Patents - Sandoz AG and others v Bayer Intellectual Property GmbH
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Patents Court (HH Judge Hacon) Sandoz AG and others v Bayer Intellectual Property GmbH [2024] EWHC 796 (Pat) (12 April 2024)
Commercial Context
Rivaroxaban helps to prevent blood clots thereby reducing the risk of heart attacks and strokes. The monopoly of the active ingredient of the product had been extended until 31 March 2024 by a supplementary protection certificate ("SPC"). The expiry of the SPC would have enabled the claimants and other generics manufacturers to supply rivaroxaban from 1 April 2024. They were prevented from doing so by the Patent which was a Swiss-type claim for the manufacture of a medicament for the treatment of a thromboembolic disorder. The claimants complained that the Patent was an attempt by Bayer to extend its monopoly beyond the expiry of its SPC
The Invention
The Patent states that the invention relates to the field of blood coagulation and more particularly to a method of treating a thromboembolic disorder. It observes that coagulation can stem bleeding which is welcome but also thrombosis which is not. The body strikes a balance between bleeding and thrombosis which is sometimes lost. The loss of such balance leads to serious illnesses. Anticoagulants have been developed to prevent or treat thrombosis but they have serious disadvantages. The Patent discusses those products and their properties. The specification considers their dosage and states at para [12]:
"Surprisingly, it has now been found in patients at frequent medication that once daily oral administration of a direct factor Xa inhibitor with a plasma concentration half life time of 10 hours or less demonstrated efficacy when compared to standard therapy and at the same time was as effective as after twice daily (bid) administration."
The next paragraph describes the invention:
"The present invention relates to the use of an oral dosage form of a direct factor Xa inhibitor for the manufacture of a medicament for the treatment of a thromboembolic disorder administered once daily for at least five consecutive days, wherein said inhibitor has a plasma concentration half life of 10 hours or less when orally administered to a human patient."
"The present invention relates to the use of an oral dosage form of a direct factor Xa inhibitor for the manufacture of a medicament for the treatment of a thromboembolic disorder administered once daily for at least five consecutive days, wherein said inhibitor has a plasma concentration half life of 10 hours or less when orally administered to a human patient."
Claim 1 of the Patent claims:
"The use of a rapid-release tablet of [rivaroxaban] for the manufacture of a medicament for the treatment of a thromboembolic disorder administered no more than once daily for at least five consecutive days, wherein said compound has a plasma concentration half life of 10 hours or less when orally administered to a human patient."
"The use of a rapid-release tablet of [rivaroxaban] for the manufacture of a medicament for the treatment of a thromboembolic disorder administered no more than once daily for at least five consecutive days, wherein said compound has a plasma concentration half life of 10 hours or less when orally administered to a human patient."
Claim 2 claims:
"The use as claimed in Claim 1, wherein the thromboembolic disorder is ST Segment Elevation Myocardial Infarction (STEMI), Non ST Segment Elevation Myocardial Infarction (NSTEMI), unstable angina, reocclusion after angioplasty or aortocoronary bypass, pulmonary embolisms, deep vein thromboses or stroke."
"The use as claimed in Claim 1, wherein the thromboembolic disorder is ST Segment Elevation Myocardial Infarction (STEMI), Non ST Segment Elevation Myocardial Infarction (NSTEMI), unstable angina, reocclusion after angioplasty or aortocoronary bypass, pulmonary embolisms, deep vein thromboses or stroke."
Grounds of Revocation
The claimants claim revocation of the Patent on grounds of obviousness and insufficiency, In response to the allegation of insufficiency Bayer offered to amend the Patent. The claimants replied that the proposed amendments would be invalid on grounds of added matter,
Obviousness
One of the grounds upon which the Patents Court may revoke a patent is that the invention is not a patentable invention (see s.72 (1) (a) of the Patents Act 1977). One of the conditions for the grant of a patent is that the invention involves an inventive step (see s, 1 (1) (b) Patents Act 1877). S.3 of the Act provides:
"An invention shall be taken to involve an inventive step if it is not obvious to a person skilled in the art, having regard to any matter which forms part of the state of the art by virtue only of section 2 (2) above (and disregarding section 2 (3) above)."
"An invention shall be taken to involve an inventive step if it is not obvious to a person skilled in the art, having regard to any matter which forms part of the state of the art by virtue only of section 2 (2) above (and disregarding section 2 (3) above)."
In para [111] of his judgment, Judge Hacon observed that Bayer submitted that the four-stage approach to inventive step in Pozzoli SpA v BDMO SA [2007] EWCA Civ 588 at [23] was to be applied and that the claimants did not dissent. Lord Justice Jacob had set out that approach in para [23] of his judgment in Pozzoli:
"(1) (a) Identify the notional "person skilled in the art
(b) Identify the relevant common general knowledge of that person;
(2) Identify the inventive concept of the claim in question or if that cannot readily be done, construe it;
(3) Identify what, if any, differences exist between the matter cited as forming part of the "state of the art" and the inventive concept of the claim or the claim as construed;
(4) Viewed without any knowledge of the alleged invention as claimed, do those differences constitute steps which would have been obvious to the person skilled in the art or do they require any degree of invention?"
At para [112] Judge Hacon referred to para [74] of Mr Justice Kitchin's judgment in Generics (UK) Ltd v H Lundbeck A/S [2007] RPC 32, as approved by Lord Hoffmann in para [42] of his speech in Conor Medsystems Inc v Angiotech Pharmaceuticals Inc [2008] UKHL 49:
"The question of obviousness must be considered on the facts of each case. The court must consider the weight to be attached to any particular factor in the light of all the relevant circumstances. These may include such matters as the motive to find a solution to the problem the patent addresses, the number and extent of the possible avenues of research, the effort involved in pursuing them and the expectation of success."
Citing para [42] of Lord Hodge's judgment in Actavis Group PTC EHF v ICOS Corporation [2019] UKSC 15, Judge Hacon said at para [113] of his judgment in Sandoz that there was no dispute that the legal standard applicable to the obviousness or otherwise of a dosing claim was the same as any other. He noted that the parties had agreed that on the present facts "obvious to try with a reasonable expectation of success" was the relevant criterion. He added that the Supreme Court had held at para [65] of Actavis that that criterion may be applied to the assessment of inventive step where it is appropriate on the facts.
Persons Skilled in the Art
Judge Hacon noted at para [43] of his judgment that it was common ground that the skilled team would consist primarily of a pharmacologist and a clinician interested in the treatment of thromboembolic disorders and that the two members of the team would work closely together when forming a composite view of the prior art. It was also common ground that the skilled team would call upon the expertise of an information specialist if needed. Such specialist would be familiar with the process of finding from published sources information about research conducted by pharmaceutical companies.Common General Knowledge
The learned judge identified the relevant common general knowledge of the persons skilled in the art between paras [8] and [35] of his judgment. He began with a discussion of haemostasis and thromboembolism. He defined haemostasis as "a process which gives rise to the formation of blood clots when an individual suffers injury and there is a need to close up damage to blood vessels" and thrombosis as "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." His Honour added at para [10] that thrombosis has long been treated by the administration of anticoagulants.
The judge then turned to the "coagulation cascade", that is to say "a series of reactions culminating in the formation of an insoluble clot." He continued at [14]:
"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", the condition is "embolism". "Thromboembolism" describes the combined conditions of thrombosis and embolism."
He noted that 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. He added that if anticoagulant drugs 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 available enough to have a sufficiently anticoagulant effect, but not so available and effective such that the patient suffers from unwanted bleeding.
"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", the condition is "embolism". "Thromboembolism" describes the combined conditions of thrombosis and embolism."
He noted that 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. He added that if anticoagulant drugs 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 available enough to have a sufficiently anticoagulant effect, but not so available and effective such that the patient suffers from unwanted bleeding.
Judge Hacon mentioned the anticoagulant drugs drugs in use before the priority date of the Patent and those that were being developed. He covered clinical trials and coagulation assays for pharmacodynamic studies. There was further discussion of the common general knowledge between paras [158] and [168].
Inventive Concept
The judgment does not identify the inventive concept or contain a construction of the claims presumably because there was no dispute as to their meaning,
Prior Art
The claimants relied on the following prior art:
- A poster entitled "Effects of Bay 59-7939, an Oral, Direct FXa Inhibitor, on Thrombin Generation in Healthy Volunteers", by Sebastian Harder et al., ("Harder") which was made available to the public at the 45th Annual Meeting of the American Society of Hematology in San Diego, USA, between 6-9 Dec 2003; and
- A paper entitled "In vitro and in vivo studies of the novel antithrombotic agent BAY 59-7939 – an oral, direct FXa inhibitor", authored by Elizabeth Perzborn et al., ("Perzborn") which was published online on 26 Jan 2005.
Perzborrn was to be read with other publications known as "the blood abstracts",.
Differences between Harder and the Claims
Bayer had identified four differences between the phase I data of Harder and other posters similar to Harder called "the Kubitza posters" on the one hand and the phase II use of rivaroxaban covered by the claims of the Patent (para [203] of Judge Hacon's judgment). His Honour disposed of those supposed differences between [204] and [213]. He concluded at [214] that the only real issue in the case on inventive step was whether it was obvious for the skilled team to conduct a phase II trial which included once daily dosing after having read the posters.
Whether those differences would have been obvious to a Skilled Addressee
Whether those differences would have been obvious to a Skilled Addressee
Having considered the expert evidence the judge concluded at [254] that the skilled team would have believed that it was reasonable for the authors of Harder to say that there was data which suggested that rivaroxaban was suitable for orally administered once daily administration. That left the question of whether the data indicated that there was a dose which would be both safe and effective. The data in Harder and the Kubitza posters gave reasonable grounds for the belief that a once-daily dose of 30 mg would be likely to have a sustained effect over 24 hours. The data as a whole offered no reason to believe that such a regimen would cause excessive bleeding. Neither the possibility of excessive bleeding nor insufficient efficacy could be completely ruled out with such a regimen, but some risk was inevitable. It followed that the skilled team would have found it obvious to conduct a phase II trial which included such a regimen.
Differences between Prezborn and the Claims
The claimants did not press their case on Prezborm The judge said that had he been required to do so he would have found that as at the priority date, the skilled team would have discovered the identity and chemical structure of rivaroxaban.Insufficiency
S.14 (3) of the Patents Act 1977 requires the specification of a patent application to disclose the invention in a manner which is clear enough and complete enough for the invention to be performed by a person skilled in the art. One of the grounds for revoking a patent is that the specification of the patent does not disclose the invention clearly enough and completely enough for it to be performed by a person skilled in the art (see s.72 (1) (c) of the Act).
The claimants alleged that the claims contained no limitation as to dose or types of thromboembolic disorders. Only one once daily dose was disclosed in Example I, being 30 mg administered once daily for 7-9 days. Accordingly, the specification did not render it plausible that the use of rivaroxaban as claimed would be effective for the treatment of
(a) a thromboembolic disorder in any dose, or alternatively any dose other than 30 mg; or
(b) all thromboembolic disorders, or the sub-set identified in claim 2, at substantially all doses, or alternatively at any dose other than 30 mg, or further alternatively at a dose of 30 mg.
The claimants alleged that the claims contained no limitation as to dose or types of thromboembolic disorders. Only one once daily dose was disclosed in Example I, being 30 mg administered once daily for 7-9 days. Accordingly, the specification did not render it plausible that the use of rivaroxaban as claimed would be effective for the treatment of
(a) a thromboembolic disorder in any dose, or alternatively any dose other than 30 mg; or
(b) all thromboembolic disorders, or the sub-set identified in claim 2, at substantially all doses, or alternatively at any dose other than 30 mg, or further alternatively at a dose of 30 mg.
For the law on insufficiency by reference to plausibility, Judge Hacon referred to para [37] of Lord Sumption's judgment in Generics (UK) Ltd v Warner Lambert Company LLC [2018] UKSC 56 and paras [338] to [347] of Mr Justice Meade's judgment in Teva Pharmaceutical Industries Ltd v Grünenthal GmbH [2023] EWHC 1836 (Pat).
Judge Hacon said at [286] that the practical idea of the claims of the Patent is to treat thromboembolic disorders by the administration of rivaroxaban in tablet form no more than once daily. He found that the specification and the CGK of the skilled team would permit the performance of the claimed invention across the scope of the claims. The claims being limited with regard to dosage, as would be understood by the skilled team. The claims were therefore not insufficient on that ground.
Judge Hacon said at [286] that the practical idea of the claims of the Patent is to treat thromboembolic disorders by the administration of rivaroxaban in tablet form no more than once daily. He found that the specification and the CGK of the skilled team would permit the performance of the claimed invention across the scope of the claims. The claims being limited with regard to dosage, as would be understood by the skilled team. The claims were therefore not insufficient on that ground.
Added Matter
This was to be raised only if the claims were to be found invalid on grounds of insufficiency and Bayer applied to amend, As neither event had occurred the judge did not consider the issue,
Comment
The structure of this judgment is not easy to follow but it contains a useful analysis of the issues commonly found in dosage patents and a review of the applicable authorities, Anyone wishing to discuss this article may contact me by phone on 020 7494 5252 during UK office hours or send me a message through my contact form at any other time,
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