Alkaline reacting compound
14 The formulation and manufacturing details provided by Alphapharm, in relation to its product, describe the first (active) coat as comprising omeprazole, HPMC and purified talc. Experiments were conducted in Sweden to measure the pH of the first coating layer (containing omeprazole) of the Alphapharm product and also to measure the pH of pure omeprazole. The Brisbane tests included measurement of the pH of a mixture, made for the purpose of the test, of what were said to be samples of the actual components of the first coating layer of the Alphapharm product. A further test was made after sugar spheres had been added to that mixture, which was then stirred for ten minutes. It is unnecessary, at this stage, to discuss the substantially controversial aspects of any of the experiments, but some of the reported results are important. In Sweden, Dr Lindquist measured a sample (it was suggested in evidence led by Alphapharm that the sample may have been contaminated by particles of other layers) of the inner, omeprazole‑containing, layer of the Alphapharm product, to which four microlitres of de‑ionised water had been added. To perform the test, Dr Lindquist used an ISFET (ion selective field effect transistor) pH electrode connected to a pH meter. The pH thus measured was 8.8. Dr Lindquist also tested the pH of pure omeprazole mixed with de‑ionised water. The reported result was a pH of 6.4. He also performed a theoretical calculation based on the particular properties of omeprazole reported in Pilbrant and Cederberg, which produced the same result. In the later tests in Sweden, Dr Lindquist substantially replicated those results, testing the pH of the inner coat of the Alphapharm product and of pure omeprazole by the use of a "phenol red" indicator. The Brisbane tests did not include a measurement of the pH of pure omeprazole. Whatever conclusion one might reach about other aspects of the experiments in Sweden, the criticisms made of the measurement of the pH of pure omeprazole do not convince me that I should not accept that the pH of a saturated solution of omeprazole is approximately 6.4. Indeed, there seemed to be no serious dispute about that. The Brisbane experiments measured the pH of the mixture of purified water, omeprazole, HPMC and talc at a value greater than 7 but less than 8. The pH of the mixture to which sugar spheres were added was less, but nevertheless still above 7.
15 In that state of affairs, Astra's submission is simple: the pH of omeprazole is 6.4. If Alphapharm's evidence is accepted, the pH of the inner coating layer of the Alphapharm product is greater than 7 (if the results of Dr Lindquist's test are accepted, it is 8.8). The fact that the pH of the inner coat exceeds 7 demonstrates that it incorporates an alkaline reacting compound. It does not matter if in fact the only compound present in the mixture which might raise the pH above 7 is talc; if talc has that effect in the mixture, then it is an alkaline reacting compound.
16 I have already expressed views, in dealing with the suggestion that the patent is bad for ambiguity, about the meaning of the phrase "alkaline reacting compound" as used in the claims. It is necessary, however, to return briefly to that topic. Talc is not listed among the substances, or categories of substances, described in the specification as examples of alkaline reacting compounds. There is no dispute about what it is or about ways in which it is commonly used in pharmaceutical formulations. Dr Story described its provenance and manufacture as follows:
"I note from the Handbook of Pharmaceutical Excipients that talc is produced from naturally occurring hydropolysilicate. It is manufactured by subjecting hydropolysilicate to a flotation process to remove mineral impurities. It is then finely powdered and treated with hydrochloric acid, washed with water and dried."
17 Different grades of talc are available. A monograph on talc included in the Handbook of Pharmaceutical Excipients, 1994, lists, under the heading "Typical Properties", a pH range of 6.5 to 10. Among other things, talc is used as a lubricant or glidant in tablet or capsule manufacture, as filler for tablets and capsules and, of course, as a dusting powder. The specification lists talc as an "additive" which might be included in the sub‑coat and suggests that it may be included, as a dispersant, in the enteric coat. Talc is included in each of the seven formulations of a tablet core in table 1 of example 1 in the specification. The Handbook tells us that talc is practically insoluble in dilute acids and alkalis, organic solvents and water.
18 No test conducted by either party identified any component of the Alphapharm product's core materials other than those listed in Alphapharm's formulation details. (Dr Lindquist knew that talc was included, and suspected the presence of HPMC). The only relevant tests were the measurement of the pH of a solution of pure omeprazole, on the one hand, and the measurements of the pH of the inner coat of the Alphapharm product and of the mixture of the components of that coat on the other. Thus, relevantly, all that is known is that there is a component in the coat which raises the pH of an omeprazole solution to a value greater than 7 (or, if the accuracy of Dr Lindquist's test is accepted, 8.8). Significantly, no property of a component of the Alphapharm product's core material is revealed by those tests other than the property that it raises the pH of an aqueous solution of omeprazole. Nothing is shown as to how (if at all) such a component may react with other substances or in other contexts. One other fact is known, which may be relevant. The Brisbane experiments included one which involved testing the acid absorbance of the grade of talc said to be used in the Alphapharm product and a number of alkaline reacting compounds of kinds referred to in the specification. In brief summary, the result was that the acid absorbance of the talc was revealed to be extremely slight (though apparently not entirely non‑existent) and very much less than that of any of the other compounds tested (among which there was a substantial range of capacity to absorb acid).
19 The substantial issue on this part of the case, then, is whether a compound, the only known property of which is that it will raise above 7 the pH of an omeprazole solution, is an alkaline reacting compound within the claims of the patent, particularly claim 1. In considering that question it is unnecessary to form any view about the relative reliability of the tests in Sweden and the Brisbane tests. (In cross‑examination, Dr Lindquist gave evidence which, senior counsel for Alphapharm submitted, was to the effect that a compound whose pH in suspension or solution was measured at 7.98 might, when added to a solution of omeprazole - pH 6.4 - produce a mixture the pH of which exceeded 7.98 and might be as high as 8.8. A reading of that evidence as a whole suggests, however, that that would be so only if the measured suspension or solution was considerably less concentrated than the mixture). Certainly, if the result of the Swedish tests was accurate, the pH of the inner layer of the Alphapharm product is undeniably alkaline, even on an expanded view of a "neutral range", whereas the pH value resulting from the Brisbane test might, on some of the evidence, be regarded as falling within such a range. For reasons which will appear, however, that in my view does not matter.
20 The evidence of the experiments and of the formulation of the Alphapharm product raises, in an acute form, the question whether the view which I have expressed as to the meaning, in the claims, of the phrase "alkaline reacting compound" is literally correct. It is by no means an easy question. I have no doubt, having read and heard the evidence, that if one were to ask a formulator, or a pharmaceutical chemist, to provide a list of alkaline reacting compounds, it is highly unlikely that it would occur to the formulator to include talc of any grade. Equally, if the formulator were seeking a compound which would protect omeprazole against encroaching acid, talc would be among the last substances that the formulator would think of (indeed talc probably would not cross the formulator's mind). Talc, as I have mentioned, is not among the alkaline reacting compounds specifically mentioned in the specification, though it is included in the tablet core formulations in example 1 and is suggested as an excipient to be included in the sub‑coat and the enteric coat. Talc is barely soluble in water; and it is widely used for purposes ordinarily best served (the evidence suggests) by substances which are at least substantially inert.
21 On any view, however, there is equally no serious doubt that the particular talc raises the pH of an omeprazole solution above 7, slightly so even when sugar seeds are included in the mixture. I think I must conclude on the evidence that a compound which will increase the pH of the omeprazole above 7 must itself have a pH over 7. Dr Lindquist made that clear in re‑examination and his evidence in cross‑examination does not suggest the contrary. The only other evidence on that subject is that of Professor Rees who was asked - no doubt deliberately - a rather different question:
"Q. But it is possible to have a compound of a pH less than 7 that would raise the pH of omeprazole above 6.4?
A. Yes."
22 I conclude, therefore, that the core of the Alphapharm product includes a compound which satisfies the definition supported by Professors Rees and Brown. The evidence does not establish that it contains a compound which meets the definition supported, at least, by Dr Story, Dr Rowe and Dr Ashley.
23 I have already held that the "alkaline reacting compound" of the claims is the substance described in the specification as "an alkaline reacting, otherwise inert, pharmaceutically acceptable substance (or substances), which creates a 'micro‑pH' around each omeprazole particle of not less than pH = 7, preferably not less than pH = 8, when water is absorbed to the particles of the mixture or when water is added in small amounts to the mixture". In other words, I accept that an alkaline reacting compound is an alkali which, in the final mixture, produces that result. There is a substance in the core of the Alphapharm product - probably talc - which produces that result.
24 Clearly, the purpose of the alkaline reacting compound is to stabilise the omeprazole. It was submitted that talc would not perform that function because it will absorb very little acid, if any; and because, as the patent tells us:
"Omeprazole is susceptible to degradation/transformation in acid reacting and neutral media. The half‑life of omeprazole in water solutions at pH‑values less than four is shorter than ten minutes. Also at neutral pH‑values the [degradation] reaction proceeds rapidly. The stability profile is similar in the solid phase. The degradation of omeprazole is catalyzed by acidic reacting compounds and is stabilized in mixtures with alkaline reacting compounds. The stability of omeprazole is also affected by moisture and organic solvents."
25 Thus, it was said, talc plainly cannot have been contemplated as an alkaline reacting compound, because it will not do what is required. But the degradation results reported in Pilbrant and Cederberg and repeated in the specification refer to degradation of omeprazole in solution. I accept Professor Rees' evidence that the "stability profile" and "rate" of degradation are two quite different things: although the stability profile may be similar in solution and in the "solid phase", the rate at which degradation proceeds will decrease to the extent that free water is eliminated. That, clearly enough, is supported by the evidence that ordinarily there is no particular difficulty in applying an enteric coat directly to an alkaline or acid labile core. If that is right, there is nothing particularly surprising in the suggestion that, provided other conditions are met, it is sufficient for the stability of a solid core that the "micro‑pH" may be as low as 7 or slightly above 7. No doubt - as the examples in the specification suggest - relatively large quantities of a relatively strong alkaline reacting compound may be required if an enteric coat is applied directly to the core; and, if the core contains acidic substances (in addition to omeprazole), then a function required to be performed by the alkaline reacting compound may be to buffer the core against acid. But if the core contains no acidic substance (other than omeprazole itself, which on the evidence is amphoteric) and if there is a sub‑coat separating the enteric coat from the core, then it may be (at this point exploration of the subject in evidence substantially ceased, I think) that protection is required only against very small quantities of water, the degree of protection required depending, no doubt, on the extent to which free water is eliminated from the core.
26 In other words, the specification suggests, I think, that the essential function of the alkaline reacting compound is to produce a "micro‑pH" within the specified range. Depending upon other aspects of the formulation the alkaline reacting compound may have other work to do and particular compounds, or particular quantities of particular compounds, may be indicated. But the matter of immediate concern is not the variables but the essential or minimum requirement of an alkaline reacting compound: and that is that it produce the required "micro‑pH". On the evidence, I find that the core of the Alphapharm product includes such a compound.