Alcon Research LLC v Pharmathen SA
| Jurisdiction | England & Wales |
| Judgment Date | 28 June 2022 |
| Neutral Citation | [2022] EWCA Civ 845 |
| Docket Number | Case No: CA-2021-001749 |
| Year | 2022 |
| Court | Court of Appeal (Civil Division) |
[2022] EWCA Civ 845
Lady Justice King
Lord Justice Arnold
and
Lord Justice Nugee
Case No: CA-2021-001749
IN THE COURT OF APPEAL (CIVIL DIVISION)
ON APPEAL FROM THE HIGH COURT OF JUSTICE, BUSINESS AND PROPERTY
COURTS OF ENGLAND AND WALES, INTELLECTUAL PROPERTY LIST (ChD),
PATENTS COURT
Mr Justice Meade
Royal Courts of Justice
Strand, London, WC2A 2LL
Lindsay Lane QC and William Duncan (instructed by Penningtons Manches Cooper LLP) for the Appellant
Andrew Waugh QC and Anna Edwards-Stuart (instructed by Bristows LLP) for the Respondents
Hearing date: 15 June 2022
Approved Judgment
This judgment was handed down by the Court remotely by circulation to the parties' representatives by email and release to The National Archives. The date and time for hand-down is deemed to be 10:30 on 28 June 2022.
Introduction
The Claimants (“Alcon”) were respectively the proprietor and the exclusive licensee of European Patent (UK) No. 1 920 764 (“the Patent”) until it expired on 3 August 2014 and of Supplementary Protection Certificate SPC/GB12/038 (“the SPC”) based on the Patent until the SPC expired on 28 May 2017. The Patent concerns the use of fluprostenol isopropyl ester (“FIE”), a prostaglandin F 2α (“PGF 2α”) analogue also known as travoprost, for the treatment of glaucoma and ocular hypertension. The priority date of the Patent is 3 August 1993.
When this claim was issued on 14 July 2014 the Defendants were preparing to market generic travoprost eye drops for the treatment of glaucoma and ocular hypertension. Alcon applied for an interim injunction to restrain the Defendants from launching their product which was granted by consent with the usual cross-undertaking in damages by Alcon. The Defendants did not dispute infringement, but contended that the Patent, and hence the SPC, were invalid. Due to protracted but unsuccessful negotiations between the parties the claim did not come to trial until March 2021, by which time both the Patent and the SPC had long since expired, but Alcon's potential liability under the cross-undertaking remained.
It is very unusual for the Patents Court to have to try a patent case where the priority date of the patent in suit is as long as 27 1/2 years in the past. Furthermore, the lengthy gestation of the case caused the expert witnesses some difficulty in the preparation of their reports. These factors have no bearing on the legal issues in the case, but they mean that the dangers of hindsight are even more acute than they commonly are in patent cases.
The Defendants contended that the Patent was invalid on three principal grounds: (i) lack of novelty over European Patent Application No. 0 603 800; (ii) obviousness over J. Stjernschantz and B. Resul, “Phenyl substituted prostaglandin analogs for glaucoma”, Drugs of the Future, 17(8), 691–704 (August 1992) (“Stjernschantz”); and (iii) insufficiency, but only as a “squeeze” on obviousness. Meade J rejected all three grounds for the reasons given in his judgment dated 23 April 2021 [2021] EWHC 1026 (Pat). The Second Defendant (“Aspire”) now appeals, with permission granted by myself, on the issues of obviousness and insufficiency.
The skilled team
It was common ground before the judge that the Patent was addressed to a skilled team consisting of a pharmacologist and a medicinal chemist, but there was a significant dispute as to the attributes of the pharmacologist. The judge found at [27]–[42] that, as the Defendants contended, the pharmacologist would be someone with an interest in using prostaglandins (or analogues) in the treatment of glaucoma (a “prostaglandin specialist”). (For brevity the judge dispensed with referring to ocular hypertension as well as glaucoma, and I shall follow his example).
The judge made no finding as to the relationship between the two members of the team. Aspire criticises this omission, and I shall have to return to it when considering the appeal on obviousness.
The expert witnesses
Each side called two expert witnesses, a pharmacologist and a medicinal chemist. Alcon's pharmacologist was Dr Achim Krauss and Alcon's medicinal chemist was Dr David Cavalla. The Defendants' pharmacologist was Dr William Wilson and the Defendants' medicinal chemist was Dr Sally Redshaw. The judge considered that all four experts had done their best to assist the court, but he noted two features of their evidence that are relevant to the appeal.
First, he noted at [18] that Dr Krauss “took an approach in his first report which I found odd, in that although his own expertise included … prostaglandins, he gave evidence on the basis that the notional skilled pharmacologist was a generalist in glaucoma and would not know anything about them” and “dealt with the approach of a pharmacologist knowing of prostaglandins only in reply”. Nevertheless the judge did not consider that this adversely affected the weight to be given to Dr Krauss' evidence.
Secondly, the judge noted at [24] that, as consequence of the way in which she was instructed (which had the laudable aim of avoiding duplication), Dr Redshaw did not “tackl[e] the medicinal chemistry content of Stjernschantz at all fully”. As a result, Dr Redshaw had not:
“approached Stjernschantz in the way that an open-minded medicinal chemist without knowledge of the invention would have done. They would have read the whole thing and focused on all the medicinal chemistry content.”
Common general knowledge
The judge set out at [44]–[71] various matters which the parties were agreed were common general knowledge to one or other member of the skilled team. At [72]–[98] the judge made findings concerning five topics as to which there was a dispute. The agreed matters and findings that are relevant to the appeal may be summarised as follows.
General pharmacological principles
Compounds with a high potency for a particular biological target are often attractive candidates for drug development because they can be therapeutically active at low concentrations, reducing the risk of side effects caused by interactions between that drug and the biological targets responsible for side effects.
Generally, if a drug binds to a particular biological target with much higher affinity than to other biological targets, that drug is said to have high selectivity for that biological target. When a potent compound also has a high selectivity for the biological target responsible for efficacy it would be a prime candidate for drug development because the risk of side effects (caused by interactions with other biological targets) would be further reduced.
Prodrugs
A prodrug is a pharmacologically inactive substance that is converted within the body into an active drug. Prodrugs are used in several scenarios, but usually to improve the bioavailability of the active drug. The chemical structure of the drug is modified to create a prodrug, for example, to allow the prodrug to pass through certain barriers in the body, such as lipophilic membranes. A common method of preparing prodrugs to increase permeability through membranes is to form an ester of the parent drug.
Glaucoma
Glaucoma is a disease (more strictly, a group of diseases) of the eye characterised by progressive visual loss. It is usually associated with an elevated intra-ocular pressure (IOP), which was a known risk factor for glaucoma in 1993.
Treatment of glaucoma
In 1993 glaucoma was typically treated by using medications aiming to reduce the patient's IOP. Most treatments were administered topically as eye drops.
Patient compliance was a major issue with antiglaucoma medication for various reasons, including the unpleasant side effects. The main classes of drug available for the treatment of glaucoma were beta-blockers, carbonic anhydrase inhibitors, miotics and adrenergic agonists. The first line treatment for glaucoma in 1993 was timolol (a beta-blocker). Where one drug was insufficient to achieve the required reduction in IOP, drugs were often used in combination. There was a desire for better drugs, which were more efficacious in lowering IOP with no or minimal side effects.
Prostaglandins
Prostaglandins are endogenous signalling molecules present throughout the body. By 1993, they had been the subject of a significant body of research for potential use as drugs, particularly for cardiovascular and pulmonary diseases.
Prostaglandins and the treatment of glaucoma
Topical application of natural prostaglandins had been shown to lead to a reduction of IOP. One prostaglandin, PGF 2α, had been investigated as a glaucoma treatment and had been found to be effective at lowering IOP. The prodrug PGF 2α isopropyl ester (PGF 2α-IE) had been found to be a very potent ocular hypotensive with particularly prolonged effects.
Despite their IOP-lowering activity, natural prostaglandins were not used as anti-glaucoma drugs in the clinic due to their side effects, in particular ocular irritation (pain and so-called “foreign body sensation”) and conjunctival hyperemia (enlarged blood vessels). These side effects had effectively ended any further clinical development of PGF 2α-IE as an anti-glaucoma medication.
Animal models
There were various animal models used for glaucoma. Non-human primates (including monkeys) were the best model, but cats were commonly used to assess IOP lowering. Rabbits were commonly used to test for hyperemia. Cats were commonly used to test for ocular irritation.
The status of prostaglandins as therapeutic agents to treat glaucoma
There was no authorised prostaglandin drug (natural or analogue) to treat glaucoma. A prostaglandin called latanoprost...
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