Sandoz Ag and Others v Bayer Intellectual Property GmbH

Hearing date: 16 May 2024

Approved Judgment

This judgment was handed down remotely at 10.30am on 24 May 2024 by circulation to the parties or their representatives by e-mail and by release to the National Archives.

Introduction

This is an appeal from an order made by His Honour Judge Hacon sitting as a High Court Judge on 12 April 2024 revoking European Patent (UK) No. 1 845 961 (“the Patent”) for the reasons given in his judgment of the same date [2024] EWHC 796 (Pat). The Appellants (“Bayer”) are the owner and alleged exclusive licensees of the Patent. The Respondents are various companies which supply generic medicines. The Respondents brought these proceedings claiming an order for revocation of the Patent and Bayer counterclaimed for threatened infringement.

The Patent claims the use of rivaroxaban for the treatment of a thromboembolic disorder by means of once daily administration. Rivaroxaban is marketed by Bayer under the trade mark Xarelto. It is Bayer's largest-selling drug, and the fourth best-selling drug in the world. Rivaroxaban itself, and its use for the treatment of thromboembolic disorders, were protected first by European Patent No. 1 261 606 and then by a supplementary protection certificate which expired on 1 April 2024. The Respondents all wish to market generic rivaroxaban. If it is valid, the Patent prevents them from supplying generic rivaroxaban for once daily administration, although it does not prevent them from supplying it for twice (or more frequent) daily administration. In addition to the Respondents, a number of other suppliers of generic medicines are also interested in entering this market. As a result of the need for all players to know as soon as possible whether or not the Patent is valid, and for further reasons touched on at the end of this judgment, the hearing of the appeal was expedited. At the conclusion of the hearing the Court announced that the appeal would be dismissed with reasons to follow. This judgment sets out my reasons for reaching that conclusion.

Technical background

The judge set out the technical background at [8]–[35]. What follows is a slightly abbreviated version of that account.

Haemostasis and thromboembolism

Haemostasis is a process which gives rise to the formation of blood clots when an individual suffers injury and there is a need to close damage to blood vessels. Haemostasis is a necessary local response to injury, but vascular blood should otherwise flow freely. In healthy humans there is therefore a homeostatic balance, meaning a self-regulating process which adjusts procoagulant and anticoagulant mechanisms to prevailing conditions so as to best ensure the individual's survival.

Thrombosis is a condition in which a clot, or thrombus, causes obstruction of the blood flow in part of the vascular system away from a site of injury. Thrombosis has long been treated by the administration of anticoagulants.

The coagulation cascade

Blood has a liquid component, plasma, and three solid components: red blood cells, white blood cells and platelets. The primary purpose of red blood cells is to carry oxygen, but they have a secondary function in that they become passively trapped in thrombi, forming the bulk of a thrombus. The primary purpose of white blood cells is to combat infection. Some classes of one type of white blood cell, leukocytes, express on their surface a protein called “tissue factor” during haemostasis which activates blood coagulation. Platelets are very small cell fragments which, when activated, aggregate and adhere to nearby surfaces, forming part of a thrombus.

The “coagulation cascade” is the name given to a series of reactions culminating in the formation of an insoluble clot. The enzymes which catalyse the reactions are known as “factors”, identified by Roman numerals and given the suffix “a” when the factor is in its active form. The diagram below provides an overview of the coagulation cascade:

The upper part of the diagram shows two pathways, each contributing to the activation of Factor X to Factor Xa (“FXa”). The one on the left is known as the extrinsic pathway, the one on the right the intrinsic pathway. FXa in association with Factor Va converts prothrombin (Factor II) to thrombin (Factor IIa). Thrombin feeds back into the cascade to activate other factors and platelets, an effect shown by the dotted lines. Thrombin also converts fibrinogen to fibrin. Fibrin is an insoluble polymer in the form of threads which stabilize the structure of a clot.

Thromboembolic disorders

The primary causes of thrombosis are the improper functioning of the coagulation cascade and/or excessive platelet activation, commonly because the anticoagulation system is overwhelmed by thrombotic stimuli. A thrombus may break loose and be carried elsewhere in the circulatory system. In that form it is known as an “embolus”, and the condition as “embolism”. “Thromboembolism” describes the combined conditions of thrombosis and embolism.

Patients undergoing major surgery are at particularly high risk of venous thromboembolism (“VTE”). One form is deep vein thrombosis (“DVT”), the most serious complication of which is pulmonary embolism (“PE”) in the lung. PE remains a significant cause of death in both surgical and non-surgical patients.

The human body has its own mechanisms to modulate clot formation. There are three, each inactivating factors in the coagulation cascade and in one case also inactivating thrombin. Where urgent anticoagulation in a patient is needed, drugs are used to prevent the formation of thrombi and/or to degrade them.

The therapeutic window

An important feature of anticoagulant drugs is that, if they are not sufficiently effective, clots will remain and new clots may form. If they are too effective, clots required at the site of injury will not form, particularly after surgery, and the patient will suffer excessive bleeding. Both possibilities are dangerous for the patient and either may be fatal. There is thus a “therapeutic window” in which the drug is sufficiently available and effective to have the desired anticoagulant effect, but not so available and effective such that the patient suffers from unwanted bleeding. The wider the therapeutic window afforded by a drug, the more attractive it is for clinical use. But it is never possible to know in advance where the therapeutic window lies and how wide the window will turn out to be.

Prior art anticoagulant drugs

The principal anticoagulant drugs in clinical use at the priority date of the Patent, 31 January 2005, were warfarin, heparin (either unfractionated heparin or a low molecular weight heparin (“LMWH”) such as enoxaparin) and fondaparinux (an indirect FXa inhibitor). Three other anticoagulants had been licensed for treatment by then, namely hirudin, bivalirudin and argatroban. It was generally known that several new anticoagulants, including two direct FXa inhibitors, were undergoing clinical trials.

Clinical trials

Drugs undergoing development are subjected to pre-clinical tests which, if successful, will lead to clinical trials. All are mandatory and governed by rules issued by regulatory bodies. Pre-clinical trials include tests as to safety, toxicity and what are sometimes called “proof-of-concept” studies which give an early indication of whether the drug will have the intended effect. Tests will be in vitro or ex vivo and may also involve experiments on animals.

Clinical trials are carried out in three phases, I to III. Phase I clinical trials are conducted on a small number of healthy volunteers. At the priority date they were almost invariably young males. The primary goal is to obtain data on safety, toxicity and what are called pharmacokinetics (PK) and pharmacodynamics (PD) data. Broadly, PK data measure the effect of the body's system on the drug over time, PD data the effect over time of the drug on the body's system.

The key PK measurement is the half-life of the drug. Following administration, the drug may be metabolised to an inactive form and will be excreted. Its concentration in blood plasma therefore declines. The rate of decline varies between drugs. As the term implies, the half-life of a drug is the time taken for its concentration in the plasma to decline by half. The PK profile is a graphical representation of the plasma concentration against time from initial administration until it reaches zero. The cumulative exposure of the individual to the drug is shown by the area under the curve or AUC.

PD data measure the effect over time that the drug has on the patient using “bio-markers”, which are measurable indicia associated with the intended effect of the drug.

There may or may not be a correlation between the half-life of a drug and any one or more PD...