Section 7(3) - ascertained, understood and regarded as relevant
588 Assoc Professor French gave evidence that, at the priority date, he kept up to date by regularly reading anaesthetic journals, intensive care journals and general medical journals, including Anaesthesiology. He deposed:
For the journals I read, I scanned the table of contents to decide which articles would be of interest to me. I would then read the abstracts of the ones of interest and if, on reading the abstracts, the article seemed of particular relevance to my practice, I would read the whole article. I did not typically read articles directed to pre-clinical work or early clinical work, unless those articles related to mechanical ventilation or volatile anaesthetics, as I had a particular interest in these areas. The articles I read were typically reports of later stage clinical work as it was this work that was most relevant to my practice.
589 In cross examination, Assoc Professor French confirmed that, after looking at the index to a journal, he would scan the topics of editorials and the general articles, and if he found one of interest, then he "would first look at the abstract and if the abstract confirmed that it was of interest to [him], then [he] would read the article". He also confirmed that he did not read reports of pre-clinical work or early clinical work because "they weren't of particular interest to [him] at that time". There was no evidence to suggest that this practice of literature review was not typical of intensive care specialists in Australia immediately before the priority date.
590 It may therefore be accepted that the skilled addressee could reasonably be expected to have scanned the topics of the articles and editorials in leading journals in the intensive care field, including Anaesthesiology, and if there was a topic of interest, then the skilled addressee would read the abstract. If the abstract confirmed that the article was of interest to him or her, then the skilled addressee would read the article.
591 Let it be assumed that the skilled addressee could reasonably be expected to have thought that the topics "Effects of intravenous dexmedetomidine in humans: I. Sedation, ventilation, and metabolic rate" (Belleville) and "Effects of intravenous dexmedetomidine in humans: II. Hemodynamic changes" (Bloor) were of potential interest such that the skilled addressee read the relevant abstract. Nonetheless it cannot be concluded that the skilled addressee would have ascertained Belleville/Bloor. This is because the abstract disclosed only early pre-clinical research in a single two-minute infusion of dexmedetomidine in 37 healthy male volunteers. Reading this, the evidence indicated that the skilled addressee would not have gone on to read Belleville/Bloor since this research would not have been thought relevant to the clinical practice of sedating ICU patients by continuous infusion. Furthermore, the key words accompanying the abstract for Belleville/Bloor did not include the terms "ICU", "post-operative sedation" or "sedation", the typical search terms that the skilled addressee would have used in looking for research concerning ICU sedation. It can therefore be concluded that the skilled addressee would not have ascertained Belleville/Bloor as the abstract and keywords would not have led the skilled addressee to consider the papers relevant to clinical practice.
592 Talke, which like Belleville/Bloor, was published in Anesthesiology, was in relevantly the same position in this respect as Belleville/Bloor. The title, "Effects of perioperative dexmedetomidine infusion in patients undergoing vascular surgery", contains no reference to "ICU", "post-operative sedation" or "sedation". Nor is there any reference to these topics in the abstract or key words. Further, the article itself contains little more than a passing comment on sedation. Assoc Professor French deposed (and I accept) that had he been conducting a search using the words "ICU", "post-operative sedation" or "sedation" in April 1998, he would not have expected Talke to appear in his research results.
593 Further, Mr Cruise deposed that had the skilled addressee searched via using the words "sedation", "sedative" or any other direct variants of the word "sedation" or the search terms "ICU", "Intensive care" or any direct variant of those terms in PubMed (or the other principal database STN Medline) as at 1 April 1998, Talke would not have been located. He also deposed that it was "highly unlikely" that Talke would appear in the results of a search if a user inputted the search term "sedative", "sedation" and any other direct variants of the word "sedation" into the "all fields" search field in the PubMed database as at 1 April 1998. Mr Cruise was not called for cross-examination.
594 In view of the evidence referred to above, it cannot be concluded that the skilled addressee would have ascertained Talke before the priority date. It will be recalled that Professor Hall only found Talke by using the search term "dexmedetomidine".
595 Further, besides there being no reasonable expectation as to the skilled addressee's ascertainment of Belleville/Bloor, for the reasons set out below, the skilled addressee could not reasonably have been expected to have regarded Belleville/Bloor as relevant (within the meaning of s 7(3) of the Patents Act) to the work of intensive care sedation as it was being carried out in Australia at the priority date. This means that the skilled addressee would not have ascertained Talke by way of Belleville/Bloor and Professor Hall's further search for dexmedetomidine, being a search that, for the reasons stated below, must be put to one side as having no bearing on the issue of ascertainment before the priority date.
596 Talke was in relevantly the same position. The skilled addressee could not reasonably have been expected to have regarded Talke as relevant to the clinical work of sedating patients in the ICU because it was an early stage study in 24 patients, directed to determining if dexmedetomidine would attenuate the rise in heart rate and blood pressure in patients during and after surgery, which would not have interested the skilled addressee. Furthermore, as discussed below, Talke reported no sedative effect of dexmedetomidine post-operatively, and it is unclear whether any of the patients were in the ICU.
597 InterPharma did not establish that work in the relevant art in Australia at the priority date was directed to the development of new ICU sedative agents (see [82] above). Rather, the evidence of Professor Bellomo and Associate Professor French (which I accept) was that before the priority date the clinical research being done in Australia was focused on issues relating to major organs of the body rather than on other areas such as sedation (see [81] above). The evidence established that, although there were known limitations to the drugs available for ICU sedation before the priority date, intensive care specialists knew how to manage these limitations. The evidence was, moreover, that as at the priority date, these specialists would have seen propofol as becoming the preferred agent for ICU sedation. At most, Assoc Professor French thought that, as at the priority date, a "new agent" would be of interest. Having regard to the evidence before me, I accept his appraisal. As already indicated, I accept that the skilled addressee could not reasonably have been expected to have regarded Belleville/Bloor as relevant to the work of intensive care sedation as carried out in Australia at the priority date.
598 As previously stated, InterPharma relied on the search process undertaken by Professor Hall in support of its submission that the skilled addressee would have commenced with a literature search, and that one of the search terms the skilled addressee would use was "alpha agonist", which would have identified Belleville/Bloor.
599 Professor Hall deposed to the literature searches that he would have carried out if he had been involved in researching a potential intravenous agent for use in ICU sedation in March 1998 (immediately before the priority date) via the online database, PubMed. He deposed that had he been conducting a literature search using PubMed in March 1998 for intravenous agents for use in ICU sedation, he would have started by entering a range of generic search terms, including "ICU sedation", "sedation and critical illness", "alpha agonists and sedation", "clonidine and sedation", and also search terms for sedative agents that he knew could be administered intravenously.
600 I interpolate here that Professor Hall further deposed that the only intravenous sedative agent that he was aware of in March 1998 that was not already used in ICUs was dexmedetomidine, which he knew to be a selective alpha-2 agonist having sedative effects. Professor Hall explained, however, that he did not initially use "dexmedetomidine" as a search term, because this could be said to be "unfair hindsight bias". Professor Hall stated, nonetheless, that "any researcher with an interest in ICU sedation, and indeed physicians generally, would in March 1998 be likely to be familiar with clonidine, and that it is an alpha-agonist with sedative effects" and that he therefore used the search terms "alpha agonists and sedation".
601 Omitting the search using the term "dexmedetomidine", the result of Professor Hall's searches conducted between 31 January 2018 and 26 February 2018 was the identification of in excess of 6,000 papers. A search using the terms "alpha agonists and sedation" on 31 January 2018 located Belleville. (It may be useful to note that the relevant exhibit is confusing because the search terms appear to be "alpha agonist and post-operative" as opposed to "alpha agonist and sedation", but it was clear from Professor Hall's evidence that the reference to "and post-operative" was mistaken.) Professor Hall's evidence was that, having conducted his searches, he identified Belleville as a paper of apparent interest.
602 Professor Hall located Bloor (and Talke) by using the term "dexmedetomidine". I accept, however, that, given that dexmedetomidine was not part of the common general knowledge at the priority date, the search using that term can be put to one side: see further AstraZeneca FCAFC at [523] (Jessup J), quoted above at [510]. Nonetheless, it may be accepted that a reading of Belleville would have led the skilled addressee to the identification of Bloor.
603 It does not appear to me, however, that the skilled addressee would have taken the route identified by Professor Hall to locate Belleville and, in consequence, Bloor. This is because the skilled addressee's knowledge about alpha-2 agonists at the priority date would not have led the addressee to use the search terms "alpha agonists and sedation" if carrying out a literature search to find a new ICU sedative. The evidence of Assoc Professor French (which I accept) supported the conclusion that the skilled addressee's knowledge about alpha-2 agonists at the priority date was limited to clonidine.
604 Having regard to the evidence outlined at [519]-[524] above, clonidine was evidently not considered to be a promising drug for use in ICU sedation at the priority date and has never been approved for such use. Further, I accept that, as Pfizer submitted, the skilled addressee in Australia would have had more knowledge of and even experience in the intravenous administration of clonidine and its effects than Professor Hall because, although it was available for intravenous use in Australia, it was not so available in the US. I accept Pfizer's submission that the skilled addressee in Australia would not have used the search term "alpha agonist and sedation" if carrying out a literature search to find a new sedative for use in the ICU, having regard to the skilled addressee's limited knowledge of alpha-2 agonists, and the unpromising knowledge of and experience with clonidine. I therefore accept Pfizer's submission that, having regard to the knowledge of the skilled addressee in Australia before the priority date, the skilled addressee would not have ascertained Belleville (and, in consequence, Bloor) via such a search. As Pfizer pointed out, neither Assoc Professor French nor Professor Bellomo were asked whether they would conduct a search using that term. There was no evidence to indicate that the skilled addressee would have ascertained Belleville/Bloor in any other way.
605 In any event, as indicated at [522] above, Professor Hall acknowledged that he would not have considered clonidine a promising drug for use in ICU sedation; and, unsurprisingly, his reference to clonidine as a basis for framing his literature search was challenged in cross-examination. He defended his position with the statement that "[i]t has a niche use and it's from a class of drugs that have a potential as sedatives. … [O]ne would look at the class of alpha agonists if new ones arose that would have better balance of sedative than haemodynamic properties as sedatives". When pressed about why the skilled addressee, who was unaware of dexmedetomidine, would think there might be some other new alpha agonist that would be more promising than clonidine, Professor Hall said:
I think that a well-trained and practising intensivist, regardless of the level of particular interest in the world of sedation, at a minimum would know that the existing agents in their entirety as a group were not perfect, not any of them solely and even in combination, and that looking down the road for new sedative agents is perfectly reasonable and could be valuable in the management of patients. And they fell into broad classes and one of those classes is alpha agonists with the sole clinically available agent only used in a limited way, but other agents in the group dependent on their balance of sedative and haemodynamic effects potentially much more useful.
606 It did not seem to me, however, that this answer took the matter any further and it did not support the conclusion that the skilled addressee would have used the term "alpha agonists" in a search of the kind Professor Hall sought to simulate, on the basis that there might be some other alpha agonist that was more promising than clonidine for use in ICU sedation.
607 Having regard to the evidence, especially that to which I have just referred, I accept Pfizer's submission that, having regard to the knowledge of the skilled addressee in Australia before the priority date, the skilled addressee would not have used the search term "alpha agonists and sedation" in a literature search to find a new sedative agent for use on patients in the ICU and would not therefore have ascertained Belleville (and, in consequence, Bloor). In any event, if the skilled addressee had, before the priority date, undertaken literature searches of the kind described and undertaken by Professor Hall, then the skilled addressee would have found Böhrer 1990, which is listed in the results of one of his searches. I accept that, as Pfizer contended, reference to Böhrer 1990 would, as outlined below, have been likely to have dissuaded the skilled addressee from further exploring the literature by reference to a search term including "alpha agonists". Having regard to the entirety of the evidence concerning clonidine, it does not seem to me that the skilled addressee in Australia would have been deterred only from the use of alpha-2 agonists "for protracted periods of time", as Professor Hall claimed was true in his case.
608 As already indicated, InterPharma also submitted that Professor Hall's search process was akin to the search undertaken by Professor O'Brien described in AstraZeneca HCA. As the reasons for judgment of Jessup J in AstraZeneca FCAFC at [522] shows, however, before making his search, Professor O'Brien was not told that there was a "new statin" that was not part of the common general knowledge. Nor was he given the prior art or patent in suit before he carried out his search. It was in the absence of such information that Professor O'Brien "undertook searches and whittled down the articles of interest by reference to their abstracts. Ultimately, he requested a full copy of each of three articles": see AstraZeneca FCAFC at [531] (Jessup J).
609 Professor Hall was not in the same position as Professor O'Brien described in AstraZeneca HCA. Professor Hall's pre-search familiarity with the invention claimed in the Patent can be inferred from the fact that he had twice given evidence in proceedings in the US, on both occasions concerning a foreign equivalent of the Patent in suit. Furthermore, he agreed in cross-examination that he was "intimately aware of [Belleville/Bloor and Talke], if nothing else because [of] … the evidence [he] gave in 2012 and 2016 in the US". He deposed, furthermore, that Talke was part of the literature on dexmedomidine with which he was familiar during the 1990s and was therefore familiar with Talke well prior to beginning his searches.
610 In closing written submissions Pfizer submitted that Professor Hall was given Belleville/Bloor and Talke before carrying out his literatures searches, relying on what appears at transcript 110. It appears to me, however, that the questions that senior counsel for Pfizer put to Professor Hall were based on a misreading of the relevant parts of his affidavit (that Professor Hall had been given the papers prior to beginning his searches when in fact the affidavit did not say this at all). This misreading resulted in misleading questions and, more importantly, possibly an unintended concession that he had been given these papers by InterPharma's solicitors prior to conducting his searches. This does not, however, detract from the admitted fact that Professor Hall was clearly familiar with Belleville/Bloor and Talke prior to undertaking the literature searches for this case.
611 Further, before the priority date, Professor Hall was aware of Böhrer 1990, which was the only study of which he was aware in which clonidine was administered as an adjunct for sedation to an ICU patient by way of continuous infusion. Böhrer 1990 reported that serious problems arose following this infusion, including cardiovascular depression, and tachycardia, hypertension, agitation and sweating following abrupt clonidine withdrawal. When asked why he failed to include Böhrer 1990 in his list of papers that were "particularly relevant" in his search of the literature, Professor Hall said that he did not include it because he "was focussed on dexmedetomidine, which was the subject of this matter". Moreover, as Pfizer pointed out in its closing written submissions, the papers on clonidine that were selected by Professor Hall as "particularly relevant" in fact identified adverse effects when using clonidine as a transdermal patch for prophylaxis of withdrawal symptoms in children; did not relate to sedation at all; or did not suggest that dexmedetomidine would be any better than clonidine for sedative use.
612 Professor Hall had deposed that he had been asked by InterPharma's solicitors "what literature searches [he] would have carried out if [he] was involved in researching a potential intravenous agent for use in ICU sedation in March 1998" and "to replicate the searches that [he] would have carried out, and to identify the papers that [he] would have regarded as being particularly relevant". Professor Hall acknowledged, in cross-examination, that he knew that he needed to find Talke and, so too one might infer, Belleville. I would also infer from this, the conduct of his searches and other evidence to which I refer, that the object of Professor Hall's research task was to identify a search path using PubMed that would find Belleville/Boor and Talke. This is supported by the further fact that Professor Hall failed to draw the attention of the court to Böhrer 1990 which, as already indicated, told against the use of clonidine as a sedative agent and would have dissuaded the skilled addressee from using the term "alpha agonist" in a literature search designed to identify new sedatives for use on ICU patients. It would follow from this that the search process described and undertaken by Professor Hall was not the research process of the diligent researcher described in Lockwood (No 2) at [149] or, indeed, AstraZeneca HCA at [15].
613 These considerations lead me to conclude that, as at the priority date, the skilled addressee could not reasonably have been expected to have ascertained Belleville/Bloor or Talke and regarded them as relevant to work in Australia. Accordingly, neither Belleville/Bloor nor Talke satisfies the requirements of s 7(3) of the Patents Act.
614 If I were wrong in these conclusions, then the question would be whether, given the common general knowledge before the priority considered with Belleville/Bloor only, the skilled addressee would have been led directly as a matter of course to try the invention as claimed in the expectation that it might well produce a useful alternative to, or a better drug than, existing ICU sedatives. The same question would also arise with respect to Talke.
615 As already noted, this is not a case where the skilled addressee is confronted with a particular problem that is part of the common general knowledge or even the s 7(3) information.
616 Belleville/Bloor related to early phase studies on the effects of dexmedetomidine on healthy volunteers. Assoc Professor French's evidence was (and I accept) that:
[T]his is the first - this is a healthy human volunteer study. There's a - a great deal of uncertainty remains at this point in time regarding the effects of the drug in patients, in unhealthy individuals, particularly intensive care patients.
617 The experts agreed in their Joint Report that there was nothing in Belleville/Bloor that indicated that dexmedetomidine would be an appropriate agent for ICU sedation, and that "extensive further research [was] required". Each of them elaborated on this in evidence at trial.
618 Professor Hall's evidence was that, reading Belleville/Bloor, he would not "as a matter of routine, use dexmedetomidine as an ICU sedative". Professor Hall said in cross-examination that he would "aggregate that information [in Belleville/Bloor] and say this drug has potentials for this pre-operative protective effect on the patient as an adjunct to anaesthesia." He did not mention ICU sedation in this regard.
619 Assoc Professor French explained the matter clearly in the following exchange:
THE COURT: So your real concentration in relation to unhealthy patients is on not so much sedation, but the consequences of the drug in relation to other matters, like heart rate, blood pressure?
A/PROF FRENCH: Yes. So if you - for example, the - the sedative effects may not be able to be achieved because there could be adverse effects of the drug at this point - this point in time …known or unknown which could become apparent prior to the sedative effect being achieved.
THE COURT: Another difficulty, presumably, would be the likely pharmacokinetics, if you like, the effect with the ICU ---?
A/PROF FRENCH: Well, there ---
THE COURT: --- context of other drugs?
A/PROF FRENCH: So - so yes, as - as patients become more ill, the way that they handle drugs in terms of their pharmacokinetics, how they're distributed within the body, how the body eliminates them- metabolises and eliminates them and also, then, the interaction of that drug with the receptor and the effect that occurs - there are changes as you become more unwell.
620 Assoc Professor French made very clear in cross-examination that, given Belleville/Bloor, he would not be directly led as a matter of course to try dexmedetomidine as an agent for ICU sedation. This was consistent with his earlier affidavit evidence concerning Belleville/Bloor.
621 Professor Bellomo was not cross-examined on his evidence that Belleville/Bloor would not encourage him to conduct further research on the use of dexmedetomidine in ICU sedation.
622 There were other matters that bear on the fact that aspects of Belleville/Bloor would have deterred the skilled addressee from considering dexmedetomidine as an ICU sedative, including that:
it was an early study clearly identifying "the potential for unwanted side effects" of the intravenous use of dexmedetomidine;
the reported study environment was very different from an ICU in which patients would need much more sedative and, as Professor Hall acknowledged, as the dose of dexmedetomidine increased, so would concerns about the drug's effects on blood pressure and heart rate;
the study provided no information about whether dexmedetomidine was suitable to be administered as a continuous infusion and little information regarding the pharmacokinetics of the drug;
although the abstract for Belleville stated that dexmedetomidine was thought not to have "appreciable ventilatory effects", Belleville itself stated "our subjects were young and healthy; even the minimal ventilatory effects of [dexmedetomidine] seen in this study could be detrimental to more frail patients with pre-existing respiratory disease" and "[i]n older, less healthy patients who are receiving other medications, [dexmedetomidine] could still have clinically significant ventilatory effects". While perhaps a routine note of caution, the evidence established that ICU patients have these characteristics; Professor Bellomo's evidence was that drugs that cause ventilatory decrease can place an ICU patient in danger of respiratory complications; and Professor Hall acknowledged that caution was appropriate given that this was an early stage of testing of dexmedetomidine in healthy patients; and
Bloor reported that the administration of dexmedetomidine resulted in decreased blood pressure and heart rate. Both Professor Bellomo and Assoc Professor French expressed the opinion that this indicated that dexmedetomidine would not be useful as a sedative for use in the ICU.
623 Further, it is also relevant that Belleville/Bloor stated that:
(i) the reported increase in oxygen consumption required further investigation since the combination of increase oxygen consumption during a period of reduced ventilation and blood pressure could be detrimental;
(ii) three vagally mediated dysrhythmias were observed in the highest dexmedetomidine-treated dose group of healthy young subjects with low resting heart rates, which would be of concern; and
(iii) the marked transient reduction in cardiac output merited further study and would be undesirable in patients with impaired cardiac function. While Assoc Professor French described the authors' hypothesis to avoid this effect by slowing down the infusion as "reasonable", he also said that "a great deal of uncertainty remain[ed] at this point". Professor Hall ultimately agreed that this "all just requires further investigation".
624 Having regard to the matters to which I have referred, I would reject the proposition that, given the common general knowledge before the priority considered with Belleville/Bloor only, the skilled addressee would have been led directly as a matter of course to try the invention as claimed in the expectation that it might well produce a useful alternative to, or a better drug than, existing ICU sedatives. It is worth bearing in mind that, at the priority date, the skilled addressee would have known of the effects of propofol and midazolam. As Assoc Professor French explained:
I think the key difference, though, relates to the [fact that] propofol had been widely used in clinical anaesthesia for a number of years prior to its transitioning into intensive care. So particularly those intensivist that had an anaesthesia background had a great deal of clinical experience with the drug and understood … how it's used and understood its adverse effects. This is now evaluating a drug in a research environment. The drug had been given - you know, only given to a relatively small number of patients in contrast to the many, many, many, many thousands of people - hundreds of thousands of people - that would have been administered propofol prior to its transition into ICU.
625 The further question is, given the common general knowledge before the priority date considered with Talke, would the skilled addressee have been led directly as a matter of course to try the invention as claimed in the expectation that it might well produce a useful alternative to, or a better drug than, existing ICU sedatives? The Joint Report indicated that Professor Bellomo and Assoc Professor French agreed they would not have been directly led as a matter of course to try dexmedetomidine as an agent for ICU sedation. Professor Hall disagreed, stating that he would have conducted a trial. None of the experts stated that they would have expected dexmedetomidine to be a useful alternative to, or better drug than, existing ICU sedatives. All the experts commented "No. Further research required." Each of them elaborated on their opinions in evidence at trial.
626 In answer to questions from the bench, commencing "[b]y the time you had read the Talke paper, would you still be worried about the unpredictability of dex[medetomidine] as an alpha-2 agonist?", Professor Hall said:
In this class, all we had was clonidine. And we already knew that the balance of sedation vis-à-vis haemodynamic effect was not particularly favourable, and it also accumulated. So it wasn't offering us much over other drugs. Dexmedetomidine, in fact, was known from the animal research to be quite different in the alpha 2, alpha 1 ratio effects. As Dr Bellomo said yesterday, that at least opens the door that sedation effects could be more prominent than haemodynamic effects; but likely both are present. And after that - that's about all I would say. I would say it's in the right direction as ... alpha 2 agonist, but absolutely we need to - as of Talke, we need to establish the dose that truly has the sedative effect that's desirable and watch the haemodynamics. That's what I meant … in my affidavit by flipping it. And tachyphylaxis enters into that picture. For instance, if the sedative effect is just great for a day and then you find yourself going up, if there hasn't been tachyphylaxis to the haemodynamic effects, then that trade-off could go awry. Absolutely. So the pattern of studying these drugs that start in the perioperative period and then move to the intensive care unit is start with the less sick ICU patients and for shorter duration in your next investigation, and then just extend that.
627 Notwithstanding Professor Hall's last statement in this passage, I do not accept that the skilled addressee would have been led as a matter of course to try dexmedetomidine as a sedative agent in the ICU. The previous comments in this passage belie that proposition. In any event, Professor Bellomo deposed that, even if it were assumed that some of the patients in the Talke study were in the ICU post-operatively, based on that study, he would not have had any expectation that dexmedetomidine would be useful as a sedative in the ICU. Assoc Professor French was of the same opinion. I accept their evidence, bearing in mind that dexmedetomidine had no known or approved clinical use, and that its hemodynamic effects were of unknown quality and quantity, especially in relation to "the balance of sedation".
628 Further, I accept that, as Pfizer submitted, Professor Hall's evidence in the concurrent evidence session that he would have conducted a trial was apparently based on a combined reading of Belleville/Bloor and Talke. In this session, senior counsel for InterPharma asked Professor Hall to clarify his answer to 8.7(a) of the Joint Report, "[w]hat if anything would you have done as a consequence of reading Talke?" Professor Hall responded:
Well, I think I stated in my affidavit that nobody would take the Talke paper and then say that dexmedetomidine is now the first-line treatment for any patient in any [ICU] anywhere. And one also would be aware of the Belleville paper from Talke, because even if it eluded you somehow, it's actually cited in Talke. So Talke tells you that dexmedetomidine has been given in a set of different doses to human volunteers, healthy, totally healthy volunteers, and it had a sedative effect after a bolus administration that lasted several hours and then went away. And they even established a starting point of that dose that fairly uniformly in human volunteers had a significant sedative effect described as sleeping but easily arousable.
629 Professor Hall subsequently corrected this by saying, in answer to a question from senior counsel for Pfizer:
Well, by reference, Talke tells you, via Belleville, that it had been previously given, but, yes, I mean, if that was interpreted, then the proper interpretation is that the normal volunteers are described in Belleville. I completely agree.
630 The following exchange at trial confirms Professor Hall's approach:
THE COURT: As I understand [Professor Hall's] evidence: if you read Belleville, you would see health[y] patients referred to and then you would be taken to the Talke article; is that correct?
PROF HALL: Not only that, but that it is stated in Talke that dexmedetomidine has been given to normal volunteers, reference Belleville.
MR CORDINER: Yes?
PROF HALL: So there's a bullet point in Talke and where you could get as much information as is available is cited as one of the references, Belleville.
MR CORDINER: Belleville. And that's where you would learn the sedative [e]ffect, after bolus administration, that lasted several hours and then went away?
PROF HALL: Yes, and if you were reading Talke with a mind to any sedative [e]ffects, that would be a standout comment in the paper.
631 The only (footnoted) reference to Belleville in Talke merely states:
In healthy volunteers, dexmedetomidine … like clonidine, has antinociceptive and sedative effects.
632 Contrary to Professor Hall's evidence, there is no "comment" in Talke that dexmedetomidine had a sedative effect after a bolus administration that lasted several hours and then went away. Professor Hall's evidence that he would conduct a trial in relation to ICU sedation on this basis does not establish that he would have done so based on Talke alone (having regard, of course, to common general knowledge). It is clear from his evidence that this assertion is based on a combined reading of Talke and Belleville, such a combined reading being impermissible. As Pfizer submitted, Professor Hall's evidence in this regard was unsurprising, given that he had said that in the US proceeding he had relied on Belleville/Bloor and Talke together to say that the invention the subject of the equivalent US patent was obvious.
633 It has also to be borne in mind that Talke described the administration of dexmedetomidine for one hour pre-operatively, during surgery and 48 hours post-operatively. Talke disclosed, as all of the experts agreed in their Joint Report, that dexmedetomidine had a sedative effect in patients pre-operatively. As Assoc Professor French observed, however, Talke reported no sedative effect post-operatively, although the administration of dexmedetomidine post-operatively resulted in dose-dependent lowering of blood pressure and slowing of heart rate. Professor Bellomo and Assoc Professor French agreed that Talke would not have indicated to them that dexmedetomidine would be an appropriate agent for ICU sedation because, as noted in the Joint Report, "[n]o sedative effect was reported post-operatively with moderate hemodynamic effects". Assoc Professor French said, moreover, that Talke would have almost given him the opposite view (that dexmedetomidine would not be suitable as an ICU sedative) in that "no sedation was observed and there were haemodynamic effects observed". Assoc Professor French rejected InterPharma's senior counsel's suggestion that the skilled addressee would try a larger dose to achieve sedative effect post-operatively, observing that:
There would be significant concern that you could add - in my opinion, be a significant concern that if you increase the dose purely to try - and this is a hypothetical situation - purely to try and provide more sedation, you could potentially harm the patients by adversely affecting the haemodynamic status.
634 As already indicated Professor Bellomo and Assoc Professor French were impressive witnesses, both knowledgeable in relation to intensive care medicine in Australia, and I would accept their evidence. For the reasons given above and below, I would accept the evidence of Professor Bellomo and Assoc Professor French in preference to that of Professor Hall in so far as they disagreed with Professor Hall.
635 Amongst other things, I would not accept Professor Hall's evidence that there was nothing in Talke to indicate that dexmedetomidine would be unsuitable for use in ICU sedation. Professor Hall accepted that Talke indicated that dexmedetomidine might have unstable haemodynamics: Talke reported that dexmedetomidine significantly (that is, by a 20% decrease) lowered patient blood pressure and slowed patient heart rates in response to the first hour of treatment and that after the first hour there were some trends between dose and haemodynamic effects. He also accepted that most patients in the dexmedetomidine group were given high doses of phenylephrine (which was given when blood pressure was dangerously low) intra-operatively, and some were also given it after surgery. He further accepted that glycopyrrolate, which was given to increase heart-rate was not given in the placebo group but was given in the dexmedetomidine group.
636 As well, Talke disclosed that high dexmedetomidine plasma levels may increase blood pressure. Senior counsel for Pfizer asked Professor Hall whether "[i]f you had to titrate [dexmedetomidine] up, as it has been described to you in Talke, would you agree there would be a risk of blood pressure or heart rate increasing [or] decreasing?". Professor Hall answered that "[t]here's actually both". Further, he said:
It is most likely that you would have - if there were an adverse effect - I think it would be most likely there would be some effect on heart rate and blood pressure; it's more or less guaranteed. Whether it was tolerable, and whether it was tolerable with additional support, or whether it was simply intolerable because it was either unpredictable or there was no simpl[e] way to reverse it would be the things to be determined. Because this is an alpha agonist, on top of all of that, caution at some dosing, it is conceivable that the blood pressure could actually rise. That would be most unusual as a sustained effect but it could, and that observation came from careful looking at clonidine where you sometimes see a small uptake in blood pressure before the more dominant hypotensive effect occurs. So I think there would always be that issue as you up-dose the drug for any purpose. If you up-dosed dexmedetomidine for the purposes of perioperative protective effects on the heart, you would have to worry about these problems and if you titrated the drug for sedative purposes, you would have to worry about these problems. You would worry about them less in a group of patients that began with lower heart rates and lower blood pressures to begin with, of course, because the change in them might be more immediately adverse, whereas patients who - it's actually - it's undesirable to have those effects.
637 The above evidence, and Professor Hall's evidence that the ideal sedative would have side effects that were completely minimal because patients in the ICU have shock, unstable blood pressures and unstable heart rates, is inconsistent with his evidence that there is nothing in Talke to indicate that dexmedetomidine would be unsuitable for use as a sedative for patients in the ICU. His evidence in the latter regard should be rejected.
638 Having regard to the evidence before the Court, I accept that the skilled addressee would not have been directly led by Talke to try dexmedetomidine, being a drug that had no sedative effects post-operatively, as an ICU sedative.
639 The following considerations, amongst others, fortify this conclusion:
Talke suggested that the absence of sedative effects in post-operative patients was consistent "with recent findings of tachyphylaxis to the anesthetic effects of dexmedetomidine in rats", a possibility that indicated that long-term administration of dexmedetomidine would have rapidly diminishing sedative effects, as a consequence of which the drug would be unsuitable for use in ICU sedation;
As agreed in the Joint Report, Talke did not describe the use of dexmedetomidine for ICU sedation. Professor Bellomo and Assoc Professor French agreed that it was not possible to determine if any of the patients discussed in Talke (in particular the aortic surgery patients) were treated in the ICU. Senior counsel for InterPharma put to Assoc Professor French, "[b]ut given … the adverse effects that a number of them seem to experience … wouldn't a number of them have ended up in ICU?"; and Assoc Professor French responded that it was difficult to ascertain what the severity of the adverse events was and whether that would necessarily have meant that they needed to be in the intensive care unit or not. He was not taken, however, to that part of Talke under the heading, "Adverse events", which specifically stated that "[n]one of these events was life-threatening".
I would accept based on Professor Bellomo and Assoc Professor French's evidence discussed at [520]-[521] above, that the skilled addressee's knowledge about clonidine and its use as an anti-hypertensive would have deterred the skilled addressee from considering dexmedetomidine for use as an ICU sedative.
640 So far as concerns the dependent claims, there is no suggestion that the skilled addressee would have been directly led to try dexmedetomidine as the sole active agent or essentially the sole active agent. Further, Talke does not teach the administration of dexmedetomidine by a loading dose and a maintenance dose. It should also be borne in mind that even the highest dose reported in Talke (0.183 µg/kg/h) is outside the doses claimed in claims 11 or 12 of the Patent.
641 Having regard to the matters to which I have referred, I would reject the proposition that given the common general knowledge before the priority considered with Talke only, the skilled addressee would have been led directly as a matter of course to try the invention as claimed in the expectation that it might well produce a useful alternative to, or a better drug than, existing ICU sedatives.
642 For the reasons stated, it has not been shown that any of the claims of the Patent lacked an inventive step, having regard to Belleville/Bloor or Talke.
643 Before concluding the discussion of this topic, I would accept Pfizer's submission that an annotated version of Exhibit R19 should be disregarded, for the reasons it outlined in submissions filed on 28 May 2018. I would add that I have not found it necessary to refer to the table summarising Professor Hall's search results, which is Exhibit R19. I have instead had regard to Exhibit R4 and the evidence relevant to it.