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Cite as: [2005] EWHC 2141 (Pat)

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		Neutral Citation Number: [2005] EWHC 2141 (Pat)
		Case No: HC04 C03755

IN THE HIGH COURT OF JUSTICE
CHANCERY DIVISION

Royal Courts of Justice
Strand, London, WC2A 2LL

12 October 2005

B e f o r e :

THE HONOURABLE MR JUSTICE PUMFREY
____________________

Between:

	MAYNE PHARMA (USA) Inc MAYNE PHARMA PLC MAYNE GROUP LIMITED	Claimants
	- and -
	TEVA UK LIMITED APPROVED PRESCRIPTION SERVICES LIMITED	Defendants

____________________

Daniel Alexander QC and Thomas Mitcheson (instructed by S J Berwin) for the Claimants
Michael Silverleaf QC and Michael Tappin (instructed by Addleshaw Goddard) for the Defendants
Hearing dates: 13–18 April 2005
____________________

HTML VERSION OF JUDGMENT
____________________

Mr Justice Pumfrey :

Introduction

This is an action for the infringement of European Patent (UK) 0 835 657. The patent stands in the name of Mayne Pharma (USA) Inc, the First Claimant. The Second Claimant is a licensee in respect of the patent in the United Kingdom, and the Third Claimant is the parent company of the Second Claimant. It is not clear to me what, if any, causes of action are owned by the Second and Third Claimants, but in any event it is unnecessary to distinguish between the Claimants, to whom I shall refer as "Mayne". The First Defendant, Teva UK Limited, is a generic pharmaceutical company which admits the importation, disposal, and keeping of the allegedly infringing material in the United Kingdom. The Second Defendant denied all acts of infringement, and played no separate part in the trial. I shall refer to the Defendants as "Teva" for convenience, it being recalled that there is, as far as I can see, no evidence in respect of the activities of the Second Defendant.

Teva deny infringement, and allege that the patent is invalid upon two principal grounds: obviousness over the common general knowledge in the art, and obviousness in the light of a particular publication referred to at trial as "Richheimer". Mayne sought to answer the allegation of obviousness in the light of the common general knowledge by adducing evidence from Dr Robyn Elliott, who was closely involved in the events leading up to the making of the invention. Her evidence was in the end relied upon by Teva as reinforcing their argument on obviousness. Finally, Teva bolstered their case for non-infringement by employing a complementary allegation of insufficiency.

The Witnesses

I heard evidence from three experts, Professor Baldwin, Professor Stella and Professor Tapolczay. Professor Baldwin and Professor Tapolczay were both, to my mind, sound and reliable witnesses. Professor Stella also was a good witness, although on occasion inclined to be combative. I have no doubt that Professor Stella was doing his best to assist, and I do not regard his evidence as in any way impaired. As is not uncommonly the case, each of the witnesses was too expert to be truly representative of the person skilled in the art, and Professor Stella had substantial personal knowledge of the active ingredient of the pharmaceutical in question, paclitaxel, at the priority date. It is important to note, however, that he was (as compared with Professor Tapolczay) the more expert in non-aqueous pharmaceutical formulations. The latter had considerable expertise in solid formulations.

Dr Elliott, who gave evidence of fact, might have been hoped to provide a touchstone for assessing the actual common general knowledge at the date. I did not feel that I could employ her evidence in this way. I felt that she had little accurate recollection independent of the documents, a fact unsurprising, having regard to the lapse of time since the priority date (November 1992). Furthermore, it became clear that her skill-set was not that of the person skilled in the art: she was an inorganic chemist who had spent time as a regulatory officer and in management, and she accepted that she was not a pharmaceutical chemist of any description. It is not possible, therefore, to draw inferences as to the common general knowledge from the documents for which she was responsible. I shall deal with the impact of her evidence as a whole when I come to consider the case of obviousness in the light of the common general knowledge.

The Patent in Suit

European Patent 0 835 657 claims priority from an Australian application of 27^th November 1992 and an American application of 22^nd November 1992. It is entitled "Stable injectable paclitaxel composition". The invention is said to relate to a "solution of paclitaxel having improved stability" (column 1 line 2).

Under the heading "Background of the invention" the active ingredient, paclitaxel, is described. It is sufficient for my purposes to observe that by the priority date paclitaxel was a well-known antineoplastic agent, being the subject of a US National Cancer Institute clinical brochure. It is probably better known under the trade mark Taxol, under which it is sold by the pharmaceutical company that developed it, Bristol Myers Squibb.

At the priority date, the nature and activity of Taxol were well-known. Taxol presented two particular problems:

i) at the priority date, it was a natural compound extracted from the bark of the western yew tree and, accordingly, extremely scarce; and

ii) it was very poorly soluble in water.

At the priority date, the material had not been synthesised. A review article published in the Journal of the National Cancer Institute in August 1990 describes Taxol as "the first compound with a taxene ring that has been demonstrated to possess antineoplastic activity, and it has become one of the most important lead anti-cancer agents to recently emerge from the screening of natural products". As of the priority date, the presentation of Taxol was as a solution in 50% cremophor EL and 50% dehydrated alcohol. The pharmaceutical data are described in the article in the following words:

"Taxol is supplied by the NCI [National Cancer Institute] as a concentrated sterile solution of 6 mg/ml. in 5-mL ampoules (30mg per ampoule). Because of Taxol's aqueous insolubility, it is formulated in 50% cremophor EL and 50% dehydrated alcohol. The contents of this ampoule must be diluted further in either 0.9% sodium chloride or 5% dextrose (81). During early phase I and II studies, Taxol was diluted to final concentrations of 0.03 to 0.60 milligrams per millilitre. These concentrations were demonstrated to be stable for 24 and 3 hours, respectively, in early stability studies (81). This short stability period required the administration of large volumes of fluids and/or drug preparation at frequent intervals for patients receiving higher doses. In recent studies (91, 92) concentrations of 0.3 to 1.2 milligrams per millilitre, in either 5% dextrose or normal saline solution, have demonstrated both chemical and physical stability for at least 12 hours. Only glass or polyolefin containers and polyethylene-lined nitro-glycerine tubing have been recommended for drug administration, since significant amounts of the plasticizer diethylhexylphthalate are leached from the plastic tubing and solution bags containing polyvinyl chloride after contact with cremophor. . . ."

At column 1 line 45, the specification describes the problem of the poor stability of paclitaxel as follows:

"[0007] It is a disadvantage of the known formulation that the paclitaxel therein degrades, with the result that the shelf-life of the formulation is unsatisfactory, and there is therefore a need for a paclitaxel solution of improved stability."

The invention is then immediately described: it is a solution consisting of paclitaxel, ethanol, polyethoxylated castor oil [cremophor] and acid, the solution having a pH of 5 to 7. The remaining claims to the solution add nothing: but it should be observed that claim 8 is a claim to a method of producing a paclitaxel solution as defined in any of the preceding claims, comprising the addition of an acid to a solution consisting of paclitaxel, ethanol and polyethoxylated castor oil.

Measurement of pH and its impact on the claim

Surprisingly, this claim gives rise to a problem of interpretation. The problem is caused by the reference to pH. PH value is conventionally a logarithmic index for the hydrogen ion concentration in an aqueous solution, and is used as a measure of acidity of that solution. The pH value is defined as log₁₀(1/[H⁺]) or –log₁₀([H⁺]), [H⁺] being the molar concentration of hydrogen ions. The neutral position is defined by reference to the hydrogen ion concentration in pure water, which has a pH of close to 7. A pH below 7 in an aqueous solution indicates acidity, and one above 7 alkalinity. As I understand the evidence, it is perfectly possible to define a pH index for other solvent systems, at least if they permit a repeatable measurement of hydrogen ion concentration. It is not suggested that the reader of this patent is taught to devise such an index and calibrate an appropriate pH measuring device against appropriate standards for a 50/50 cremophor/ethanol system.

So the question arises, what has to be done in order to decide whether or not a solution of paclitaxel in the non-aqueous mixture of alcohol and chremophor infringes? The patentee's answer is to take a conventional laboratory pH meter, put it into the solution and read the answer on the dial. This approach has the merit of simplicity. Every laboratory has a pH meter, and their existence and use was at the priority date part of every chemist's common general knowledge.

The Defendants' contention is that such measurements are neither repeatable nor valid. The Kirk-Othmer Encyclopaedia contains the following passage:

'The activity of the hydrogen ion is affected by the properties of the solvent in which it is measured. Scales of pH apply to the medium, i.e. the solvent or mixed solvents, e.g. water-alcohol, for which the scales are developed. The comparison of pH values of a buffer in aqueous solution to one in a nonaqueous solvent has neither direct quantitative nor thermodynamic significance. Consequently, operational pH scales must be developed for the individual solvent systems. In certain cases, correlations to the aqueous pH scale can be made, but in others, pH values are used only as relative indicators of the hydrogen-ion activity.

Other difficulties of measuring pH in nonaqueous solvents are the complications that result from dehydration of the glass pH membrane, increased sample resistance, and large liquid-junction potentials. These effects are complex and highly dependent on the type of solvent or mixture used.'

If one uses a conventional pH meter in the cremophor/ethanol system with which the patent is concerned, it has not been demonstrated that the measured pH would be substantially the same as that obtained using an appropriate meter properly standardised. Nor has it been shown that it would be significantly different: Teva offered no evidence to this effect. Mr Alexander QC attempted to extract some comfort, at least as to repeatability, from the fact that a repetition of Sample 1 of Example 1 of the patent gave rather similar results in the experiments to those recorded for the patent. For this purpose, he says, that is enough.

Mr Silverleaf mounted a formidable attack on these experiments. He submits, on the basis of Professor Baldwin's evidence in cross-examination together with the text referred to as Westcott ('pH Measurements', by C Clark Westcott Academic Press 1978) and the instruction manual for the meter in fact used by Mayne in their experiments, that the following propositions represent the factual position. In this I think he is right.

i) None of the recommendations in Westcott for the selection of an appropriate meter or electrode^[1] for use in a non-aqueous system were followed;

ii) The electrode was not soaked in the solvent after calibration using an aqueous buffer;

iii) The readings drifted for some time before steadying;

iv) There were 16 available electrodes available for the meter used and no justification advanced for using the one in fact employed in the experiments.

Samples 1 and 2 of the patent are the basic comparison samples of the patent. Notwithstanding the various deficiencies identified by Mr Silverleaf, the results of the pH measurement are strikingly similar for sample 1. For sample 2, to which citric acid has not been added, there is a difference of 0.6 of a point. This means, Mr Silverleaf submits, that the examples and the experiments do not correlate, and that the patent does not provide enough information for a proper conclusion to be drawn as to whether any particular formulation infringes.

As I have said, Teva challenge the sufficiency of the disclosure of the patent. Because the whole of the argument of insufficiency turns upon the question of pH measurement, I should deal with it here.

The disclosure of the patent and common general knowledge in respect of pH measurement

The patent is concerned with the stabilisation of an existing formulation of paclitaxel. The addressee is thus the formulator and a chemist skilled in pharmaceutical development. The formulator will have the normal laboratory equipment, which as I have indicated includes a pH meter (and its handbook).

There is no disclosure of any special method of pH measurement. The skilled addressee must, therefore, be taken to use the common general knowledge in respect of this measurement and if the common general knowledge does not supply a method of measurement that is adequate for the purposes of the claim, the patent is insufficient because the invention is not described clearly enough and completely enough for it to be performed by the person skilled in the art.

In carrying out this assessment it is important not to attach too much importance to problems that may arise at the edge of claims. But if it is established that two different applications of the common general knowledge will give results that in the one case clearly indicate infringement and in the other clearly do not, then the patentee must either have told the skilled person which to use or will risk a finding of insufficiency.

This claim contains a simple numerical range. What is an adequate measurement for the purpose of this claim? This question cannot be answered until the reader knows why the numerical limitation is present. Answer, because all that is suggested is to acidify the paclitaxel sufficiently so that its pH is on the acid side of neutral. This is a change of 2-4 points over the presently available material (consisting of paclitaxel, cremophor and ethanol) available from Bristol Myers Squibb. The skilled person is taught that if that adjustment is made the stability of the solution is improved. My view is that this is the natural reading of the claim. No particular significance is attached to the numerical limits, and the only experimental evidence contained in the specification goes no way to support them.

I have been very concerned by Professor Stella's view that 'pH is just not something that is normally and traditionally done with non-aqueous systems.' This answer was elicited in the course of cross-examination on inventive step in the light of Richheimer, the Professor's view being that characterisation of the solution by reference to pH contributed to the invention. How can there be a common general knowledge in respect of a measurement that is not normally and traditionally done?

Contrary to Mr Silverleaf QC's submissions, to which I have been very attracted on this part of the case, the specification does in my judgment contain its own standard, of a sort, when it teaches that the pH of the existing formulation (there is no other) is 9.0-9.1 and it needs to be acidified to the stated extent. The problem is a very narrow one, and the solution simple. There is no scope, in my view, for elaboration of the potential difficulties of pH measurement.

The result of this approach to the claim is that the skilled person at the date would see it as a claim to the existing paclitaxel formulation improved in stability by acidification by 2-4 pH points or so.

I should just add that there was a certain unreality in the evidence presented on this issue. Teva, on whom the onus lay for this purpose, did no experimental work to show whether the many and various deficiencies to which I have referred above in fact made any difference at all when the cremophor/ethanol/paclitaxel system was being measured. Against this silence, I think Mr Alexander was entitled to say that the experimental results looked just the same as the ones in the patent and that was enough.

It is a consequence of this interpretation of the claim that little importance can be attached to the pH values which it recites, even though these are apparently precise values. There was no evidence that enables me to say other than that the inventive concept of the patent is the acidification of a cremophor/ethanol/paclitaxel solution. I draw further support for this conclusion from the fact that there is no disclosure in the patent (the 'consistory clause' apart) that provides any sort of support for the upper and lower limits in the claim from a technical standpoint.

It follows that the claim is infringed, and that the patent is not insufficient.

If I am wrong on the question of construction, and the claim calls for precisely measured pH values, the position is not really different. The pleaded case on sufficiency is that 'in the case of such a solution which is non-aqueous "pH" has no meaning and no meaningful measurement of pH can be made unless it is to be determined by the conventional method for non-aqueous solutions of measuring the pH of a 1:10 dilution in water. The reading obtained by inserting pH meter electrodes directly into a non-aqueous solution will depend upon, inter alia, the materials of which the electrodes are comprised and the buffers used for calibration and/or will drift over time. Accordingly the skilled person cannot work the alleged invention, which requires the said solution to have a pH of 5-7.' As appears from the decision in Lubrizol v Exxon [1998] RPC 727, the skilled person will be taken to use the common general knowledge method to perform measurements called for by the claims, unless the specification directs some other method to be used. It is not an objection that there is in the art more than one method of performing a determination, unless there is no default method. So what is the common general knowledge method? It seems that it is to recognise that one is not necessarily doing something that is appropriate, but to use a standard pH meter, knowing that what one is measuring is not pH as normally understood but is nonetheless an indication of the acidity or basicity of the solution. Professor Tapolczay, who disclaimed any expertise in pH measurement, but was a very experienced experimental chemist, would have used the pH meter. Absent actual experimental evidence to show any of the problems that the pleaded case alleges if a conventional meter is used do arise in fact (how ever objectionable the use of an ordinary pH meter is in theory) it seems to me that the allegation of insufficiency would still not be made out.

Validity—obviousness

It is necessary at this point to consider the common general knowledge in greater detail. The NCI brochure was the basis of any attempt to formulate paclitaxel for administration. This was the undisputed evidence. Dr Elliott had a copy. The brochure gives the basic information relating to formulation as follows:

'How supplied: 30 mg. ampoule/vial: 6 mg/mL, 5 mL, in polyethoxylated castor oil (Cremophor EL*) 50%. and dehydrated alcohol, USP, in 5 ml ampules/vials. THIS SOLUTION MUST BE DILUTED BEFORE USE.

Solution preparation: Taxol concentrations of 0.3 mg/ml. to 1.2 mg/ml may be obtained by diluting the solution with proper volumes of either 0.9% Sodium Chloride Injection, USP,. or 5% Dextrose Injection, USP.'

The information on stability is as follows:

'Storage Refrigerate the intact ampules and vials (2-8ºC).

Stability: Shelf-life surveillance of the ampules and vials is ongoing. Solutions of taxol diluted to the above concentrations are both chemically and physically stable for at least 12 hours. All solutions exhibit a slight haze which is common to all products containing nonionic surfactants.'^[2]

The properties of the formulation are described in the following passage:

'Taxol, due to its limited solubility in water, is prepared and administered in a vehicle containing Cremophor EL, a polyoxyethylated castor oil, and ethanol in a 50:50 ratio. Cremophor EL docs not a1ter the stability or activity of taxol, as would other vehicles…. It is also used as a vehicle for other antineoplastic agents…'

Against this background, the defendants advanced two really quite different attacks of obviousness. The first is obviousness in the light of the common general knowledge, aided if need be by the disclosure of the unpleaded document called Kingston ('The chemistry of taxol' 1991) which was accepted as representing the kind of knowledge of the chemistry of paclitaxel which existed in 1991. It was also accepted that Kingston would be likely to be turned up on any search by a chemist interested in the chemistry of paclitaxel. This document gives rise to the sort of problems I discussed in Nutrinova v Scanchem [2001] FSR at [81] ff. Mr Alexander was inclined to accept that it was to be treated as common general knowledge in the orthodox sense, and it is material which the hypothetical unimaginative skilled person has available when he approaches a problem of the chemistry of paclitaxel. The consequences of this I shall discuss below.

The second route, a much simpler one, was from the pleaded document called Richheimer. Richheimer is concerned with solutions of paclitaxel in methanol.

The law

Obviousness is a question of fact, and may be decided in the four stages identified in Windsurfing v Tabur Marine [1985] RPC 59. In short, (1) the inventive concept of the patent in suit must be identified (2) the skilled man and the appropriate common general knowledge determined (3) the step(s) needed to bridge the gap(s) between the cited matter and the inventive concept identified and (4) finally the court must decide whether to take those steps would or would not be obvious to the skilled man. The difficult question is the last one, and it must be decided in the light of all the available material. This material may include what others did, as it does in this case, and it is convenient to start with Dr Elliott's evidence.

Dr Elliott's evidence: developments at David Bull Laboratoriess and NaPro

Dr Elliott left Monash University in 1987 with a PhD in inorganic chemistry and went to work with David Bull Laboratories ("DBL") (part of FH Faulding Co Ltd ("Faulding"), and since 2001 part of the Mayne Group. She did not work as a pharmaceutical chemist at DBL but was engaged on regulatory work, which involved some technical work since she needed to communicate the content of the various studies that had to be performed for regulatory approval to those responsible for carrying them out.

In 1988, she became Product Development Manager at DBL. By 1992, she had become Scientific Affairs Manager, which meant that she was responsible for regulatory matters, product development and research and development. By this time, DBL wished to develop a generic alternative to the Bristol Myers Squibb taxol formulation, and obtained their raw material from NaPro BioTherapeutics Inc. The project was called 'Edward', a fact important for the understanding of the documents disclosed. The evidence was that while NaPro had extensive knowledge of the chemistry of paclitaxel, they lacked the formulation and regulatory skills necessary to bring a generic product to the market.

As would be expected, DBL started with the standard, BMS formulation cremophor/ethanol/paclitaxel. This was so that regulatory approval could most readily be obtained. As part of that process, it was necessary to show that the DBL formulation was as stable as the approved BMS formulation, and for that purpose Dr Elliott, in collaboration with Paul Handreck, who was a product development associate managing the development process, devised a protocol for accelerated stability tests of the formulation using the NaPro paclitaxel. It became clear quite soon that there was a major problem with the stability of the formulation.

Two initial areas of investigation were identified. The first was the NaPro paclitaxel itself. The material being used for the stability tests was not as pure as that which was being prepared for the clinical trials. The second was water: were BMS drying the cremophor they used? Both areas involved the repetition of stability tests using (1) purer paclitaxel and (2) deliberately added water in various amounts. It turned out that the purity of the paclitaxel was irrelevant, but that the degradation pathway (as revealed by degradation products) changed with the added water. The initial tests had indicated a pathway ending in baccatin III while the tests with deliberately added water went possibly via 10-deacetyltaxol. It seems that DBL were able to perform this analysis by HPLC because they had standards of the various degradation products that had been supplied to them by NaPro.

There is no doubt that no-one at DBL had any idea what the problem was. They had been supplied with a sheet by NaPro showing the various degradation pathways but had insufficient information, it would seem, to draw any inferences from them. In particular, they had identified the two possible pathways, but were unable to account for them. The answer came back a day later from NaPro. After summarising the results obtained by DBL they continue:

'5) From our experimentation. we have found that under severe acid conditions (pH=l), edward degrades into 10-deacetyledward and not into baccatin III or V.

6) From our experimentation, we have found that at pH 7 and above, edward degrades into baccatin III and 7-epi-10-deacetylbaccatin III. Only smaller amounts of 10-deacetyledward are found.

7) From our experimentation, we have found that at pH = 3.6, edward is very stable in ethanol, even over extended periods of time. Formulated in ethanol, the pH of the NBT edward is around 6.3.

From these results we can see that the variation in these routes of decomposition is very likely due to the variation in the pH of the formulation. Since we have seen our formulation of the edward in cremophor EL/ethanol be very stable over periods of weeks (see attached report of project #4001, NBT edward in cremophor EL), the decomposition of the material does not seem to be a big problem. However, we want to see the same route of decomposition as the BMS material. So the control of the pH in the final formulation is very important. Offhand, we would suggest that you closely define the pH of the cremophor EL that is supplied to you. We have used material that was obtained through Sigma Chemical. This may be different from the material that you have used, and both of these may be different from the cremophor in the BMS sample.

We suggest that you first check the pH of the creamaphor [sic] EL that you have. Then try to adjust the pH of the creamaphor EL with acetic acid (that would be produced from the degradation of the edward via the acid hydrolysis route, anyway) before you do the formulation. Also you may want to try the same experiments on the primary standard material that was sent to you. This material is slightly more pure than the process A material (we do not think you will see any difference at all, but it would help "pin down" the pH sensitivity issue).'

This response is interesting in many ways. There may be some doubt as to who the source of the information contained in it was, but that does not matter. First, it suggests that the main impulse for the invention came not from a stability problem as such, but from the fact that the degradation product of the DBL formulation was different from that of the BMS material, and NaPro, who appear to have been responsible for the chemistry, viewed the problem as one of obtaining degradation by the same pathway. Second, and more important for present purposes, is that NaPro were enabled to give the recommendation that they did on the basis of their own experimentation summarised in the quotation above. At this stage, all the necessary information had been conveyed, and DBL formulated using citric acid rather than acetic acid for reasons explained by Dr Elliott. The HPLC standards for the degradation products appear to have been obtained from NaPro but Richheimer indicates that they are available from the NCI, as perhaps might be expected for such an important drug. So in principle anyone could do the analytical work involved.

Obviousness in the light of common general knowledge.

This basis of this challenge to the patent is Professor Tapolczay's evidence. He set out his reaction to the formulation as follows. It should be remembered that he is an experienced development chemist:

'8. When I was first approached by Addleshaw Goddard, I was presented with one page from the Clinical Brochure. This was page 3, at the top of which is shown the chemical structure of paclitaxel. I was simply asked for my thoughts and observations, and, as a chemist, I immediately looked at the structure to identify parts of the molecule to see what it contained, and, in particular, to see which parts would be likely to undergo chemical reaction. This is the same as I would have done in 1992, and is also what any development chemist would do. The parts of the molecule that struck me as the most reactive were the various ester groups and an amide group. I knew that ester groups are prone to hydrolysis and transesterification reactions. Amides tend to be somewhat less reactive, but are also subject to hydrolysis and analogous reactions.

9. I next noticed the formulation that is set out lower down on the same page of the Clinical Brochure. I saw that this formulation contained a high concentration of absolute ethanol. My immediate concern was that this formulation would be likely to be unstable because of transesterification of the ester groups of the paclitaxel molecule by the ethanol. I saw that on the next page of the Clinical Brochure (which I had subsequently been shown) the NCI instruct that the formulation that they used should be stored under refrigeration. This suggested to me that the NCI had indeed encountered a problem with stability, as I had expected.

10. The obvious course of action to me, if I had been responsible for developing a product containing paditaxel based upon this formulation, would have been to add various concentrations of acid and base, and examine the effect on the stability of the paclitaxel in the formulation. This would have been an obvious thing to do, because it was well known that transesterification reactions take place by two different mechanisms, one of which is catalysed by acid, and the other catalysed by base. By examining the effect of varying levels of add and base, I would have expected that I would have been able to find a level of acidity/basicity at which the overall combined rate of transesterification by the two different mechanisms was at a minimum. This would have been the optimum level of acidity/basicity for stability of the formulation.

11. I was subsequently shown Richheimer, in which it is actually stated that solutions of paclitaxel in methanol (an alcohol chemically very similar to ethanol) can be stabilised by the addition of low concentrations of acids. This not only confirmed my initial thoughts, but would have told me that I needed to add a small amount of acid to improve the stability of the formulation, rather than adding base.'

There are a number of stages in this analysis. The first is whether the skilled man is going to appreciate on the basis of the published data whether there is a problem with the stability of the taxol formulation at all. There is not much indication of that, as Professor Tapolczay acknowledged, other than in the direction to store the drug in a refrigerator. As the Professor said, that, together with the statement that stability studies were ongoing, either suggested that there was no instability data, in which case the NCI's recommendation to refrigerate would continue whether the material was stable or not, or it might support the inference that there was an instability problem. Whether or not that is so, the history of Dr Elliott's development shows that when accelerated stability studies are done, a standard stage in formulation development, there is a problem. It is with a formulator in Dr Elliott's position that the patent is concerned, although I readily accept that Dr Elliott is hardly representative of the skilled person, being an inorganic chemist engaged in what can be properly described as a technical management role.

The defendants say the right approach is that taken by Professor Tapolczay, who essentially provides a solution by inspection of the molecule. He says, and this is accepted, the molecule has a number of reactive sites (nine at least) many of which will obviously be susceptible to the analogous hydrolysis/solvolysis/transesterification reactions. Such reactions are likely to be catalysed by acids or bases, or both, and so stability studies should have been conducted on both acidified and basified solutions. There should be a point at which overall degradation due to the various competing reactions achieves a minimum. It is essential to realise that this is not quite the same problem as that confronted by DBL and NaPro, who were also interested in getting the same degradation products as the BMS baseline product. In particular, it is not necessary to know what the degradation products actually are. This approach does not depend upon an a priori assessment of the degradation paths or products, but merely of the mechanism.

I thought Professor Tapolczay was a very fair and helpful witness. Mr Alexander QC relies on a short passage in his cross-examination at transcript page 451 as demonstrating that he accepted that there was nothing in the mixture itself that might lead one to think about adding acid to stabilise it: the point is that you would think there is a transesterification/solvolysis going on, and the nature of the catalyst was unknown, so you would do stability studies using both acid and base. I accept the answer given under re-examination as reflecting the witness's own opinion.

On analysis, there are two approaches to obviousness on the basis of the common general knowledge. The first is the one I outline above. This is based on the routine performance of stability studies in acid and basic conditions because it is obvious that the material is undergoing either acid-catalysed or base-catalysed reactions.

The second follows more closely what NaPro and DBL did. This is to perform a stability study and analyse the degradation products. Mr Silverleaf QC submits that Kingston clearly indicates that the dominant degradation path is base catalysed. So far as an ethanolic solution is concerned, that is not quite the case. In section 3.1 of the paper Kingston reports a hydrolysis study at pH 9 in methanol, not ethanol. The paper clearly states that taxol is reasonably stable to acids, but is very labile (i.e. reactive) to basic reagents. It is right also that it is reactive to Lewis acids under vigorous conditions. Nonetheless, Professor Stella accepts, and it is therefore common ground, that in fact base-catalysed solvolysis of paclitaxel yields baccatin III, while acid-catalysed solvolysis produces the 10-deacetyl products. We know that in fact the 'BMS formulation' will be basic and will degrade, a prominent product being baccatin III. So after his stability study, the skilled man will be confronted, as DBL were confronted, with a product that has degraded to produce baccatin III. Professor Stella considered that the first thing that would be done would be to find out what the degradation products were.

Assuming, therefore, that the skilled man has this information, is the invention obvious from this perspective? The steps to the invention appear to be the following: (1) appreciate that there is a problem with stability; (2) analyse the degradation products by HPLC; (3) obtain baccatin III (this will happen); (4) appreciate that the presence of baccatin III is characteristic of base-catalysed reactions; and (5) acidify, or at least carry out further stability studies using different degrees of acidification.

Both approaches to the invention from the common general knowledge seem to me to point up the weaknesses of the other. The first depends upon the insight possessed by Professor Tapolczay into the structure of the molecule being attributable to the skilled person confronted with a stability problem of some kind, who must be capable of translating it into a series of acidified and basified stability trials, but without any knowledge of what was in fact happening: in other words, a blind approach which might well encounter success. The other, which is not a blind approach, depends upon the skilled person appreciating that the baccatin III was indeed characteristic of basic degradation and translating that knowledge into a series of acidified stability trials.

This aspect of the case is difficult, but I think the answer is pretty clear. The basic problem is that both courses of action I am asked to attribute to the skilled person are open-ended. Despite Mr Siverleaf QC's compelling submissions, I do not have any confidence that this patent lacks invention in the light of the common general knowledge, and so this allegation is dismissed.

In rejecting this allegation, I should add that I do not accept either that the skilled man should not be taken as appreciating that there is a stability problem. Nor do I consider that pH has anything to do with the actual invention, in the sense that if the skilled man does not measure the pH he will not have arrived at the destination. If he were to acidify to achieve stability and then characterise his results by pH measurements, whether conducted conventionally using the correct apparatus correctly calibrated or using the first laboratory pH meter that came to hand, I think that would be enough. In this connection, I observe that Dr Elliott seems to have wanted to call it "pH", conscious that what was being measured was not pH in the normal sense.

Obviousness in the light of Richheimer

Richheimer is concerned with the separation of taxol from 7-epi-10-deacetyltaxol and from cephalomannine in a reverse-phase HPLC technique. Essential to any HPLC technique is the availability of reliable standards. It appears from the article that the taxol and the 7-epi-10-deacetyltaxol standards were prepared in-house, and cephalomannine, baccatin III and 10-deacetylbaccatin III were obtained from NCI. There are a number of passages that bear on the stability of the taxol solutions used. It is to be noted that these are solutions for use in HPLC, and therefore do not contain the cremophor of the formulations with which I am concerned.

The first passage, a short one, is on page 2324 in the first column, where sample and standard preparation is described. The pure taxol is dissolved in '100.0 mL of methanol containing approximately 100 µL (0.1%) of acetic acid. Acetic acid was used to neutralize traces of alkali present in the methanol and increase the shelf-life of the standard solution.'

Then, on page 2325, the following passage appears:

'Stability of Standard and Sample Solutions. Taxol underwent hydrolysis and transesterification in methanolic solutions. A standard consisting of reagent or HPLC-grade methanol typically lost about 30% of the taxol peak area after storage for 2 weeks at room temperature…A sample with 0.1% acetic acid added to the methanol showed no sign of degradation. The preservation effect of acetic acid appeared to be due to its ability to neutralize traces of alkali (probably ammonia) present in methanol. Experiments indicated that taxol standards containing 0.1% acetic acid showed no detectable degradation when stored 7 weeks at room temperature or 3 months at 4ºC.

…

Degradation of Taxol by Alkali. In aqueous or methanolic alkaline solution, [taxol] was destroyed rapidly and totally. … In methanolic solution, [methyl ((S)-(benzoylamino)-((R)-hydroxybenzenepropanoate] was produced in addition to [baccatin III] and [10-deacetylbaccatin III]. Other deacetylated and debenzoylated derivatives of [baccatin III] were probably also produced by alkaline hydrolysis, but debenzoylated derivates of [baccatin III] would be poorly retained on the column and have weak UV absorbance at 227 nm, and none were observed.

Degradation of Taxol by Acid. Taxol was degraded rapidly at room temperature in a 1:1 mixture of methanol and concentrated HCl. Several polar degradation products were produced…However, unlike base-catalyzed degradation of [taxol], the chromatographic and UV data indicated that no derivatives of [baccatin III] formed. In contrast to weakly alkaline solutions, [taxol] was stable in methanol containing 0.1% acetic acid. In dilute methanolic HCl solutions, the rate of degradation of [taxol] was dependent on the concentration of acid (see Figure 10).'