Teva Pharmaceutical Industries Ltd v Astellas Pharma Inc.
| Jurisdiction | England & Wales |
| Judge | Lord Justice Arnold,Lord Justice Stuart-Smith,Lady Justice Falk |
| Judgment Date | 25 July 2023 |
| Neutral Citation | [2023] EWCA Civ 880 |
| Year | 2023 |
| Court | Court of Appeal (Civil Division) |
| Docket Number | Case Nos: CA-2022-001348, 001349 |
[2023] EWCA Civ 880
Lord Justice Arnold
Lord Justice Stuart-Smith
and
Lady Justice Falk
Case Nos: CA-2022-001348, 001349
IN THE COURT OF APPEAL (CIVIL DIVISION)
ON APPEAL FROM THE HIGH COURT OF JUSTICE, BUSINESS AND PROPERTY
COURTS OF ENGLAND AND WALES, INTELLLECTUAL PROPERTY LIST (ChD),
PATENTS COURT
Mr Justice Meade
[2022] EWHC 1316 (Pat)
Royal Courts of Justice
Strand, London, WC2A 2LL
Justin Turner KC and Stuart Baran (instructed by Pinsent Masons LLP) for the Appellants
Piers Acland KC and Anna Edwards-Stuart (instructed by Hogan Lovells International LLP) for the Respondent
Hearing dates: 17–18 July 2023
Approved Judgment
Introduction
This is an appeal from an order of Meade J dated 24 June 2022 dismissing the Appellants' claim for revocation of European Patent (UK) No 1 559 427 (“the Patent”), and in consequence Supplementary Protection Certificate No. SPC/GB13/035, and granting the Respondent relief for infringement, for the reasons given in the judge's judgment dated 1 June 2022 [2022] EWHC 1316 (Pat). The Patent claims mirabegron, or a salt thereof, for use in the treatment of overactive bladder (“OAB”). Mirabegron is a β3 adrenoreceptor (“β3-AR”) agonist. There is no challenge to the claimed priority date of 7 November 2002. The Appellants contend that the claimed invention was obvious over Australian Patent Application AU 199889288 (“288”).
The skilled team
The judge found that the Patent was addressed to a skilled team consisting of a clinician and a pharmacologist working on new or improved treatments for OAB.
The expert witnesses
The Appellants' experts were Prof Paul Abrams (clinician) and Dr Thomas Argentieri (pharmacologist). The Respondent's experts were Dr Ian Mills (clinician) and Dr Gordon McMurray (pharmacologist). As the judge explained, Prof Abrams' role in the case was fairly limited. The judge's assessment of the other witnesses concluded at [25]:
“Overall these points left me with the impression that Dr Argentieri was trying a little too hard to find points in favour of the Claimants. It was not enough to lead me to reject his evidence outright, and many of his points were well made and solidly supported, but I bear it in mind and I thought that Astellas' witnesses were overall more fair and balanced when it came to the issues on CGK and obviousness, and put themselves in the position of the ordinary uninventive addressees better than him.”
Agreed common general knowledge
The parties provided the judge with a statement of agreed common general knowledge. The judge reproduced most of it at [50]–[87]. The key points are as follows.
Bladder physiology
The lower urinary tract in humans consists of the urinary bladder and the urethra. The bladder is a hollow, muscular organ which stores urine and is divided into its two main parts: the body and the base. Urine enters the bladder from the kidneys via the ureters. The bladder body is mainly comprised of a muscular wall with smooth muscle cells, referred to as the detrusor muscle, which is by far the largest part of the bladder. The bladder base consists of the trigone and the bladder neck, which leads to the urethra in the wall of which the urethral sphincter is embedded.
The smooth muscle in the detrusor is structurally and functionally different from the muscles found in the bladder base, the urethra and the pelvic floor. Within the wall of the urethra, just above the pelvic floor, is the intraurethral (also termed intramural) striated muscle sphincter which prevents urine leakage during filling and relaxes to allow the bladder to empty.
The urethra is the conduit through which urine flows during voiding. It passes through the pelvic floor muscles and comprises both striated and smooth muscles. Together, the striated muscle and smooth muscle form the urethral sphincter mechanism, whose contraction during urine storage causes increased resistance in the urethra which prevents urine leakage.
The main functions of the bladder are to store urine as it flows from the kidneys into the bladder during the “storage phase” and to rapidly empty the urine during the act of urination, also known as micturition or voiding, which is referred to as the “voiding phase”.
The interactions of the anatomical features of the lower urinary tract and the human nervous system comprise a tightly-controlled feedback loop mechanism involving the brain, the spinal cord, peripheral nerves and the lower urinary tract. The lower urinary tract is innervated by peripheral nerves of the parasympathetic and sympathetic branches of the autonomic nervous system (“ANS”), and by the somatic nervous system.
The ANS is a division of the peripheral nervous system. It acts mostly unconsciously and regulates bodily functions such as breathing, digestion and urination. The parasympathetic and sympathetic branches of the ANS essentially act in opposition to one another. Put simply, the sympathetic nervous system is active during the storage phase and the parasympathetic nervous system is active during the voiding phase.
The somatic nervous system is associated with the voluntary control of movement through skeletal muscle, as well as involuntary control via reflexes. The somatic nerves innervate the striated muscles of the pelvic floor and the urethral sphincter and are active during bladder filling to maintain continence.
The autonomic and somatic nervous systems exert their control through chemical messengers known as neurotransmitters. The relevant neurotransmitters are acetylcholine (“ACh”) and noradrenaline.
During the storage phase, there are no signals from the parasympathetic nervous system to the detrusor, and therefore no contraction occurs. Activation of the sympathetic nerves triggers the release of noradrenaline which binds to adrenoceptors causing the detrusor to relax. Noradrenaline is also released in the smooth muscle of the urethral sphincter where it binds to a1 adrenoceptors, causing contraction. The somatic nerves innervating the striated muscles of the pelvic floor and the urethra release ACh triggering them to remain tightened and closed. In this manner pressure in the bladder remains low whilst pressure in the urethra remains high, allowing urine storage.
In the voiding phase the somatic nerves are inhibited, as is the sympathetic outflow to the bladder base and the urethral smooth muscle, to allow relaxation of the bladder outlet and pelvic floor. The parasympathetic nerves that supply the detrusor release ACh, which stimulates muscarinic receptors leading to detrusor contraction. Thus pressure in the bladder increases whilst the pressure in the urethra is reduced, allowing urine to flow out of the bladder.
This is shown in schematic form in the diagram below (omitting sympathetic nervous system innervation of the smooth muscle of the urethral sphincter).
OAB
OAB is a set of symptoms which are presumed (in the absence of indication to the contrary) to be caused by involuntary detrusor contractions that occur during the storage phase. The symptoms associated with OAB include urgency (having to rush to the toilet suddenly), frequency (having to urinate too often during the day), nocturia (getting up at night to urinate) and urge incontinence (associated with urgency).
Treatment of OAB
In November 2002 antimuscarinics were the frontline pharmaceutical treatment for OAB. They work by blocking muscarinic receptors, preventing binding of acetylcholine to the receptors and therefore impeding detrusor contraction. It was well known that the existing antimuscarinic compounds had significant side-effects caused by “off-target” responses at receptors elsewhere in the body, the most common and troublesome being dry mouth. It was also known that antimuscarinics can interfere with proper bladder emptying.
As a result of these well-known problems with antimuscarinics, there was a strong interest in the development of new drugs for treating OAB.
Methods of investigating new therapies
Methods of pre-clinical research into new therapies included both in vitro and in vivo tests.
A common in vitro test was the organ bath method. Strips of detrusor muscle (derived from a variety of different animal species or from humans) are dissected, suspended under tension in an organ bath and perfused with physiological saline. Carrying out this process in the absence and then in the presence of a potential agent may be useful in demonstrating that the agent prevents the contraction of the bladder or causes relaxation. In comparison to live models, a bladder strip assay has the limitation of being outside of the influence of the rest of the body (e.g., the effects of the nervous system).
Common in vivo tests comprised both physiological and pathological animal models.
β3 adrenoreceptors
In November 2002 it was known that the β adrenoceptor family included β1 and β2 adrenoceptors. It had recently been determined that “atypical” adrenoceptors reported in earlier research were in fact a third sub-class, β3 adrenoceptors. β1 adrenoceptors were known to be located predominantly on cardiac muscle, mediating increased heart rate and force of contraction. β2 adrenoceptors were known to be located predominantly on smooth muscles mediating relaxation, especially in blood vessels where they mediated vasodilatation, in the lung where they mediated bronchodilatation, and in the uterus where they mediated uterine relaxation. β2 adrenoceptor activation was also known to elicit tremors in humans due to activity at the level of skeletal muscle.
It was thought that the main β...
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