Bristol-Myers Squibb Holdings Ireland Unlimited v Norton (Waterford) Ltd T/A Teva Pharmaceuticals Ireland

• Jurisdiction: Ireland
• Court: Court of Appeal (Ireland)
• Judge: Ms. Justice Costello
• Judgment Date: 28 November 2024
• Neutral Citation: [2024] IECA 287
• Docket Number: Court of Appeal Record Number: 2024/34

In the Matter of Irish Patent Number European Patent (IE) 1 427 415 “Lactam-Containing Compounds and Derivatives thereof as Factor XA Inhibitors” and Registered in the Name of Bristol-Myers Squibb Holdings Ireland Unlimited Company and in the Matter of the Patents Act 1992 to 2019

Between/

Bristol-Myers Squibb Holdings Ireland Unlimited

Respondent/Appellant

and

Norton (Waterford) Limited T/A Teva Pharmaceuticals Ireland

Petitioner/Respondent

[2024] IECA 287

Costello P.

Allen J.

O'Moore J.

Court of Appeal Record Number: 2024/34

High Court Record Number: [2021 No.1 PAP]

THE COURT OF APPEAL

CIVIL

Appeal of order - challenge of validity - appeal held and remitted to High Court

Facts: Bristol-Myers Squibb Holdings appealed the 8th December 2023 findings and order of the High Court Judge on 2 Feburary 2024 in which it was declared the 415 Irish patent and registered name of Bristol-Myers Squibb Holding Ireland Unlimited Company is, and at all times has been, invalid and should be revoked along with the Supplementary Protection Certificate. The validity was challenged on the following two grounds; (1) on the ground of priority, and (2) on the ground of plausability. The High Court had rejected the case based on priority but held that the patents as filed failed the test for plausibility and accordingly was invalid. BMS appealed the finding of invalidity. The Court grouped BMS's submissions into the following three headings; "(a) the correct test for plausibilty; (b) assessment of the technical evidence; (c) the requirements of judicial comity".

The Court held that the appeal should be allowed and remitted to the High Court to be heard by a different judge. The case was to be confined to a challenge to the validity of the patent on the grounds of plausibility. The test of plausibility set out in the judgement of EBA in G 2/21 Sumitomo

Appeal allowed

[approved]

JUDGMENT of Ms. Justice Costello delivered on the 28 ^th day of November 2024

Introduction:

1 . This is an appeal from the judgment of the High Court (Barrett J.) of 8 December 2023 ( [2023] IEHC 744) and consequent order of 2 February 2024 declaring that Irish patent number EP (IE) 1 427 415 “Lactam – Containing Compounds and Derivatives Thereof as Factor Xa Inhibitors” (“the 415 patent”) and registered in the name of Bristol-Myers Squibb Holdings Ireland Unlimited Company (“BMS”) is, and at all times has been, invalid and should be revoked; and that Supplementary Protection Certificate (“SPC”) No. 2011/032 is, and at all times has been, invalid and should be revoked. The validity of the patent was challenged by the respondent, Norton (Waterford) Limited trading as Teva Pharmaceuticals Ireland, (“Teva”) on two bases; (1) on the grounds of priority, and (2) on the grounds of plausibility. The High Court rejected the case based on priority but held that the patent as filed failed the test for plausibility and accordingly was invalid. BMS appealed the finding of invalidity. There was no cross-appeal against the finding on priority.

Background:

2 . This Court has concluded that, on critical matters, the High Court either made no findings of fact or failed to explain such findings that it did make. In those circumstances, it is difficult to set out in a completely satisfactory way the background to these proceedings. However, it is possible to understand the issues giving rise to the dispute on plausibility by reference to the undisputed facts (agreed between the parties), the first witness statement of Dr. Robert Young (a medicinal chemist called by BMS), and the second witness statement of Dr. Paul Edwards (a medicinal chemist called on behalf of Teva).

3 . The patent which grounds the relevant asserted intellectual property rights on the part of BMS is, as already noted, the 415 patent. The patent is entitled:-

“Lactam containing compounds and derivatives thereof as factor Xa inhibitors.”

4 . As we shall shortly see, factor Xa is an oral drug which can prevent the formation of blood clots. The patent includes 140 embodiments, 110 of which are made in the laboratory. Example 18 in the patent is the production of 3.07g of apixaban. The SPC in respect of the patent has been granted in respect of the product apixaban (“ELIQUIS”). The SPC has an expiry date of the 19 May 2026.

5 . The agreed statement of Common General Knowledge (“CGK”) gives a very helpful background to the issues between the parties.

6 . The parties agree about the significance of thrombosis as one of the leading causes of disability and death in the world. It was well known at the priority date (the date by reference to which the validity of the patent is assessed), that thrombotic / thromboembolic disorders could be treated by reducing blood clotting through inhibiting the coagulation cascade. There were two main pathways for triggering the coagulation cascade. These were the intrinsic (or contact) pathway and the extrinsic (or tissue factor) pathway.

7 . The intrinsic and extrinsic pathways converge in the common pathway with the activation of Factor X to Factor Xa. I will return to Factor Xa shortly.

8 . The agreed CGK continues:-

“40. When patients are treated with anticoagulants, systemic hypocoagulation can occur where clots take too long to form. For this reason, anticoagulants are sometimes referred to as “blood thinners.” However, anticoagulants do not make the blood “thinner,” rather they prolong the time it takes for blood to form a clot. As a result, patients on anticoagulants can bleed easily and suffer spontaneous internal bleeding that can manifest as excessive bruising, gum bleeds, nose bleeds, and in serious cases, intracranial bleeding which can cause a stroke. These side effects are a direct result of the therapeutic action of anticoagulants and can outweigh the benefits of decreasing thrombotic risk. Weighing these risks is particularly important when considering preventative long-term treatment with anticoagulants.”

9 . For these reasons, it was well-established by 2001(the priority date) that an alternative oral anticoagulant was needed. In practice such an oral anticoagulant was to replace Warfarin (first approved for medical use in the 1950's) and Heparin (used as an anti-coagulant since the 1930's). The agreed CGK continues:-

“43. In particular, the clinical need in 2001 was for an oral antithrombotic that:

• (a) Was effective at preventing thrombotic disease. It would be even more desirable if the drug was effective at preventing further growth of existing clots;

• (b) Was safe and non-toxic;

• (c) Had minimal side-effects, in particular with respect to bleeding;

• (d) Could be given orally once, or at most twice, a day. This would make it convenient for patients outside of hospital settings who were taking the drug long term, and therefore would be expected to affect patient compliance;

• (e) Had low interpatient variability, including low drug-drug and low drug-food interactions;

• (f) Had no need for frequent patient monitoring.”

10 . The agreed CGK goes on:-

“50. Factor Xa was identified as a promising target for the development of new synthetic anticoagulants following the isolation and characterisation in the late 1980s of the first naturally occurring specific factor Xa inhibitor, antistasin, isolated from leeches, and Tick Anticoagulant Peptide (TAP). TAP is a potent and specific inhibitor of factor Xa which inhibits thrombosis without causing excessive bleeding.

51. By 2001, essentially all the major pharmaceutical companies were attempting to discover novel factor Xa inhibitors … A variety of potent, selective, small molecule factor Xa inhibitors had been described in the scientific literature and some had been taken forward to clinical trials.

52. Factor Xa was considered to be a promising target with several potential advantages:

(a) Both the extrinsic and intrinsic pathways of coagulation culminate in factor Xa activation. Factor Xa then triggers thrombin generation and fibrin formation via the common pathway. Due to its position of convergence of the two separate pathways and because it catalyzes the conversion of prothrombin to thrombin, factor Xa was understood to play a central and crucial role in the coagulation cascade;

(b) Factor Xa inhibitors were predicted to have a lower risk of bleeding than heparin and VKAs and a much wider therapeutic window than direct thrombin inhibitors because they specifically inhibit coagulation without directly affecting platelet function;

(c) Unlike thrombin, factor Xa was not thought to have functions outside the coagulation cascade and therefore negative side-effects as a consequence of inhibition were hoped to be limited; and

(d) When the clotting process begins, many molecules of factor X are activated and each factor Xa molecule can activate more than one substrate molecule. In fact, it was known in 2001 that one molecule of factor Xa could generate many molecules of thrombin per minute.

It was therefore hypothesized that factor Xa inhibition could be a more effective and safer way to prevent blood clot formation than direct thrombin inhibitors as less drug would be needed.”

11 . This naturally led to the search for a potent and effective Xa inhibitor. At para. 102 of the agreed CGK, it is noted:-

“102. The ability of an inhibitor to inhibit the activity of an enzyme can be measured, and is termed ‘potency’. In general, the more tightly an inhibitor binds to the active site, the more ‘potent’ it is said to be and, the more potent the inhibitor, the less of that compound that is needed to achieve a given level of inhibition.”

12 . There was also general agreement on the drug discovery process. Paragraph 110 of the agreed CGK reads:-

“110. In 2001, the drug discovery process typically encompassed a number of stages:

• (a) The first stage, often referred to as “Target...