Glenmark Generics (Europe) Ltd Generics [UK] Ltd (T/A Mylan) v The Wellcome Foundation Ltd Glaxo Group Ltd (Defendants/Part 20 Claimants)
| Jurisdiction | England & Wales |
| Judge | Mr Justice Arnold,THE HON MR JUSTICE ARNOLD |
| Judgment Date | 07 February 2013 |
| Neutral Citation | [2013] EWHC 148 (Pat) |
| Docket Number | Case Nos: HC12A2137, HC12E02314 |
| Court | Chancery Division (Patents Court) |
| Date | 07 February 2013 |
[2013] EWHC 148 (Pat)
IN THE HIGH COURT OF JUSTICE
CHANCERY DIVISION
PATENTS COURT
Rolls Building
Fetter Lane, London, EC4A 1NL
The Hon Mr Justice Arnold
Case Nos: HC12A2137, HC12E02314
Piers Acland QC and Tom Alkin (instructed by HGF Law) for Glenmark
Piers Acland QC (instructed by Taylor Wessing LLP) for Mylan
Justin Turner QC and Thomas Hinchliffe (instructed by Rouse Legal LLP) for Wellcome and Glaxo
Approved Judgment
Hearing dates: 22–24, 28 January 2013
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.
Contents
| Topic | Paragraphs |
| Introduction | 1–4 |
| The witnesses | 5–11 |
| Technical background | 12–55 |
| Malaria | 12–21 |
| Treatments of prophylactics | 22 |
| Anti-malarial drugs | 23–40 |
| Aminoquinolines | 27–30 |
| Folate inhibitors | 31–32 |
| Antibiotics | 33 |
| Hydroxynaphthoquinones | 34 |
| Artemisinins | 35 |
| Combinations of anti-malarials | 36–40 |
| Resistance | 41–43 |
| Recommended drugs in 1992 | 44–46 |
| The outlook for malaria control in 1992 | 47–49 |
| Drug development | 50–53 |
| Clinical trials | 54–55 |
| The Patent | 56–66 |
| The claims | 67–69 |
| The skilled team | 70–71 |
| Common general knowledge | 72–88 |
| Potentiation/potentiating | 74 |
| Pyrimidine synthesis | 75–77 |
| Limiting the spread of resistance | 78–80 |
| Combinations of anti-malarials | 81–88 |
| Additive combinations | 82–87 |
| Synergistic combinations | 88 |
| The prior art | 89–107 |
| The Hutchinson presentation | 90–105 |
| The Hudson abstract | 106–107 |
| Obviousness | 108–155 |
| The law | 108–112 |
| The skilled team and the common general knowledge | 113 |
| The inventive concepts of claims | 1, 3 and 9 114 |
| Differences between claim 1 and the Hutchinson presentation | 115 |
| Obviousness of claim 1 over the Hutchinson presentation | 116–144 |
| Atovaquone was not suitable for use on its own | 119 |
| The combination trial was small, uncontrolled and incomplete | 120–121 |
| No disclosure of synergism | 122–125 |
| Difficulties in testing for synergy | 126–128 |
| The combination was irrational if merely additive | 129–130 |
| Other avenues of research | 131–133 |
| Commercial factors | 134–135 |
| The experts' overall opinions | 136–139 |
| Secondary evidence: reactions of the audience | 140–142 |
| Secondary evidence: commercial success | 143 |
| Conclusion | 144 |
| Independent validity of claim 9 | 145–147 |
| Obviousness over the Hudson abstract | 148–155 |
| Conclusion | 156 |
Introduction
In these two actions the Claimants ("Glenmark" and "Mylan") seek revocation of European Patent (UK) No. 0 670 719 ("the Patent"). The Defendant and First Part 20 Claimant ("Wellcome") is the registered proprietor of the Patent. Beneficial ownership of the Patent has been assigned to the Second Part 20 Claimant ("Glaxo"), which is also the exclusive licensee. Wellcome and Glaxo are both part of the GlaxoSmithKline group of companies. In the remainder of this judgment I will refer to them both as "Wellcome".
The Patent relates to an anti-malarial pharmaceutical composition comprising a combination of atovaquone and proguanil in the ratio 5:The priority date of the Patent is 26 November 1992. The sole ground on which the Claimants allege that the Patent is invalid is that of obviousness.
Wellcome sell a composition comprising a 5:2 combination of atovaquone and proguanil under the trade mark Malarone. Malarone is the most successful anti-malarial prophylactic in the UK. Glenmark and Mylan each wishes to sell a generic version of Malarone. In the light of this threat, Wellcome have counterclaimed against both for infringement. There is no dispute that both Mylan's and Glenmark's proposed products would infringe the Patent if it is valid. Both Mylan and Glenmark have undertaken not to launch any atovaquone/proguanil product pending the trial of the actions. In return, Wellcome have given cross-undertakings in damages. Because of this, the trial has been expedited.
Wellcome have made an unconditional application to amend the Patent to delete granted claim 1. This is not opposed by either Glenmark or Mylan. Accordingly, I shall refer to the claims as proposed to be amended.
The witnesses
The Claimants called two expert witnesses, Professor Malcolm Molyneux and Professor Raymond Hill. Prof Molyneux is a clinician who has specialised in the treatment of malaria and other tropical diseases since 1974. Having qualified as a doctor in 1968, he practised in Malawi from 1974 to 1984. In 1984 he became Senior Lecturer and Honorary Consultant Physician at the University of Liverpool School of Tropical Medicine and in 1993 he became Professor of Tropical Medicine. His research interests have been focused on severe malaria in children and the efficacy of drugs to treat malaria. He has published extensively in those areas. He is currently Emeritus Professor of Tropical Medicine at the Liverpool School of Tropical Medicine and Honorary Professor of Medicine at the University of Malawi.
Counsel for Wellcome submitted that Prof Molyneux lacked experience which the person skilled in the art would have had since he had not been involved in drug development. I do not accept that submission for two reasons. First, Prof Molyneux had been involved in the development of the anti-malarial drug isoquinine, albeit after the priority date. Secondly and in any event, Prof Molnyeux was well qualified to assist the court as to the knowledge and attitudes of a clinician working in the field of malaria regardless of the extent to which he personally had been involved in drug development.
Prof Hill initially trained as a pharmacist and then obtained a PhD in neuropharmacology. From 1974 to 1983 he was a Lecturer in Pharmacology at the University of Bristol. From 1983 to 1988 he was a supervisor in Pharmacology at Downing College, Cambridge. From 1988 to 1990 he was employed by Smith Kline & French. From 1990 to 2008 he was employed in various roles by Merck, initially as Executive Director, Pharmacology. He is currently visiting Professor of Pharmacology at Imperial College, London as well as a non-executive director of a number of pharmaceutical development companies.
Counsel for Wellcome submitted that Prof Hill was unable to assist the court because his area of expertise was pain relief and he had no experience of anti-malarials or even other anti-infectives. I do not accept that submission. Prof Hill is an experienced pharmacologist. His evidence was directed to the dose-ranging studies that would be conducted if the clinician considered the Hutchinson presentation (as to which, see below) worth pursuing. It was not suggested that the approach to such studies is different in this field to that adopted in other fields such as pain relief. Indeed, Prof Hill's evidence was scarcely challenged.
Wellcome's only expert was Dr John Horton. Dr Horton qualified as a doctor in 1969 and worked in general practice. He joined Smith, Kline & French in 1977 to work as a clinical research physician. In 1985 he was appointed as Medical Director of the Overseas Division. Between 1985 and 2002, he was involved in the development of a number of anti-malarial drugs and other tropical anti-infectives successively for Smith Kline & French, SmithKline Beecham and GlaxoSmithKline. In 2002, Dr Horton left GSK and set up as an industry consultant. He was an Honorary Professor of Therapeutics at Liverpool University from 2003 to 2007.
Prof Molyneux and Dr Horton were both very knowledgeable, helpful and fair witnesses. Cross-examination revealed that there was not a great deal of difference between them on technical matters.
A number of factual witnesses also gave evidence. Some of these are no longer relevant due to the abandonment by Glenmark and Mylan of an item of prior art. Those who remain relevant are as follows. First, Dr David Hutchinson, who was employed by Wellcome as a clinical research physician from 1974 to 1997 and who is named as one of the inventors of the Patent. He gave the presentation which constitutes the principal item of prior art. Secondly, Professor Angus Bell of Trinity College, Dublin, who attended Dr Hutchinson's presentation. Thirdly, Professor David Arnot of the Universities of Edinburgh and Copenhagen, who also attended the presentation. All three were good witnesses, but they faced inevitable difficulties in trying to recall the contents of an oral presentation nearly 21 years ago. (Dr Horton also attended the meeting, and probably the presentation, but had no recollection of it.)
Technical background
Malaria
Malaria is one of the oldest, most debilitating and most prevalent of tropical diseases. It is caused by four species of parasitic protozoa (single-celled organisms) of the genus Plasmodia: P. falciparum, P. vivax, P. malariae and P. ovale.
Malaria parasites have a lifecycle consisting of a sexual stage in the mosquito and an asexual stage in humans or other vertebrates. When an infected mosquito bites a human, a small motile form of the parasite, called a sporozoite, is released into the blood. Sporozoites invade host liver cells where they undergo rapid asexual multiplication and differentiate into forms called merozoites inside a structure known as a schizont. The schizont and infected liver cell eventually rupture, releasing merozoites into the host's circulation. Here they invade the host's red blood cells and undergo further rounds of multiplication inside further schizonts. In time these further schizonts and...
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