10.4.4 Consideration
591 The submissions of Sandoz and Bayer proceeded on the basis that the claimed invention of the 226 Patent was directed to an improved treatment for thromboembolic diseases over the existing treatments, warfarin and LMWH.
592 The evidence was that, at the First Priority Date, there was an unmet need for a safe and effective new oral anticoagulant to replace warfarin or to be an oral substitute for LMWH that had a wider therapeutic index than these existing drugs and did not require monitoring. A once per day dose was considered ideal, but any dose regime for oral dosing was considered better than the current treatments.
593 None of the oxazolidine derivatives described in WO 919 (including rivaroxaban) or their chemical structures were part of the common general knowledge as at both priority dates.
594 I accept that, given the description of (the compound now known as) rivaroxaban as the "very preferred" compound, its low IC50 value, its selection as one of the few compounds used in the rat test examples and the patentee's selection of that compound as the only one to be individually claimed, the skilled person reading WO 919 is likely to select rivaroxaban as a lead candidate to take into further drug development work, if not the lead candidate. By further drug development, I mean the full suite of pre-clinical tests that Professors Roberts, Evans and Baker said they would carry out to in order to consider whether Example 44 was suitable to take into Phase I, first in human trials.
595 However, choice of the lead candidate to take into the pre-clinical testing stage is not the end of the story. As Professor Roberts acknowledged, even when a lead compound has been selected, there is "absolutely" an enormous amount that can go wrong and, if it did, the consequence for a human with this class of compounds can be "catastrophic".
596 The identification of a potential lead candidate to take into pre-clinical testing, which far precedes trials in humans, is a very early step along the drug development pathway. There are many further steps along the way to achieving a safe and efficacious antithrombotic pharmaceutical composition, each of which presents an opportunity for failure or change in direction, including changes to chemical structure, formulation, release rate and dosage form. The risks of failure or a change in direction are even more likely when, as in this case, the compound is a first in class NCE, the side effects are entirely unknown, other unrelated compounds in the relevant field are known to have failed in early phase studies, and where the therapeutic window lies between uncontrolled bleeding and the formation of clots which can cause strokes or heart attacks.
597 At first glance, there may appear to be superficial similarities between the facts of this case and those of AstraZeneca which might therefore suggest a similar result. Namely, the selection of a lead candidate molecule from a piece of prior art - in this case, from the WO 919 Patent, in AstraZeneca, from the Watanabe Article - routine dose ranging trials and then, as a matter of obviousness and inevitability, the patented invention. However, there are at least the following important differences between the facts of this case and those in AstraZeneca. As at the AstraZeneca priority date:
(a) statins were well established and well known in Australia as a safe and effective treatment for reducing LDL cholesterol in patients with, or at risk of, cardiovascular disease or with elevated cholesterol levels;
(b) statins were a known chemical class about which predictions could safely be made about safety and efficacy;
(c) the side effects of statins were known;
(d) there was a known dose-efficiency-side effect relationship;
(e) rosuvastatin was not the first statin, or even amongst the first few statins developed - a number of statins were available on the market and being prescribed in Australia;
(f) the prior art documents, the 471 Patent and Watanabe Article, identified the structure of rosuvastatin (only relevant for the Blood Abstracts); and
(g) predictions could be made about the safety and efficacy of rosuvastatin on the basis of the other statins already approved and on the market.
598 In contrast to the facts of AstraZeneca, as at the priority date of the 226 Patent:
(a) there were no factor Xa inhibitors on the market;
(b) there were no approved direct factor inhibitors on the market;
(c) there had been mixed results for other new anticoagulant agents, such as ximelagatran and razaxaban, in clinical trials;
(d) rivaroxaban was an NCE, first in class molecule; and
(e) rivaroxaban was not a member of a known class of drugs about which predictions could reliably be made about efficacy, side effects and safety.
599 In summary, in contrast to the situation in AstraZeneca, the drug in this case was a new compound, from a new class of compounds to those anticoagulant agents being prescribed (warfarin and LMWH) and with a different mechanism of action (factor Xa inhibition) to those existing agents. In AstraZeneca, rosuvastatin was one of a class of statins which were commonly being prescribed as once a day oral treatment for hypercholesteremia, and rosuvastatin worked via the same mechanism of action in the human body as the currently prescribed statins. The only purported inventive step of the 051 Patent was the low dosage level - and therefore reduced side effects and need for monitoring patients - of rosuvastatin compared to existing statins: see AstraZeneca HC at [2] and [27] (per French CJ).
600 The experts in this case considered the statements in the WO 919 specification to be speculative and aspirational general statements for the class of compounds disclosed. Whilst the information in WO 919 might cause the person skilled in the art to choose Example 44 as a starting point, the speculative statements of the patentee could not be relied upon as the sole basis for putting Example 44 into Phase I trials in humans. Professor Roberts would conduct his own pre-clinical tests to get the full suite of information about Example 44 before proceeding further with the compound.
601 The experts considered that there were risks involved in testing a new anticoagulant for the first time in humans and that there may be potentially risky side effects. They were also aware that other anticoagulants (such as ximelagatran in late 2004) had not progressed along the drug development pathway.
602 WO 919 does not provide information as to many relevant matters which are important to considering whether to take Example 44 forward in the drug development process. These matters are listed earlier, and include, but are not limited to: the LADMET properties, toxicology and stability.
603 Some predictions, such as the initial starting dose, could be made on the basis of the rough estimates calculated by Professor Roberts, as discussed above at [548]-[550], but the experts agreed that these predictions were not indicative of success, rather they gave an indication of whether a molecule should be rejected before going further in the testing process.
604 Once all the data from the pre-clinical testing was obtained, the team would then consider whether Example 44 was suitable to progress into Phase I clinical trials in humans.
605 On Sandoz's case, once the lead candidate has been selected, the drug development process moves along the conveyor belt of pre-ordained routine steps. These steps start with pre-clinical testing and conclude with Phase III trials. As Sandoz submits, "if the data from one step in the drug development process is positive, it is routine to progress to the subsequent step in the process". The process continues along the set path until either the project is stopped due to a problem experienced in one of the routine clinical testing steps, or a regulatory authority approves the drug for administration to patients. In the case of rivaroxaban, there were no difficulties to overcome and no severe concerns regarding safety or side effects (such as occurred with ximelegatran or razaxaban). Thus, the compound proceeded along the well-established dug development path moving from pre-clinical testing to Phase III clinical trials without hiccups until it was approved.
606 According to Sandoz, nothing about the journey other than the choice of compound has the potential to be inventive. Given that the lead candidate is suggested by WO919, Sandoz submits that there is nothing inventive in the choice of Example 44 in the 226 Patent. That may well have been the case if there were factor Xa inhibitors already being commonly prescribed as a once a day anticoagulant, and therefore rivaroxaban would be the fifth or so factor Xa inhibitor on the market if approved - as was the case in AstraZeneca. But that is not the case here.
607 At one level, all steps along the research and development path of a new drug are well established and follow a routine, or well known, path. The successful completion of one step, and the information obtained from that step, leads to the next step in the series. However, I do not consider that the passage of a drug along a well-known path for drug discovery, including the range of pre-clinical testing and phases of clinical trials, constitutes "routine steps" in the way Aickin J intended in Wellcome.
608 Sandoz's routine step argument relies on comments by Heerey J in Eli Lilly & Co v Pfizer Overseas Pharmaceuticals (2005) 64 IPR 506 at [193] to the effect that tests for oral bioavailability and toxicity are "essentially routine" for those skilled in the area (cited with approval in Apotex Pty Ltd v Warner-Lambert Co LLC (No 2) (2016) 122 IPR 17 at [261]-[274] (per Nicholas J) and Warner-Lambert Co LLC v Apotex Pty Ltd (No 2) (2018) 129 IPR 205 at [134] (per Jagot, Yates and Burley JJ)). These comments were made in the context of considering whether a person skilled in the art could work the claimed invention for the purposes of the sufficiency requirement, without the need for inventive ingenuity. The question whether a skilled person can work a claimed invention using standard or routine steps is very different to whether an invention results from the person skilled in the art taking routine steps taken as a "matter of course". In the case of sufficiency, the invention has been made and the skilled addressee is seeking to make the invention, knowing the endpoint and filling in the gaps in the description of the invention in the specification, if any. That is a very different perspective to the person skilled in the art looking forward from the common general knowledge and embarking on their voyage of discovery with no known endpoint.
609 Not only must the person skilled in the art take the steps in question as a matter of routine, but they must also be carried out with an expectation of success. As was explored in the second joint session with the experts, there are risks inherent at each step along the drug development path. There is only around a 10% chance that a candidate drug will progress the entire way along the drug development path from pre-clinical testing to reach the approval stage. It is only from the successful endpoint looking back that it can be said in the case of a particular drug that there were no hurdles or obstacles that had to be overcome along the drug development pathway. This is the opposite of the s 7(2) test for inventive step which is a prospective test, looking forward from the prior art. Whether or not Bayer's actual development path of the drug the subject of the Patent claims was straightforward and "routine" cannot be taken into account in an assessment of obviousness for the purposes of s 7(2).
610 At the First Priority Date, rivaroxaban was a new chemical entity. The experts accepted that there was vast difference between the expectations for a first in class drug selected as a lead candidate and a fifth in class molecule. For an NCE, particularly where the NCE is the first in class, there is a much higher risk of failure compared to a research and development process for a generic drug. There is also less confidence with a NCE than with a third or fourth (or more) generation of a chemical class used in other drugs. With a third or fourth generation drug (such as the statins at issue in AstraZeneca), the team would have more confidence that there will be less unpredicted adverse events and toxicities than for a first in class candidate drug. Where the other earlier members of the class are already on the market, there would be information as to side effects, toxicities and stability, which would likely form part of the common general knowledge.
611 Therefore, in the drug development project to develop Example 44, the development team had no guidance from other compounds of the same class or with the same mechanism of action that have successfully passed through the drug development pathway to be approved for use as a once a day anticoagulant agent in humans. Namely, there was no body of knowledge from which predictions as to side effects could be reliably made.
612 As I said above, the well-known standard series of steps of a drug development pathway are not the "routine steps" contemplated by Aickin J in Wellcome at 286. They are beyond tests carried out merely to confirm that a formulation works, or for regulatory purposes: Boehringer at [110] (per Perram, Nicholas and Burley JJ).
613 The steps foreshadowed by Professors Roberts and Baker form part of a new, arduous, comprehensive, risky and unpredictable research project for a first in class NCE. Each test or step is undertaken with the purpose of trying to obtain information and to explore possibilities with the aim of ascertaining a full suite of information to enable a determination of whether to proceed with the compound into the next phase of testing. The pre-clinical tests are not undertaken with the requisite expectation of developing a safe and effective drug to treat thromboembolic disorders. Rather, the information gathered at each stage of the drug development process (cumulatively with the information gathered at the previous stages) will be used by the team to decide whether or not to proceed to test the compound in the next phase of clinical studies. As such, I do not consider that a person skilled in the art, equipped with the common general knowledge and the information in WO 919, would have the requisite expectation of success at the time of selecting Example 44 that the chosen compound would pass through all the drug development stages, from pre-clinical testing to successful completion of Phase III trials, to be approved for use in humans as a safe and effective once per day treatment for thromboembolic disorders.
614 Sandoz's "routine steps" argument is somewhat reminiscent of that run by Apotex in Apotex Pty Ltd v ICOS Corporation (No 3) (2018) 135 IPR 13. In that case, Besanko J at [346] summarised Apotex's argument as "the proposition that, providing one could characterise a particular trial, test or experiment as routine or conventional, then it satisfied the 'requirement' that it be carried out with an expectation of success". In response to that proposition, his Honour observed at [347] and [348]:
[347] It is not easy to grasp the full extent of Apotex's argument. It cannot be that all the Court is required to do is to identify the test or experiment which led to the invention and then ask whether a test or experiment of that nature has been carried out many times before and is, in that sense, routine. A dose ranging study involving amounts of 1-20 mg of a compound might be a study that is carried out in the case of many clinical trials involving pharmaceutical compounds, but that does not make it routine in this case. …The step must be one that the development team is directly led to and would carry out as a matter of course. It is at least implicit that that step would be taken because it may well succeed.
[348] In this context, it is important to remember that in this country the fact that the development team would consider a step or series of steps worthwhile to try or worth a try does not mean that the resulting invention is obvious or lacks an inventive step.
615 Justice Besanko then referred to the High Court's rejection of the "worthwhile to try" test in AB Hässle and observed at [349] that the Court in that case endorsed a requirement that the step or series of steps be carried out with an expectation of success.
616 Further, as set above at [293], the plurality in AB Hässle considered at [51] what Aickin J had in mind by his use of "routine" by referring to an earlier passage of Wellcome (at 280-281):
Evidence of what he did by way of experiment may be another matter. It might show that the experiments devised for the purpose were part of an inventive step. Alternatively it might show that the experiments were of a routine character which the uninventive worker in the field would try as a matter of course. The latter could be relevant though not decisive in every case. It may be that the perception of the true nature of the problem was the inventive step which, once taken, revealed that straightforward experiments will provide the solution. It will always be necessary to distinguish between experiments leading to an invention and subsequent experiments for checking and testing the product or process the subject of the invention. The latter would not be material to obviousness but might be material to the question of utility.
617 The plurality referred, without determining the point, to the working trials the subject of Dr Cederberg's evidence, and mused at [52] that those trials might be an example of the "subsequent experiments for checking and testing" to which Aickin J referred. The evidence in AB Hässle was that Dr Cederberg's trials in humans were conducted to confirm that various formulations proposed in the laboratory actually worked in the body: see at [25].
618 In Eli Lilly and Co Ltd v Apotex Pty Ltd (2013) 100 IPR 451, Middleton J at [554] distinguished the trials for "checking and testing" in AB Hässle from the clinical trials of olanzapine, as follows:
In [AB Hässle], the High Court acknowledged the possibility (but did not ultimately decide) that the evidence of the clinical trials given by Dr Cederberg was "checking and testing" (and thus, not evidence that was material to the question of obviousness). However, the difference between [AB Hässle] and the present case is that in [AB Hässle], the compound omeprazole was already known to be safe and effective. With olanzapine, it could not be known that the inventors had developed a safe and effective drug until after the clinical trials. There was no stopping of the inquiry at the time of synthesis of the compound in April 1982.
619 As explained by Middleton J in Eli Lilly v Apotex, the experiments for "checking and testing" contemplated by the High Court in AB Hässle are different to the skilled team undertaking a suite of pre-clinical trials to decide whether or not to put a compound into humans for the first time. Having made the decision to proceed to trials in humans, the Phase I clinical trials are carried out to ascertain whether the compound is safe in humans and to obtain information to support the next decision in the process - whether to proceed with the compound into Phase II trials. As also observed by Middleton J in Eli Lilly v Apotex, there is no stopping the inquiry at the point of synthesis of the compound (or its selection from a s 7(3) document) for a new compound from a novel class of compound that has not been previously tested in humans.
620 In AB Hässle, the plurality at [58] distinguished the tracing of a course of action which was complex and detailed, as well as laborious, "with a good deal of trial and error, with dead ends and the retracing of steps" from the taking of routine steps to which the hypothetical formulator was taken as a matter of course.
621 As Professor Evans observed, none of the compounds on WO 919 had ever been administered to a human being. There was the possibility that the compounds, including Example 44, may have adverse events or toxicities that may make them far worse than warfarin in terms of their side effects on people. Professor Evans gave as an example gastrointestinal erosion causing ulcers. A drug that might cause gastrointestinal erosion that also blocks coagulation of blood would cause disastrous gastrointestinal bleeds. Professor Roberts agreed that there were issues of potential toxicity with Example 44 which would have to be worked out. It is not possible to predict before testing that these risks of side effects and toxicities would eventuate.
622 In AB Hässle, the plurality referred at [67] to Buckley LJ's "voyage of discovery" passage from his judgment in Re Beecham Group Ltd's (Amoxycillin) Application [1980] RPC 261 at 296, describing it as the "vital passage":
I am fully prepared to assume on the evidence before the court that [prior patent] 978, should be regarded as having made clear to one skilled in the field of penicillins that the epimers of the para-hydroxy and the meta-hydroxy compounds were likely to prove fruitful avenues of research, possibly the most promising avenues known to exist. I accept that the lines which that research would follow would be what [the opponent's] witnesses described as 'routine', ie well-known. I accept that anyone experienced in penicillin research who pursued research along those avenues would probably have found what Beecham found. But with great deference to the learned judge, I do not agree that this is enough to constitute the claim to Amoxycillin as a penicillin for administration to humans obvious for the purposes of section 14(1)(e) of the [1949 UK Act]. To reach the discovery of the particular characteristics of Amoxycillin and its suitability for treating humans the research worker would have had to embark upon a voyage of discovery. It is possible now to see that his voyage would have been short and perhaps uneventfully straightforward, but where each of his two, or possibly more, vessels would make landfall and what those places would be like would not have been obvious to him at the outset. The voyage might have been clearly worth trying but not as a means of reaching a specific hoped-for destination.
(Emphasis added.)
623 In my view, Bayer's drug development journey is more akin to the voyage of discovery described by Buckley LJ than the "working towards the invention with an expectation of success" referred to in AB Hässle. Although I am loathe to put a figure on the expectation of success, it seems to me that a 90% (or thereabouts) chance of Example 44 not making it through Phase III clinical trials is not in the realms of an "expectation of success".