Novartis AG (a company incorporated under the laws of Switzerland) v Generics (UK) Ltd (trading as Mylan) (Respondent/Claimant)
| Jurisdiction | England & Wales |
| Judge | Lord Justice Kitchin,Lord Justice Lewison,Lord Justice Munby |
| Judgment Date | 12 December 2012 |
| Neutral Citation | [2012] EWCA Civ 1623 |
| Court | Court of Appeal (Civil Division) |
| Docket Number | Case No: A3/2011/2970 |
| Date | 12 December 2012 |
[2012] EWCA Civ 1623
Lord Justice Munby
Lord Justice Lewison
And
Lord Justice Kitchin
Case No: A3/2011/2970
IN THE COURT OF APPEAL (CIVIL DIVISION)
ON APPEAL FROM THE HIGH COURT OF JUSTICE
CHANCERY DIVISION (PATENTS COURT)
THE HON MR JUSTICE FLOYD
Royal Courts of Justice
Strand, London, WC2A 2LL
Iain Purvis QC and Miss Anna Edwards-Stuart (instructed by Bristows) for the Appellant
Daniel Alexander QC and Henry Ward (instructed by Taylor Wessing LLP) for the Respondent
Hearing date: 14 November 2012
Introduction
This is an appeal against the judgment of Floyd J dated 30 September 2011 and his consequential order made on 20 October 2011 revoking Supplementary Protection Certificate SPC/GB98/038 ("the SPC") and its basic patent, UK Patent No. 2,203,040 on the basis that claims 1 to 9 of the basic patent were invalid.
The SPC and the patent are owned by the appellant, Novartis, and protect a drug called rivastigmine which is used for the treatment of Alzheimer's disease. Novartis markets rivastigmine under the trade name Exelon.
In these proceedings the respondent, Mylan, sought revocation of the SPC and claims 1 to 9 of the patent in order to market a generic version of rivastigmine which it accepts falls within the product claims and is the direct product of the process claims of the patent. The trial was therefore only concerned with validity.
Rivastigmine is the (-)-enantiomer of N-ethyl-3-[(1-dimethylamino)ethyl]-N-methylphenyl–carbamate. This is a racemic compound which was made and tested in about 1985 by a team of scientists led by Professor Marta Weinstock at the Hebrew University of Jerusalem and was disclosed by them in two prior publications relied upon in these proceedings, European Patent Application No. 0, 193, 926 ("the Weinstock application") and an article published in the proceedings of the thirtieth OHOLO conference on Alzheimer's disease and other related neuropsychiatric disorders ("the Weinstock article"). The racemic compound is referred to in these publications as RA7. As the judge explained, RA7 was one of a number of compounds proposed by Professor Weinstock for the treatment of Alzheimer's disease, but the publications did not suggest that it should be resolved into its individual enantiomers. The issue at trial was therefore whether, in the light of either of the Weinstock publications, it would have been obvious to a skilled team working in the pharmaceutical industry to select RA7 and resolve it into its individual enantiomers and use the (-) enantiomer as a medicinal product for the treatment of Alzheimer's disease.
The judge concluded there was nothing inventive in deciding to resolve and test RA7 to see if there were advantages or disadvantages associated with one of its enantiomers. Further, a pharmaceutical composition for the treatment of Alzheimer's disease comprising rivastigmine was conceptually obvious. It followed that the narrowest of all the claims relied upon by Novartis, namely rivastigmine in pharmaceutically acceptable form for use in the treatment of Alzheimer's disease, was invalid for lack of inventive step.
Upon this appeal, Novartis contends that the judge's finding was based on a number of errors of law and fact. Mylan responds that, on analysis, Novartis is simply inviting this court to reverse the judge's evaluation of the facts, something this court should be very cautious about doing for the reasons explained by Lord Hoffmann in Biogen Inc v Medeva plc [1997] RPC 1 at 45.
Technical background
The judge set out the technical background to the patent in his judgment at [6] – [25]. Novartis does not challenge any part of this description. Nor does it contest the judge's finding that all of this background formed part of the common general knowledge of the skilled team to whom the patent is addressed.
For the purpose of this appeal, I would emphasise the following. Alzheimer's disease is a degenerative and irreversible brain disorder. Patients suffer a progressive decline in cognitive function and exhibit various behavioural symptoms, many of which can be particularly stressful for the patients' families and carers. Even today, it has no cure.
By March 1987, the priority date of the patent, there was a consensus that the cognitive symptoms associated with Alzheimer's disease were due, at least in part, to a deficit of cholinergic transmission in the central nervous system. Studies had shown that patients suffering from the disease exhibited reduced synthesis and release of acetylcholine (ACh) and reduced activity of acetylcholinesterase (AChE), the enzyme primarily responsible for its hydrolysis. These studies suggested that ACh replacement or enhancing therapies might prove beneficial, the so-called "cholinergic hypothesis". As the judge explained at [11], of the possible ways of achieving enhancement, the most promising was a proposal to use chemicals called cholinesterase inhibitors to block the active site of AChE and so inhibit its activity. If ACh cannot bind to AChE, it cannot be broken down and its level can be maintained.
Other than the compounds described in the Weinstock publications, only two cholinesterase inhibitors had shown some therapeutic promise for the treatment of Alzheimer's disease by the priority date. One was physostigmine, a naturally occurring compound found in the Calabar bean. It had shown some efficacy in limited experimental trials. But it was known to be far from ideal as a treatment because it suffered from the drawbacks of having a short duration of action and a small therapeutic window, meaning that intolerable side effects are observed at or close to a therapeutic dose. In addition, it has variable bioavailability and is chemically unstable. Another compound, tacrine, had generated interest in the light of a study published in the New England Journal of Medicine in 1986 which indicated that its oral administration resulted in a significant cognitive improvement in Alzheimer's disease patients without causing side effects.
It was, in the end, common ground at the trial that the cholinergic hypothesis presented the most promising line of research into the treatment of Alzheimer's disease at the priority date. Tacrine was the first potential treatment to emerge from this hypothesis, but there was a need for others.
Finally, I should say a word about chirality. As the judge recorded at [24], it was also common ground at the trial that the skilled team reading the patent would have had an expectation that the activity of a drug molecule would be affected by chirality. It is unusual to find that the activities of the (+) and (-) enantiomers of a racemic compound are the same. In some cases one enantiomer is completely inactive, but usually one enantiomer is more active than the other.
The patent
The judge summarised the disclosure of the patent at [29] – [43]. The specification explains that the invention relates to rivastigmine which it describes as a novel phenyl carbamate with anticholinesterase activity. It recognises that the racemic mixture of which rivastigmine is the (-) enantiomer was known from the Weinstock application but continues:
"It has now surprisingly been found that the (-) enantiomer of formula I and its pharmacologically acceptable acid addition salts exhibit a particularly marked and selective inhibition of the acetylcholinesterase.
These findings are unexpected, particularly since it is not believed that the dialkylaminoalkyl side chain, which contains the optically active centre, is mainly responsible for the acetylcholinesterase inhibiting activity of the phenyl carbamates."
However, as the judge held at [32], the evidence showed that the skilled team would not entirely agree that the findings were unexpected because it was common ground that the chiral part of the molecule would be expected to influence the activity and hence the potency of the compound.
The skilled team
The judge described the addressee of the patent at [46]. The patent is, he found, addressed to a team of skilled researchers in a pharmaceutical company with an interest in developing drugs for use in the treatment of Alzheimer's disease. Such a team would include a medicinal chemist and a pharmacologist who would likely be a neuroscientist.
Both parties therefore called two experts, a medicinal chemist and a neuroscientist with experience of Alzheimer's disease. Mylan called Dr Roger Newton and Professor David Smith; Novartis called Dr David Cavalla and Professor Paul Francis.
Until his retirement in 1996, Dr Newton was employed by Glaxo and Allen & Hanburys as a medicinal chemist, ultimately directing their global research into respiratory diseases. Professor Smith is Professor Emeritus of Pharmacology and Honorary Associate Director of the MRC Anatomical Neuropharmacology Unit at the University of Oxford. He has had a particular interest in Alzheimer's disease since the late 1970s.
Dr Cavalla was, like Dr Newton, employed by Glaxo for a number of years as a medicinal chemist. After the priority date he moved to the Napp Research Centre in Cambridge. Professor Francis is a Professor of Neurochemistry at King's College London where he leads a research team studying the biochemistry of dementia. He has more than 25 years' experience in the study of Alzheimer's disease.
As the judge recorded (at [56]), all of these witnesses...
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