Generics (UK) Ltd v H Lundbeck A/S
| Jurisdiction | England & Wales |
| Judge | Mr Justice Kitchin |
| Judgment Date | 04 May 2007 |
| Neutral Citation | [2007] EWHC 1040 (Pat) |
| Docket Number | Case No: HC05C03689 HC06C02767 |
| Court | Chancery Division (Patents Court) |
[2007] EWHC 1040 (Pat)
the Honourable Mr Justice Kitchin
Case No: HC05C03689
HC06C00457
HC06C02767
IN THE HIGH COURT OF JUSTICE
CHANCERY DIVISION
PATENTS COURT
Mr Christopher Floyd QC and Mr Adrian Speck (instructed by Taylor Wessing) for the First Claimant
Mr Christopher Floyd QC and Mr Mark Chacksfield (instructed by Forsyth Simpson) for the Second Claimant
Mr Simon Thorley QC (instructed by Roiter Zucker) for the Third Claimant
Mr Andrew Waugh QC and Mr Justin Turner (instructed by Simmons & Simmons) for the Defendant
Hearing dates: 6 – 9, 12 – 16, 20 March 2007
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 Kitchin:
Introduction
This is the trial of three claims for revocation of European Patent (UK) No 0,347,066 (“The Patent”) in the name of the defendant (“Lundbeck”). As a result of an earlier direction, the evidence in each claim stands as evidence in the others and the three claimants have provided a single set of expert reports. For practical purposes I can therefore treat the three claims as a single claim for revocation.
The Patent has a priority date of June 1988 and concerns an antidepressant drug called escitalopram. It is sold by Lundbeck which is a comparatively small research based pharmaceutical company located in Denmark. Lundbeck specialises in diseases of the central nervous system. Escitalopram was launched in 2002 and accounts for approximately 60% of Lundbeck's turnover. It is currently the world's top selling branded antidepressant in terms of volume.
The challenges to the validity of the Patent are founded upon the prior art drug called citalopram. This was first synthesised by Lundbeck in 1972 and launched as an antidepressant in Denmark in 1989. Citalopram is a racemate and so comprises (+) enantiomers and (-) enantiomers, as I shall explain. Escitalopram, on the other hand, comprises the pure (+) enantiomer. The Patent has seven claims of which claims 1, 3 and 6 are alleged by Lundbeck to have independent validity. Claim 1 is a product claim and is directed to the (+) enantiomer (and salts thereof). Claim 3 is to a pharmaceutical composition in unit dosage form containing the compound of claim 1. Claim 6 is to a method of preparing the compound of claim 1 which comprises converting the (-) enantiomer of an intermediate made during the synthesis of citalopram to the (+) enantiomer, which is isolated as such or as a salt.
The attacks on the Patent can be summarised as follows:
i) Claims 1 and 3 are alleged to be invalid for lack of novelty over:
a) US Patent number 4,136,193 (“193”);
b) US Patent number 4,650,884 (“884”).
The lack of novelty attack turns upon a question of construction: Does the claim exclude the (+) enantiomer in the racemic mixture? Lundbeck has met this allegation with a conditional application to amend, which is opposed.
ii) Claims 1, 3 and 6 are alleged to be invalid for obviousness in the light of the 193 and 884 patents and common general knowledge.
iii) Claims 1 and 3 are alleged to be invalid for insufficiency. It is said that the inventive concept disclosed by the Patent was not the idea of resolving citalopram. The scope of the invention lay, and lay only, in devising a way to obtain it. Claims 1 and 3 therefore extend beyond any possible inventive contribution of the Patent in that they monopolise all ways of arriving at (+) citalopram.
Lundbeck relies upon commercial success to counter the obviousness allegation. It points to the very large sales of escitalopram and to unexpected technical benefits. This is answered by the claimants who say that the commercial success is not attributable to the invention, that escitalopram is not technically superior to citalopram and, in any event, the alleged unexpected technical benefits are not described in the Patent and so cannot be relied upon.
Background
Before describing the disclosure of the Patent, I must set out some of the technical background.
Depression
Depression and, in particular, Major Depressive Disorder (“MDD”) is one of the most common psychiatric disorders with a very wide distribution in the population. It has an early age of onset, beginning in the teenage years and twenties, and in almost all cases tends to become recurrent or chronic over time. According to the World Health Organisation, MDD is the second most common cause of disability by a chronic disorder. The underlying biochemical processes of depression are far from fully understood, however the basis of depression is thought to be a disruption of normal neural transmission. Serotonin (“5-HT”) and noradrenaline (“NA”) are neurotransmitters which allow messages to pass from nerve to nerve in the body. By June 1998, it was understood that neurotransmission by these agents was poorer in people suffering from MDD than in non-depressed people. The thinking was that if the reuptake of 5-HT and NA by nerve cells could be inhibited, this would leave more free 5-HT and NA in the synapses between nerve cells, and neurotransmission would be improved.
Treatment of MDD
Antidepressant treatments alleviate the symptoms of an episode of depression rather than effecting a cure of the underlying condition. By June 1988, the tricyclic antidepressants (“TCAs”) were the most widely prescribed class of antidepressants. These were introduced in 1955 and act by inhibiting NA or 5-HT reuptake. It is thought that they lead to an increase in the level of NA or 5-HT in the brain and that this accounts for their therapeutic action. However, it was found that they are not selective and have a number of other actions at postsynaptic receptors which cause serious side effects. They therefore tend to be prescribed in low doses.
Another group of molecules developed soon after the TCAs were introduced were the monoamine oxidase inhibitors. These inhibit the enzymes involved in the metabolism of 5-HT and NA. Although effective in treating in MDD, this class of drugs also has very severe side effects.
Escitalopram belongs to another class of drugs called the selective serotonin reuptake inhibitors (“SSRIs”). These are compounds which are selective in blocking only 5-HT reuptake and have little or no NA inhibitory or other action. By 1988 there were no SSRIs on the market in the UK. Two had been launched prior to that date but withdrawn due to toxicity problems. Nevertheless a number of SSRIs were in development. Fluoxetine (sold under the brand name Prozac) was the first successful SSRI to be launched into the UK and it was closely followed by paroxetine (sold under the brand name Seroxat) and citalopram. Fluoxetine and citalopram were launched as racemates and paroxetine as a single enantiomer. Of these, citalopram was known as the most selective SSRI. Since 1988, a number of other SSRIs have been introduced, namely sertraline and, most recently, escitalopram. There is evidence of the efficacy of all SSRIs in the treatment of moderate to severe depression. Most of the side effects of SSRIs are short term and occur immediately on starting treatment. The drugs are generally well tolerated and significantly fewer patients discontinue treatment due to side effects than is the case with the TCAs.
Alternative approaches have included the development of compounds of which are highly selective NA reuptake inhibitors, such as reboxetine, and compounds that are selective inhibitors of both 5-HT and NA reuptake, such as venlafaxine and duloxetine.
Stereochemistry
The basic principles of stereochemistry necessary to understand the Patent were explained by Dr Newton, one of the experts called on behalf of the claimants. Stereochemistry is the science of structures in three dimensions. Isomers are different compounds that have the same molecular formula. If isomers differ from each other only in the way the atoms are orientated in space they are called stereoisomers. Of particular relevance to these proceedings is the stereochemistry of the carbon atom. When a carbon atom is bonded to four other atoms its bonds are directed towards the corners of a tetrahedron. Two simple molecules illustrating this stereochemistry are shown below:
Sometimes, as in the case of the illustration of the methane molecule, the direction of the bonds is depicted. By convention a carbon-hydrogen shown by a dotted line or broken wedge goes into the page and away from the viewer (as in the case of the bond marked d); and one shown by a solid wedge comes out of the plane of the paper and towards the viewer (as in the case of the bond marked c).
Molecules that are not superimposable on their mirror images are chiral. If a molecule is superimposable on its mirror image it is achiral. This is illustrated by the molecule depicted below. Each of the atoms bonded to the central carbon atom is different. It can be seen that the stereoisomer on the left cannot be superimposed on the mirror image stereoisomer shown on the right. Such stereoisomeric molecules that are not superimposable are called enantiomers and the central carbon atom to which the four different atoms are attached is the chiral centre. These molecules are sometimes said to have a “handedness”. They are designated R or S depending upon their chiral configuration according to certain rules which it is not necessary to explain for the purposes of this case. It is one of the characteristics of enantiomers that they rotate the plane of polarised light in opposite directions and so are examples of optically active substances. A molecule...
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