secretion of acid in the stomach. It is therefore used in the treatment of gastric ulcers and other gastro-intestinal diseases. By the relevant priority date in April 1986, omeprazole was recognised as a breakthrough. It has been sold under the proprietary name "Losec". The basic patent for omeprazole was applied for in the 1970s. It has expired by now but omeprazole is the subject of a Supplementary Protection Certificate. That expires in April of this year.
Omeprazole is taken orally in the form of a tablet. The drug has to pass through the stomach and into the intestines of the patient. It is in the latter location that it can be absorbed into the patient's blood stream and thereby reach the sites in the body which control secretion of gastric juices. The patents in suit are concerned with the form and performance of the tablets. They have a few years to run.
A drug must be administered to a patient in a form in which it is "bioavailable", that is to say it must be presented in a form which allows it to carry out its desired pharmaceutical function. Unfortunately 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 acidic. To ensure that the active ingredient reaches the intestines without suffering significant degradation, it has to be in a form which protects it during its passage through the stomach but which allows it to be released in the intestine. The invention which is the subject of the patents is a form of oral administration of the drug which is resistant to stomach acid but is bioavailable in the intestines.
I will consider the disclosure and claims in the patents in a moment, but first I should say something about the technical background to this dispute. When a drug is to be administered orally, say as a tablet, it is almost never administered neat. Other substances, called excipients, are present. The claimants' expert witness, Dr Rue, annexed a glossary to his report which explains what excipients are and do. They include lubricants to reduce friction in the die machinery in which the tablets are made, binders to keep granules in the tablet together, glidents to aid the flow of powder if the tablet consists of powder, bulking agents or diluents where only small quantities of drug are contained within the dosage, disintegrants to assist the tablet to release its active ingredients rapidly into solution, coating materials to mask taste, affect dissolution or protect the core of the tablet and plasticisers which can be incorporated into the coat of a tablet, if it has one, to improve its physical properties. A number of excipients will be used together in a single tablet. For example I was told that about 6 excipients would be used in a standard tablet of antibiotic.
One method of protecting acid labile drugs in a tablet from attack within the stomach is to give it a coating which is acid resistant. This is called an enteric coating. It consists of a layer of material, enclosing a core containing the active drug, which does not dissolve or disintegrate in the acidic environment of the stomach but dissolves or disintegrates in the more alkaline environment of the intestines. Although, as of 1986, enteric coatings were only used in a very small number of formulations, they were well known. For example the use of such coatings was taught to undergraduates. Enteric coatings may be very thin films. They normally consist largely of polymers, that is to say long molecules made by joining together smaller building blocks, called monomers. They work by keeping the acid in the stomach away from the molecules of drug within the core of the tablet so that they cannot react together. Enteric coatings are but a sub-group of a larger group of substances used as coatings for tablets. For example for many years it has been well known to coat tablets with layers of sugar. This is to give the tablet bulk and to make it more palatable. Sometimes the top coat includes a dyestuff so that the tablet can have a desired colour. Coating materials, including enteric coating materials, are excipients.
The '983 Patent
The problems associated with making a dosage form of omeprazole suitable for oral administration are described in '983. Very sensibly, both sides have approached this case on the basis that there is no need to carry out experiments to prove that the patent's description of technical phenomena is accurate. There is no suggestion that anything in the patent is technically incorrect or misleading or that the simple chemical experiments referred to in it could not be carried out by skilled formulators to produce essentially the same results. The patent describes the problem faced by the formulator of an orally administered dose of the drug as follows:
"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." (page 3 lines 8 to 25)
Low pH means acidic, high pH means alkaline. These passages make it clear that the obvious way forward to protect the omeprazole is to enteric coat it so as to protect it from acid. It will be noticed that the inventors refer to a paper by Pilbrant and Cederberg, one of the documents relied on by the claimants in this action. The inventors summarise its contents as follows:
"The publication describes a conventional enteric coated dosage form and states that it has an acceptable storage stability—for clinical studies." (patent p 3 lines 39–42)
It is not in dispute in this case, not least because of the contents of Pilbrant and Cederberg, that a skilled worker in the field in 1986 would have firmly in mind that oral administration was the preferred route and that an enterically coated dosage form was either necessary (as the patent itself says) or highly desirable because omeprazole is so acid labile. That would be his starting point in trying to formulate an acceptable dosage form of omeprazole. The inventors also describe the nature of the problem encountered if a standard enteric coating is used:
"Ordinary enteric coatings, however, are made of acidic compounds. If covered with such a conventional enteric coating, omeprazole rapidly decomposes by direct or indirect contact with it, with the result that the preparations become badly discolored and lose in (sic) omeprazole content with the passage of time." (patent p 3 lines 25–28)
The reason for the discolouration is that one of the breakdown products of omeprazole is intensely red in colour. The discolouration is a clear sign that degradation is taking place. In relation to the enterically coated omeprazole described in the Pilbrant and Cederberg paper the inventors say:
"It was later found that the stability of this dosage form was insufficient during long-term storage required for a marketed pharmaceutical dosage...
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