3943 The four documents that appear to have dominated the argument before the trial judge were as follows:
· Australian Patent No. 563842 ("the Salts Patent") relating to a series of compounds that are alkaline salts of omeprazole and pharmaceutical compositions containing salts of omeprazole. Astra is the grantee of the Salts Patent.
· An article published in 1985 in the Scandinavian Journal of Gastroenterology, the authors of which were Dr A. Pilbrant and Dr C. Cederberg ("the Pilbrant-Cederberg Article"). The article is entitled "Development of an Oral Formulation of Omeprazole". Both Dr Pilbrant and Dr Cederberg were members of the scientific and medical team within Astra that developed the dedicated to the development and formulation of omeprazole the subject of the Formulation Patent.
· Technical Information Sheet No. H-17 issued by the Shin-Etsu Chemical Co ("Shin-Etsu H-17"). The sheet is dated March 1975 and is entitled "Enteric Coating on Tablets Containing Alkaline Matter".
· Notes of a course conducted by Röohm Pharma on the coating of tablets ("the Röohm Pharma Notes"). The document was published in 1983.
44 It should be noted that the contentious documents did not include the Compound Patent. It seems to have been accepted that this document would be available to the hypothetical formulator.
4045 The trial judge found that none of the four documents mentioned in para 42 was comprised in the relevant common general knowledge as at the priority date. However, he also found that the hypothetical formulator, if asked in April 1986 to formulate omeprazole, would have done a literature search that would have uncovered, not only the Compound Patent, but also the Pilbrant-Cederberg Article and the Salts Patent.
4146 The Pilbrant-Cederberg Article reveals a number of important aspects of omeprazole. It shows that omeprazole is onlyvery slightly soluble in water, but is very soluble in alkaline solutions and degrades rapidly in water solutions at low pH values. It disclosesd that moisture, solvents and acidic substances have a deleterious effect on the stability of omeprazole and should be avoided in pharmaceutical formulations. Two principal options for the formulation of an oral solid dosage of omeprazole arewere suggested. The first iswas a conventional oral dosage form, from which omeprazole is released and absorbed rapidly enough to avoid degradation in the stomach. The second iswas an enteric coated dosage form which iswas said to offer the best possibility.
4247 The Salts Patent discloses the instability of omeprazole and, in particular, that upon storage without any special precautions being taken, it is degraded at a rate that is higher than desired. None of Alphapharm's witnesses suggested that the Salts Patent disclosed a subcoat.
4448 At para 110 of his reasons, Lehane J said:formulated the question of inventive step as follows:
"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." (Paragraph 110) (emphasis added [Emphasis added])
49 After dealing with some submissions about witnesses, the trial judge commented, at para 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."
50 Lehane J said it was difficult to resist the force of an observation by Dr Story, an expert witness called on behalf of Alphapharm,"that it is irrational to suppose that the hypothetical formulator's tests would have produced results substantially different from those of Astra's tests". Astra's tests showed immediate discolouration, on coating, of a core to which no alkaline reacting substance had been added. His Honour also said that, if it was accepted, as he thought it should be, that a hypothetical formulator would have used an alkaline substance to stabilise omeprazole (an acid labile drug) there was no reason to suppose that further testing would not have revealed the two problems 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.
51 The learned judge noted a controversy between the expert witnesses as to whether the hypothetical formulator would have concluded that either or both these problems stemmed from interaction between the enteric coat and the alkaline material. This was the most contentious factual issue in the case. The experts called by Alphapharm put the gastric resistance problem down to undermining of the enteric coat by its interaction with the core, rather than permeation of water or acid through a properly applied and intact enteric coat.
52 However, his Honour thought this controversy to be immaterial. At paras 116-117 he said he found nothing improbable in the assertions of the witnesses called by Alphapharm:
"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.
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, andthat 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."[Emphasis added]
53 The trial judge continued, at para 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." [Emphasis added]
54 The judge said he was "fortified in that way of viewing the matter" by the evidence of Dr Marshall, an organic chemist who has had considerable experience in the research and production of pharmaceutical products. Dr Marshall did not read the Formulation Patent prior to the trial. But he had provided a series of reports to Alphapharm's solicitors, each of which responded to particular items of information supplied, or questions asked, by the solicitors. The idea was to replicate the thought processes of the hypothetical formulator, who had no knowledge of the teaching contained in the patent, so far as this would be possible without conducting any tests. His Honour said, in para 119:
"Astra took comfort of a number of aspects of his evidence: that he accepted that the task [of] 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 [sic] 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 ethycellulose and HPMC; but HPMC was among a number of alternative sub-coating materials which, he suggested, would be considered."
Ethylcellulose is not water soluble, but HPMC (Hydroxypropylmethlcellulose) is. It will be recalled that the Amended Specification stipulated that the subcoat be soluble in water, rapidly disintegrating in water or a polymeric, water soluble, film forming compound.
55 His Honour concluded (at para 120), in relation to obviousness:
"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."
45His Honour also said as follows:
"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… there was nothing unusual about the use of an alkaline substance to stabilise an acid labile drug;…
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."
(Paragraphs 113-114) (emphasis added)
4655Later on, however, his Honour said:
"…it is not difficult finally to accept that the element of a water soluble sub-coat, in combination with the other elements… of the combination, might have been arrived at by the skilled, though not particularly imaginative, formulator." (Paragraph 117) (emphasis added)
4755His Honour then went on to state the following proposition:
"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." (Paragraph 118) (emphasis added)
4855His Honour accepted that the process in which the hypothetical formulator would engage would have been a complex, detailed and laborious one, involving a good deal of trial and error, dead ends and retracing of steps. His Honour considered that the particular process would not have been a simple or quick one and that numerous possibilities might have been tried. His Honour also referred to the evidence of Dr Marshall, to whom reference will be made later, who accepted that the task of formulating omeprazole was likely to be a difficult and complex one.
4955Despite finding that there was no evidence that what was contained in Shin-Etsu H-17 and the Rohm Pharma Notes had entered the stock of common general knowledge, his Honour held that the witnesses called by Alphapharm were entitled to rely on those documents for the purposes of their evidence. His Honour accepted their evidence that one does not look at such documents only for the purpose of finding precise directions but that one reads them "for more general ideas".
5055Further, his Honour accepted that Shin-Etsu H-17 deals with a situation somewhat different from that which arises in the case of omeprazole. Shin-Etsu assumed the use of an intermediate coating and recommended the inclusion of stearic acid in that coating. Further, while a subcoat is suggested by the Rohm Pharma Notes, the particular subcoat suggested was a second enteric coat. Such a coating, of course, was hardly likely to solve a problem of interaction between the core material and an enteric coating. Notwithstanding that neither document pointed towards the intermediate coat of the Formulation Patent, his Honour concluded that reference to Shin-Etsu H-17 and the Rohm Pharma Notes might have led the hypothetical formulator to the idea of subcoating, albeit a subcoating of a different nature from that suggested by either of the documents.