Generics (UK) Ltd (trading as Mylan) v Novartis AG (a company incorporated under the laws of Switzerland)
| Jurisdiction | England & Wales |
| Judge | THE HON MR JUSTICE FLOYD,Mr Justice Floyd |
| Judgment Date | 30 September 2011 |
| Neutral Citation | [2011] EWHC 2403 (Pat) |
| Court | Chancery Division (Patents Court) |
| Docket Number | Case No: HC11C00492 |
| Date | 30 September 2011 |
[2011] EWHC 2403 (Pat)
IN THE HIGH COURT OF JUSTICE
CHANCERY DIVISION
PATENTS COURT
Royal Courts of Justice
Strand, London, WC2A 2LL
The Hon Mr Justice Floyd
Case No: HC11C00492
Daniel Alexander QC and Henry Ward (instructed by Taylor Wessing Llp) for the Claimants
Iain Purvis QC and Anna Edwards-Stuart (Instructed by Bristows) for the Defendants
Hearing dates: 5 th to 7 th September 2011 -
A Supplementary Protection Certificate ("SPC") extends the life of a granted "basic patent" in certain circumstances beyond the date on which the patent would otherwise come to the end of its statutory term. Generics (UK) Limited (who trade as "Mylan") seek declarations of invalidity in respect of such a certificate—SPC/GB98/038—and also of its basic patent, UK Patent No 2 203 040. The basic patent, and the SPC, protect a drug for the symptomatic treatment of Alzheimer's disease ("AD") called rivastigmine. The patentees, Novartis, market rivastigmine under the trade name Exelon. By counterclaim, Novartis allege that Mylan's threatened marketing of a generic version of rivastigmine will infringe the SPC, and seek appropriate relief.
The action has come to trial very quickly. The claim form was issued on 3 rd March 2011. Following an application for an interim injunction, an expedited trial of the action was ordered on 30 th June 2011. The action was tried over three days from September 5 th to 7 th, just over six months from the issue of the claim form. Expedition was justified because Mylan intended to launch a product prior to the expiry of the SPC, which will occur on 30 th July 2012.
Rivastigmine is the modern name for the (-)-enantiomer of N-ethyl-3-[(1-dimethylamino)ethyl]-N-methylphenyl–carbamate. In around 1985 a team of scientists led by Marta Weinstock, working at the Hebrew University of Jerusalem, made and tested a compound named RA 7, which is the unresolved racemic compound of which rivastigmine is the (-) enantiomer. RA 7 was one of a number of compounds proposed by Weinstock for the treatment of AD, but her publications made no mention of resolving it into its individual enantiomers. The sole question which arises in this action is whether a relevantly skilled pharmaceutical development team, in ignorance of the patent in suit, would find it obvious in the light of the Weinstock publications to resolve the racemic mixture of RA 7 into its individual enantiomers.
The only ground of attack on the patent is therefore lack of inventive step. An insufficiency argument which was expressed to be conditional on a factual argument being run by the patentee was not pursued. No separate issues arise on the counterclaim.
This is not the first patent action in recent years in which the question of inventive step has involved consideration of whether it is obvious to resolve a chiral compound, already used or proposed for use in therapy, into its individual enantiomers. Generics v Lundbeck [2009] UKHL 12 and Generics v Daiichi [2009] EWCA Civ 646 are examples. Although both sides attempted to draw comparisons with the facts of those cases, the present case has to be decided on its own facts.
Technical Background
The patent in suit assumes that the skilled reader has a certain amount of technical knowledge in the field of AD and general medicinal chemistry. All of what follows in this section of my judgment would be part of the reader's common general knowledge at the priority date in March 1987.
Alzheimer's disease
AD is a form of dementia. It is a progressive, degenerative, irreversible and ultimately terminal brain disorder.
The cholinergic system
Acetylcholine (ACh) is a neurotransmitter active in the central nervous system (CNS) where it binds to receptors. Within the CNS, ACh and the associated neurons form the cholinergic system. ACh-containing neurons in the brainstem and basal forebrain deliver ACh to areas of the brain.
ACh is synthesised within nerve terminals. When released from the nerve terminals the ACh diffuses across the synaptic cleft. Some ACh will bind to receptors on the pre- and post-synaptic cells, but most ACh will be hydrolysed by the enzyme acetylcholinesterase (AChE) (or in some cases by butyrylcholinesterase (BuChE)) which converts ACh into the inactive metabolites choline and acetate. The choline produced by the action of AChE is recycled to synthesise new ACh molecules.
The cholinergic hypothesis and AD
By the priority date, various neurochemical studies had shown an involvement of the cholinergic system in AD. In patients with AD, reduced activities of AChE had been reported, as had a reduced release and synthesis of ACh.
These studies suggested that enhancing cholinergic activity could be of benefit to those suffering from AD. Of the possible ways of achieving this enhancement, the most promising was the proposal to inhibit the enzyme AChE by chemical interaction. Initial support for this approach had been gained from preliminary trials using the drugs physostigmine and tacrine.
Cholinesterase inhibitors
Both AChE and BuChE are enzymes with an active site that comprises two distinct regions: an anionic site and an esteric site. These active sites interact with different parts of the ACh molecule. The anionic site binds to the (basic) choline moiety and the esteric site reacts with the (acidic) acetyl (or butyryl) group, leading to spontaneous hydrolysis of the substrate.
Cholinesterase inhibitors (also called anticholinesterases) act by inhibiting (i.e. by blocking the active sites of) AChE and/or BuChE. The inhibitor binds with the two sites of the cholinesterase molecule so as to prevent access by ACh. If a molecule of ACh cannot bind to the site, it cannot be hydrolysed there, and levels of ACh can be maintained.
As at the priority date, drugs for cholinesterase inhibition fell into three categories according to the nature of their interaction with the active site of cholinesterase: short-acting, medium-acting and irreversible. Of these only the medium acting inhibitors showed promise. Medium-acting cholinesterase inhibitors include neostigmine, pyridostigmine and physostigmine. These drugs contain (basic) groups that bind to the anionic site of the cholinesterase and also interact with the esteric site in a way which leads to much slower hydrolysis and a longer lasting effect.
Physostigmine and tacrine
Physostigmine is a naturally occurring compound found in the Calabar bean. It was available for clinical use to treat the CNS effects of anticholinergic drug overdoses. Physostigmine had been shown to show some efficacy for treating AD in some limited experimental trials.
Physostigmine was far from ideal as a treatment. This was primarily because of its short duration of action (typically 30 minutes) and its small therapeutic window (which meant that intolerable side effects were observed at or close to therapeutic doses). In addition it had variable bioavailability and was chemically unstable.
A study published in the New England Journal of Medicine in 1986 by Summers and others indicated significant cognitive improvement, without side effects, amongst people with AD who had been given oral tacrine. This paper attracted significant interest on its publication as it appeared to be the first potential treatment for AD to have emerged from the cholinergic hypothesis.
Brain regions
Four regions of the brain are known as the cortex, hippocampus, striatum and medulla. Cholinergic degeneration was known to be more pronounced in the hippocampal and cortical regions of the brain in patients with AD and these areas were associated with cognitive impairment.
Other lines of research
The cholinergic hypothesis was not the only line of research activity into the treatment of AD at the priority date. But it was, in the end, common ground between the experts that this hypothesis represented the most promising line at the time.
Chirality
A molecule is said to be chiral when it is non-superimposable on its mirror image. If a molecule is superimposable on its mirror image, it is termed achiral. For example, the right and left hands of the human body are chiral objects since they are mirror images and not super-imposable. "Chiral" derives from the Greek word for "hand".
If a carbon atom has four different types of atoms or groups bonded to it designated as A, B, C and D in the figure below, then the molecule is chiral:
No matter how it is moved about, the molecule on the left side cannot be superimposed on its mirror image shown on the right side. Molecules of this type are referred to as stereo-isomers or enantiomers. Enantiomers have identical physical and chemical properties in every respect, except two. They differ in their optical properties (the direction in which they rotate the plane of polarised light) and in the fact that they react at different rates with other chiral compounds. Since living beings contain chiral proteins and constitute a chiral environment, the chirality of compounds administered to humans is of importance for therapy.
A racemate is an equimolar mixture of a pair of enantiomers. Because a racemate consists of a mixture containing equal amounts of the (+) and (-) enantiomers, it is not optically active (i.e. it does not rotate the plane of polarised light).
It was common ground that at the priority date the skilled reader would have an expectation that the activity of a drug molecule would be affected by chirality. Cases where the activities of the (+) and (-) enantiomers were the same would be unusual. In some cases one of the enantiomers may be completely inactive, but in the more general case one...
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