Neutral Citation Number: [2012] EWHC 2545 (Pat)
Case No: HC12C02525
IN THE HIGH COURT OF JUSTICE
CHANCERY DIVISION
PATENTS COURT
Rolls Building
Fetter Lane, London, EC4A 1NL
Date: 20 September 2012
Before :
THE HON MR JUSTICE ARNOLD
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Between :
(1) ACTAVIS GROUP PTC EHF(2) ACTAVIS UK LIMITED / Claimants
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SANOFI / Defendant
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SANOFI PHARMA BRISTOL-MYERS SQUIBB SNC / Claimant by Counterclaim
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Richard Meade QC instructed by, and Tim Powell of, Powell Gilbert for Actavis
Daniel Alexander QC and Andrew Lykiardopoulos instructed by Herbert Smith LLP for Sanofi
Hearing date: 13 September 2012
Further written submissions: 14 September 2012
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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.
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THE HON MR JUSTICE ARNOLD
THE HON MR JUSTICE ARNOLDApproved Judgment / Actavis v Sanofi
MR JUSTICE ARNOLD :
THE HON MR JUSTICE ARNOLDApproved Judgment / Actavis v Sanofi
Contents
Topic Paragraphs
Introduction 1-5
The witnesses 6-10
Technical background 11-37
Hypertension 12
Other conditions mentioned in the Patent 13-18
Heart failure 14
Venous insufficiency 15
Glaucoma 16
Diabetic retinopathy 17
Disorders of the central nervous system 18
The Renin-Angiotensin System 19-20
Diuretics 21-27
Thiazide diuretics 22
Thiazide-like or thiazide-related diuretics 23
Potassium-sparing diuretics 24
Loop diuretics 25
Osmotic diuretics 26
Carbonic anhydrase inhibitors 27
Other antihypertensive drugs available in 1990 28-34
Beta-blockers 29
Calcium channel blockers 30
Alpha-blockers 31
ACE inhibitors 32
Combination therapies 33-34
Angiotensin II receptor blockers 35
Other kinds of drug mentioned in the Patent 36-37
Non-steroidal anti-inflammatory drugs 36
Tranquilizers 37
The Patent 38-43
The claims of the Patent 44-47
Construction of claim 20 48-49
What is the inventive advance (or technical contribution)
of the Patent? 50
Sanofi’s marketing authorisations for Aprovel and CoAprovel 51-54
The Regulation 55-57
Interpretation of the Regulation 58
Issue 1: Article 3(a) of the Regulation 59-77
Issue 2: Article 3(c) and (d) of the Regulation 78-96
Conclusion 97
Introduction
1. Sanofi was the proprietor of European Patent (UK) No 0 454 511 entitled “N-substituted heterocycle derivatives, their preparation, compositions containing them” (“the Patent”). The Patent had an earliest priority date of 20 March 1990, an application date of 20 March 1991, was granted on 17 June 1998 and expired on 20 March 2011. As described in more detail below, the Patent covered an antihypertensive drug whose international non-proprietary name is irbesartan.
2. Sanofi obtained Supplementary Protection Certificate GB98/037 for “[irbesartan] optionally in the form of one of its salts” (“the Irbesartan SPC”) based on the Patent and European marketing authorisations EU/1/97/046/001-009 for irbesartan (marketed by Sanofi under the trade mark Aprovel) granted on 27 August 1997. The Irbesartan SPC was applied for on 1 October 1998, granted on 8 February 1999 and expired on 14 August 2012.
3. Sanofi also obtained Supplementary Protection Certificate GB99/008 for “[irbesartan] optionally in the form of one of its salts and hydrochlorothiazide” (“the Combination SPC”) based on the Patent and European marketing authorisations EU/1/98/086/001-006 for a fixed dose combination of irbesartan and hydrochlorothiazide (marketed by Sanofi under the trade mark CoAprovel) granted on 15 October 1998. The Combination SPC was applied for on 12 March 1999, granted on 21 December 1999 and will expire on 14 October 2013. Sanofi Pharma Bristol-Myers Squibb SNC is the exclusive licensee under the Combination SPC. For present purposes it is not necessary to distinguish between this company and Sanofi, and in the remainder of this judgment I will refer to them collectively as “Sanofi”.
4. Now that the Patent and the Irbesartan SPC have both expired, the Claimants (collectively “Actavis”) intend to market generic versions of both Aprovel and CoAprovel. It is common ground that the latter will infringe the Combination SPC if the Combination SPC is valid. Actavis contend that it is invalid on the two grounds discussed below. As is so often the case, these contentions raise difficult issues of interpretation of European Parliament and Council Regulation 469/2009/EC of 6 May 2009 concerning the supplementary protection certificate for medicinal products (codified version) (“the Regulation”).
5. These proceedings were commenced on 26 June 2012 and have been tried on an expedited basis. Thanks to the efficiency of both parties’ counsel, the trial was completed in one day.
The witnesses
6. It is common ground that, as is normal in patent cases, the Patent must be interpreted in the light of the common general knowledge of the skilled person, or team of skilled persons, to whom it is addressed as at the priority date. It is also common ground that the Patent is addressed to a skilled team comprising a medicinal chemist, a pharmacologist and a clinician. Both parties called an expert witness who is a clinical pharmacologist to educate the court as to the common general knowledge which is relevant for the purposes of the present dispute. Somewhat unusually, the expert witnesses are colleagues in the same institution.
7. Actavis’ expert was Dr Michael Schachter. Dr Schachter is a Senior Lecturer in clinical pharmacology and therapeutics at the Department of Clinical Pharmacology, Faculty of Medicine, Imperial College, London, which is an internationally recognised centre for hypertension research. He is also a fellow of the Royal College of Physicians and a hypertension specialist consultant at the Peart-Rose Clinic at the International Centre for Circulatory Health at Imperial. The ICCH is a specialist cardiovascular unit which carries out the assessment, investigation and management of patients with hypertension and associated cardiovascular risk factors and is engaged in clinical research including therapeutic trials. Dr Schachter qualified as a doctor at University College London in 1974, having undertaken an intercalated BSc in biochemistry. After his pre-registration year he worked successively at the Royal Marsden Hospital, King’s College Hospital, the Department of Clinical Pharmacology in Oxford and St Mary’s Hospital Medical School before moving to Imperial in 1996. He has published widely, including on hypertension.
8. Sanofi’s expert was Prof Peter Sever. Prof Sever is Professor of Clinical Pharmacology at Imperial. He is also Honorary Consultant Physician at the Imperial Healthcare NHS Trust; Co-Director of the International Centre for Circulatory Health; Head of the Cardiovascular Disease Prevention Section at the National Heart and Lung Institute; Theme Leader for Cardiovascular Disease Prevention, Biomedical Research Centre, Imperial College Healthcare NHS Trust; and Panel Member of the National Specialty Group for Cardiovascular Medicine, UK Clinical Research Network. He was a Senior Investigator at the National Institute for Health Research in 2009-2012. He graduated from the University of Cambridge in 1965 and completed his medical training at St Mary’s. After various appointments, he became Honorary Consultant Physician and Senior Lecturer at St Mary’s in 1976 and Professor in 1980 (St Mary’s was subsequently incorporated into Imperial). He too has published widely, including on hypertension.
9. Both experts were very knowledgeable and helpful. Unsurprisingly, there was very little if any difference between them.
10. In addition, Sanofi called Bénédicte Sergent. She is Sanofi’s Regulatory Affairs Manager. She was a straightforward witness, but through no fault of her own her evidence was of relatively little value. The purpose of her evidence was to explain the procedure by which, and in particular the studies in reliance upon which, Sanofi had obtained the marketing authorisations for Aprovel and CoAprovel. She was not employed by Sanofi at that time, however. Furthermore, as she made clear, her expertise was in regulatory procedure rather than in clinical matters. Thus she was not able to add much to the relevant documents.
Technical background
11. The relevant technical background, all of which would have formed part of the common general knowledge of the skilled team, may be summarised as follows.
Hypertension
12. Hypertension is the technical name for high blood pressure. Hypertension is classified as mild, moderate, severe or very severe depending on how high the blood pressure is compared to normal. A distinction is made between primary (or essential) hypertension, which is predominantly caused by genetic and lifestyle factors, and secondary hypertension, which is due to specific underlying abnormalities. Primary hypertension accounts for about 95% of individuals with raised blood pressure.
Other conditions mentioned in the Patent
13. In addition to hypertension, the Patent refers to a number of other conditions.
14. Heart failure. Heart failure results from a divergence between cardiac output and the requirements of the body. This leads to pulmonary oedema (i.e. excess fluid in the lungs), leg or more generalised swelling, shortness of breath and fatigue. The main cause is coronary heart disease (for example, after a heart attack or due to a gradual decrease in the rate at which the heart pumps the blood around the body). Other causes include hypertension, cardiomyopathies (primary and often genetic diseases of the heart muscle) and valvular disease which results in “leaky” valves in the heart.
15. Venous insufficiency. Venous insufficiency is a term used to describe swelling of the legs usually caused by damage to the veins or to their valves. Venous insufficiency is usually treated with compression stockings and/or surgery.
16. Glaucoma. Glaucoma is a condition in which loss of vision occurs because of abnormally high pressure in the eye.
17. Diabetic retinopathy. Diabetic retinopathy results from damage to the blood vessels in the retina in sufferers from diabetes.
18. Disorders of the central nervous system. These include anxiety, depression, memory deficiencies and Alzheimer’s disease. Such conditions have nothing in common with the conditions discussed above.
The Renin-Angiotensin System
19. There are many important factors that together keep blood pressure at a certain level. A central role in maintaining blood pressure is, however, played by the Renin-Angiotensin System (also known as the Renin-Angiotensin-Aldosterone System) ("the RAS"). In this system, the inactive peptide angiotensinogen is cleaved by renin to form inactive angiotensin I. Angiotensin I is converted to angiotensin II by angiotensin converting enzyme ("ACE"). Angiotensin II is a potent vasoconstrictor and causes an increase in blood pressure.
20. A number of classes of drugs, including diuretics, ACE inhibitors and angiotensin II receptor blockers have a direct effect on the RAS and thus can be used to control hypertension.
Diuretics
21. The term “diuretic” is used to describe a broad class of medicinal products with widely differing molecular structures and mechanisms of action which increase the excretion of water and electrolytes (notably sodium ions, but often also potassium ions). Diuretics decrease blood fluid volume, as result of which they were amongst the earliest drugs which were used to treat hypertension in the 1950s. They also appear to affect the RAS. By 1990 they were also used to treat patients with conditions such as congestive heart failure and, in the case of one sub-class, specifically in the treatment of glaucoma. They were not, however, used to treat diabetic retinopathy or disorders of the central nervous system. Diuretics may be divided into the following sub-classes.
22. Thiazide diuretics. Thiazide diuretics (or benzothiadiazines) are the oldest sub-class of diuretics, having been administered to patients for over 50 years. Thiazides are moderately potent diuretics that act by inhibiting the re-absorption in the kidney of sodium and chloride ions, which produces a corresponding loss of water, reduction in blood volume and cardiac output. They also cause an increase in the excretion of potassium ions. The first effective oral diuretic was chlorothiazide, but many analogues have subsequently been produced. These include hydrochlorothiazide (“HCT”), which was first marketed in 1958. HCT and bendrofluazide (also known as bendroflumethiazide) were both commonly-prescribed thiazide diuretics for patients with hypertension in 1990. Although HCT was one of the most popular diuretics for this purpose, that was not because there was any good clinical data to show that HCT was better than other diuretics. Rather, it appears to have been because HCT was included in official prescribing recommendations and guidelines.
23. Thiazide-like or thiazide-related diuretics. The compounds in this sub-class are chemically different (albeit related), but pharmacologically similar, to the thiazides. Chlorthalidone was a member of this sub-class which was widely used to treat hypertension in 1990. Metolazone was used to treat heart failure in circumstances where the administration of previous drug combinations proved to be ineffective.
24. Potassium-sparing diuretics. Potassium-sparing diuretics have a relatively weak diuretic effect and reduce the loss of potassium from the body which is associated with the administration of thiazide diuretics. Well-known examples in 1990 included amiloride, triamterene and spironolactone. Amiloride and triamterene were mainly used in combination with a thiazide, particularly HCT. Spironolactone was used to treat hyperaldosteronism, where there is excessive secretion of the hormone aldosterone leading to hypertension. This is probably the most common cause of secondary hypertension.
25. Loop diuretics. Loop diuretics are a heterogeneous group of chemicals that share the common property of being potent, relatively short-lived diuretics whose effects are usually complete within four to six hours. These agents act on the ascending loop of Henle in the renal tubule of the kidney. They tend to be administered in the treatment of heart failure as opposed to hypertension. In some circumstances, notably where excess circulating volume is the main factor in maintaining high blood pressure, loop diuretics can be used as antihypertensive agents. Well-known examples of this class in 1990 included furosemide and bumetanide.
26. Osmotic diuretics. Osmotic diuretics, such as mannitol, were used to reduce or prevent cerebral oedema and to reduce acutely elevated pressure in the eye. They were not regarded as having an antihypertensive effect and were not used in heart failure.
27. Carbonic anhydrase inhibitors. These agents, such as acetazolamide, inhibit the enzyme carbonic anhydrase and therefore reduce the build up of aqueous humour between the lens and the cornea in the eye. Since this reduces the pressure in the eye, these inhibitors were often prescribed for the treatment of glaucoma in 1990.