2.9.
In de beschrijving van EP 961 is – voor zover hier van belang – het volgende opgenomen:
[0008] Recently, a novel therapeutic approach for the treatment and prophylaxis of thromboembolic disorders has been described. This novel therapeutic approach aims to inhibit factor Xa [cf. WO-A-99/37304; WO-A-99/06371; J. Hauptmann, J. Stürzebecher, Thrombosis Research 1999, 93, 203; S.A.V. Raghavan, M. Dikshit, "Recent advances in the status and targets of antithrombotic agents" Drugs Fut. 2002, 27, 669-683; H.A. Wieland, V. Laux, D. Kozian, M. Lorenz, "Approaches in anticoagulation: Rationales for target positioning" Curr. Opin. Investig. Drugs 2003, 4, 264-271; U.J. Ries, W. Wienen, "Serine proteases as targets for antithrombotic therapy" Drugs Fut. 2003, 28, 355-370; L.-A. Linkins, J.I. Weitz, "New anticoagulant therapy" Annu. Rev. Med. 2005, 56, 63-77]. It has been shown that, in animal models, various both peptidic and nonpeptidic compounds are effective as factor Xa inhibitors.
[0009] In general, oral application is the preferable route of administration of a drug, and a less frequent dose regimen is desirable. In particular, once daily oral application is preferred due to favourable convenience for the patient and for compliance reasons. However, this goal is sometimes difficult to achieve depending on the specific behaviour and properties of the drug substance, especially its plasma concentration half life. "Half life" is the time it takes for the plasma concentration or the amount of drug in the body to be reduced by 50 % (Goodman and Gillmans "The Pharmacological Basis of Therapeutics" 7th Edition, Macmillan Publishing Company, New York, 1985, p 27).
[0010] When the drug substance is applied in no more than a therapeutically effective amount, which is usually preferred in order to minimize the exposure of the patient with that drug substance in order to avoid potential side effects, the drug must be given approximately every half live (see for example: Malcolm Rowland, Thomas N. Tozer, in "Clinical Pharmacokinetics, Concepts and Applications", 3rd edition, Lea and Febiger, Philadelphia 1995, pp 83).
[0011] In the case of multiple dose application the target plasma concentration (approximate steady state) can be reached after 3 to 5 half lives (Donald J. Birkett, in "Pharmacokinetics Made Easy", McGraw-Hill Education: 2000; p 20). At steady state the concentrations of drugs which rise and fall during each interdose interval are repeated identically in each interdose interval (Goodman and Gillmans "The Pharmacological Basis of Therapeutics" 7th Edition, Macmillan Publishing Company, New York, 1985, p 28).
[0012] 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.
[0013] 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.
[0014] In a preferred embodiment, the present invention relates to 5-Chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)-phenyl]-1,3-oxazolidin-5-yl}-methyl)-2-thiophenecarboxamide (I), a low molecular weight, orally administrable direct inhibitor of blood clotting factor Xa (see WO-A 01/47919) as the active ingredient.
(…)
[0030] Tablets are preferred, in particular tablets rapidly releasing the active compound. In the context of the present invention, rapid-release tablets are in particular those which, according to the USP release method using apparatus 2 (paddle), have a Q value (30 minutes) of 75 %.
(…)
a. a) Efficacy results:
[0044] On the basis of total daily doses the 30 mg once daily dose fits well into the dose dependance observed in the range of 2.5 to 20 mg bid, which corresponds to total daily doses of 5 to 40 mg.
(…)
Summary: The above data clearly demonstrate the efficacy of od administration of (I), namely fewer occurrence of composite endpoint events, i.e. fewer cases of DVT, PE or death compared to untreated conditions, and in the range of standard therapy. Furthermore, the od administration is surprisingly perfect in line with bid administration.
b) Safety results:
(…)
[0046] On the basis of total daily doses the 30 mg once daily dose fits very well into the dose dependence observed in the range of 2.5 to 30 mg bid which corresponds to total daily doses of 5 to 60 mg.
(…)
Summary: The above data clearly demonstrate the safety of od administration of (I). The occurrence of any major bleeding events is low, approximately in the range of standard therapy and again perfectly in line with results from bid administration.
Correspondentie over generiek geneesmiddel van Sandoz
2.16.
Bij beslissing van 9 juni 2023 heeft de rechtbank te Oslo, Noorwegen, uitspraak gedaan in de procedure waarin Sandoz AG heeft verzocht het Noorse octrooi NO 344 278, dat inhoudelijk gelijk is aan EP 961, nietig te verklaren wegens gebrek aan inventiviteit ten opzichte van de stand van de techniek (Kubitza, Harder abstract en Harder Poster). De Noorse rechtbank heeft geoordeeld dat het octrooi inventief is en daarmee geldig en heeft het verzoek tot nietigverklaring afgewezen. De Noorse rechtbank heeft onder meer als volgt overwogen (in de Engelse vertaling15):
“The parties agree that Kubitza is suitable as a proximate cause. The Court also agrees with this. In the Court's view, there is no reason in our case to distinguish between the two
Kubitza abstracts (which are almost identical) or between the abstracts and the posters. The
abstracts and posters for the Kubitza study express roughly the same thing.
The next question the court must consider is whether the Harder poster is also suitable as the closest prior art, as Sandoz argues.
The Harder study is an experimental study in 12 healthy male volunteers conducted in
collaboration between outside researchers (including Harder) and Bayer. It was a
crossover study in which 8 men received single doses of 5 and 30 mg of oral rivaroxaban,
while 4 men received placebo. Various coagulation assays (fibrin formation) or thrombin
generation (endogenous thrombin potential, ETP) were measured in platelet-rich plasma
(PRP) after stimulation with tissue factor (TF) or collagen before and at various times up
to 24 hours after administration of the drug or placebo. The ETP method was originally
developed by Dr. Hemker. In the Harder study, no pharmacokinetic measurements were
made.
Sandoz believes that the Harder poster presented at the ASH conference in the USA in
2003 is suitable as the closest prior art. Of the information contained in this poster, Sandoz
has been particularly concerned with the following:
• The introduction states that rivaroxaban is a "selective, highly potent"
factor Xa inhibitor with a half-life of "9-12 hours"
• Several of the four graphs in Figure 3 showing the results of different
parameters of the thrombograms ("peak" thrombin and "area under the
curve" (AUC)) after TF and collagen stimulation in PRP show the
anticoagulant effect of rivaroxaban on thrombin generation for up to 24
hours after ingestion of both 5 and 30 mg (e.g. ETP peak after collagen
stimulation)
• The conclusion explicitly states that "[s]ome parameters (e.g. ETP
peak) indicate a long lasting pharmacodynamic effect of BAY-59-7939
[rivaroxaban], which suggests suitability for a once-daily dosing
regimen"
The Court is of the opinion that it would not be natural for the skilled person to use the
Harder poster as a starting point for solving the technical problem. As mentioned, the
Harder study did not assess pharmacokinetic parameters. The information about a half-life
of 9-12 hours therefore appears undocumented. In light of the pharmacokinetic data from
the Kubitza studies (which were presented at the same ASH conference), the expert would
use the results from Kubitza as far as half-life is concerned. The results from the
pharmacodynamic tests in Harder would, in the court's view, be of limited value to the
skilled person. Of the 12 people who participated in the study, only 8 people actually
received rivaroxaban in different doses. The various thrombin generation tests (collagen
and TF stimulation of PRP) with subsequent measurement of various parameters of the
thrombogram ("peak" and ETP) were experimental with no correlation to efficacy
(prevention of blood clots) or safety (bleeding risk) at the time of prioritization or later.
Furthermore, the results in Figure 3 in the Harder poster showed large variation in the
measurement results (large standard deviations), especially for collagen-induced peak
thrombin and ETP, indicating large inter-individual variation and probably large technical
variation in the measurement method itself. These limitations mean that the subject would
question how much these results could really add to finding a dose range for rivaroxaban
that is both safe and effective. The information provided about the ETP tests in the poster,
especially after stimulation with collagen, does not, in the court's view, provide a basis for
the conclusion of possible "suitability for a once-daily dosing regimen". In view of the fact that the Harder study does not measure pharmacokinetic parameters and that the results of the ETP tests appear to be so uncertain and without correlation to clinical efficacy or safety, the Court finds that the skilled person would in any case have had to take Kubitza as a starting point when solving the technical problem.
Was it natural for the subject to test once-daily dosing at the start of the phase II studies?
The Court then goes on to assess which dosage regimens it was obvious for the skilled
person to test in phase II, in light of Kubitza, general professional knowledge and available
studies, such as the Harder study. As the Court sees it, this is the question that constitutes
the most central point of contention in the case.
As pointed out during the review of the skilled person's general knowledge, the Court
believes that the skilled person would have assumed that there were serious health risks
associated with both underdosing and overdosing when testing rivaroxaban in phase II. In
the court's view, the results from Kubitza's phase I studies would have given the subject
sufficient confidence to initiate phase II studies. In this respect, both the studies of bleeding
risk and the pharmacodynamic tests of efficacy in Kubitza are relevant to the subject's
assessment of what could be tested in phase II.
II. As the Court will come back to, there is nevertheless a leap from daring to conduct
phase II studies to daring to conduct such studies with once-daily dosing of rapid release
tablets.
With regard to the risk of overdose (bleeding), the Court finds that the majority of the
experts agree that Kubitza's bleeding test on healthy persons would not have given the
expert sufficient assurance that patients could not bleed with similar doses of rivaroxaban.
Sandoz's one expert witness, Dr. Jørn Dalsgaard-Nielsen, expressed in court that the expert could not derive much from the bleeding test in phase I with a view to testing in phase II and that the subjects in phase I would have had to be "cut up" if anything of value could be derived from phase I with a view to assessing bleeding risk. Sandoz's other expert witness, Dr. Stig Waldorff, for his part expressed that he does not see any real difference between patients and healthy persons in terms of bleeding risk, and that he would therefore have thought that 30 mg once a day with rapid release would have been safe for patients, as 30 mg twice a day was safe for healthy persons. The Court finds that the subject would not have dared (or obtained approval) to test 30 mg on patients without any prior dose escalation. The professional would not have felt confident that patients who need anticoagulant drugs have a similar risk of bleeding as healthy people, especially in light of the fact that such patients are older, have additional diseases, and may use other drugs that can potentiate the risk of bleeding. It is also not certain that the bleeding test in Kubitza captured all elements of importance for the assessment of bleeding risk in patients. Bristol-Myers Squibb terminated several of its phase II trials with higher doses of razaxaban due to bleeding in the patients, despite the fact that corresponding doses of razaxaban had not produced any results in the bleeding tests performed on the healthy trial subjects in phase I. On this basis, the court assumes that the subject would have been concerned about bleeding in phase II, and that the team that is the subject in our case would therefore want to start the phase II studies with relatively low doses given at least twice daily.
With regard to the risk associated with underdosing (blood clots), the Court perceives that
there is greater disagreement between the experts. Bayer's inventors and experts expressed
in court that the interaction study on enoxaparin and the conclusion that this could function
as a "rescue drug" was the only thing that made it justifiable to test low doses of
rivaroxaban (several times a day) on patients. Sandoz's expert stated that underdosing
would not have been as dangerous in phase II as Bayer claims (Dr. Dalsgaard-Nielsen) and
that more information could be obtained from the pharmacodynamic studies in Kubitza than what Bayer assumes (both Dalsgaard-Nielsen and Waldorff). The Court has
already commented on Dalsgaard-Nielsen's view that underdosing is not so dangerous
under the point concerning the testing of anticoagulant drugs. As regards the results of the
pharmacodynamic tests in Kubitza, the Court finds that these would not have given the
skilled person any reason to believe that the patients would get sufficient effect from
rivaroxaban with once-daily dosing of a rapid-release tablet. The subject would not have
felt confident that the results of the laboratory tests performed on blood samples taken
from healthy subjects in phase I could be transferred to testing in the phase II trials since
no correlation was (or is) established between these test results and clinical efficacy
(prevention of blood clots and bleeding risk) in patients. It is also a key point that the
pharmacodynamic tests in Kubitza do not indicate that once-a-day dosing will be
sufficient. The Kubitza abstract states that "[e]ffects were maintained for 8-12 hours at the
5 mg dose, and ~12 hours at the 10, 20 and 30 mg doses" and that "[r]elevant changes in
the PD parameters were still present after 12 hours".
However, the fact that a medicine can be effective for around 12 hours does not mean that
it should be dosed every 24 hours.
In summary, the Court believes that the subject would be afraid of both overdosing and underdosing rivaroxaban at the transition to phase II studies. At the time of the priority review, no phase II studies of any other factor Xa inhibitors had been published. The subject wanted to know that there were some categories of anticoagulant drugs that were dosed more frequently than the half-life (vitamin K antagonists) and other categories that were dosed less frequently (low-molecular-weight heparins or acetylsalicylic acid (platelet inhibitor)). However, as these other categories function differently, the subject would not be able to rely on the dosing logic of these drugs when determining the dosing regimen for the rivaroxaban phase II studies. In the absence of other evidence, the natural starting point for the expert in such a situation would be the half-life of the drugs. As can be seen from the quote from the Kubitza abstract above, the half-life of rivaroxaban in the phase I studies was measured at 4-6 hours. Even with optimistic adjustments, it is not possible to reconcile this half-life with a dosing regimen of one tablet a day.
[…]
If the team of experts in our case had read the poster or abstracts from the Harder study, the Court believes that the team's assessment would still have been that it was not justifiable to initiate phase II studies with once-daily dosing of a rapid-release tablet. The reasoning for this is largely the same as for the pharmacodynamic tests in Kubitza. Firstly, the qualified person could not feel confident that an effect measured in pharmacodynamic tests would also constitute a corresponding clinical effect in patients. Secondly, based on the divergent results and the large variation in the ETP tests, the qualified person could not feel confident that the sum of the ETP tests indicated that rivaroxaban had a significant effect on thrombosis formation, especially for more than 12 hours.
The Court agrees with Bayer that Bayer's original plan for phase II testing, where all doses were to be given twice daily or more often, supports the point that once-daily dosing did not appear obvious to the skilled person. The fact that once-daily dosing was instead tested for other factor Xa inhibitors developed during the same period also supports the same point.
Accordingly, the Court concludes that it would not have been obvious for the subject, at the start of the phase II trials, to test once-daily dosing of rivaroxaban.
[…]
There can be no doubt that the initial results from phase II - which showed that patients both tolerated and had an effect from relatively large and small doses of rivaroxaban - made it less of a concern to test once-daily dosing with rapid release than it was before these results were available. In the court's view, however, such testing does not appear to be an inevitable or routine next step for the skilled person. Firstly, the high costs associated with drug trials indicate that the subject would have had a threshold for changing an established and approved plan for a phase II study. Secondly, there is reason to believe that the subject would still have had concerns about patient safety in such a trial. It is in the nature of the matter that once-daily dosing of rapid-release tablets results in greater fluctuations in drug concentration than dosing several times a day. Although the initial results of the phase II study provided useful information about the therapeutic window for rivaroxaban, it will not be possible to establish clear boundaries for this type of drug as to what is safe or unsafe in terms of efficacy or tolerability. There is therefore also reason to believe that the professional would see value in keeping the medication at a relatively stable level. The evidence surrounding the decision-making process to include once-daily dosing in the phase II trials suggests that this did not appear to be an obvious, routine or inevitable solution to the subject. The proposal was strongly opposed both internally at Bayer and by the external steering committee for the phase II trial. Even after the decision was made to include once-daily dosing in the study, much of Phase II continued to investigate higher frequency dosing regimens. Consequently, even with the initial Phase II results, it may not have been obvious to Bayer what the frequency of the final dosing regimen should be.”
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