“[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. … … [0012] Surprisingly, it has now been found in patients at frequent medication that once daily oral administration of a direct FXa 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.”
“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.”
“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.”
“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.”
“BAY 59-7939 is a selective, highly potent, direct Factor Xa (FXa) inhibitor that is being developed for the prevention and treatment of thromboembolic disease. It has been shown to be well tolerated at single and multiple doses up to 30 mg, and is rapidly absorbed after oral administration, with a terminal half-life of 9-12 hours.”
“The aim of this study was to evaluate the effect of orally administered BAY 59-7939 on thrombin generation in healthy male volunteers.”
“ETP (peak or AUC) was reduced significantly (compared with placebo profiles) by both the 5 mg and 30 mg doses of BAY 59-7939, with maximum effect at 2-4 hours. Inhibition of ETP-peak and ETP-AUC (induced by tissue factor or collagen) by 30 mg BAY 59-7939 was sustained over 12 hours (Figure 3).”
“PITT (Tc) was prolonged significantly (compared with placebo profiles) by the 30 mg dose of BAY 59-7939. Maximal prolongation of Tc was approximately 2-fold by 5 mg BAY 59-7939 and approximately 4-fold by the 30 mg dose (compared with placebo group), and was observed 2-4 hours after dose administration. The increase in PITT was sustained by 30 mg BAY 59-7939 over 12 hours (Figure 4a).”
“PICT was prolonged significantly (compared with placebo profiles) by both the 5 mg and 30 mg doses of BAY 59-7939. Maximal prolongation was approximately 2-fold by 5 mg BAY 59-7939 and 3-fold by the 30 mg dose, and was observed 2 hours after administration. PICT was prolonged over 12 hours after treatment with 5 mg and 30 mg BAY 59-7939 (Figure 4b).”
“In agreement with other phase I data [the Kubitza posters], FXa was inhibited dose dependently after administration of BAY 59-7939. Maximum inhibition was observed 2 hours after treatment (28% and 56% inhibition after treatment with 5 mg and 30 mg BAY 59-7939, respectively). FXa inhibition correlated closely with ETP, as demonstrated by the values of the ETP-peak.”
“● Orally administered BAY 59-7939 dose-dependently inhibited both intrinsic (collagen) and extrinsic (tissue factor) pathways of thrombin generation. ● The effect of BAY 59-7939 on thrombin generation was demonstrated in platelet-free assays and in PRP-based assays. In contrast, indirect (i.e. antithrombin III-dependent) FXa inhibitors obviously only inhibit FXa that is not protected by the platelet-prothrombinase complex. ● BAY 59-7939 not only inhibited the lag time of thrombin generation (PITT-Tc), but also had a profound effect on both the maximum extent of thrombin generation (ETP-peak) and the total amount of generated thrombin (ETP-AUC). This observation suggests an additional feature of BAY 59-7939, because weaker FXa inhibitors may only prolong lag-time without affecting the total amount of thrombin generation. ● Some parameters (e.g. ETP-peak) indicate a long-lasting pharmacodynamic effect of BAY 59-7939, which suggests suitability for a once-daily dosing regimen. ● The effects of oral BAY 59-7939 on intrinsic and extrinsic thrombin generation and PICT, which are mediated by direct inhibition of FXa, indicate that BAY 59-7939 is a promising anticoagulant that merits further clinical investigation.”
“A single 30 mg dose exerted a sustained effect in some assays of thrombin generation for up to 24 hours.”
“● Pharmacodynamic effects were evaluated using FXa activity, prothrombin time (PT), activated partial thromboplastin time (aPTT) and HepTest; selectivity was assessed by measuring Factor IIa (FIIa) and antithrombin III activity. ● The pharmacokinetic parameters measured included area under the plasma concentration-time curve from zero to infinity (AUC) maximum drug concentration in plasma (Cmax), and half-life associated with terminal slope (t1/2).”
“All pharmacodynamic parameters had similar dose-dependent time-response curves, although the magnitude of the curves varied depending on the parameter. Overall, pharmacodynamic parameters were slightly more affected after administration of oral solution than after tablet administration. FXa activity and specificity Median FXa inhibition ranged from 20% for 5 mg tablets to 61% for 80 mg tablets (Figure 1). The maximum inhibitory effect on FXa activity was observed 1-4 hours after tablet administration, and returned to the normal range (0.7-1.2 U/mL) within 24 hours for doses up to 40 mg. [Inhibition of] FXa activity remained elevated beyond 24 hours for the 60 mg and 80mg doses. BAY 59-7939 was specific for FXa and did not affect FIIa (Figure 2) or antithrombin III (Figure 3).”
“Plasma concentration-time profiles showed rapid absorption after administration of the solution. Maximal plasma concentrations were achieved after 30 minutes and t1/2 was estimated to be 3-4 hours.”
“● Cmax was reached 2.5-4 hours after administration, and the [half-life] of the 5 mg dose was 5.4 hours. ● For the 10 mg and 30 mg doses, the mean [half-life] was 5.8 hours, and for the 20 mg dose it was 3.7 hours.”
“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.”
“… it is relevant to consider whether at the priority date something was ‘obvious to try’, in other words whether it was obvious to undertake a specific piece of research which had a reasonable or fair prospect of success: Conor v Angiotech, para 42 per Lord Hoffmann; MedImmune Ltd v Novartis Pharmaceuticals UK Ltd[2012] EWCA Civ 1234 ;[2013] RPC 27 , paras 90 and 91 per Kitchin LJ. In many cases the consideration that there is a likelihood of success which is sufficient to warrant an actual trial is an important pointer to obviousness. But as Kitchin LJ said in Novartis AG v Generics (UK) Ltd[2012] EWCA Civ 1623 , para 55, there is no requirement that it is manifest that a test ought to work; that would impose a straightjacket which would preclude a finding of obviousness in a case where the results of an entirely routine test are unpredictable. As Birss J observed in this case (para 276), some experiments which are undertaken without any particular expectation as to result are obvious. The relevance of the ‘obvious to try’ consideration and its weight when balanced against other relevant considerations depend on the particular facts of the case.”
“121. The difficulty is quite marked in relation to an anticoagulant such as rivaroxaban. As I have discussed, administering the new drug in a dosage that was too low posed a real risk of harm to patients in the study. Due to invasive surgery or for other reasons they would be vulnerable to clot formation. If such formation were not inhibited, or not sufficiently inhibited, a fatal thromboembolism in the brain or a lung or elsewhere could be the result. Equally, a high dose causing excessive anticoagulant activity could lead to bleeding, not just at the site of a wound but elsewhere, such as the brain, again leading to harm and even, potentially, the patient’s death. 122. The hypothetical team planning a phase II trial on the back of Bayer’s phase I data would therefore have approached the trial with caution. If the team were to have considered trying a once daily dosing regimen, a reasonable expectation of success would have amounted to a reasonable expectation that such a regimen would not put the welfare of the patients in the phase II trial at unacceptable risk.”
“124. In the present case there would have been no … perceived technical barrier to the claimed invention on the part of the skilled team. The team would have known that it could conduct a phase II trial using a wide range of once-daily doses from one small enough to be sure that there is no excessive bleeding up to a dose large enough to be sure of an antithrombotic effect over 24 hours. Such a range would have been likely to find the therapeutic window somewhere – in the lucky patients administered with one of the doses fitting the window. 125. Rather, the skilled team here would have been held back (if that was the case) by an ethical barrier. Since the size and location of the therapeutic window was unknown, administration of a wide range of once-daily doses would have posed a real risk of including one or more that missed the window, causing harm to patients.”
“129. Given that the ethical question will be resolved by an ethics committee rather than the skilled team, the real criterion in the present case is whether the skilled team would have thought that it was worth applying to the committee for permission to conduct a phase II trial which included a once-daily regimen with a reasonable expectation that the committee would give permission, and whether it was likely that permission would be given. 130. The case was not argued in that way. The criterion applied was just whether there would have been a reasonable expectation on the part of the skilled team that a once-daily dose falling would be both safe and effective. Of course, this and the two-part criterion just mentioned could on one view be seen to amount to the same thing.”
“I am not in a position to accept Collis J’s findings or to reach any view on them. I note however that the invention story or a version of it was advanced before the judge and that she rejected it, reaching the conclusion that for the reasons she gave, Bayer’s phase II study was based on their phase I data.”
“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 having read Harder and the Kubitza posters.”
“First, the authors of Harder, two clinicians stated by Professor Crowther to be of international renown and scientists from a world-leading pharmaceutical company, told the reader expressly that the data disclosed suggested the suitability of BAY 59-7939 for once-daily dosing.”
“The parties argued the case according to whether the skilled team would have thought that [a once daily] regimen was worth trying in a phase II trial with a reasonable expectation of success, where success would mean that such a regimen would be both sufficiently safe and sufficiently effective in a phase II study.”
“… data from a phase I trial can never be predictive of what may happen in a phase II trial. In the case of a study involving a drug for treating thromboembolic disorders a phase I trial of the type disclosed in Harder and the Kubitza posters can only test anticoagulant activity ex vivo. That is not the same thing as, and need not necessarily correlate closely with, antithrombotic activity. The results of the trial do not strictly prove anything with regard to antithrombotic activity. A highly risk averse approach would mean that phase II trials would seldom if ever be conducted. That would not be in the public interest and is clearly not the approach adopted in the real world.”
“With that in mind, I turn to the question whether the skilled team … would have considered that there was a reasonable expectation that a once daily regimen, using any chosen dose, would be sufficiently safe by avoiding an unacceptable risk of bleeding and also sufficiently effective by avoiding an unacceptable risk of thromboembolism during the course of a phase II trial.”
“A problem I have with the evidence of Professors Crowther and Meibohm taken together is that theirs was primarily a counsel of despair. Taken jointly, as it should be, their evidence was that the data from Harder and the Kubitza posters would have led the skilled team to abandon the idea of a phase II trial altogether. Of course, the quality of phase I data must vary from study to study and in theory this data could have been of a quality below the threshold required to go ahead with any sort of phase II study. But even Bayer’s counsel in oral submissions was not prepared to go that far. He accepted that the skilled team would not only have contemplated a phase II trial, it would have conducted one. The only issue was whether it would have included a once daily regimen. This does not mean that the evidence of Professors Crowther and Meibohm was of no value – it was both valuable and helpful and they had a fallback position on the assumption, of which they disapproved, that the skilled team would have conducted a phase II trial, evidence which I have taken into account. But it seemed to me that there was to some extent a determination to be negative.”
“249. It follows that the skilled team would have found the statement in Harder that some parameters investigated in the document suggested the ‘suitability [of orally administered BAY 59-7939] for a once-daily dosing regimen’ both striking and encouraging. The authors of Harder were either, like Dr Harder himself, distinguished clinicians of apparently international renown or, like Dr Misselwitz, senior figures in Bayer, very much a leader in the field. The skilled team would in my view have considered carefully why these authors had been prepared to put their names to that statement. Further, Blood 3003 … said that some assays pointed to an anticoagulant effect lasting 24 hours after a single 30 mg dose. 250. The skilled team would have been likely to consider first the reported evidence on the half-life of BAY 59-7939. Harder reported a figure of 9-12 hours, supportive of the idea of once daily dosing. But as Professors Crowther and Meibohm pointed out, there was no PK data to support it and the study involved only 8 participants treated with BAY 59-7939. The numbers of volunteers in both the Kubitza posters were much larger and there was supporting data. The figures of 3.7 and 5.8 hours in the two Kubitza posters would have been seen as more reliable. 251. The authors of Harder must have had the data in the Kubitza posters in mind when the statement regarding suitability for once daily dosing was made. Harder refers to the data of the Kubitza posters as being supporting of at least some of the PD data reported in Harder. And the authors would probably not have pointed out that some data supported once daily dosing if such data were to be dismissed as of no value because of other data in Harder and/or the Kubitza posters. 252. The skilled team would therefore have turned to the PD data. Harder stated that the ETP results showed that the inhibitory effect of BAY 59-7939 was sustained over 12 hours. As Professor Hirsh said, the graphical evidence gave some limited support for a sustained anticoagulant effect over 24 hours, although the authors had not seen fit to state this and the error bars meant that the evidence may not have had statistical significance. 253. The larger and therefore more reliable studies in the two Kubitza posters suggested in their graphs that anticoagulant effect as measure[d] by some parameters was significantly sustained 24 hours after administration in the case of 30, 40 and 60 mg doses. On the other hand these posters also concluded that anticoagulant activity according to a PD assay was closely correlated to plasma concentrations. The apparent contradiction, if it was seen as such by the experts, was not directly confronted. I note that the graphs in the Kubitza posters show that at low plasma concentrations of BAY 59-7939 there is not a close correlation between concentration and FXa inhibition. Even at zero concentration prothrombin time did not fall to zero. It could be that at the low plasma levels expected 24 hours after administration anticoagulant activity would no longer have been expected to correlate with plasma levels of BAY 59-7939, but the detail of the graphs was not addressed. As against that, it was resolved in the evidence of Professors Hirsh and Wilkins, and conceded by Professor Meibohm, … that the SAD Kubitza study shows graphical evidence of anticoagulant activity 24 hours after administration, including 24 hours after administration of a 30 mg dose. 254. Taking all the evidence together, I think that the skilled team would have believed that it was reasonable for the authors of Harder to say that there was data in Harder and the Kubitza posters which suggested that BAY 59-7939 was suitable for orally administered once daily administration. That left the question whether the data indicated that there was a dose which would be both safe and effective. 255. The experts were agreed that the data indicated a wide tolerance of BAY 59-7939 in healthy patients, up to a dose of 80 mg. A once-daily dose of 60 or 80 mg would be the most likely to prove effective in treating and preventing thrombi in phase II patients, though high doses of that order were more likely than lower doses to cause excessive bleeding. The question would have been whether the data provided sufficient support for a lower once daily dose that would have a sufficiently sustained antithrombotic effect over 24 hours. 256. In my judgment, the overall views taken by Professors Hirsh and Wilkins in this regard were the more realistic. 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 as I have discussed, some risk was inevitable. 257. Therefore I think that the combined evidence of Professors Hirsh and Wilkins was correct in taking the position that the skilled team would have believed that conducting a phase II trial which included a 30 mg once daily regimen would not have caused an unacceptable level of risk. 258. It follows that the skilled team would have found it obvious to conduct a phase II trial which included such a regimen.”