EXISTENCE OF THE SUBCOATING LAYER
38 In this case both parties made detailed submissions as to the strength of their respective arguments, particularly on the factual questions relating to infringement. While the Court does not undertake a preliminary trial with a view to forecasting the ultimate result (Beecham Group v Bristol Laboratories, at 622), it is appropriate to refer, at least in outline, to the evidence given by the technical experts. This evidence bears on whether Astra has established that there is a serious issue to be tried as to whether the subcoating layer exists and, if so, whether it is omeprazole free.
39 It is common ground that, assuming Astra's construction of claim 1 of the Patent to be correct, Biochemie has not infringed unless the Probitor pellets have integer (B) in claim 1, namely an inert reacting subcoating layer on the core material. As I have explained, Biochemie disputes that Astra has made out an arguable case that the Probitor pellets have a subcoating layer. In order to address this issue, Dr Lindquist's first affidavit explained that he bisected a pellet from a Probitor capsule using a microtome blade. He applied hydrochloric acid vapour to the exposed surface of the bisected pellet. This stained the omeprazole a yellow-brown colour because omeprazole degrades quickly when exposed to hydrochloric acid vapour. The bisected pellet was heated at 60° to 65° Centigrade to promote degradation.
40 Dr Lindquist then took photomicrographs of the stained pellet. The micrographs are in evidence as Exhibit JL3. One of the micrographs was taken with a stereomicroscope, while the other was taken with a fluorescent microscope. According to Dr Lindquist, the second of the micrographs clearly show the structure of the pellet, as follows:
· a sugar sphere (non-pareil);
· a yellow-brown omeprazole-containing layer, which also contained excipients, apparently spraycoated onto the sugar sphere;
· a middle layer; and
· an outer layer.
41 Dr Lindquist then took another whole pellet and removed a thin slice from the outer layer by shaving the surface. He used the FT-IR, ATR (Fourier Transform Attenuated Total Reflectance) spectrometer to record spectra of the outer layer thus exposed (Exhibit JL4). This showed methacrylic acid-ethyl acrylate polymer to be present, together with talc.
42 Next, Dr Lindquist removed the enteric coat of a new pellet by dissolving and rinsing it sequentially in two 0.5ml portions of acetone. He proceeded to record an FT-IR, ATR spectrum of the surface (Exhibit JL5). The comparison with a reference spectrum of HPMC and talc showed that the "middle layer" contained these two substances.
43 In view of these findings, Dr Lindquist concluded that all elements of claim 1 of the Patent were present in the pellets in the Probitor capsules. In particular, he identified a middle layer containing HPMC, a water soluble polymer, and talc.
44 Dr Crank made several criticisms of Dr Lindquist's methodology. I refer to some of them shortly. It is important to appreciate, however, that Dr Crank was not asked by Biochemie to conduct any experiments of his own on Probitor pellets. He acknowledged in cross-examination, as one would expect, that to form an opinion as to the existence of the subcoat it would have been desirable for him to conduct his own examination of pellets taken from Probitor capsules.
45 First, Dr Crank said that the use of hydrochloric acid vapour is a very aggressive process that can degrade and char excipients, possibly forming structures that could be mistaken for distinct layers. In his view, Exhibit JL3 is a photomicrograph of a chemically altered pellet that could have reflected a chemical effect within the test sample. In short, the apparent subcoat could have been an artefact of the exposure of Probitor pellets to hydrochloric acid vapour.
46 Dr Lindquist responded by undertaking further tests of Probitor pellets on 14 April 2003. These included taking photomicrographs of a bisected Probitor pellet without exposing it to hydrochloric acid vapour. Dr Lindquist obtained tests corresponding to those in Exhibit JL3 (Exhibits JL10a and JL10b). Dr Crank in his second affidavit maintained that the apparent subcoat might well be explained by changes in the relative concentrations of HPMC and omeprazole at the margins of the active layer.
47 Secondly, Dr Crank expressed the view, based on his scrutiny of Exhibit JL3, that the apparent layer identified by Dr Lindquist as a subcoat "is likely to be an artefact", that is something that appears to be part of the sample material but which in fact is the result of the technique being utilised by the experimenter. In his second affidavit, Dr Lindquist restated his view that the lower of the two photomicrographs showed a distinct layer distinguishable from the other layers of the formulation. He rejected the suggestion that what could be seen from the use of fluorescent microscopy in Exhibit JL3 was merely the interface and the change in refractive index between the omeprazole-containing layer and the enteric coat. Dr Lindquist considered that the fluorescence of the middle layer or subcoat is far greater than at the interface between the enteric coat and the air and is continuous and consistent, in contrast to the fluorescence of the interface between the omeprazole layer and the sugar non-pareil.
48 Thirdly, Dr Crank suggested that the acetone washing left a residue of talc (from the enteric layer) and HPMC (from the surface of the active layer), which Dr Lindquist mistook for a distinct middle layer. Dr Lindquist said that this could not be the case because HPMC is insoluble in acetone and because the spectrum of the subcoat is different from that of the enteric coat. Moreover, as he explained in his second affidavit, Dr Lindquist repeated the procedure and took photomicrographs of a Probitor pellet after it had been washed with acetone. According to Dr Lindquist, this revealed the existence of a subcoat or separate layer (Exhibit JL11).
49 Professor Cox also criticised Dr Lindquist's methodology. Like Dr Crank, Professor Cox acknowledged that he could have undertaken tests or experiments on Probitor pellets, but had not been asked to do so. Indeed he was not asked to express an opinion as to whether the subcoat is present. I mention two of Professor Cox's criticisms.
50 First, Professor Cox suggested that Dr Lindquist should have used advanced techniques of fluorescent microscopy to overcome the problem of distortion of the images of fluorescent objects. In response to this criticism, Dr Lindquist, in his second set of tests, analysed a pellet using confocal laser scanning microscopy ("CLSM") and again observed the existence of a subcoat or layer (Exhibits JL9, 10, and 11). Professor Cox offered further criticisms of Dr Lindquist's use of CLSM, suggesting, for example, that he had failed to make effective use of the technique.
51 Secondly, Professor Cox expressed the view that in order to establish that the bright line appearing on the image created by the fluorescent microscopy is in fact a specific subcoat or layer, it is necessary to exclude purely optical explanations resulting, for example, from the optical properties of any layered structure where there is a variation in refractive index between layers. In Professor Cox's opinion, Dr Lindquist had neither done this nor had he identified a source of fluorescence for the apparent layer. Professor Cox suggested that a micrograph should be taken of a bisected pellet, after the enteric layer had been removed. If this showed the purported "middle layer" it would be the "clearest evidence" for the presence of two layers external to the omeprazole layer.
52 Dr Lindquist's response was to rely on Exhibit JL11. In his oral evidence, Professor Cox disputed a suggestion (made by Professor Junginger) that the layer revealed by Exhibits JL10 and JL11 was of uniform thickness. Otherwise, however, Professor Cox accepted that Exhibit JL10, in particular, shows a quite clear region of enhanced fluorescence.
53 Mr Darder offered the opinion that Liconsa's manufacturing process could not produce a "middle layer" as thin as that identified by Dr Lindquist. While he was not cross-examined on that opinion, he did not conduct or participate in any tests or experiments to support that view.
54 Dr Lindquist's conclusions on the existence of the subcoating layer received support from the evidence of Professor Junginger, who observed the second series of tests carried out by Dr Lindquist. Professor Junginger gave two explanations for the existence of the intermediate layer or subcoat. One related to the method of spraying the drug-containing layer, but that is inconsistent with the evidence of Mr Darder and, as Professor Junginger accepted, in view of that evidence is not tenable. The second explanation is that the drug-containing layer includes excipients which have a low molecular weight and therefore will dry the most quickly. The highest amount of agent is HPMC. This is a high molecular substance that will dry more slowly, due to its high water binding capacity. Professor Junginger explained in his oral evidence that the relatively low temperature used during the spraycoating process would leave a watery layer to which the HPMC would diffuse. Accordingly, there may have been diffusion of the HPMC molecules to the surface during the spray coating process, thereby resulting in the formation of an intermediate layer or subcoat. Dr Crank challenged this theory and Mr Darder thought it "highly unlikely", but their evidence does not lead me to conclude, at this interlocutory stage of the proceedings, that Professor Junginger's theory is implausible.
55 I think that Astra has established that there is a serious issue to be tried as to the existence of a separate subcoating layer between the omeprazole-containing core and the enteric layer. That is not to say that Dr Crank and Professor Cox have not advanced some substantial criticisms of Dr Lindquist's methodology and conclusions. Nor is it to deny that some aspects of Dr Lindquist's evidence may not have been entirely satisfactory. I have in mind his failure to disclose in his affidavits a TOF-SIMS ("Time of Flight - Secondary Ion Mass Spectrometry") image which, on one reading, does not support the existence of a subcoating layer. I also have in mind that Dr Lindquist's oral evidence indicated that the results recorded in Exhibit JL3 were rather more equivocal than his affidavit may have suggested. Nonetheless, the fact remains that neither Dr Crank nor Professor Cox has yet conducted tests themselves that (depending upon the outcome) would enable them to refute the evidence given by Dr Lindquist and Professor Junginger. I appreciate that the timing of these proceedings may have given Dr Crank and Professor Cox a limited opportunity to conduct their own experiments, but the evidence does not establish that they could not have done so. At the trial, of course, with the benefit of further experiments, Biochemie may be able to make out its contention that the subcoating layer observed by Dr Lindquist is a mere artefact or a residue produced by his investigative techniques. But on the evidence before me there is a serious issue to be tried.