(vi) Discussion
104 "It is trite law that a 'scintilla of inventiveness' is sufficient and that 'no smallness or simplicity will prevent a patent being good' … ." (Meyers Taylor Pty Ltd v Vicarr Industries Ltd (1977) 137 CLR 228 at 249). Meyers Taylor is authority also for the proposition, perhaps equally trite, that "subsequent analysis of the invention - 'the dissection of the invention' - is not often helpful in resolving the question of obviousness" (at 242). Astra placed some reliance on the former of those propositions; but it is not, I think, one which assists much in this case. There is hardly room, on the evidence, for a finding that there is, in the claims of the patent, a scintilla of invention. The competing possibilities are that there was a very significant inventive step and that there was no inventive step at all. The evidence also leaves no room for doubt that formulators working in Australia before the priority date knew that a compound which tended to degrade in acid or neutral media might be stabilised by the addition of a substance, an aqueous solution of which had an alkaline pH; equally they knew about enteric coats; and they knew of the existence, properties and some uses of coats made of substances such as ethylcellulose and HPMC. That, however, does not advance matters far, because the question is, was the claimed combination obvious? And I think there is a real difficulty in this case, as I have already indicated, about the extent of relevant common general knowledge outside the boundaries of the three general areas to which I have referred.
105 No doubt I may take it that the competent formulator would have had to hand a number of the major pharmaceutical textbooks which were referred to, would have had a good working knowledge of their contents and would have been well able to make full use of them as tools of their trade. But what of patents? It may well be - but there is no evidence of it - that competent formulators would be aware of a number of important patents relevant to their profession. Dr Story's evidence was to the effect that patents were often mines of useful and practical information. But no witness gave evidence that at the priority date he knew, as part of his general background knowledge, anything taught by, for example, the Abbott patent or the Clymer and MacDonnell patent. And what of manufacturer's literature? Here there was a distinct divergence between those witnesses whose experience was primarily academic and those who had primarily been engaged in industry. The former (Dr Thiel was an exception) tended to dismiss manufacturers' literature as of lesser quality and utility than peer reviewed writings; Dr Ashley had not heard of Shin‑Etsu (it is not clear whether he knew of FMC) and Professor Brown knew neither of Shin‑Etsu nor of FMC. On the other hand, Dr Story knew the manufacturers well, was accustomed to receiving their literature and had a quantity of it to hand; that was true also of Dr Rowe and of Dr Thiel. But it does not of course follow that what was is in a particular item of a manufacturer's literature, though that item may have been held in a library readily accessible to a particular formulator, formed part of the common general knowledge of formulators in Australia before the priority date. Dr Thiel had Shin‑Etsu H‑17 in a folder of Shin‑Etsu literature, but there was no evidence that what was in it had, before the priority date, entered the stock of common general knowledge.
106 The matter may be approached from a somewhat different direction. Dr Ashley gave evidence that:
"The physical separation of incompatible substances was a well‑known tool of formulators before the Priority Date. It would have been obvious to me and to the skilled formulator that this interaction could be prevented by physical separation of the omeprazole from the enteric coat by use of an inert subcoat between the omeprazole‑containing core and the enteric coating layer. Before the Priority Date this was a known use of coating materials."
Dr Ashley also said that "[the] potential for interaction between the acidic enteric coat and the acid labile omeprazole would have been apparent to me, and to any skilled formulator, before the Priority Date". Dr Thiel put the same point even more strongly:
"The potential for a basic drug (e.g. omeprazole) to interact with an enteric polymer film is discussed in [the Röhm Pharma course notes, a similar, later (April 1986) set of course notes and Shin‑Etsu H‑17]. Each of these references discusses the potential for a reaction between a basic drug and an enteric film and recommends the use of an intermediate film to isolate the drug‑containing core from the enteric film coating. I would expect an Australian undergraduate pharmacy student as at the Priority Date to appreciate that such an interaction could occur."
107 If that is so, it may not be unfair to comment that a large scientific team at Astra spent prodigally both time and resources in stumbling towards, and finally upon, what should have been an Australian undergraduate's first thought. But, more importantly, why should it have been thought that the core and the enteric coat were incompatible? No one gave evidence that he had previously, or since, encountered such a problem; there was no evidence of any product manufactured or marketed, before the Priority Date, in the making of which such a problem had had to be dealt with; there was evidence that other drugs which were both acid labile and alkaline (particularly erythromycin) had been successfully, and directly, enteric coated; each of the Alphapharm witnesses who gave evidence of the approach he would have followed in formulating omeprazole would have first tried a directly enteric coated formulation and (as senior counsel for Astra pointed out) Dr Marshall had no hesitation in applying an enteric coat directly to a core containing a significant quantity of a highly alkaline excipient; and, as the witnesses called by Astra said, there was a perfectly sound scientific explanation: in summary, that interaction should not occur in the absence of any significant quantity of free water.
108 I shall return to the question of the relevance of certain of the documents, including those relied on by Dr Thiel in the passage I have quoted. For the present, however, it is worth noting that Shin‑Etsu H‑17 refers to a loss of stability of enteric coated tablets containing alkaline matter "when storing at higher temperature", that problem being alleviated by "putting stearic acid in the intermediate film": the examples given suggest that (water soluble) Pharmacoat 606 (HPMC) does not by any means solve the problem if no stearic acid is added. Certainly it is true that the Röhm Pharma documents teach the use of an insulating coat if there is an "interaction on drugs coming into direct contact with the lacquer [enteric] coating". However, it does not suggest that such a reaction might be expected in the case of a drug having the characteristics of omeprazole or of such a drug mixed with an "alkaline reacting compound"; and the particular "insulating layer" suggested is one which comprises a Röhm Pharma product which itself is an enteric coating material which has free carboxylic acid groups.
109 In short, the strength of Astra's case on obviousness may be summarised in this way. The combination ultimately found to work was by no means obvious to a highly qualified team within Astra but, on the contrary, was the unexpected outcome of a great deal of experimentation and "brainstorming". Secondly, though it became apparent early in the process that an enteric coated dosage form was likely to be appropriate, omeprazole presented difficulties in the formulation of such a dosage form, which no other drug, sharing any of its characteristics, had previously presented; and the problem had several possible causes. Thirdly, if the hypothesis that poor acid resistance was due to the leaching of liquid through the enteric coat, then a water soluble sub‑coat was an unlikely solution. Fourthly, the particular combination arrived at had never been used in the manufacture of any marketed drug.
110 Certainly, considered at the commencement of a hypothetical attempt, immediately before the priority date, to formulate omeprazole, the combination claimed in the patent was not obvious. The question is whether the hypothetical, not particularly imaginative skilled formulator, equipped with common general knowledge and embarking on the task at that time, would be likely to have arrived at the combination by taking routine steps which such a formulator would take for the purpose of formulating a drug. The test is whether the hypothetical addressee, faced with the same problem, would have taken as a matter of routine whatever steps might have led from the prior art to the invention, whether they be the steps of the inventor or not: Wellcome Foundation at 286. In my view, each of the expert witnesses sought conscientiously to fulfil the proper role of such a witness. Thus, for instance, I accept the general descriptions given by Dr Story and Dr Rowe of the way in which they would go about the formulation of a new drug. Nor do I see any reason to doubt the evidence of Dr Story, Dr Rowe and Dr Thiel about the importance of the role played by manufacturers' literature or the evidence of Dr Story and Dr Rowe about the significance, to formulators in Australia, of patent searches. That was evidence of factual matters within the knowledge and experience of the witnesses and which no one, with experience of the practice of formulators in Australia, was called to contradict.
111 Submissions were made by Astra concerning aspects of the evidence of witnesses called by Alphapharm which, it was said, ought to suggest caution in evaluating their evidence and, in particular instances where that evidence conflicted with evidence given by witnesses called by Astra, to require a preference for the latter. Certainly there are in the evidence some mistakes and inaccuracies, which may be attributable, in part, to shortness of time, and, in some instances, to a degree of carelessness. For example, Dr Story said in his initial affidavit, and repeated in his affidavit in reply, that the use of an alkaline compound to stabilise omeprazole had been suggested in Pilbrant and Cederberg, but it is not. Similarly, in commenting on the specification, Dr Story suggested - incorrectly, as he conceded in cross‑examination - that the specification mentioned the use of sodium, aluminium and potassium oxides or hydroxides as buffers. The extent to which Dr Rowe would actually at the outset have read much of the material to which he referred was qualified, and narrowed, by his evidence in cross‑examination; and in his initial affidavit he plainly misunderstood the extent to which, according to Pilbrant and Cederberg, omeprazole would be soluble at the pH levels found in the small intestine. Some inaccuracies were found in Dr Thiel's list of documents which he had, or could have had access to, as at 30 April 1986. Indeed, Dr Story and Dr Rowe also placed some reliance on the FMC Aquateric document which, though dated 1986, was not proved to have been published before 30 April.
112 What is important, however, is the steps which the hypothetical formulator would have taken and where those steps would have led. I have no difficulty with the proposition that a formulator asked, in April 1986, to formulate omeprazole would have done a literature search at least in order to discover what learning there was about omeprazole itself and its characteristics. Clearly enough such a search would have uncovered the compound patent, the omeprazole salts patent and Pilbrant and Cederberg. Pilbrant and Cederberg both indicated a number of the characteristics of omeprazole and pointed the formulator in a particular direction: an enteric coated dosage form seemed most likely to be the best possibility. That being so, there can be no surprise that the witnesses would have first tried directly enteric coating an omeprazole core, or that the particular "controlled release" dosage form that Dr Marshall would have tried was an enteric coated one. I accept that that is what the hypothetical formulator would have done. I accept also that the process which would then have followed would have been a complex, detailed and laborious one, involving a good deal of trial and error, dead ends and the retracing of steps; and it is easy to fall into the twin traps of hindsight and over simplification. But there is no reason to doubt that the hypothetical formulator would, having tried the first simple formulation, have done substantially what Astra did: submitted it to appropriate tests, including tests for stability on manufacture and on storage and for acid resistance.
113 It is difficult then to resist the force of Dr Story's observation that it is irrational to suppose that the hypothetical formulator's tests would have produced results substantially different from those of Astra's tests. The Astra tests showed immediate discolouration, on coating, of a core to which no "alkaline reacting" substance had been added; there was no suggestion that the core was formulated or made in any other than a well known way, that is a way in which the hypothetical skilled formulator might well have chosen. Dr Rowe's evidence (and similarly to Dr Ashley's) was that there was nothing unusual about the use of an alkaline substance to stabilise an acid labile drug; and, as I have mentioned, Dr Marshall included an alkali in his formulation of the cores.
114 If that also is accepted, as I think it should be, as a step which the hypothetical formulator was likely to take, there is no reason to suppose that further testing would not have identified the "Scylla and Charybdis" identified by the Astra tests: either inadequate stability on storage or inadequate gastric resistance, depending on the quantity and character of the alkaline material included in the core. Whether a formulator would have concluded that either or both of the problems was due to an interaction between the enteric coat and alkaline material in the core was a matter of great controversy between the parties and between the expert witnesses. There can be no doubt that the twin problems would have been unexpected: so much is common ground. But whereas Professors Rhodes and Rees, particularly, strongly expressed the view that such an interaction was so contrary to experience and to well understood science that the formulator would have thought of other causes and would therefore have pursued solutions other than the one which Astra found, Dr Story and Dr Rowe (and Dr Ashley and Dr Thiel as well) expressed the view that a formulator would have suspected interaction between core and enteric coat as a likely cause of what was seen to be happening.
115 It must be borne in mind that the cause of the gastric resistance problem suggested by the patent, "diffusion" of "water of [sic] gastric juice" was hypothesis, not established fact. In judging whether the interposition of a water soluble sub‑coat involved an inventive step, what the hypothetical formulator would have thought, or surmised, is of greater significance than Astra's hypotheses. The experts called by Alphapharm all gave evidence that they would have regarded the problem as resulting, not from permeation of water or acid through a properly applied and intact enteric coat, but because the enteric coat was undermined by interaction, which they would have taken to be occurring, between coat and core.
116 To a considerable extent that proposition relied on the use that the witnesses said they would have made of the manufacturers' literature and, to a lesser extent, earlier patents. But I find nothing improbable in their assertions that, once problems were identified resulting from applying an enteric coat directly to the core, the formulator would have consulted manufacturers' literature and would have found, if not FMC Aquateric, then at least the Röhm Pharma course notes (1983) and Shin‑Etsu H‑17. It is true that Shin‑Etsu H‑17 deals with a somewhat different situation in which "imaginable ion exchange" might occur and suggests that, whereas in that situation a water‑soluble sub‑coat (HPMC) will not work, a water insoluble sub‑coat will (and, of course, a water insoluble sub‑coat was likely to present serious difficulties with a drug that was only slightly soluble and had to be released in the upper part of the small intestine). And the particular sub‑coat suggested by the Röhm Pharma document is a second enteric coat: one, therefore, hardly likely to solve a problem of interaction between an alkaline core and enteric coat.
117 More generally, there is apparent force in the comment made in submissions for Astra that, as at the priority date, references to sub‑coats included for the purpose of separating incompatible substances were few and scattered among some obscure publications. Nevertheless, if one accepts, as I do, that it was generally known by Australian formulators that there was commonly to be found in manufacturers' literature information relevant to the use of their products in formulations, and that the particular publications were likely to have been found by the formulator as a result of routine steps taken in the course of the formulation process, the force of the comment is significantly weakened; and if one accepts also, as again I do, the evidence, particularly of Dr Story, that one does not look at documents only for the purpose of finding precise directions but that one reads them for more general ideas, and that one would first try the simpler solutions rather than the more complex, then it is not difficult finally to accept that the element of a water soluble sub‑coat, in combination with the other elements (a core of omeprazole with which alkaline substance has been mixed and an enteric coat) of the combination, might have been arrived at by the skilled, though not particularly imaginative, formulator.
118 To look at the matter in that way is not, I think, to ask the irrelevant question, were the individual integers of the combination obvious, rather than the relevant question, was the combination obvious. That which is obvious, or non‑inventive, in this context is that at which the skilled, but not particularly imaginative or inventive, formulator might have arrived by following the routine processes of the craft. Of course, the particular process would not have been a simple or quick one and numerous possibilities might have been tried. But, given Pilbrant and Cederberg and all the expert evidence, an enteric coated dosage form was the highly likely starting point (as it was for Astra) and, to a large extent, the likelihood that particular subsequent steps would be taken must depend on the firmness with which the view was maintained that the selected starting point was appropriate. The evidence of the formulators suggests, and Astra's experience confirms, that that view was likely to have been maintained with considerable firmness.
119 I am fortified in that way of viewing the matter by the evidence of Dr Marshall. Astra took comfort of a number of aspects of his evidence: that he accepted that the task formulating omeprazole was likely to be a difficult and complex one; that he did not arrive at the precise combination of the patent; and (as it was submitted) that the instructions he was given from time to time directed him along a path towards the combination. I have already described his evidence in some detail. Of course, the exercise undertaken by Dr Marshall was not an actual formulation of a substance which he had but a theoretical or hypothetical one, and that presented difficulties and (as he commented) frustrations. It was conducted in 1998 not 1986, though it was not suggested that that fact particularly affected the value of his evidence as he was effectively blinkered (I do not think that it is of any consequence that he obtained his copy of Pilbrant and Cederberg from Alphapharm's solicitors: he found the abstract by his own researches). But, despite the limitations of the exercise, several aspects of his report are striking. He, like all the other witnesses, thought that an enteric coated dosage form was an appropriate. He moved quickly to that position following his initial general comments about the formulation process and about sustained and controlled release; I do not doubt that it was his own independent idea to opt for an enteric coat, not merely the product of a suggestion to him by someone else. His formulation of the core included, apparently as a matter of course calling for no particular comment, a strongly alkaline substance (as I have mentioned, he thought it probable that he could successfully apply an enteric coat directly to that core). When presented with scenarios, which had to take the place of actual tests but were, I think, a reasonable reflection of the Astra experience, one of the things which he thought might be occurring was an interaction between core and coat and one of the steps which he suggested was the incorporation of a sub-coat, initially of (water insoluble) ethylcellulose. Perhaps the question he was then asked, "why ethylcellulose?", was a "nudge" but, more importantly, when asked to consider what he would do if tests showed poor bioavailability, he suggested changes to the sub‑coat. Certainly, his preferred (theoretical) solution was a "leaky" sub‑coat comprising a mixture of ethylcellulose and HPMC; but HPMC was among a number of alternative sub‑coating materials which, he suggested, would be considered.
120 Cumulatively and allowing as best I can for the insidious effects of hindsight, the evidence persuades me that the combination claimed in claim 1 of the patent did not, having regard to common general knowledge at the priority date, involve an inventive step. That being so, the same conclusion must apply equally, I think, in relation to each of the claims (certainly there was no suggestion that any of them might be considered independently in this context). The consequence is that, on the ground of obviousness, Alphapharm succeeds on its cross‑claim.
121 Before proceeding to the topic of novelty, I should mention that, in its amended particulars of invalidity, Alphapharm relied on "admissions made in the specification and the Original Specification". The alleged admissions comprise, principally at least, a number of references to prior art, and to matters that were known, in the specification of the unamended patent and removed by the amendment. But, whatever importance those references may have elsewhere, they have in my view little significance here. Their origin is in the British patent, from which the patent in suit derived its priority date. They cannot, I think, be taken as admissions as to common general knowledge in Australia, and certainly not as establishing that any particular matter formed part of that body of knowledge.