Sandoz GmbH v Roche Diagnostics GmbH

Obviousness over common knowledge;

The Claimant relies on the contents of eight works which Professor Allwood says in his first report were current in 1991 and would have formed part of the common general knowledge of the skilled addressees. They are:

The need to use excipients previously used in recombinant injectable protein formulations; and

A desire to keep the formulation as simple as possible.

He would know (or would have learnt from the HPE) that benzalkonium chloride was primarily used in ophthalmic products and had never been used before to preserve a therapeutic recombinant protein. He would also know that its usual concentration was 0.01%. More importantly the HPE would have confirmed that benzalkonium chloride was incompatible with proteins. It would also have told him that chlorobutanol was bacteriostatic rather than bactericidal and would not therefore meet the standard required to obtain regulatory approval in the UK. He would have realised that it did not provide sufficient anti-microbial effect to satisfy the standard set by the British Pharmacopoiea. Its use would also raise issues of stability depending on the solution pH. The HPE states that its activity is “considerably reduced” at a pH above 5.5 and that its chemical stability decreases with each increase in pH until at pH 7.5 the half life is stated to be about three months.

Professor Randolph says in his report that the skilled person would begin by looking at the preservatives listed in the PDR as used in multi-dose formulations of recombinant proteins and would have seen that the formulations listed used m-cresol, phenol or benzyl alcohol singly. Even if these preservatives used singly did not achieve the necessary stability for the EPO based formulation the skilled person would not, he says, have considered experimenting with a combination of preservatives because of the information available on their preservative efficacy and side effects. There was every possibility that combinations of preservatives would be even more damaging to the protein than single preservatives.

Before I come to consider Professor Allwood’s position on these issues I need to say something about Professor Randolph’s emphasis on the use of recombinant proteins and also about EPO. Proteins are large molecules with a structure analogous to a folded coiled chain where each link is an amino acid. Each amino acid which makes up the protein chain is linked by a chemical bond called a peptide bond. Proteins are made up of long chains of amino acids (polypeptides) and EPO is made up of 165 such amino acids. The sequence of amino acids forms the primary structure of the protein. Different amino acids have different chemical structures in themselves, different shapes and sizes, and participate in different kinds of chemical interaction. The chains fold to form what are described as coiled and folded domains forming the protein’s so called secondary structure and the domains are arranged together to create the tertiary structure of the protein.

The information encoding for the primary sequence of a protein is contained in the cell’s DNA. It is possible to link the segments of DNA to DNA from another source in order to create what is referred to as “re-combined” or recombinant DNA. Recombinant DNA technology permits the production of large quantities of a protein encoded by a particular gene. In 1977 the first human protein was produced using recombinant technology and by 1991 eight recombinant protein formulations were listed in the PDR. This is a US publication which is a combination of manufacturers’ data sheets for selected drugs. Both Professor Randolph and Professor Allwood agree that the protein scientist would have known of its purpose and had access to it or (in the UK) would have been aware of the ABPI Data Sheet Compendium which was its equivalent. Prior to the advent of genetic engineering very few proteins (Professor Allwood thought about 10) were available for therapeutic administration. The two best known at the time were insulin and human growth hormone. Recombinant proteins enable laboratories to produce large quantities of material without having to rely on organs from cadavers or other unreliable sources. In 1991 recombinant proteins were however still a new class of product made by companies such as Genentech Inc. and other specialists.

EPO is a glycosylated protein which regulates the production of red blood cells by stimulating the erythroid marrow. It is used in the treatment of anaemia. This protein was not available from natural sources in any significant quantities and it was only by gene technology and the production of recombinant EPO that sufficient quantities were made available for therapeutic use. It was first purified from anaemic sheep plasma in 1971 and from human aplastic anaemia patients in 1977 but only in small quantities and after a complicated purification process. Recombinant versions avoided these difficulties. By 1991 recombinant EPO had been approved for use in the treatment of anaemia associated with chronic renal failure. Professor Allwood accepted that the protein formulator would have been aware of the recombinant therapeutic proteins available on the market at the time and would have had basic information about EPO, its structure and its properties. In fact the only recombinant EPO product listed in the PDR at the time was Amgen’s EPOGEN which was produced as a single dose vial containing between 2,000 and 10,000 units of EPO with human albumin (2.5mg), sodium citrate (5.8mg), sodium chloride (5.8mg) and citric acid (0.06mg) in sterile water.

It is common ground between the experts that the protein formulator’s knowledge of the general nature and properties of proteins would have included their susceptibility to chemical and physical degradation. Professor Randolph’s evidence on this (which is not really challenged) is that to exhibit their proper biological function proteins must remain properly folded with their secondary and tertiary structures intact. These structures can be altered by what are described as chemical and physical degradation pathways which are often linked. The two main types of chemical degradation are oxidation and deamidation which would have been known to a skilled protein formulator in 1991. Chemical degradation in proteins is influenced by formulation pH and can lead to alterations in the protein activity, structure and/or function.

Physical degradation is of three main kinds; denaturation, surface adsorption and aggregation. These are referred to in the specification in the Patent. Denaturation occurs when the protein unfolds thereby losing its higher order structure. This results in the loss of its biological function. It could be caused in a number of ways including by elevated temperatures, adsorption on vial or syringe surfaces, exposure to air-water interfaces and extremes in pH. Conversely denaturation can not only result from but may also result in adsorption on surfaces and aggregation. Denaturation leads to the protein precipitating out of solution or aggregating with resulting turbidity of or physical particles in the solution. Surface adsorption speaks for itself. Proteins are surface active resulting in the loss of or a serious reduction in biological activity. Aggregation takes place when proteins partially unfold and combine to form what Professor Randolph describes as non-native higher-order assemblies. Eventually the aggregates increase in size until precipitation occurs. The unfolding is caused primarily by the solvent environment including pH, salt and additives like preservatives or by temperature or surface interactions. Aggregation leads to visible particulates in the solution and can cause severe allergic responses in the patient.

One issue raised by Professor Randolph in his first report concerned the stability of EPO. He says that it has low stability and is easily inactivated by environmental factors such as temperature. The maintenance of the stability of the protein solution is obviously an essential part of the formulation process but Professor Allwood approached this issue on the basis that EPO was no less stable than any other human protein and did not therefore necessitate a different approach. He is not however, by his own admission, a protein scientist and has not sought to address the issue of formulation from that perspective. When his first report was served it therefore contained reference to a draft report by Professor Richard Perham in which he expresses the view that EPO was considered to be a relatively stable protein. This was objected to by Roche because there was only permission for each side to call a single expert and it led to an application to admit Professor Perham’s evidence which I heard and acceded to shortly before the trial. One of the striking features of this case is the mismatch between the expert evidence. As already indicated the parties in their written evidence have approached the question of the identity of the skilled addressee and therefore the issue of obviousness from very different standpoints. Professor Allwood has a background in microbiology and experience and expertise as a formulator including in relation to parenterals. But in 1981 he became a member of the Committee on the Safety of Medicines and from 1989 to 1992 was director of the Medicines Research Unit of South Derbyshire Health Authority. He has never worked for a pharmaceutical company nor has he had any personal experience of formulating an injectable product containing a recombinant protein. He accepted that he had very limited knowledge and experience of the stability of EPO or other proteins in an aqueous solution and was not able to comment directly on Professor Randolph’s analysis of the structure of proteins and EPO and the causes of their possible degradation.

It was for this reason of course, that the Claimant instructed Professor Perham to respond to Professor Randolph’s evidence about the stability of EPO. However Professor Perham’s evidence is restricted to that topic and does not address the wider issues of the approach to formulation and the obviousness or not of employing preservatives in combination in a protein based formulation. Professor Randolph gives evidence about both but of course approaches the matter differently than Professor Allwood who looks at it in what are essentially microbiological terms.

In the light of Professor Allwood’s upgrading of the role of the protein scientist in his notional team I have (as previously explained) concluded that the input of this scientist is likely to be highly influential if not critical. This causes (for want of a better word) obvious difficulties for the Claimant which are not really remedied by Professor Perham’s evidence. He is the Professor of Structural Biochemistry in the University of Cambridge and a scientist of considerable distinction. He has obvious experience and expertise in relation to proteins although he has never worked with EPO. He was asked to set out in his report what a protein scientist on the skilled team would have been able to tell the other members about EPO. He was not asked to indicate what input the notional protein scientist would have had in determining the likely course of any trials because consistently with Professor Allwood’s written evidence the protein scientist in the team would not have had a leading role in that regard.

Professor Perham’s evidence was therefore limited to a description of EPO and the ways in which it was extracted (from human urine) prior to the introduction of recombinant techniques in the 1980’s. He says in his report that recombinant EPO was readily available in 1991 and based on this and also the evidence of Professor Randolph I take the view that it would have been a recombinant version of the protein which would have been used by the skilled addressee in 1991.

Although more detailed Professor Perham’s evidence about the structure of EPO does not differ significantly from that of Professor Randolph. Where they diverge is on the issue of stability. Professor Perham says that glycoproteins tend to be relatively stable molecules because their biological function must be carried out after they have been transported in the circulatory system. He refers to a number of papers in the mid 1980`s which reported that EPO was able to withstand temperatures of 80 C (most proteins denature at 50 C) and to be stable across a wide range of pH from 3.5 to 10 compared to most human proteins which are stable over a range of about pH 5 to 8. Similar views are expressed in relation to oxidation and aggregation. He accepts that EPO ( like other proteins) is prone to adsorption but says that this can be combated by the use of suitable surfactants.

Professor Randolph has produced a report commenting upon the evidence of Professor Perham. He makes the point that Professor Perham does not deal with the effect of preservatives on EPO in an aqueous solution and says that he disagrees with Professor Perham's conclusion that there was nothing known in 1991 which suggested that EPO was less stable in aqueous solutions than the average protein. He relies for example on the specification in the Konings patent which refers to EPO as being not stable and particularly not in an aqueous solution. However, he then goes on to say that the conclusions in his first report about the approach of the skilled person to the development of a multi-dose formulation of EPO are not based on the relative stability or instability of EPO compared to any other protein. In these circumstances it seems to me to be both unprofitable and unnecessary to attempt to resolve the conflicting views of the experts on something which is not ultimately relevant to the issues in this case. Therefore although the Patent teaches ways of protecting the EPO based formulation from infection the obviousness or not of using the preservatives in combination does not depend upon EPO being treated differently from any other human protein in a similar solution.

Professor Allwood says in his first report that the formulation team would approach their task on the basis of the following known factors:

Professor Allwood accepts that some interactions are inevitable either immediately or during storage depending on the excipients used. These may be chemical reactions leading to the degradation of the protein or the excipients or physical interactions between the active substance and the excipients. Chemical reactions causing loss of preservation activity will include oxidation and ionic neutralisation caused by mixing a positively charged (cationic) preservative with a negatively charged (anionic) active ingredient. Physical reactions include precipitation and adsorption. These reactions were documented in the HPE and other literature and needed to be taken into account when selecting candidates for inclusion in the preservative system.

In his first report Professor Allwood’s assessment of claim 1 regards the disadvantages outlined in the Patent as no more than routine considerations which the skilled addressees would have readily overcome in the course of their normal working life. In formulating an EPO based multi-dose parenteral they would have looked to use the conventional preservatives already in use for parenterals having regard to the three requirements referred to in paragraph 33 (i) above. Professor Allwood says that the three preservatives used in the Patent would not in his opinion have been regarded as differing markedly from other conventional preservatives suitable for use in parenterals. The skilled addressee would have looked for a preservative system with a fast kill rate and would have been aware that some of the preservatives (such as benzalkonium chloride) might exhibit incompatibilities with proteins when used in higher concentrations.

The critical step is the use of the chosen preservatives in combination. Professor Allwood says that it would have been routine for the skilled addressees to have tried a range of preservatives and to have tested synergistic combinations of conventional preservatives as part of that process. Concentrations would have been minimised to reduce the possibility of adverse reactions between ingredients. In the Guide synergistic combinations including benzyl alcohol and benzalkonium chloride and benzyl alcohol and chlorobutanol for parenterals are reported and the HPE also indicates advantageous combinations of benzalkonium chloride and benzyl alcohol, benzalkonium chloride and phenylethyl alcohol, and chlorobutanol and phenylethyl alcohol. The statement in the HPE that benzalkonium chloride has exhibited incompatibilities with proteins would have been noted as a warning but would not have been taken as a bar to using the chemical. In all the circumstances the skilled addressee would have regarded benzyl alcohol and benzalkonium chloride or benzyl alcohol and chlorobutanol as among the combinations of preservatives worth testing for use in an EPO based parenteral formulation.

Professor Randolph’s starting point in his evidence is that neither of the relevant preservatives, benzalkonium chloride or chlorobutanol, would have been regarded as suitable for use in a multi dose EPO formulation by the skilled addressee with access to the standard reference works agreed between the experts to represent common general knowledge. The HPE lists both as anti-microbial preservatives but the primary stated use of benzalkonium chloride is as a preservative in ophthalmic or nasal preparations and its incompatibility with proteins is also recorded. The HPE also states that the usual concentration used for benzalkonium chloride in small volume parenteral products is 0.01% which exceeds the upper limits of the concentrations in claims 6 and 7 by a factor of 2 and a factor of 4.

Chlorobutanol is described as for use in ophthalmic or parenteral preparations but the HPE says that its activity is bacteriostatic rather than bactericidal. To obtain regulatory approval it needs to be bactericidal. It also raises the stability problems depending on the solution pH which I have mentioned.

Professor Randolph’s view is that the protein formulator would have wanted to select from preservatives which had previously been used in a multi dose formulation. He would have consulted the PDR which would have told him that of the recombinant protein formulations then on the market none used either benzalkonium chloride or chlorobutanol. He would have avoided preservatives used in the hepatitis B vaccine formulations simply because vaccine formulations are designed to provoke an immune response in the patient which would be dangerous in relation to a chronically administered therapeutic protein and he would have considered thimerosal (one of the preservatives used in the existing formulations) to be unacceptable for chronic use because of its toxicity over a long period of time. Based on his review of existing formulations he would have selected m-cresol, phenol and benzyl alcohol as worth trying. The selection of the last of these three is presumably the reason why the validity of the claims in their unamended form was unlikely to have been upheld.

Testing would then have commenced involving various concentrations of each of the three preservatives being added to formulations containing all the ingredients except EPO. Anti-microbial efficacy would be tested in a dose-ranging study. The next stage of the testing would involve varying the pH and if necessary the contents of some of the other excipients to determine the minimum preservative concentration required for short term efficacy. The skilled person would then go on to determine the formulation necessary to achieve preservation for the 28 day period prescribed by the Pharmacopoeias. At this stage the skilled person would have available to him a number of formulation variants that could achieve adequate anti-microbial protection. From these he would select a smaller number for testing with EPO. Professor Randolph considers that benzyl alcohol is likely to have given encouraging results and was used by Amgen in the US in its EPO based formulation. If further testing resulted in an unacceptable loss of biological activity in EPO other formulations would have to be tried which perhaps allowed the concentration of preservative to be lowered by changing the pH. The critical question at this stage is whether the skilled addressee would have tried out combinations of preservatives. Professor Randolph considered this to be unlikely because none of the existing recombinant protein multi-dose formulations listed in the PDR used combinations. If the previously used preservatives could not achieve stability in the formulation the skilled addressee would have considered it unlikely that better results could be obtained by testing the preservatives in combination. If anything more powerful and effective combinations of preservatives would have been seen as more likely to damage the protein than the use of a single preservative.

The main differences between the experts (at least in their written reports) is therefore that Professor Allwood regards the complications inherent in formulating the protein-based multi-dose parenteral as no more than a particular facet of the formulation process as a whole which can be addressed by essentially the same methodology and more to the point which does not call for a different or more restricted approach to experimentation than would apply to any other formulation research. He therefore considers that the known reservations about benzalkonium chloride in relation to proteins would not have ruled it out and that the use of a combination of preservatives would be tried because in microbiological terms it would prove more effective (synergistic) than the use of single preservatives. Professor Randolph on the other hand regards this essentially microbiologic approach as simply inappropriate in relation to a protein based formulation where the maintenance of the integrity of the protein structure is the guiding principle and the primary objective. His main criticism of Professor Allwood’s evidence is that he treats the formulation of therapeutic proteins as routine although as generally recognised at the time it was anything but. He referred (for example) to a passage in Remington’s which described protein drugs as “more expensive to produce, more potent and more difficult to analyse” than non-protein drugs and two articles by Manning (1989) and Oeswein & Shire of Genentech (1991) which refer to the greater difficulties involved in the formulation of proteins due to their greater structural complexity compared to smaller organic molecules. These works were not of course relied upon as general common knowledge but they are useful in testing Professor Randolph’s evidence based on his own experience that this was the common perception among protein formulators in 1991.

I do not accept that protein formulation particularly in relation to multi-dose applications would have been considered to be in any sense routine in 1991 by those skilled in the art. I believe that it was generally recognised that formulations of this type presented particular challenges over and above the microbiological issues inherent in devising any preservative system for use in an injectable multi-dose formulation. I also accept (as is obvious from the PDR and the other evidence) that as of 1991 no pharmaceutical manufacturer had chosen to use a combination of preservatives in relation to a protein based parenteral. This is not of course conclusive in itself and there may be reasons for it unconnected to the issue of inventiveness. Although there is an issue as to whether the use of a combination of preservatives (particularly one involving benzalkonium chloride) was obvious what is clear is that it was something new.

For something to be obvious to try the Court has to be satisfied that the skilled addressee would have tested it as something which held out a prospect of producing valuable results. He is not to be taken to be someone who carries out trials for the sake of doing so. His approach is more structured than that. He restricts his tests to what he believes may assist him in solving his problem (see Hallen Co v Brabantia (UK) Ltd [1991] RPC 195 at pp 212-3) and “may” in this context has to be read as subject to his innate lack of inventiveness. Subject however to that limitation what needs to be shown is that the skilled addressee thought the likelihood of success not to be certain but at least to be sufficient to warrant the trial: see Johns-Manville Corporation’s Patent 18 RPC 479.

I have already outlined the different starting points and approaches of the two experts. During their cross-examination some measure of agreement emerged as to the way in which the skilled addressee is likely to have proceeded. As set out in his second report Professor Allwood accepted that the starting point would be to produce a stable EPO formulation with the other excipients present to which the preservative would be added. This would be chosen for compatibility not only with the protein but also with the other excipients. The formulator would not wish to alter the pH and the other excipients which were compatible with the EPO (as in a single dose formulation) unless he had no alternative. The preservatives for the multi-dose formulation would be chosen with this in mind. The criteria to be met under the US and UK Pharmacopoeia were given and are not in dispute. Within these parameters the formulator would therefore proceed to test the efficacy of the chosen preservative and its impact on the biological activity of the protein.

Both experts are agreed that testing was expensive in terms of both the time and money involved and it would not have been practicable for the skilled addressee to test all known preservatives. Each expert has proceeded on the basis that a selection would be made although as is already indicated their suggested choices differ. Professor Allwood suggested in cross-examination that there would be a short list of three or four preservatives to test and that the skilled addressee would adopt a strategy to determine which three or four were worth testing. Professor Randolph’s view is of course that the formulator would select preservatives which had already been used commercially to preserve proteins and Professor Allwood agreed that this would be what he described as the first part of the strategy. He also recognised Professor Randolph’s objective of keeping it simple but expressed the caveat that this was not always possible. There is however agreement that it would at least have been desirable had all else been equal.

The first real issue to determine is which preservatives would have been selected by the skilled addressee for testing. It is common ground between the experts that there were between 28 and 33 preservatives listed in the standard reference works such as the British and US Pharmacopoeia as anti-microbial agents. These included benzyl alcohol, benzalkonium chloride and chlorobutanol. However when one refines the list to include only preservatives for use in parenterals it is reduced to a much smaller number of perhaps between 8 and 12 preservatives. In an article entitled Adverse reactions to parenterals published in 1990 Professor Allwood lists the anti-microbial preservatives commonly used in existing parenteral products. The list includes benzyl alcohol but not benzalkonium chloride or chlorobutanol. In an earlier article (Anti-microbial agents and preservatives in pharmaceutical and cosmetic products. Anti-microbial agents in single and multi-dose injections) published in 1978 Professor Allwood included a table of recommendations based on the entries in the British and US Pharmacopoeia at the time. This included benzyl alcohol and chlorobutanol but not benzalkonium chloride. In relation to chlorobutanol he says in the article that the chemical is far less active above pH 5.0 and unstable above pH 6.0. Its use is therefore very limited. The optimum pH for a protein formulation is as near as possible to physiological (body) pH which is 7.4. Benzalkonium chloride is not included in the standard reference books as a preservative suitable for use in parenterals although it was of course recognised as an anti-microbial preservative. Professor Allwood accepted that as of 1991 its use as a preservative in injectables was almost unheard of and that the use of chlorobutanol had declined due to problems about its stability.

Ultimately there was agreement between the experts that the likely short list for testing would be based on an examination of existing protein products by reference to the PDR or (in the UK) the ABPI data sheets. This produces the list drawn up by Professor Randolph in his report to which I have already referred. Thimerosal would be excluded because of its mercury content leaving a short list of metacresol, phenol, benzyl alcohol and chlorocresol. Selection on the basis of prior use would therefore exclude both benzalkonium chloride and chlorobutanol and their inclusion on the short list would in my judgment only have occurred if the skilled addressee on the basis of his common knowledge (confirmed by the standard reference material) was aware that they were obvious candidates to use and that their non or limited commercial use in the past was due to factors other than their chemical attributes.

An examination of the material shows that the skilled addressee is likely to have concluded that they were simply unsuitable chemically for inclusion in the short list of preservatives for this EPO product. I have already referred to most of the relevant points and I can summarise them quite shortly. Benzalkonium chloride is referred to in the HPE as incompatible with protein. Similar references can be found in the Guide, in Remington’s and in Martindale. Although it is active at low concentrations across a wide range of pH its recognised incompatibility with protein would have excluded it from the short list. Professor Allwood accepted this when he said it would not be a preservative of first choice for a protein based solution. However he held to the view that it would be retained in a longer reserve list of possible preservatives. There were other points taken against its inclusion such as that it was cationic whereas EPO is anionic but its incompatibility with protein would in my view have been sufficient to exclude it given the availability of other preservatives such as benzyl alcohol which was tried and tested in at least one protein formulation.

The objections to the inclusion of chlorobutanol are its instability at a pH above 6.0 and the fact that it is said in the HPE to be bacteriostatic rather than bactericidal. Professor Allwood accepted that the second of these two points would discourage the skilled addressee from accepting it for testing and that the use of chlorobutanol in a product with a pH of more than 6.0 would be (to use his words) bad science. Denaturation of the protein would begin at about pH 4.6 and at a pH of 4.0 the protein would unfold. All the evidence suggests to me that the use of chlorobutanol presented the skilled formulator with difficulties he would have regarded as best avoided when drawing up a short list. I do not consider that chlorobutanol would have been included.

That leaves the question of the use of a combination of preservatives including benzalkonium chloride and chlorobutanol. The Claimant’s argument is that it was well recognised and known to the skilled addressee at the time that combinations of preservatives could produce synergy and could therefore allow concentrations of the individual preservatives used to be reduced. In considering what combinations to test the HPE records that a combination of benzyl alcohol and benzalkonium chloride enhances microbial activity and that chlorobutanol is compatible with most excipients and has produced greater anti-microbial activity when used in combination with phenylethyl alcohol. Because it was common knowledge that the formulation process was empirical no inventive step was involved it is said in the selection of benzalkonium chloride and chlorobutanol for use in combination in this particular formulation. It was obvious the claimants say to try benzyl alcohol with any of the other known preservatives contained in the list of those suitable for use with parenterals.

I am not persuaded by this argument. It takes as its premise the existence of a shortlist of preservatives for testing which includes benzalkonium chloride and chlorobutanol. It therefore requires one to assume that the skilled addressee, having proceeded to select three or four preservatives for single use by excluding those which would be unsuitable in combination with proteins would then consider it obvious to abandon that strategy (and with it the choices he has made) in favour of testing preservatives in combination from a wider class of chemicals which included those that had already been rejected as unsuitable due to their incompatibility with proteins. The premise behind this argument is that the skilled addressee would have decided that it was worth trying combinations of benzyl alcohol and benzalkonium chloride or chlorobutanol as a way of lowering the concentration of benzyl alcohol and thereby avoiding the allergic responses which were known sometimes to occur when it was used in higher concentrations. He would know from the HPE and other literature that benzyl alcohol and benzalkonium chloride could produce a synergistic combination as could benzyl alcohol and chlorobutanol. He would therefore (guided by this knowledge) test these combinations as obviously worth trying notwithstanding that a protein ingredient was involved.

Professor Randolph accepted that the anti-microbial synergies which could be obtained from combining agents such as benzyl alcohol and benzalkonium chloride were known at the time and were obvious. The HPE was put to him as one example and the Guide as another but there are other references spread across the standard works. He also accepted that in order to know whether it would have been a valuable application in the case of a protein based formulation one would have to test. But that evidence does not answer the question whether the testing of combinations of benzyl alcohol, benzalkonium chloride and chlorobutanol would have been considered obvious or routine as opposed to experimental.

Professor Randolph’s position remained that the synergistic combinations referred to were recorded for their anti-microbial effect without reference to protein formulations. Once that factor entered the equation benzalkonium chloride and chlorobutanol were ruled out. No pharmaceutical manufacturer was going to expose its expensive protein component to such obvious risks.

The premise put by Mr. Lykiardopoulos to Professor Randolph is of course attractive. Why not test combinations of preservatives with a known synergistic effect on formulations containing proteins to see if they work? Professor Randolph accepted that everything in pharmaceutical science was concentration dependant. Why not therefore test benzyl alcohol and benzalkonium chloride to see if at a low concentration even with a protein the reported increase in anti-microbial effect could be achieved without damage to the active ingredient? One answer to that question is that such trials would be interesting to carry out but that does not make the process obvious or routine. The validity of the Patent when tested against common knowledge ultimately turns on the relatively narrow question whether the uninventive but skilled formulator would in 1991 have regarded the anti-microbial synergies I have referred to as sufficient to override the generally accepted reservations about the use of benzalkonium chloride and chlorobutanol in relation to proteins.

I am not satisfied on the evidence that it would. I think that however obvious it may now seem a decade later to have tested these combinations, that is very much the product of hindsight. I believe that the skilled person in 1991 would have taken a selective and conservative approach designed to identify which of the preservatives known to be of use with proteins would provide the most effective longer term protection for the solution. There is nothing in the evidence which convinces me that based on his common knowledge the skilled addressee would have regarded it as obvious to use a combination of preservatives which he had previously rejected for single use. On the contrary I believe he would have qualified his knowledge that the combination of (for example) benzyl alcohol and benzalkonium chloride could produce a better microbial effect with an assumption that they would retain their same chemical characteristics if applied to a protein. He would not therefore have regarded it as obvious to test whether that assumption was correct. That is the province of general experimentation which is the very thing which the skilled addressee with his lack of inventive capacity is supposed not to indulge in. The highest that Professor Allwood put it is that the benefits of using combinations of preservatives were well known but that is not enough. What matters is whether that would be translated by the notional formulator or formulating team into a belief that it could have equal application to an EPO multi-dose parenteral which had hitherto been marketed using only a single preservative. On this only Professor Randolph is really qualified to assist and I prefer his evidence to that of Professor Allwood in relation to the assumptions which have to be made. The claim based on obviousness over common knowledge fails in relation to Claims 1 and 3 and also therefore to claims 6 and 7. Had I been of a different view about Claims 1 and 3 it is unlikely that I would have upheld Claims 6 and 7. It seems to me that if a combination of benzyl alcohol and benzalkonium chloride was obvious to try so would the use of these chemicals in the small concentrations referred to. That would have been no more than a function of the same tests.

The Konings patent is entitled: “Improved Cyclodextrin Based Erythropoeitin Formulation”. It relates (inter-alia) to ways in which EPO in an aqueous solution can be prevented by the use of cyclodextrin from being adsorbed onto the surface of its container. The aim of the patented formulation is stated to be to preserve the functional stability of the glycoproteins over a long period of time in an aqueous solution intended for parenteral administrations.

The critical passage relied on appears at page 6 line 31 to page 7 line 5 of the specification where it says this:

“The addition of an appropriate preservative to the preparations such as alcohols, for example, ethanol, 1,3-propanediol, benzylalcohol or derivatives thereof, phenyl ethyl alcohol, phenol or phenol derivatives such as butylparaben, methylparaben, m-cresol or chlorocresol; acids, for example, benzoic acid, sorbic acid, citric acid, sodium propionate, EDTA disodium; chlorhexidine; hexamidine diisetionate; hexetidine; optionally in combination with sodium bisulfite, or with propyleneglycol, or less preferably quaternary ammonium salts, metallic compounds such as zinc oxide, thiomersal and phenyl mercury salts, e.g. phenylmercuric acetate allows one to prepare safe multidose formulations of erythropoietin for parenteral and especially for local (e.g. nasal or ocular) administration. The preservative in said multidose formulations obviously is chosen so that it is compatible with the route of administration. Such a multidose formulation constitutes an economical and practicable advantage over the art-known single dose formulations.”

Professor Allwood in his first report says that the reference to “preservation” in the passage quoted appears to be used in a general sense and not to be limited to anti-microbial preservatives but, he says, a safe multi-dose formulation will clearly have to have anti-microbial properties and Konings envisages that at least one of the anti-microbial preservatives listed is added for that purpose. The skilled addressee would have put into this category benzyl alcohol; phenylethyl alcohol; phenol; quaternary ammonium salts; thimerosal and the phenyl mercury salts. Others listed would typically have been used for either topical or oral preparations. The primary example of a quaternary ammonium salt is benzalkonium chloride. Professor Allwood says that although its use is said in the patent to be less preferable it is still included as one of the preservatives which could safely be used in an EPO multi-dose parenteral. Mr Lykiardopoulos therefore submits that Konings teaches the use of “benzyl alcohol …optionally in combination with …quarternary ammonium salts (i.e. benzalkonium chloride) … to prepare a safe multi-dose formulation of EPO for parenteral administration”

Professor Randolph in his report says that he is unsure what the passage quoted above means. It would, he said, be remarkable if each of the listed compounds had been tested and found to preserve EPO and the passage appears to him to be what he describes as a shopping-list of chemicals without any real thought having been given as to their suitability. Some of the compounds (e.g. zinc oxide and hexetidine) are he says unsuitable for use in an injectable preparation and sodium bisulfite would be incompatible with EPO and can cause severe allergic reactions in some patients. As stated earlier both experts agree that thimerosal is excluded because of its mercury content. Professor Randolph’s conclusion is essentially that the passage would not have been regarded by the person skilled in the art as reliable and he could not have proceeded and would not have proceeded to experiment with any of the compounds listed without first carrying out the searches in the established list referred to earlier in this judgment. This would have led him to reject benzalkonium chloride for the reasons already given.

There are points of interpretation which can be made about the contentious passage quoted and some were put by Mr Arnold to Professor Allwood. It might, for example, be said that the absence of the word “with” before the word “quarternary” indicated that the latter was not qualified by the words “in combination with” at all. But the more one analyses the language the more clear I think it becomes that this is an opaque and confusing passage which recites a list of very different preservatives intended for a wide spectrum of use and fails to make it clear which are to be combined with which and in relation to what type of product. One can as a matter of grammar get almost any number of permutations out of it regardless of their scientific validity. However in order to derive anything meaningful from it the reader has to use his pre-existing scientific knowledge. Therefore in reality this passage in Konings teaches him nothing that he does not already know. I do not accept (given the rather cavalier and confusing way in which the contents of the passage were put together) that the person skilled in the art would have felt able to take anything from Konings unless verified by his own common general knowledge. The passage is not critical to the inventive concept in the patent and was clearly not intended to form part of its didactic content. For these reasons I reject the claim of obviousness over Konings.

Obviousness over Denyer

This is a review article by Denyer, Hugo & Harding published in 1985. It cross-refers to the earlier articles by Stock and Boehm although they are also relied on separately in the pleadings. The Denyer article is relied upon as teaching that:

On page 248 of the Denyer article there is a table setting out a summary of some 48 reported synergistic combinations of anti-microbial preservatives. These include combinations of benzyl alcohol + benzalkonium chloride and of benzyl alcohol + chlorobutanol. The first of these reported combinations is based on the Boehm article. In the conclusions at the end of the article the authors say this:

“When considering combinations of antimicrobial agents, it should always be remembered that in vitro observations do not always produce the same results in vivo and particular attention should be paid to eliminating combinations or concentration ratios which may prove antagonistic. The activity of the system must ultimately be tested in the product to be preserved since many factors, including ingredients and formulation design, could influence the potential for synergy”

The Denyer article does not in terms seek to deal with the specific question of preservatives in a protein based formulation. It is a general review article covering pharmaceuticals and cosmetics. Professor Allwood accepted that it would have given the skilled addressee no hint as to which of the 48 combinations might be useful for preserving a protein and would not degrade EPO. He disagreed however that it added nothing to the addressee’s common general knowledge. He said that it provided the addressee with a summary of possible synergistic systems. But the reality is that this would have provided him with very little information which he did not already have based on (for example) the HPE and no information about the use of the synergies in relation to a protein.

Of more interest is the Boehm article. Both experts accept that if the addressee was interested in the particular combination of benzyl alcohol and benzalkonium chloride he would follow up the reference to Boehm. This is the text of a lecture delivered to the Society of Cosmetic Chemists in January 1968. The paper (as its title suggests) is concerned with synergism in the use of anti-microbial preservatives. It refers to the possibility of increasing the range of micro-organisms which can be killed by combining preservatives and to the reduction in concentrations which can be achieved. The paper includes a number of tables. Table XII illustrates the bactericidal effect of a combination of benzalkonium chloride and benzyl alcohol against E-coli bacteria at 22° C in a pH of 4.7. This indicates that the combination achieves a complete inhibition of growth over a twenty-four hour period whereas the two chemicals when used singularly but in the same concentrations are much less effective. With benzyl alcohol as the sole preservative there were still signs of growth after twenty-four hours and with benzalkonium chloride alone growth still continued after three hours.

This table is said in the paper to contain some of the results obtained and described in an article by Clausen and Raugstad in 1965 from tests conducted in 20% horse serum. Boehm says this about them:

“Since the antimicrobial effect of many substances is considerably reduced by blood, the results obtained give an idea of the antiseptic effect of the products involved, i.e. a determination of their usefulness in preventing infection in topical therapy. We have already seen that the glycol ethers, e.g. Phenoxetol and its derivatives, are readily compatible with organic material of this type and combined with their non-irritant effect on the skin they may be considered well suited to external therapy. Quaternary compounds on the other hand, e.g. benzalkonium chloride or cetyl pyridinium chloride, as well as organic mercury compounds exhibit considerably reduced antimicrobial activity in the presence of organic matter and by using these products in combination with products not inactivated in this way, a system is obtained that is not only synergistic but also more effective in the presence of organic material. Clearly, however, the compatibility of each component of these synergistic systems and also their final intended application must be ascertained before such systems are used in any given preparations.”

At first sight this might have been of some interest to the skilled addressee concerned to formulate a protein for multi-dose application. But there are a number of qualifications which need to be made. The first is that the Boehm article (and in particular the passage quoted above) is directed to the topical use of preservatives in cosmetic products. It is not concerned with the formulation of injectable pharmaceuticals. Professor Allwood accepted in cross-examination that the text quoted really adds nothing to Denyer but merely underpins what Denyer is saying about synergistic combinations. By using benzalkonium chloride with products which are not inactivated by organic material the preservative system which results is said to be made more effective but the paper tells the reader nothing about its potential for use in an injectable EPO formulation. Mr Arnold put it to him that paragraph 192 of his first report where he refers to Boehm explaining that a combination of benzalkonium chloride with other preservatives such as benzyl alcohol was more effective in the presence of protein was not an accurate summary of what Boehm in fact says. He accepted that.

The second qualification relates to the data in Table XII. The results as shown do not in fact exhibit synergy because the concentrations of each chemical used are not reduced in that combination. However, the more important point concerns the reliability of the table. Professor Allwood was reluctant to accept that the skilled addressee would look beyond Boehm. I do not accept that. On one view he would not look beyond Denyer itself but that would tell him nothing about synergic combinations in relation to proteins. If he considered it appropriate to look at Denyer’s sources (which Professor Allwood says he would) and he came to consider Table XII it seems to me reasonable to suppose that he would have been interested in the tests carried out by Clausen and Raugstad which are said to form the basis of the table.

Professor Randolph has carried out this exercise and has read Clausen and Raugstad. Surprisingly there is no reference in it to the results contained in Table XII nor any reference to either benzyl alcohol or benzalkonium chloride. This is hardly encouraging and would, I think, have led the skilled person to discount Boehm as unreliable.

This leaves the article by Stock. One gets to this from the table in Denyer where it refers to a combination of benzyl alcohol and chlorobutanol. The Stock paper was published in 1962 in the Australasian Journal of Pharmacy. It indicates that with a combination of benzyl alcohol and chlorobutanol all organisms were killed in six minutes. It also records that chlorobutanol is not a reliable bactericide at temperatures of 18° C and lower. The paper is not concerned with proteins but with chlorobutanol when used in ophthalmic products. Professor Allwood was I think minded to agree that this would if anything discourage the use of it in refrigerated formulations but the main point is that the paper really adds nothing to common general knowledge and therefore takes the case on validity no further.

Conclusions

For these reasons the claim fails and will be dismissed. In the absence of agreement I will hear counsel on the form of the order and on costs.