CAIRNSTORES LIMITED GENERICS (UK) LIMITED v AKTIEBOLAGET HÄSSLE [2002] EWHC 309 (Ch)

IN THE HIGH COURT OF JUSTICE
CHANCERY DIVISION
PATENTS COURT
[2002] EWHC 309 (Ch)Case No Claim No: HC01C05083Venue Royal Courts of Justice, Strand, London, WC2A 2LL
Between
CAIRNSTORES LIMITED GENERICS (UK) LIMITEDClaimantsAKTIEBOLAGET HÄSSLEDefendant
Before
Mr Justice LaddieMr Christopher Floyd QC and Mr Michael Tappin (instructed by SJ Berwin & Co for Cairnstores Ltd)Mr Christopher Floyd QC and Mr Adrian Speck (instructed by Taylor Joynson Garrett for Generics (UK) Ltd)Mr Simon Thorley QC and Mr Colin Birss (instructed by Simmons & Simmons for the Defendant)Date 6 March 2002
[1]Mr Justice Laddie: This is the judgment in two conjoined actions for revocation of two patents, European Patent (UK) No. 0 247 983B1 (“’983”) and European Patent (UK) No. 0 496 437 B1. The claimants are Cairnstores Limited and Generics (UK) Limited. The defendant proprietor of both patents is Aktiebolaget Hässle (“Hässle”). Although there are small differences between the patents, none of them are of any significance to the issues I have to decide and I will adopt the course adopted by the parties at the trial, namely consider only ‘983.[2]‘983 is concerned with a formulation of an oral preparation containing a drug known as omeprazole. Omeprazole is a potent inhibitor of the secretion of acid in the stomach. It is therefore used in the treatment of gastric ulcers and other gastro-intestinal diseases. By the relevant priority date in April 1986, omeprazole was recognised as a breakthrough. It has been sold under the proprietary name “Losec”. The basic patent for omeprazole was applied for in the 1970s. It has expired by now but omeprazole is the subject of a Supplementary Protection Certificate. That expires in April of this year.[3]Omeprazole is taken orally in the form of a tablet. The drug has to pass through the stomach and into the intestines of the patient. It is in the latter location that it can be absorbed into the patient’s blood stream and thereby reach the sites in the body which control secretion of gastric juices. The patents in suit are concerned with the form and performance of the tablets. They have a few years to run.[4]A drug must be administered to a patient in a form in which it is “bioavailable”, that is to say it must be presented in a form which allows it to carry out its desired pharmaceutical function. Unfortunately omeprazole is acid labile, that is to say it is very sensitive to, and can be degraded by, acid. The contents of the stomach are acidic. To ensure that the active ingredient reaches the intestines without suffering significant degradation, it has to be in a form which protects it during its passage through the stomach but which allows it to be released in the intestine. The invention which is the subject of the patents is a form of oral administration of the drug which is resistant to stomach acid but is bioavailable in the intestines.[5]I will consider the disclosure and claims in the patents in a moment, but first I should say something about the technical background to this dispute. When a drug is to be administered orally, say as a tablet, it is almost never administered neat. Other substances, called excipients, are present. The claimants’ expert witness, Dr Rue, annexed a glossary to his report which explains what excipients are and do. They include lubricants to reduce friction in the die machinery in which the tablets are made, binders to keep granules in the tablet together, glidents to aid the flow of powder if the tablet consists of powder, bulking agents or diluents where only small quantities of drug are contained within the dosage, disintegrants to assist the tablet to release its active ingredients rapidly into solution, coating materials to mask taste, affect dissolution or protect the core of the tablet and plasticisers which can be incorporated into the coat of a tablet, if it has one, to improve its physical properties. A number of excipients will be used together in a single tablet. For example I was told that about 6 excipients would be used in a standard tablet of antibiotic.[6]One method of protecting acid labile drugs in a tablet from attack within the stomach is to give it a coating which is acid resistant. This is called an enteric coating. It consists of a layer of material, enclosing a core containing the active drug, which does not dissolve or disintegrate in the acidic environment of the stomach but dissolves or disintegrates in the more alkaline environment of the intestines. Although, as of 1986, enteric coatings were only used in a very small number of formulations, they were well known. For example the use of such coatings was taught to undergraduates. Enteric coatings may be very thin films. They normally consist largely of polymers, that is to say long molecules made by joining together smaller building blocks, called monomers. They work by keeping the acid in the stomach away from the molecules of drug within the core of the tablet so that they cannot react together. Enteric coatings are but a sub-group of a larger group of substances used as coatings for tablets. For example for many years it has been well known to coat tablets with layers of sugar. This is to give the tablet bulk and to make it more palatable. Sometimes the top coat includes a dyestuff so that the tablet can have a desired colour. Coating materials, including enteric coating materials, are excipients. The ‘983 Patent[7]The problems associated with making a dosage form of omeprazole suitable for oral administration are described in ‘983. Very sensibly, both sides have approached this case on the basis that there is no need to carry out experiments to prove that the patent’s description of technical phenomena is accurate. There is no suggestion that anything in the patent is technically incorrect or misleading or that the simple chemical experiments referred to in it could not be carried out by skilled formulators to produce essentially the same results. The patent describes the problem faced by the formulator of an orally administered dose of the drug as follows: “Omeprazole is however 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, e.g. at pH = 7 the half-life of omeprazole is about 14 hours, while at higher pH-values the stability in solution is much better (Pilbrant and Cederberg, Scand. J. Gastroenterology 1985; 20 (suppl. 108) p. 113-120). The stability profile is similar in 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. From what is said about the stability properties of omeprazole, it is obvious that an oral dosage form of omeprazole must be protected from contact with the acid reacting gastric juice in order to reach the small intestine without degradation. In human pharmacological studies it was found that the rate of release of omeprazole from a pharmaceutical dosage form can influence the total extent of absorption of omeprazole to the general circulation (Pilbrant and Cederberg, Scand. J. Gastroenterology 1985; 20 (suppl. 108) p. 113-120). A fully bioavailable dosage form of omeprazole must release the active drug rapidly in the proximal part of the gastrointestinal canal. In order to obtain a pharmaceutical dosage form of omeprazole which prevents omeprazole from contact with acidic gastric juice, the cores must be enteric coated.” (page 3 lines 8 to 25)[8]Low pH means acidic, high pH means alkaline. These passages make it clear that the obvious way forward to protect the omeprazole is to enteric coat it so as to protect it from acid. It will be noticed that the inventors refer to a paper by Pilbrant and Cederberg, one of the documents relied on by the claimants in this action. The inventors summarise its contents as follows: “The publication describes a conventional enteric coated dosage form and states that it has an acceptable storage stability - for clinical studies.” (patent p 3 lines 39 – 42)[9]It is not in dispute in this case, not least because of the contents of Pilbrant and Cederberg, that a skilled worker in the field in 1986 would have firmly in mind that oral administration was the preferred route and that an enterically coated dosage form was either necessary (as the patent itself says) or highly desirable because omeprazole is so acid labile. That would be his starting point in trying to formulate an acceptable dosage form of omeprazole. The inventors also describe the nature of the problem encountered if a standard enteric coating is used: “Ordinary enteric coatings, however, are made of acidic compounds. If covered with such a conventional enteric coating, omeprazole rapidly decomposes by direct or indirect contact with it, with the result that the preparations become badly discolored and lose in (sic) omeprazole content with the passage of time.” (patent p 3 lines 25 – 28)[10]The reason for the discolouration is that one of the breakdown products of omeprazole is intensely red in colour. The discolouration is a clear sign that degradation is taking place. In relation to the enterically coated omeprazole described in the Pilbrant and Cederberg paper the inventors say: “It was later found that the stability of this dosage form was insufficient during long-term storage required for a marketed pharmaceutical dosage form.” (page 3 lines 40 – 42)[11]Thus, the core of the tablet contains the very reactive alkaline omeprazole and this reacts with the acidic coating material. As the inventors explain: “The omeprazole containing alkaline reacting cores must be separated from the enteric coating polymer (s) containing free carboxyl groups, which otherwise causes degradation/discolouration of omeprazole during the coating process or during storage.” (patent p 5 lines 1 – 3)[12]The solution, which is the major feature of the claimed invention, is to prevent the acidic enteric coating from reacting with the omeprazole-containing core by keeping them apart by use of a separating layer. Because the omeprazole has to be bioavailable when it reaches the intestine, it must be released from the tablet. The enteric coating breaks down in the intestines. It is necessary for the separating layer to do likewise. Thus it must either be water soluble or water dispersible. Finally, the omeprazole in the core is itself made more resistant to acid degradation either by putting additional alkali in the core (which will sacrificially react with the enteric coating) or by using a less acid-sensitive form of omeprazole, namely one of its alkaline salts.[13]Claim 1 is in the following terms:
“An oral, pharmaceutical preparation stable to discolouration containing omeprazole as the active ingredient characterized in that it is composed of core material in the form of small beads or tablets containing omeprazole together with an alkaline reacting compound, or an alkaline salt of omeprazole optionally together with an alkaline reacting compound, and on said core material one or more inert reacting subcoating layers comprising tablet excipients which are soluble or rapidly disintegrating in water, or polymeric, water soluble, filmforming compounds, optionally containing pH-buffering, alkaline compounds between the alkaline reacting core and an outer layer, which is an enteric coating.”
[14]This contains a number of optional additives or alternatives. It will be appreciated that a typical product falling within this claim could consist of a tablet with a core containing an alkaline salt of omeprazole, an enteric coat and a separating coat between the two which is water soluble or dispersible. The patent describes a number of water soluble materials for use as the separating layer. They include hydroxypropyl methyl cellulose (commonly referred to as “HPMC”). This was a well known excipient. It also describes typical enteric coatings. They include various products sold under the trade mark “Eudragit L” and cellulose acetate phthalate (commonly referred to as “CAP”). Both of these were well known for this purpose at the time. Thus typical products covered by the patent would include the following: Core Subcoating layer Enteric coating Magnesium salt of omeprazole HPMC Eudragit L Magnesium salt of omeprazole HPMC CAP[15]The claimants argue that such products are obvious on the basis of common general knowledge or, as their counsel, Mr Floyd, puts it, common sense alone. However they also support their case by relying on certain pleaded prior art. It is conceded by Hässle that if the attack of obviousness succeeds against claim 1, none of the other claims survive. The claimants also advance an attack of anticipation against claim 1. Until just before the commencement of the trial, the claimants believed that Hässle had confirmed that it was only arguing independent validity for claim 1, so that if the anticipation attack were to succeed, then no independent validity of any subsidiary claim would be asserted. There is little doubt that that was the position which had been adopted by Hässle in correspondence. However at the beginning of the trial Mr Thorley for Hässle said that no such concession had been intended and that if his client defeated the obviousness attack directed at claim 1 but lost on the issue of anticipation, it would want to assert independent validity for each of the 9 subsidiary claims – some of which appear to be remarkably trivial. However, to allow withdrawal of Hässle’s concession in relation to the subsidiary claims and to allow the trial to continue would mean that, if there is no finding of obviousness but a finding of anticipation against claim 1, the claimants would have to attack the validity of the subsidiary claims and would be bound both here and in subsequent infringement proceedings in relation to their validity, when none of the witnesses have given any evidence in relation to that issue. That seemed to me to be potentially unfair to the claimants. In the end I adopted a middle course. Mr Thorley was allowed to withdraw the concession which he says was made in error but the issue of the validity of the subsidiary claims in the event of anticipation but not obviousness succeeding against claim 1 is stayed and reserved for consideration at a separate hearing. All questions of costs in relation to any such hearing are reserved.[16]Returning to the main issue of obviousness, although all three ingredients in claim 1, i.e. use of a separating layer, the fact that it is water soluble or dispersible and the use of alkali or alkaline salts of omeprazole in the core, were the subject of discussion during the trial, the greatest emphasis was placed on the first two.[17]Having considered the evidence and the submissions made, it seems to me that two major questions arise for consideration in this case. First, would the notional uninventive worker in the field be aware that there was a problem in making enterically coated oral dosage forms of omeprazole? Second, if he was, would it be obvious to him to try to solve the problem by making a dosage form falling within the ambit of claim 1? The Witnesses[18]In considering the issue of obviousness, it is necessary to determine what the notional non-inventive addressee would have thought and done at the priority date on the basis of the common general knowledge in the field and the pleaded prior art. In the end this is a question which must be answered by the court. In doing so it is normally assisted by evidence given by experts on either side. It is not necessary to repeat what was said in Lilly Icos v. Pfizer [2001] FSR 16 concerning the need to distinguish between the views of witnesses, who frequently will be at the top of their fields, may well be inventive and will come to the case with personal idiosyncrasies, and the approach of the notional uninventive worker in the field. Subject to that caveat, the evidence of experts is valuable and frequently essential in helping the court to understand a field of technology and the approaches which are likely to have occurred to relevant workers.[19]In this case only two witnesses were called for cross examination. The claimants called Dr Peter Rue. No criticism was levelled at Dr Rue’s fairness in giving evidence. In my view Mr Thorley was right not to do so. Dr Rue struck me as an impressive and reliable witness. However Mr Thorley did assert that he did not have relevant expertise and that his evidence should be, in large part, disregarded for this reason.[20]Dr Rue obtained a BSc degree in Pharmacy in 1973 from the University of Aston in Birmingham. He carried out research on the physical properties of pharmaceutical tableting excipients. He was awarded a Ph.D. in 1978. From 1977 to 1980 he was employed by Beecham Pharmaceuticals Research Division in their Formulation Development Department. While at Beecham, he was a member of a team investigating fundamental aspects of tablet compression. Additionally, he was investigating the technique of film coating using HPMC, in an Accela Cota, a machine used to apply film coats. This work was concerned with the effect of using solvent or aqueous solutions of HPMC on the efficiency of the process and the appearance of the tablets. In 1980 he joined the Pharmaceutical Research Department of Glaxo Group Research. In 1982 he was made Process Development and Formulations Services Manager; in 1985 Unit Manager; in 1986 Head of Marketed Product Formulation Department and in 1990 Head of Pharmaceutical Development Department. Throughout this time he was involved with the formulation and development of both new active drug substances and product line extensions. He continued detailed hands-on work in the drugs delivery field until 1999 when he retired for health reasons.[21]From this it will be seen that he had extensive experience in the field of formulating drug dosage forms. This included experience of film coating. In addition, under cross examination he explained that he had learned about enteric coating while still an undergraduate and had kept abreast of the developments in the field. The criticism was that, since he did not have direct experience of enteric coatings, he was not qualified to give evidence.[22]I reject that criticism for a number of reasons. First, what the attack of obviousness is directed to discovering is whether or not the claimed invention would have been made by the notional uninventive person or team in a pharmaceuticals company faced with the task of making an oral dosage form of omeprazole. As mentioned already, enterically coated tablets were, in 1986, a rarity although the existence of the technology was well known and taught at undergraduate level. It would be unrealistic to assume that the notional skilled addressee was already experienced in enteric coating. Most of the addressees would have or would acquire experience in tablet making and coating generally. Second, it was not suggested that there was anything different, unusual or clever involved in enteric coating as opposed to applying any other type of coating. The patents themselves give virtually no teaching relating to enteric coating. They simply require the dosage forms to be enterically coated and state that this is done by “conventional coating techniques” (‘983 p 5 line 31). Furthermore, the objection seems somewhat misplaced since Hässle’s expert, Dr Rees, also appeared to have no or virtually no hands-on experience. As Mr Floyd points out, this had not disqualified him from being put in charge of an enteric coating project which led to the only enterically coated drug in relation to which he acquired any experience.[23]The other witness was Dr Rees. He clearly is highly qualified and has great experience in the formulation field. There was no attack on his expertise. However Mr Floyd did suggest that Dr Rees’ approach was more akin to that of an advocate than an expert. He said that this might well have been because of over exposure to the patentee’s case, having been involved on Hässle’s side in similar litigation in Australia, Canada, Norway, Israel and the EPO.[24]It would have been much more pleasing to say that Dr Rees was as impressive a witness as Dr Rue, but I cannot. He was cross-examined with courtesy but great precision by Mr Floyd. The overwhelming impression on me was of an able man who was acting as an advocate for the defendant’s case. Reading the transcript does not give a full feel for how the cross-examination went. As it progressed, Dr Rees appeared to experience growing difficulty in answering questions. Towards the end there were frequent and embarrassingly long pauses while he tried to find answers to simple, but telling, questions put to him by Mr Floyd. Furthermore, when one looks at his evidence as a whole, the impression is given of an attempt, no doubt unwitting, to think up as many alternatives as possible to the use of a separating layer between the enteric coating and the omeprazole-containing core. All of these were then said to be more likely to be thought of than the use of a separating layer. Indeed, he said that he did not believe that, before the priority date, the skilled formulator would have thought of using any kind of subcoat (Bundle G Tab 1 paragraph 155). This resulted in him advocating possible alternative routes which were obviously untenable. Some of these I will have to touch upon later in this judgment. At this stage it might be useful to refer to just a few examples of the difficulties with his evidence.[25]Dr Rees suggested in his report that the worker in the field would think of using a prodrug, rather than omeprazole, to avoid the discolouration problem. Under cross examination, he accepted that this would be far more speculative than the use of a separating layer as a barrier (Transcript 3/342). Similarly, in his first report he suggested that, rather than think of using a separating layer, the man in the art would turn away from oral administration. He said:
“As an alternative to tackling the problems head on, one could develop an alternative formulation system designed, say, for buccal, sub-lingual, transdermal or rectal administration, thereby avoiding the need for an enteric coating altogether. However, rectal administration is often unpopular with patients. And I do not know whether omeprazole can be absorbed via the transdermal route, or by buccal or sub-lingual administration. Thus, a further research programme would likely have been required .”
(emphasis added First Report paragraph 153)[26]The message conveyed by this passage, taken in the context of the rest of Dr Rees’ first report, is that the worker in the field was likely to be driven to carrying out a research program to replace oral administration of omeprazole by some other form of administration. Once again he would do this because he would not think of using a separating layer between the omeprazole and the enteric coat it reacts with. Under cross examination Dr Rees agreed that this was a far more speculative route than using the separating layer.[27]Similarly, Dr Rees said that it would not occur to a man in the art that discolouration was caused by a reaction between the omeprazole and the coating layer. He said this in his first report:
“[The worker in the field] would have investigated (as another possible source of the discolouration problem) the quality of the synthetic polymers used in the formation of enteric film coats. Polymers may include trace amounts of monomers from which the polymer chains are synthesised, or of initiators used to promote the polymerisation reaction. Although I have not encountered this as a problem, the monomers and initiators are likely to be much more reactive than the enteric coating polymer itself, and thus would be more likely culprits than the enteric film-formers themselves.”
(emphasis added - First Report paragraph 135)[28]The suggestion that the worker in the field would have attributed the discolouration to reaction between the omeprazole and monomers or initiators which, if present at all, would be present only in trace amounts, and not think of the possibility or likelihood of reaction between the omeprazole and the coating polymer which was present in very large amounts, was initially defended by him under cross examination but then conceded as wrong (Transcript Day 3 p 321). Dr Rees was concentrating on the pin rather than the haystack.[29]Another criticism of Dr Rees was the way in which he had changed his evidence. For example, in Australian proceedings relating to the equivalent patents in that country, he had said:
“One could simply decide to accept the discolouration of the formulation, or even to hide it using a pigmented film coating or an opaque coloured capsule. However, ignoring the problem is likely to cause problems with patient compliance, since patients finding variations in the colour of their medication may fear the product had “gone off”
. Also, either ignoring or trying to hide the discolouration would be unacceptable to the regulatory authorities in many countries.” (X8)[30]The meaning of this is clear. Even if one were to consider trying to mask the discolouration, this would not be a route to go down because patients would not like it and, more importantly, it would be unacceptable to regulatory authorities “in many countries”. However, for the purposes of the trial, Dr Rees changed his evidence by deleting the crucial last two sentences. Now it reads: “He could simply decide to accept the disclouration of the formulation, or even hide it using a pigmented film coating or an opaque coloured capsule.” (First Report paragraph 151)[31]Far from suggesting that accepting or masking the discolouration was not acceptable, as he had said in Australia, in these proceedings he was saying it was. When this change was put to him under cross examination, he accepted that it would have been fairer to have retained the full passage as in his Australian evidence. When he was asked why he did not his response was that it was probably for the sake of brevity (Transcript Day 3 p 339).[32]Mr Floyd relied on other areas where he said that Dr Rees’ evidence appeared to be unbalanced. Some of those will be mentioned below. In his reply speech he submitted that Dr Rees’ evidence must be treated with caution and that it is to be contrasted with that of Dr Rue which was straightforward, objective and fair. I accept that submission. (A) Would the skilled worker realise that a problem existed?[33]The claimants’ case on the central issue of whether a separating layer would be used is very simple. They say that it would have been anticipated or discovered that there was a degradation problem caused by reaction between the omeprazole-containing core and the enteric coat. Once that was appreciated, the, or an, obvious route to take was to keep the two apart by a separating layer. Concentrating on the first part of this two step analysis, the claimants say that the skilled worker at the priority date would have anticipated that the acid-sensitive omeprazole would be attacked by the acidic enteric coat and that, whether he anticipated it or not, he would have found it out almost immediately. I can leave the question of anticipation for the moment and concentrate on the question of whether or not the worker would have discovered the problem almost immediately.[34]Dr Rue’s evidence was that he, and any skilled worker in the field, would carry out pre-formulation studies before fixing on a final dosage form. These studies are designed to find out at an early stage whether there are likely to be any unacceptable problems in making the dosage form of the drug. He explained his starting point in his first report. The first thing he would have done was to gather data on omeprazole. Prior to conducting any experiments, as part of the information gathering exercise, he would have carried out a literature search. He said that it is standard when researching a new drug to search for and read what is known about that drug and its formulations, both clinically and pharmaceutically. None of this was in dispute. Nevertheless, for the purpose of his evidence, he assumed – contrary to what both parties accepted was likely to be the case – that he had found none of the prior art material relating to the characteristics of omeprazole which are pleaded in this case.[35]He said that in considering the type of formulation that would be suitable for omeprazole, he would have needed information, inter alia, on the stability of the drug. He put this as follows: “The stability of the active substance would be investigated, both in solution over a range of pH values, typically 1 to 8 and in its solid state. The solid state stability would use a range of temperature and humidities (typically - -18ºC, 20ºC, 20ºC/80% relative humidity, 30ºC, 40ºC, 40ºC/80% relative humidity and 60ºC) to stress the samples so as to accelerate any degradation that might occur. The testing would consist of appearance, colour, odour, assay (measurement of purity), an assessment of the concentration of degradation products and, in the solid state stability tests, determination of moisture content. A comparison of the results obtained for 40ºC samples and the 40ºC/80% relative humidity samples would have determined the sensitivity of omeprazole to moisture.” (First report paragraph 6.3(ii))[36]This is not disputed by Dr Rees. Dr Rue’s evidence was that the results of these stability tests (which include subjecting the drug to abnormally high temperatures and moisture levels so as to “stress” it) would have taught him, and the average formulation scientist, that omeprazole was prone to degradation by acid and moisture. Once again this is not disputed. Indeed, as the patent states, and is accepted as technically accurate, omeprazole is very sensitive to acid environments (see paragraph 7 above). He also said that it would be normal to find out if other forms of the drug were more stable and the sodium, calcium and magnesium salts would have been the most obvious to try. This is not disputed by the defendant.[37]The crucial point of dispute arises at this stage. Dr Rue’s evidence is encapsulated in the following passages from his first report:
“6.6 As part of the pre-formulation studies, I would have carried out compatibility tests between omeprazole (and the salts if shown to be more stable) and each of the standard excipients used in oral dosage forms. From the results of the stability tests, (para 6.3 (ii) above) I would have realised that the rate of degradation at the stomach pH range (less than 4) was so large that in order to achieve acceptable oral bioavailability, omeprazole would need to be in an enteric coated dosage form. I would have included an enteric coating material, most certainly Eudragit L30 (with which I was familiar at the time) and one or more of the other enteric coat materials such as HPMCP, PVPP or CAP in the compatibility studies. 6.7 In the compatibility studies omeprazole (and the salts if shown to be more stable) would have been mixed individually with each excipient and the powder mixture would be stored at different conditions (typically 20ºC, 40ºC, 40ºC/80% relative humidity and 60ºC). The mixtures would have been examined periodically at appropriate time intervals for signs of degradation. The degradation may have been seen visually as a change in appearance (colour, aggregation, odour ) . Any discolouration would have been considered significant. An assay would be carried out on the mixture using the analytical methodology developed during the forced degradation studies. The mixture would also be examined by thin layer chromatography to look for known and unknown impurities and degradation products and the moisture content of each mixture would have been measured. These studies would have determined which excipients could be used without causing degradation. The sensitivity of the mixture to moisture would have been shown by comparison of the results obtained after storage at 40 o C with those obtained after storage at 40 o C/80%RH. 6.8 … Given the results of the Patents which show that a discolouration is seen when an enteric coat is applied directly to an omeprazole core (example 1(I) in table 3), I would expect to have found discolouration in my compatibility studies even though my studies were on the powder mixture. Any such discolouration would have been unacceptable.”
[38]The evidence that it would have been apparent, even without any of the pleaded prior art, that an enteric coating was needed, is not disputed. Indeed, as can be seen from the passage quoted from the patent in paragraph 7 above, it is conceded that the need for an enteric coating was obvious. The issue of the need to carry out compatibility studies between the omeprazole or its salts and the excipients (including enteric coating material) which were being contemplated for use in the formulation, was also addressed by Dr Rue in his second report: “Dr Rees is correct that if discoloration is first seen when a formulation is produced, there are several factors which could be responsible. It is for this very reason that pre-formulation studies are carried out before a formulation is produced. The accelerated stability and compatibility studies at the pre-formulation stage ensure that any degradation is seen early on, before the stage when a formulation is produced containing a large number of different ingredients. Although, as Dr Rees acknowledges (paragraph 32), different formulation scientists would have carried out pre-formulation studies to different degrees, I believe that all of them would have carried out at the very least the following tests as part of their pre-formulation studies: … compatibility studies using binary mixtures of the active and each excipient (paragraphs 6.6 and 6.7 of my first Report). The above is the very least that would be studied, …. The last thing a formulator would want is to produce a formulation only to find degradation several months into a stability study on the formulation, for example, caused by an excipient which could have been avoided had compatibility studies been carried out. Any graduate will learn very soon after leaving academia the importance of carrying out well controlled basic experiments before formulating a product rather than relying on theoretical predictions.” (Second report paragraphs 4 to 6)[39]This evidence was only partly challenged during cross examination. It did not seem to be suggested that pre-formulation trials, including compatibility studies, would not be undertaken. The cross examination concentrated on the suggestion that the pre-formulation studies would not have included compatibility testing between omeprazole and the enteric coating material. On this latter point, Dr Rue was pressed hard. His evidence was consistent and firm. Although there are many references to this issue in the transcripts, two will serve to illustrate the nature of Dr Rue’s evidence: “…excipients are designed and market[ed] to be inert whenever possible. The active drug substance is a very different matter. It is a novel chemical. Its chemistry is not particularly well understood, certainly its degradation chemistry is not well understood in the early stages. It would be a very unwise person who assumed that a particular drug substance was compatible with any excipient. Indeed, I think it is extremely unusual for a drug substance to react with for example starch or microcrystalline cellulose. Nevertheless, one of the early experiments that any formulator would do is to endeavour to put those two materials together in such a way that if they were going to react, they would do. You try to stress the system to give it a maximum chance of reacting so that we know there is a potential problem. If we do not see a potential problem under highly stressed circumstances then we are much more comfortable that we are unlikely to see it under normal storage conditions.” (Transcript Day 1 p 107) And “Q. Can I suggest that with that degree of concern, the skilled formulator would have done as Dr. Rees suggests and said let us keep it as dry as we can? A. Yes, certainly. Q. That he would not have seen the necessity, in the light of his experience in the past where enteric formulations had been used in relation [to] the acid labile materials without interaction, he would not have seen the necessity to do pre-formulation exercises with it? A. I disagree. I think it would be very unwise for somebody to dismiss the possible of an interaction between an enteric coat or any other coating material and the drug. Q. Notwithstanding the fact that this had never, as far as we can see, occurred in the past? A. Indeed.” (Transcript Day 2 p 136)[40]The different approaches adopted by the two experts could not be more stark than in relation to this issue. Dr Rees’ evidence was that a typical formulation team would be very selective on the pre-formulation work it undertook. First, he suggested that it would not do one-on-one computability trials between a new drug and the excipients which were likely candidates for use in the final dosage forms. Instead it would make up the final dosage form and do compatibility tests on that. Second, he said that even if one-on-one compatibility studies were performed, omeprazole would be tested against the other excipients to be used in the tablet but not against the excipients being contemplated for use as the enteric coating material. For both these reasons, the person skilled in the art would not discover that there was an incompatibility problem between omeprazole and the enteric coating with the consequence that he would not turn his mind to solving it.[41]First, I shall deal with the suggestion that a skilled but uninventive formulation team would not do one-on-one compatibility trials. Dr Rees said this at an early stage in his cross-examination: “Q. You agree that again, a skilled formulator in 1986 would ordinarily conduct compatibility studies as part of that preformulation exercise? A. No, I do not agree that that would be shall we say the normal course of events for an individual formulation scientist to do preformulation excipient compatibility studies. There was a very wide range of approaches and attitudes towards the benefits that might, or could be obtained from doing excipient compatibility tests. The reasons for that were several fold, but one of the reasons was that if one had done no formulation work, in order to try to identify which particular types of excipient were likely to be useful to achieve formulation, a particular formulation of a particular compound, then one might be wasting time looking at materials that actually were not suitable from a technical point of view in formulating that particular new chemical entity. So, there was shall we say, disagreement I think one could say, between formulation scientists as to whether one should spend time doing excipient compatible studies ab initio when presented with a new compound or alternatively, start formulation work in order to identify from a technological standpoint what was appropriate, what excipients were suitable for shall we say preparing a core the new chemical entity in the form of the tablet. There was a range of approaches, shall we say. Certainly not all individuals, not all groups concerned with formulation started from this position of doing excipient compatibility studies. There were other reasons for that difference in approach and one of them was that if one simply studied compatibility with one individual material, then that actually told one little about what the situation would be in a multicomponent mixture, for example as used to prepare a core. Another approach which was advocated certainly in the 1970s was to use a multifactorial approach and to actually mix the active compound with a number of excipients and to study the stability of that mixture, being a mixture of the drug plus several excipients and to do a number of these different mixtures for study. There were different approaches. Q. Can I put it this way, ordinarily a formulator would conduct compatibility studies on the components that he knew were going to be part of his formulation? A. One cannot say that, because he did not know what is going to be component of a formulation. He could make some predictions as to what he might want to use, but would have no certainty. As I explained a moment ago, that was part of the reason why certain groups, and for example during my period from 1979 to 1981, the group that I was responsible for at this point did not do excipient compatibility tests prior to embarking on formulation work, my Lord.” (Transcript Day 2 pp 238-9)[42]Having thus said that carrying out compatibility testing was not the normal course to adopt, Dr Rees was pressed further by Mr Floyd: “MR. FLOYD: Can I suggest to you that there was at the very least a respectable and substantial body of formulators in 1986 who would have conducted compatibility studies on the components of the formulation before embarking on the formulation itself. A. It was one approach and there was a considerable group of individuals who did that. Equally well, there were considerable number who did not embark on formulation work by starting with excipient compatibility studies. Q. You do not disagree with my formulation, a respectable and substantial body of formulators who would do it? A. There would be that and equally there would be a respectable body who would not do it.” (Transcript Day 2 p 241)[43]His evidence on this subject modified during cross examination. He said that as a result of a particular experience that he had while working for Abbottt Laboratories which was, incidentally, his only experience of enteric coating and then at a managerial level rather than on a hands-on basis, his attitude was to go straight to doing compatibility studies on the complete formulated dosage form. If there proved to be no problem with the complete dosage form, this would indicate that doing the testing against individual excipients would have been a waste of time. However he also accepted that if there was a compatibility problem with the proposed final dosage form (as there would be with enterically coated omeprazole without a separating layer) then the necessity of individual one-on-one compatibility trials would arise and were carried out. Eventually he gave the following evidence: “MR. FLOYD: I think what you were saying is that at Abbott, you changed to doing things in parallel rather than in sequence, is that a fair summary? A. It is partly true, in that in fact we rarely did move to a situation of doing the sort of excipient compatibility tests that are referred to; one to one excipient compatibility tests. We did that occasionally, if we ran into problems. We did that, as you say, alongside the formulation work on occasions when problems were encountered.” (Transcript Day 2 p 244)[44]Thus his final position was that, even at Abbott, if a problem arose one-to-one compatibility trials would be carried out. He further accepted that he knew of no textbook in 1986 which supported his view that preformulation studies with excipients can be a waste of time (Transcript Day 2 p 246).[45]It follows that, even had Dr Rees’ approach of not starting with compatibility studies between individual excipients and the drug been the norm in 1986, the skilled worker would still have had to do such studies as a matter of course as soon as he discovered, as he would very rapidly, that the simple enterically coated tablet discoloured because of the rapid decomposition of the drug caused by contact with the coating material as stated in the patent.[46]However, I am not satisfied that the approach suggested by Dr Rees would have been that adopted by the notional skilled addressee in 1986. Dr Rue gave compelling and convincing evidence that the simple and logical course, and the course which would be adopted by virtually all formulators, would be to test the new drug against excipients before they are all combined into a dosage formulation, i.e. at the pre-formulation stage. This view was supported by a number of standard textbooks which were referred to in the trial and put to the witnesses. For example the authors of Pharmaceutical Dosage Forms say:
“Preformulation testing is the first step in the rational development of dosage forms of a drug substance. It can be defined as an investigation of physical and chemical properties of a drug substance – alone and when combined with excipients.”
And “Compatibility Studies: Stability in the Presence of Excipients In the tablet dosage form the drug is in intimate contact with one or more excipients; the latter could affect the stability of the drug. Knowledge of drug-excipient interactions is therefore very useful to the formulator in selecting appropriate excipients. This information may already be in existence for known drugs. For new drugs or new excipients, the preformulation scientist must generate the needed information. A typical tablet contains binders, disintegrants, lubricants, and fillers. Compatibility screening for a new drug must consider two or more excipients from each class.” The book then goes on to list the quantities of individual excipients which are recommended for testing against a drug.[47]Similarly, in The Theory and Practice of Industrial Pharmacy the authors say:
“Stability with Excipients Drug-excipient studies are designed to assist in selecting a basic list of excipients, which can be successfully used in the final dosage forms. Lactose, starch, stearic acid, magnesium stearate, dicalcium phosphate, calcium sulfate, and sucrose are some of the substances that are routinely tested in combination forms.”
[48]The passage then goes on to refer to mixtures containing 20:1 drug-lubricant, and 1:5 drug-excipient mixtures being analysed and gives a table which illustrates the type of results one can expect by testing aspirin in mixture with single additives. It also refers to mixtures containing 1:1 drug-excipient being used for rapid determination of incompatibilities.[49]In fact the only evidence of anyone following the route suggested by Dr Rees consists of Dr Rees’ experience in Abbottt Laboratories. Even in relation to this, it appears that the Abbottt approach was different to that adopted by other pharmaceutical companies for whom Dr Rees had worked and, even in Abbottt, it appears that the one-on-one compatibility trials were carried out at the same time as the compatibility trials on the complete formulation: “Q. Are you saying that is not an approach that you, yourself would have adopted? A. My approach actually changed from the time that I spent with Sandoz in Switzerland to the time when I spent a period of three years with Abbottt Laboratories, in that as I have indicated a moment ago, this approach to combining the drug with individual excipients was not an approach which we used. We embark[ed] on formulation work and then at the same time we might have undertaken some work such as this alongside the formulation work. In other words, not starting out with doing one to one mixtures of the drug with individual excipients.” (Transcript Day 2 p 242-3)[50]It follows that I accept the evidence given by Dr Rue that one of the first pre-formulation steps which any uninventive skilled formulator would take would be to test the compatibility of omeprazole or its salts with individual excipients.[51]This leads to Dr Rees’ second point, namely that such compatibility studies, if carried out, would not be carried out in relation to the material used for the enteric coating. Although Dr Rees accepted that a coating material would be considered an excipient, he said that, in 1986, a skilled formulator would ordinarily have restricted his pre-formulation compatibility studies to components contained within that part of the formulation that contained the active compound, which is usually the core. Thus incompatibility between the contents of the core would have been tested for but possible incompatibility between the enteric coating and the core would not. Dr Rees advanced two reasons for coming to this conclusion. First, he said that, compared with the situation of ingredients combined within the core of a dosage form, the potential for interaction between a constituent of the core and an applied film coating is very much less. The reason for this was the “relatively small area of interfacial contact between a core and an applied coating” (Second Report paragraphs 18 & 19). Secondly, he said “… it was commonly known in April 1986 that an enteric coating polymer was not expected to be incompatible with other substances under conditions encountered in pharmaceutical systems.” (Second Report paragraph 20).[52]Mr Thorley accurately referred to this latter point as Dr Rees’ “theory” which was based on the assumption that the enteric coating was compatible with the materials in the core of the tablet and for this reason compatibility tests were not necessary (Transcript Day 2 p 139).[53]Dr Rue disagreed with these views. He said that one could not assume that the coating material was compatible with the new drug. This was something that had to be tested. As he said, all excipients are meant to be inert, but it would be an unwise person who took that for granted (see the passages from the transcript set out in paragraph 39 above). He said that the skilled worker would not assume that there is no reaction. One would always prove there is no reaction (Transcript Day 2 p 189). Second he disagreed with the suggestion that because the enteric polymer was used as a coating it could be ignored. Once again, one could not take the risk of interaction (Transcript Day 2 p 132 –6)[54]It is convenient to deal with these points in turn, starting with the suggestion that one would not carry out compatibility studies on the drug/coating polymer because the latter was only to be applied as a coat rather than mixed with the drug in the core. This can be taken in a number of stages. First, Dr Rees accepted that there was no suggestion in any textbook that coating materials should be excluded from compatibility testing (Transcript Day 2 p 252). Nevertheless he said: “Q. You exclude all [coating] materials from that caution? A. As I say, I am only saying that on the basis of experience that would be the expectation, that one did not need to concern oneself with a material that was not intimately mixed with the active drug substance. Q. Could you turn on to tab 13? MR. JUSTICE LADDIE: Are you saying that you do not treat a coating material which is adhering to molecules of the active drug as being intimately in contact with the active drug? Is that the point you are taking? A. No, I could not say that there would be no contact at all under that circumstance, but I am saying that the amount of contact between such material applied as a coating to a core was generally accepted to be so limited that problems were not anticipated.” (Transcript Day 2 p257 – 8)[55]Mr Floyd challenged this. In particular, in relation to the evidence that it was generally accepted that one need not concern oneself with the possible interaction between the active drug in the core and coating, Mr Floyd put to Dr Rees one of the standard textbooks in this field, Pharmaceutical Dosage Forms (Tablets) by Lieberman and Lachman. At page 362, under the sub-heading “Drug-Excipient Interactions” it says:
“It is well known that the preparation of tablets involves the use of so-called ‘inert’ ingredients. Excipient or adjuvant materials are added as binding agents, lubricants, disintegrants, diluent, or coating materials and are necessary for the preparation of good-quality drug product. Since these ingredients often constitute a considerable portion of the tablet, the possibility exists for drug-excipient interactions to influence drug stability, dissolution rate, and drug absorption; …”
[56]Dr Rees accepted that since this referred to problems with tablets it was talking about drug-excipient reactions in the dry state. He also accepted that coating materials were properly classified as excipients. However he disagreed with Lieberman and Lachman: “Q. … It is right that at least the authors of this textbook consider that coating materials do display a potential for reaction with drugs? A. Yes, they identify a possibility. Q. Do I take it that you regard that concern and that possibility as quite unwarranted? A. I know certainly now after being involved with the patent that that is not right. Q. Lieberman and Lachman had not been involved with the patents and they were expressing that view in a respected textbook in 1982? A. Yes, they were expressing that possibility. I did read this section and I found nothing further to support any (inaudible). Q. I take it that the evidence that you give to my Lord is that you could not disagree more with what he says there about coating materials? A. On the basis of experience, my Lord, certainly I would disagree.” (Transcript Day 2 p 259).[57]I have found it difficult to accept Dr Rees’ evidence on this issue. It is based on his theory that the enteric coating is stable and will not react with the new drug. This, in turn, appears to be based on his experience of a single enterically coated product at Abbottt. However, as Dr Rue pointed out (see paragraph 39 above), each drug is a novel chemical whose chemical reactivity is little understood. Dr Rees’ theory involves an assumption that all excipients will be stable and will not react with any new drug, no matter what its reactivity. Even ignoring the contents of Pharmaceutical Dosage Forms (Tablets) and other basic literature in this field, which I will turn to in a moment, I do not accept that it would have been regarded as safe to assume that the new drug and an enteric coating material would not interact. Dr Rue said that no such assumption would or could be made by a skilled worker. I accept that evidence which accords with common sense. It also accords with the published literature. The passage from Pharmaceutical Dosage Forms (Tablets) set out at paragraph 55 above refers to the excipients as “so called ‘inert’ ingredients” and warns that interaction can take place between them and the drug. All excipients are hoped to be inert in the majority of applications but, as a matter of course, they are subjected to compatibility studies with new drugs. Furthermore the same volume states expressly that compatibility studies between drugs and excipients “must” be carried out whenever new drugs or excipients are proposed for use (see the passage set out at paragraph 46 above). The same point is made in other documents. For example in Remington’s Pharmaceutical Sciences the authors say:
“ Drug Substance-Excipient Interaction – Drug substance-excipient studies are designed to determine a list of excipients that can be used routinely in the final dosage forms. Lactose, sucrose, calcium sulfate, dicalcium phosphate, starch and magnesium stearate are some of the substances routinely tested in combinations. Some basic observations with the drug substance and/or its salt form can sometimes dictate what excipients can be used. For example, one would not consider using sucrose or lactose if the drug substance being considered is a primary amine. This system has the potential for interaction to form a colored compound readily detected by a color change. … At this point in the stability evaluation, which is a preliminary screening process, it is not necessary to know exactly how much has degraded. It is an all-or-none effect. The search is for the excipients that have no effect on the stability of the active ingredient .”
(emphasis added)[58]It hardly needs saying that one would hardly engage in a search for excipients which have not effect on the stability of the drug if, as Dr Rees said, a worker would assume that all excipients are inert. Furthermore Dr Rees’ evidence on this point was undermined by his concession under cross examination that enteric coating materials were not thought to be inert and were covered with reactive groups (Transcript Day 3 page 262). However, as telling as any evidence on this subject, are the documents published by Dr Rees himself before he became involved in this litigation. For example in a review article entitled “Tableting Research and Technology” published in the Journal of Pharmaceutical Sciences in 1972, Dr Rees wrote:
“FORMULATION General Principles – Recognition of the risk that “inert” excipients in tablet compositions might lead to undesirable effects on the stability or bioavailability of the drug has led formulators to exercise caution in the selection and inclusion of such additives. This selectivity requires a greater understanding of the inherent physical and chemical properties of excipients so that within the framework of processing necessities there will be no interference with the ultimate quality of the finished product”
[59]Under cross-examination, Dr Rees accepted that he had criticised the use of the term “inert” in relation to excipients. The above passage was put to him by Mr Floyd. He accepted that it accurately reflected his views in 1972 and he accepted also that it was a fair summary of the attitude of the skilled formulator in April 1986. Mr Floyd reminded Dr Rees that the review article went on to discuss various excipients and included a section on coating materials yet it did not suggest that a different approach should be adopted to coating materials than to any other excipients. Dr Rees agreed (Transcript Day 3 p 267-8)[60]Dr Rees wrote another article, under the title “Formulation of medicines for oral administration” which was published in the September 1974 edition of T he Pharmaceutical Journal . The article contains a subheading “Excipients” which includes the following:
“When developing a dosage form the choice of excipients is restricted particularly if the same formulation is to be marketed in several countries. Limitations include the compatibility of excipients with the drug in question … Several types of drug-excipient interaction can occur, such as adsorption and changes in equilibrium solubility, partition coefficient and dissolution rate. Many drugs form complexes with macromolecules such as cellulose derivatives, gums and non-ionic surfactants commonly used as excipients; the effect may be to increase or decrease absorption. So-called solid-solid interactions between insoluble drugs and excipients occur most readily in aqueous suspension but there is normally sufficient moisture present in a solid dosage form to induce the same effects. Polyvinylpyrrolidone, frequently used to prepare tablet granulations, interacts in the solid state with several drugs of low solubility including salicylamide and griseofulvin with a significant increase in the dissolution rate.”
[61]These passages were put to Dr Rees under cross-examination. He agreed that what he had written would represent the view of the skilled formulator in 1986. As he said at that point in his cross-examination, the skilled formulator “would have recognised that there was this potential for reaction” between the excipients and the drug (Transcript Day 3 page 270).[62]Similarly, Dr Rees wrote an article entitled “Film coating: 1 Formulation and process considerations” which was published in the April 1974 edition of Manufacturing Chemist & Aerosol News . It contains the following warning:
“Possible incompatibilities between the excipients in a water-based dispersion and the active drug in a tablet core should also be considered.”
[63]This passage was put to Dr Rees under cross examination: “Q. The thrust of my question was going to be about the next sentence: ‘Possible incompatibilities between the excipients in a water-based dispersion and the active drug in a tablet core should also be considered.’ A. Yes. Q. Is that not advice that you are giving to skilled formulators in 1974, that they should be concerned about interactions between coating materials and active drugs in the tablet core? A. Certainly it refers to excipients, so components within the water-based dispersion, yes. Yes, that is true. Q. That was your view in 1974. Is there any reason why your view in 1986 would have changed? A. I can only say that thinking back to 1974 I was aware of the types of system which were being offered by companies like Rohm and Haas at the time, which were very unstable dispersions, and where there were fears about the stability of those dispersions, and that was certainly a point of considerable concern to formulators using those dispersions. Could I just read this again to see if that may explain what I have written here? Q. Yes, of course. A. It would not explain the wording “active drug” certainly, on the basis that these aqueous dispersions were unstable to electrolytes, for example, they were unstable to mechanical forces such as shearing, and so certainly there was a possibility there of destabilisation of those suspensions. Q. That is, with the greatest respect A. Here it does say “active drug”, I agree with you. Q. It is talking about incompatibilities between the excipients and the active drug as something which should be considered? A. Yes, it does appear so. I agree. It does say that, yes. Q. On the basis of your advice, it would be sound practice to include the film forming excipients in preformulation studies, would it not? A. That could suggest that that would be a way to identify if that problem existed; yes, I accept that.” (Transcript Day 3 pp 293-4)[64]No explanation was offered for the inconsistency between all of these publications, including Dr Rees’ own publications, and the theory advanced by him for the purpose of these proceedings that a skilled formulator would not carry out compatibility studies because he would assume that the excipient was inert to the new drug. In my view Dr Rees’ theory is ill-founded. All competent formulators at the priority date would have been alert to the possibility of incompatibility between a new drug and excipients.[65]This takes me to the second of Dr Rees’ points, namely that, even if one contemplated the possibility of incompatibility between the coating material and the active drug, one would not test for incompatibility because the former was only used as a coating. As I understood it, the suggestion was that the coating material was in some way in less close contact with the drug than when the excipients were located in the core. There was a lot of cross examination on this issue.[66]On first principles, this suggestion appears unconvincing. For the purpose of avoiding a subsidiary issue of anticipation, the defendant was anxious to point out that a coating adheres to the surface of the core in the tablet. At the surface of the core, the contact with the coating material could not be more intimate. Furthermore, the documents referred to above, including in particular, Dr Rees’ own publications, make it clear that the possibility of interaction between drug and coating material was indeed something that the formulator would have in mind, notwithstanding the fact that one was to be used as a coating. See, for example, the last question and answer in the extract from the transcript at paragraph 63 above.[67]Further, even had Dr Rees’ initial evidence on this issue represented the views of the notional skilled formulator, he would inevitably have been driven to consider and test for incompatibility between the drug and the coating. This is because, on Dr Rees’ approach, the only compatibility trials would be carried out as between the drug and the excipients in the core. On the basis of this, excipients would be chosen which showed no incompatibility with omeprazole. Cores made with all the excipients and the drug would then be formed. Again, no incompatibility would be found (a fact confirmed by the experiments in the patent). It is only when the coating goes on that incompatibility would raise its head. So, even if Dr Rees’ views were those of the notional addressee, one would be driven to the conclusion that the discolouration which would be seen rapidly once the coating was applied is likely to be associated with the application of the coating material. Again, this is consistent with what standard textbooks in the art said before the priority date. In particular in Remington’s Pharmaceutical Sciences the authors say:
“ Formulation Ingredients Although preliminary screening of commonly used excipients with new drug substances has become routine in preformulation studies, there are occasions when problems arise because of the interaction with additives such as preservatives, stabilizers, dyes, and possibly flavors. A discussion of some problems that have arisen is in order to make formulators aware that they should be concerned about the potential for interaction whenever another ingredient is added to a formulation .”
(emphasis added)[68]In my view, the overwhelming weight of the evidence and common sense is that the possibility of chemical interaction between a new drug and each of the excipients contemplated for use in the dosage form, including the coating material, would have been recognised by the skilled formulator. Compatibility tests would have been carried out as a matter of course. That would have shown incompatibility between the acid labile omeprazole or its salt and the enteric coating material. In these circumstances, I do not need to consider Dr Rue’s evidence that the notional worker would have anticipated a problem because of the common knowledge that the coating material contains exposed acidic groups which were likely to react with omeprazole. Whether he anticipated that problem or not, he would have carried out the same compatibility tests and rapidly would have discovered the problem. (B) Would the skilled worker think of trying to solve the problem by making a dosage form falling within the ambit of claim 1?[69]Once again, the claimants’ case is simple. Use of multi-layer tablets was well known. Physical separation of ingredients in a tablet was known. It was obvious to try to overcome the incompatibility between a new drug and the coating film by keeping them apart. Use of an intermediate layer between them was an obvious route to try. Indeed, the claimants argue that this suggestion was made in a number of publications before the priority date. Before turning to the detailed evidence on this issue, it is worth bearing in mind just how basic the concept is. The idea of placing a physical barrier between two reacting chemicals is the rationale behind the use of enteric coatings. They create a physical barrier between the acid in the stomach and the acid-sensitive drug in the tablet. As already noted, this was so well known that it was taught to undergraduates.[70]Furthermore it was common knowledge that one could physically separate components which have a tendency to react with each other. I have already referred to the knowledge of enteric coatings, but there is more. For example it was well known that if two proposed ingredients in a tablet core were incompatible, they could be separated by leaving one in the core and dispersing the other in a coating layer. Dr Rees accepted that this was well known (Transcript Day 3 p 278). It was also well known that one could make multi-layered tablets to keep incompatible components away from each other. This was referred to in The Theory and Practice of Industrial Pharmacy (1976) in which the authors state:
“ Multilayer Tablets . Multilayer tablets are tablets made by the compressing of several different granulations fed into a die in succession, one on top of the other, in layers. Each layer is from a separate feed frame with individual weight control. At present, machines have been designed for two and three layers; more are possible but the design becomes very special. … Multilayer tablets are not new, but with the great interest in press coating, the advantages of the form have been better realised, especially since new machine designs have made it possible to check the weight of the layers by sampling without stopping the machine. The general advantages are: (1) two incompatible drugs may be kept separate by interposing a center, inert layer between them ; …”
(emphasis added)[71]This was put to Dr Rees. In particular his attention was drawn to the underlined words in the above-cited passage: “A. Yes, I see that. Q. That is the practice that was referred to and would be, is this right, adopted where simply putting them in two adjacent layers was not sufficient to avoid interaction? A. I can only imagine that that is what is being implied. In my experience, two-layer tablets were used and there was no need for any separate interposing layer. Q. It is fair to say that is the 1976 version. A. Yes. Q. You do not have any reason to suggest that the position would not have been identical in 1986 so far as this book is concerned? A. No, I would say not. MR. JUSTICE LADDIE: This is Lachman, Lieberman and Kanig Is this particular book well-known. A. Very well-known. Q. Is this the sort of thing everybody ought to have available? A. Yes. I would say in the field, yes.” (Transcript Day 3 pp 286-7)[72]The authors of The Theory and Practice of Industrial Pharmacy were stating unequivocally that an isolating layer could be inserted between incompatible components. I do not consider that Dr Rees was reading this fairly when he said that the authors were ‘implying’ that.[73]The same point about separating incompatible ingredients is to be found in the preface to Pharmaceutical Dosage Forms (Tablets) :
“Some tablets are layered to keep chemically reactive materials apart, and other tablets are coated to help cover the bad taste of the medicines, and also to keep medicines in the coating away from the chemically reacting materials in the tablets or atmosphere”
[74]The use of multi-layered tablets was not only referred to in standard textbooks in the field but, during the trial it became apparent that it was something which formed a part of Dr Rees’ standard lectures well before the priority date. An example of such a lecture was put to Dr Rees by Mr Floyd. It was given at the 1979 Pharmacy Refresher Course organised by the Pharmaceutical Society of Australia, Bali and Singapore in the early summer of 1979. In it, Dr Rees said:
“Compression coated tablets, and multi-layer or multi-granule tablets, consist of separate ‘compartments’ which can be used to provide different drug release rates or to isolate incompatible components of the dosage form.”
[75]Nevertheless Dr Rees suggested that, even though separation by use of multilayers was well known, it was not known to put a separating layer or film between incompatible components notwithstanding the express wording in The Theory and Practice of Industrial Pharmacy set out in paragraph 70 above. This leads me to another instance in which Dr Rees’ evidence in these proceedings differed from the evidence he gave elsewhere. In his first report he stated as follows:
“43. Although film coating generally involves the application of only a single layer of polymer, various additional layers have had to be used beneath a film coat in particular cases. For example, there are a few passing references in the textbooks to the possible use of a sealing coat beneath a film coat, in order to prevent water or solvents from affecting the core during processing (see below at paragraph 173 “Hagers Handbuch” and paragraph 191 - “Praktikum des Lack-Dragierens”). A sealing coat comprises a thin layer of a water-resistant or solvent-resistant polymer, such as one that is used for producing enteric film coats, and thus it is different from the water soluble subcoat used in the inventions in the Patents. However, to my knowledge, such a sealing coat has very rarely been used in practice with film coats, as the rapid drying characteristics of the process render this unnecessary. It certainly was not a common technique. 44. A soluble film coat has been used in extreme cases to improve adhesion between a core and a second film coat. Furthermore, certainly in the 1970s, some manufacturers favoured the use of an outer gloss coat, especially over a coloured film coat but again this was not common practice of formulators before the priority date of the Patents.”
[76]Essentially identically worded evidence was given in Dr Rees’ expert report in Australia subject to one important difference. In the latter, the second paragraph read as follows:
“80. Soluble film coats have been used in extreme cases to improve adhesion between a core and a second film coat. Soluble film-formers have also occasionally been used to separate incompatible active ingredients within a tablet. Furthermore, certainly in the 1970s, some manufacturers favoured the use of an outer gloss coat, especially over a coloured film coat.”
(emphasis added)[77]The underlined sentence, which is clearly directly relevant to one of the major issues in these proceedings, was removed from the evidence given here. This matter was put to Dr Rees under cross-examination:
“Q. Then paragraph 80 seems to correspond to paragraph 44, yes? A. Yes. Q. Except that a sentence has been missed out, has it not, Doctor, the middle one: “Soluble film-formers have also occasionally been used to separate incompatible active ingredients within a tablet.”
A. It is certainly not in the present statement, that is correct. Q. Do you know why that statement has apparently been removed between the time when you made this affidavit and your report in this case? A. I am not certain. May I just read that just to check. No, it was certainly nothing that I did intentionally in terms of, shall we say, starting from that point, my Lord. Q. Can you tell his Lordship when you swore your Australian affidavit what examples of soluble film formers were being used to separate incompatible active ingredients within a tablet did you have in mind? A. As I say, at the moment I cannot think of a situation where a soluble film former was used in that way. It may have been as a result of that that on subsequent reflection I have not referred to that point subsequently. I must confess, I am not aware of having removed that intention[ally]. Q. You must therefore be speculating as to the reason why it does not appear any longer? A. Yes, that is all I can do. As I said a moment ago, I cannot think of a situation in the context of what you asked me where a film former was used in order to -- a film coat was used to separate incompatible materials. … MR. FLOYD: I am asking you to cast your mind back. What did you have in mind when you wrote that sentence in sworn evidence in Australia? A. I am not certain.” (Transcript Day 3 pp 238-4)[78]It is unfortunate that Dr Rees could not recall why he removed this important statement from his Australian evidence. I have no reason to think that he did not believe its accuracy when he made it for those proceedings. On the contrary, it appears to be consistent with what he wrote in his April 1974 article in Manufacturing Chemist & Aerosol News to which I have already referred in paragraph 62 above. There he included a table entitled “Uses of Soluble Film-Formers as Tablet Coatings”. The second suggested use was:
“To separate incompatible components of a dosage form.”
[79]Dr Rees suggested that what he could have meant in his article was that one of the incompatible ingredients could be dispersed in the film coating rather than using the film coating as a separator. This did not survive cross-examination:
“MR. FLOYD: You thought of it in 1974, you still thought it was the position when you saw your Australian affidavit, but then subsequently discovered that it was not right? A. I now know that it certainly is not within my experience, that is correct. Q. I thought you told his Lordship that you could not carry in a thin film coating the incompatible component? A. I was saying that I have certainly no example that I can quote to that effect. In theory there is no reason why, in the same way a film coat contains particulate materials there is no reason why it should not be used to contain a small amount of a low dose drug. Certainly, I have no example of that actually being done. Q. Can I suggest that the natural reading of this, whatever may have been your intention, that a skilled formulator reading this in 1986 would say, “ Well, he cannot mean putting the second drug in the thin film coating, he must be talking about using a film coating as a separate inert layer to keep the two apart.”
Would you agree with that? A. It was certainly not something that I recall having intended to convey by this statement. Q. But answering my question? A. It could be read that way, I agree. Q. Would you accept that is the likely reading of somebody who understands film coatings? A. Somebody who understands film coatings, you are thinking of somebody who has knowledge of what was available as a product? Q. Yes. A. Yes, that could be true.” (Transcript Day 3 pp 291-2)[80]Dr Rue’s evidence was that at the priority date well known uses of separating layers, which could be made in a variety of ways with a variety of materials, included separating components, for example as in the case of layered tablets where non-reactive pharmaceutical excipients would be used to form the separating layer. I accept that evidence which is consistent with all the documents in the case, including Dr Rees’ Australian evidence. It is only contradicted by Dr Rees’ evidence given in these proceedings, evidence which I do not find convincing.[81]This, however, is not the end of the matter. It is Hässle’s position that if the skilled worker thought of using an intermediate layer, he would only contemplate making it out of a water insoluble material. Both sides agree that this would be a most unattractive and, indeed, a self-defeating option. To put the drug in a coating which would not dissolve or disintegrate in the intestine would mean that more, or all, of it would pass through the patient without being absorbed, thereby seriously compromising its bioavailability. Based on this, Hässle argues that an intermediate coat would not be used at all. On the other hand the claimants argue that there would be nothing which would deter a skilled worker from using a water soluble or dispersible intermediate coating and that such a coating would be the obvious thing to try.[82]Once again, the burden of advancing Hässle’s case fell on Dr Rees. As Mr Floyd demonstrated during cross-examination, all of Dr Rees’ written evidence concentrated on the alleged difficulty of thinking up an answer to what was called the “gastric resistance” problem. This is described in the patent. It is said that the enteric film coating allows sufficient gastric juices or water to pass through while the tablet is in the stomach and that parts of the core in close proximity to the coating form an alkaline solution. The patent says that this will interfere with the enteric coating and eventually dissolve it. If that happens in the stomach, the protection of the omeprazole from the acid environment will be removed and much of the pharmaceutical efficacy of the drug will be lost before it reaches the intestines. Dr Rees’ evidence was to the effect that the use of a soluble intermediate layer would not be expected to overcome this gastric resistance problem.[83]However this topic is something of a red herring. Assuming that gastric resistance was a problem and that the use of a soluble intermediate layer solved it, it would have played no part in the thinking of the notional skilled worker in the field at the priority date. The reason for this is that this problem was not known to exist. There was therefore nothing to solve. Even if it were true, which I will assume for present purposes, that a skilled worker would have been deterred from using a soluble intermediate layer by a fear that it would not solve the gastric resistance problem, that has no bearing here because the skilled worker would not know or find out that there was any such problem. In fact the inventors of the patent put forward the discovery of the gastric resistance problem as one of their contributions to the technology in this area. As Mr Floyd explained in his reply speech, this problem depended upon a belief that water was getting in from the outside of the tablet through the enteric coating. However Dr Rees accepted that in 1986 it was assumed that the enteric coat itself stopped water ingress and this was its perceived function (See Transcript Day 3 p 332-3). Furthermore, on the evidence, the problem, if it exists at all, only occurs when a substantial amount of alkali is added to the core before it is coated. There was no challenge to Dr Rue’s evidence that it would not be obvious to add substantial quantities of alkali to the core. The result is that there was no such known problem to solve and the notional skilled worker’s choice of material for the intermediate layer would not be affected in any way by these considerations.[84]In place of the gastric resistance point, Dr Rees’ put forward another theory as to why the man in the art would be deterred from using a soluble intermediate layer. He suggested that the notional addressee would think that the reactive molecules themselves would dissolve in water and pass through the soluble barrier so as to react with each other. This theory was advanced for the first time during cross examination. Dr Rees accepted that he had not put this suggestion in his reports in this action (including his first one which ran to some 256 paragraphs) nor in any report he had prepared for any corresponding proceedings in other countries. It followed that it was not put to Dr Rue.[85]It will be appreciated that this explanation for why the notional skilled worker would not use a soluble intermediate layer depends upon him thinking that three things will happen. First he must fear that sufficient water will pass through the enteric coating to enable a solution of one or the other of the reactive molecules to be made. Second he must suspect that the reactive molecules are sufficiently soluble to enable such a solution to come into existence. Third he must suspect or fear that the intermediate layer will allow one or other of the reactive molecules to pass through it. In other words it must have pores of sufficient size to allow the reactive molecules to pass through it. In my view there is no evidence to support the existence of any of these three points, all of which would need to be present before this could act as a deterrent to the use of a soluble intermediate layer. I shall deal with each of these points in sequence.[86]First, as I have already said, Dr Rees’ evidence was that in 1986 it was generally believed that enteric coatings would not allow water to pass through. The man in the art could not fear the creation of a solution since there was no water to form it.[87]Second, Dr Rees was not suggesting that the enteric coating – consisting of long chain polymer molecules – was capable of going into solution. What he was suggesting was that a solution of omeprazole would be formed and it was this which the worker in the field would fear would cross the intermediate layer. However in his first report, Dr Rees said: “On the basis of common general knowledge, I do not believe that the average skilled formulator would have had any reason to suspect that a reaction between the active ingredient and the enteric film-former was a likely source of the discolouration. Moreover, from a theoretical standpoint, especially given the low aqueous solubility of omeprazole there would be minimal opportunity for a molecule of the active ingredient in the formulation to find itself in solution in close proximity to one of the immobilised carboxylic acid groups of the enteric coat.” (paragraph 136)[88]It should be noticed that this passage is considering the case where there was no intermediate layer. What Dr Rees was saying was that even when the enteric coating was in direct contact with the core, one would not expect a solution of omeprazole to be formed. For this reason one would not expect reaction with the “immobilised” groups on the enteric coat. In other words neither the omeprazole nor the coating would be expected to go into solution. On this basis, the introduction of an intermediate layer between the omeprazole and the enteric coating would have made the possibility of a reaction between the two molecules even more unlikely. No explanation for the inconsistency between this passage in the report and Dr Rees’ oral evidence was offered.[89]As an aside I should explain that the evidence referred to in paragraph 87 was given in support of Dr Rees’ suggestion that the man in the art would not expect there to be a reaction between omeprazole and the enteric coating because a tablet is “dry” and moisture needs to be present to facilitate the reaction. However, eventually this point came to nothing because it was accepted, and confirmed in published material, that one would expect sufficient moisture to be present to mediate the reaction between ‘dry’ ingredients. In any event, for reasons already given, a skilled worker could not safely assume that reaction would not occur and he would have to carry out compatibility tests.[90]Third, even if the notional skilled worker had thought of the possibility of the creation of a solution of omeprazole, there is nothing to suggest he would have considered it remotely possible that the intermediate layer would have pores in it of sufficient size to allow the molecules of omeprazole to pass through it so as to reach the enteric coating. As Dr Rue explained, the fact that a substance may be capable of dissolving does not indicate whether or to what extent in the solid state it can allow molecules to pass through it.[91]I have come to the conclusion that on the evidence the notional skilled worker would have expected a soluble intermediate layer or coat to work, or to be sufficiently likely to work to warrant trial. I should only add on this point that the fear of solutions of reactive components passing through an intermediate layer apparently did not occur to Dr Rees either when he gave his evidence in Australia (see paragraph 76 above) nor when he wrote his 1974 article (see paragraph 78 above) in both of which he said that soluble films could be used to separate incompatible components.[92]It follows that the notional skilled worker embarking on the task of making a formulation of omeprazole for oral administration would have found out almost immediately that an incompatibility problem existed as between the omeprazole and the enteric coating. He would have thought that an obvious route to try to overcome this would be to put a separating layer between the two. It would have been immediately apparent to him that such a separating layer would need to dissolve or disintegrate in the intestine to avoid bioavailability problems. There is nothing which would have deterred him from trying such a separating layer. In these circumstances Claim 1, and therefore all the remaining claims, fail for obviousness.[93]I can deal rather more quickly with the alternative way in which the obviousness case was put. I have assumed up to this point that the notional formulator started with no published material and had little except a knowledge that omeprazole was a worthwhile drug which he was trying to formulate into a convenient dosage form. It is not in dispute that he would have found out virtually immediately that the drug was very acid labile and that it would need to be enterically coated. Further it is not in dispute that he would have thought of using the salts, including in particular the sodium and magnesium salts, of the drug. In fact he would not need to have thought of any these things for himself because they are all disclosed in the Pilbrant and Cederberg paper referred to in the patent and in Hässle’s own earlier patent 012445A both of which are prior art. It is not in dispute that anyone engaged in trying to produce an oral dosage form of omeprazole would have obtained and read both of these documents as part of his basic education into the features of the drug.[94]The skilled worker is assumed to have read and understood all the available prior art. It is not in dispute that he will be taken to have read each of the pieces of prior art pleaded by the claimants and referred to below. (i) “Up-to-Date Pharmaceutical Technology Series ‘No 1’ Coating of Drugs” (1969)[95]This is a technical leaflet published by the Japan Industrial Technology Federation. The pages relied upon relate to the well known type of coating material, HPMC. The particular brand of HPMC the subject of the paper is sold under the name “TC-5”. TC-5, like other HPMCs, is water soluble. On the second page of the translation, the following is said:
“TC-5 was developed by Shin-Etsu Chemical Co. for use as a film coating agent and announced in 1964. It is now used in film coating as a substitute for sugar coating. It is also used as an undercoating agent in coating with AEA, Eudragit L, SE, CAP, MPM, etc., for the purpose of preventing them from reacting with the active component.”
[96]As Dr Rees explains, CAP was one of the first synthetic enteric film formers to be used. Eudragit L is also a well known enteric film coating material which was less permeable than other enteric coating materials. It will be recalled that these are two of the examples of known enteric film materials which the patent in suit says can be used for making dosage forms of omeprazole (see, in particular, paragraph 14 above). The document goes on to discuss Eudragit L and S and records, as was well known, that they are both resistant to dissolution in gastric juice. Under the heading “How to use” relating to the Eudragit compounds the authors explain how much other additive may be allowed in the coating (not more than 2%) and gives guidance on how thick the coating should be. They then say:
“When tablets contain an alkaline substance, the Eudragit coating shows decreased acid resistance; when they contain an acidic substance, the rate of Eudragit coating dissolution in alkaline conditions decreases. In such cases, it is necessary to provide a neutral subcoating under the Eudragit coating.”
[97]Dr Rue gave evidence as to what his reaction would have been had he read this document when producing a formulation for omeprazole. As noted above, Dr Rue says, and I accept, that, as a result of compatibility studies, a notional skilled worker would have found out rapidly and almost as of course that there is an interaction between the enteric polymers and omeprazole and omeprazole salts. Dr Rue said that, in the light of that knowledge, this document would have reinforced his decision that a separating layer such as HPMC should be applied between the core and enteric coat (see First Report paragraph 7.19). Mr Thorley did not challenge this evidence on cross examination.[98]Dr Rees advanced a number of points against the relevance of this document. For example he suggested that the document was concerned with sugar coating. This seems to be inconsistent with the contents of the document itself which refers to the TC-5 being used as a substitute for sugar coating. Dr Rees’ interpretation was disputed by Dr Rue in his second report. Again, Dr Rue was not challenged on this point in cross examination. The other point taken by Dr Rees was that the document does not explain the nature of the interaction between the enteric coating and the core. That, however, seems to be beside the point. Whatever the nature of the reaction between the coating and the core, this document suggests it can be counteracted by insertion of a separating layer between them.[99]I accept the claimants’ argument in relation to this document also. On the assumption that the notional skilled worker would have found out or anticipated the incompatibility between omeprazole or its salts and enteric coating material, this would have encouraged him to try using HPMC as a subcoat. The result is that he would have tried to make formulations such as those identified in paragraph 14 above, which fall within the scope of claim 1 of the patent. I should only add that HPMC is, of course, a water soluble coating material, which is why it is one of those recommended in the patent in suit. Dr Rees did not suggest that that feature, which is recorded in this prior art document, would deter him from trying to use it as recommended. (ii) A Shin-Etsu brochure relating to its TC-5 coating material (1975)[100]This is a promotional leaflet published by Shin-Etsu in respect of its TC-5 HPMC product. It records that the product has been used widely as a coating agent or binding agent for tablets and granules. It also lists suggested uses of the product. These are stated to be, first, as a coating for tablets and granules and second, as an undercoat for sugar coatings. The leaflet then proceeds as follows:
“Undercoat for enteric-preparation bases and acid soluble bases When the enteric preparation base or acid-soluble base is reactive with the active ingredient, the use of TC-5 for undercoat formation can result in production of preparations having good stability.”
[101]Once again, the fact that this brand, like all HMPCs, is soluble is set out in the brochure (see Bundle C1 page 48).[102]Dr Rue’s evidence in relation to this document was substantially the same as that given in relation to the “ Up-to-Date ” document referred to above. Once again, his views were not challenged under cross-examination.[103]Dr Rees’ written evidence in relation to this contains a general statement to the effect that this document would not lead him to use TC-5 to overcome a gastric resistance problem. For reasons set out above, even if this were accurate it would not be relevant because the man in the art would not be aware that there was a gastric resistance problem to resolve. Furthermore, as noted, there is not a gastric resistance problem, save in the case where the core is loaded with large amounts of additional alkali – a course the man skilled in the art would not take. Dr Rees went on to advance two arguments against the teaching in the passage cited in paragraph 100 above. He said that this was a promotional statement and that it “provides no assurance of success”. Neither of these points seem to me to address the question of obviousness. Dr Rees did not suggest, for example, that because this was a promotional document that it would be considered inaccurate.[104]This document was put to Dr Rees under cross-examination. The relevant passages are as follows: “Q. Go on to the next one, 4A, the TC-5 brochure, page 51. Is this not again a general teaching that where you observe a reaction between the enteric coating and the core, TC-5 can give you preparations of good stability? A. Yes. It appears to come from some knowledge which Shin-Etsu had, yes, I agree, and it teaches what it says.” (Transcript Day 3 p 347) And : “MR. FLOYD: Dr. Rees, I will try once more. If you have observed a reaction with your film coating, does this document not give you what you want, in other words, something to stop reactions between the film coating and the core? A. That is what it says and, as I say, I would therefore go back to the supplier and find out more.” (Transcript Day 3 p 350)[105]In the light of this evidence, the only difference between the experts is Dr Rees’ suggestion that he would go back to the manufacturer to find out more. Dr Rue said that he would have carried out tests himself at the same time as going back to the manufacturer. Dr Rees did not suggest that that was not a course which a notional skilled worker would take. Furthermore there was no suggestion that the manufacturer would have done anything other than reiterate the recommendation in its brochure that TC-5 should be used as an undercoat.[106]Once again, on the same assumptions as are set out in paragraph 99 above, this document also renders claim 1 obvious. (iv) Practical Course in Lacquer Coating (1983)[107]This document is the 1983 version of notes produced to accompany an annual practical course run by Rohm Pharma, makers of the well known Eudragit range of film-forming polymer preparations. The course was first run in 1972. Study 1 is concerned with enteric coating for tablets. It contains a general introduction to enteric coatings and how they work. Section 4 of Study 1 is entitled “Production of Enteric-coated Tablets” and, as its name implies, it is concerned with teaching the reader how to produce such tablets. This it does by reference to a figure which cross refers to the descriptive text. The figure is as follows:[108]It will be seen that the figure illustrates three types of tablet structure. The two on the left represent the structure of tablets made by two kinds of fractional application, namely application with organic lacquers (left-most part of the illustration) and application with aqueous dispersions (center part of the illustration). The right hand part of the figure is a diagram of a multi-layer tablet made by spray coating. It will be seen that it consists of a core and three overlying layers;(i) a 5(m insulation layer,(ii) a 15(m enteric-coating layer and(iii) a 10(m pigmented layer. The text describes each of the three forms of tablet illustrated. The paragraph which describes the spray coating tablet illustrated on the right of the figure is in the following terms:
“An insulating coat against penetrating water, formed from Eudragit L solution in isopropyl alcohol/acetone, is desirable when the subsequent processes involve the use of the aqueous dispersion Eudragit L 30 D. This insulating coat may frequently be dispensed with on using rapid drying application processes. Other insulating coats may be necessary if there is any interaction on drugs coming into direct contact with the lacquer coating. An enteric layer is intended to form a non-porous sealing layer which is largely stable to gastric juice and to mechanical stress”
[109]As Dr Rue explained, the document describes the features of Eudragit L and confirms that it would be suitable for use as an enteric coating. Furthermore he notes that an earlier passage in the document teaches that Eudragit L could be used on cores which contained a highly moisture sensitive drug in order to reduce the rate of moisture ingress into the core. He then said: “On reading this document when formulating omeprazole, it would have confirmed that Eudragit L was a good choice as an enteric coating material because of its low permeability allowing it to be used for cores containing highly moisture sensitive materials. The high moisture sensitivity of omeprazole would have been known already from the results of preformulation studies on the active drug. When the interaction between the enteric coat and the core was discovered in our tests, the use of a water soluble, inert separating layer between the core and enteric coating would have been an obvious solution.” (First Report paragraph 7.33)[110]The only substantial point of difference between the parties was as to the meaning of the words:
“Other insulating coats may be necessary if there is any interaction on drugs coming into direct contact with the lacquer coating.”
Dr Rees, partly basing himself on a post-priority date version of the same document, expressed the view that that this sentence meant that: “[I]f any interaction occurs, as a result of active ingredients (in the core) coming into contact with the aqueous-based film coating dispersion, more layers of the solvent-based Eudragit-L may need to be applied.” (First Report paragraph 200, emphasis as in the original)[111]In other words, all that the authors are saying is that if there is interaction, then a thicker layer of Eudragit-L should be used.[112]In my view this is not a fair or reasonable interpretation of the document. If, as Dr Rees argues, the authors were only suggesting the use of a thicker coat of Eudragit-L, they could have said so simply. But neither the text nor the figure illustrating it is consistent with that meaning. The figure illustrates both a 15( “enteric-coating layer” and, between it and the core, a distinct 5( “insulation layer”. There is nothing in this which suggests that what the authors really meant to illustrate was a 20( layer of the enteric coating material. In my view the notional skilled worker would interpret the illustration as showing two distinct layers, the lower one being for the purpose of insulating the enteric coating above it from the core below. Furthermore that is what the text says. It is concerned to deal with problems of incompatibility caused when a drug comes “into direct contact” with the enteric coating. The solution is to insert an insulating coat between them. According to Dr Rees, the authors are suggesting that the problem caused by this direct contact between core and enteric coating is to be solved by adding more enteric coating. It is obvious that that would not prevent the direct contact which the authors are suggesting should be avoided. Once again, in my view the notional skilled worker would interpret this as a general teaching to separate a core containing a drug from an enteric coating layer with which the drug is incompatible by putting a different insulating layer between them.[113]I accept Dr Rue’s evidence in relation to this document. Claim 1 of the patent is obvious in the light of it. I should only add that the post priority date version of this document relied on by Dr Rees to support his construction, in fact does not do so. But since it is a post priority date document it is, in any event, irrelevant. (iv) Hager’s Handbook of Pharmaceutical Practice (1971)[114]This is a textbook aimed at chemists, pharmaceutical manufacturers, doctors and medical officers which, among other things, discusses the formulation of tablets. In a section with the sub-title “Film coating” it states:
“If the constituents of the core can be chemically or physically influenced by the constituents of the film or by the additives and solvents or the constituents of the core influence the material of the film (e.g. high concentrations of soluble electrolytes, alkaline substances in the coating raw materials with carboxyl groups, acid substances in the case of those with amine groups), the core must first be coated with non-reactive undercoats.”
And later it says:
“The chemical composition of the core can have a substantial influence on the properties of the film (in some cases on its very success) or may even break it down so that a standard precoating becomes necessary .”
[115]Dr Rue’s view was that this would have confirmed his view that, on discovering an incompatibility between the omeprazole-containing core and the enteric coating, a separating layer should be used. Once again, he said that it was obvious that the separating layer would be water soluble. His understanding of this general teaching was not challenged under cross-examination, nor was his conclusion. I accept this evidence as representing the views and understanding of the notional skilled worker in the field at the priority date. It follows that, on the same assumptions as are made at paragraph 99 above, this renders claim 1 obvious. However, I do not think that this document is any better a starting point for the obviousness attack than the three referred to above. (v) Shin Etsu H-17 leaflet . (1978)[116]Finally reliance is placed on a technical bulletin issued by Shin-Etsu which contains a section entitled “Enteric Coating on Tablets Containing Alkaline Matter No. H-17”. It contains the following teaching:
“Enteric coated tablets containing alkaline matter such as ammonium chloride, lithium carbonate or sodium-salicylate might lose the stability when storing at higher temperature, it has been sometimes experienced. It has been found to be improved by putting stearic acid in the intermediate film which is considered to work as some buffer to imaginable ion-exchange reaction between alkaline and enteric material.”
[117]The bulletin then goes on to give examples of tablets made with an intermediate film. The latter is made from “Pharmacoat” which is another trade name for Shin-Etsu’s HPMC. The criticism of this document advanced by Dr Rees appeared to concentrate on the issue of whether or not it would deter a worker in the art who was concerned about gastric resistance. I have dealt with this point already and, for reasons given, the issue of gastric resistance is irrelevant. Once again, on the assumptions set out in paragraph 99 above, this document also renders claim 1 obvious although it adds nothing more to the obviousness case made out on the other admittedly published documents referred to above.[118]There are two additional points worth making. First, it seems to me that the five pieces of prior art considered in paragraphs 95 to 117 above are consistent with the claimants’ case that the use of an intermediate layer was obvious. It appears to have been a concept which was thought of and published by many in this field over the three decades before the priority date. Second, it appears that the Shin-Etsu documents are consistent with the version of Dr Rees’ evidence given in Australia before the excisions referred to in paragraph 76 above.[119]For these reasons, I find that claim 1 is invalid for obviousness and, in the light of the concessions made by Mr Thorley on the issue of independent validity of subclaims, it follows that all the claims in the patent fail. In those circumstances it is not necessary to consider the issues of anticipation, added matter and insufficiency raised by the claimants.

Cited in 1 later judgment