Ipsofactoj.com: International Cases [2002] Part 1 Case 1 [Ch.D]


CHANCERY DIVISION (PATENTS COURT)

Coram

Minnesota Mining &

Manufacturing Co

– vs –

North American Science

Associates Inc

MR. JUSTICE PUMFREY

31 OCTOBER 2000


Judgment

Pumfrey J

1. INTRODUCTION

  1. This is an action for infringement of European Patent (UK) number 0371682, of which the claimant ("3M") is the proprietor. I shall refer to the defendants, who do not need to be distinguished, as NAMSA. The patent, whose title is "Rapid method for determining efficacy of a sterilization cycle and rapid read-out biological indicator", is concerned with devices which can be placed in sterilisation equipment such as autoclaves. Infringement and validity are both in issue, but the major part of the trial was concerned with issues of validity. The patent in suit is alleged both to be obvious and to be insufficient. This is not one of those cases in which the two allegations are inconsistent: the allegation is that the patent covers sufficiently what is obvious, but that the width of the claim is such that it also covers embodiments of the invention as to which it is insufficient. This allegation gives rise in its turn to the need to determine whether such an attack of insufficiency has a sound legal basis.

  2. The parties cooperated to provide a very useful Primer, which sets out a great deal of material which I shall only repeat to the extent that is necessary for an understanding of my reasons. There was no dispute that the primer represented at least part of the common general knowledge of the skilled man at the priority date.

    2. THE BACKGROUND TO THE INVENTION

  3. In hospitals and elsewhere it is necessary to disinfect bedding and the like. Sterilisation is a different concept. In hospitals, certain equipment must be sterilised, not merely disinfected, and in the course of industrial production, it is also necessary to sterilise certain equipment, such as surgical equipment, objects which are to be implanted in the human body and liquids which are to be transfused. The patent in suit is concerned, as its title indicates, with indicators which are intended to show that a sterilisation cycle in a sterilisation apparatus has completed successfully, by which one means that the material has in fact been sterilised.

  4. Sterility is an intuitively understandable concept: it is the complete absence of viable microorganisms. The purpose of a sterilising treatment is to render an object sterile, but it has long been recognised that in practice complete sterility cannot be detected, although it is possible to reduce microbial contamination to a level which cannot be detected by bacteriological tests. Such tests include, for example, incubating samples from the material on a suitable culture medium over a suitable period to detect growth of any surviving organisms.

  5. Such a method of detecting sterility is impractical. In a hospital what is needed is a test which is easy to carry out and which gives reasonable confidence that the material which has been processed in the sterilising apparatus is in fact sterile. Such a test must reflect the statistics of the problem. As is explained in more detail in the primer, a population of microbes exposed to a sterilising treatment (such as heat, radiation, or a toxic gas) will diminish by a constant factor per unit of time. This means that the population has a half-life (the period in which it will have reduced by one-half) and the surviving population follows a logarithmic relationship with time. It follows that in determining the parameters of a sterilising treatment (how long, how hot, and so on) one is dealing with an exercise in probabilities. By the priority date of the patent in suit in 1988, this was well recognised, and standards prescribed a confidence level (the sterility assurance level, or SAL) which sets a maximum probability of non-sterility following a treatment. Pharmaceutical and medical device industries apply an SAL of 10-6, which in English means that the probability that a sterilising treatment complying with this standard will produce an unsterile result is one in a million. This is considered an acceptable risk.

  6. How then to provide a suitable test? At the priority date, a common solution was to provide a test strip inoculated with a population of bacterial spores known to be resistant to heat. Obviously the probability of a surviving spore after any given duration of treatment increases with the size of the population at the outset of the treatment, so there must be a known initial population (a tolerance to imprecision in this population is built into the test). The idea is that this strip is exposed to the sterilisation cycle, and is then incubated. If the attempt to incubate the strip shows no results after a given time, which is a day or more, the product of the process is considered to be sterile. This method involves the inconvenience that the period required to check the sterilisation process is long, and that during the period of the test the material which has been subjected to the treatment must be quarantined.

  7. The organisms used in test strips at the priority date were heat resistant (thermophilic) bacteria in their spore form. Certain bacteria are capable of existing either as live "vegetative" organisms capable of immediate growth and multiplication or as spores. The bacterial spore was far from fully understood at the priority date. In general terms the spore is a quiescent, dehydrated cell which is relatively very resistant to damage by heat, drying, freezing, toxic chemicals and radiation. Certain bacteria produce spores in circumstances which are unfavourable to bacterial growth and multiplication, with a view to resuming active existence when conditions are more favourable. All that matters for present purposes is that test strips carrying spores were commonly used at the date as sterilisation indicators. When activated, spores are said to germinate to produce an active bacterium capable of division.

  8. The spores of two species of bacteria were used in test strips at the priority date. The spores of Bacillus subtilis were used to detect sterilisation by ethylene oxide. The spores of Bacterium stearothermophilus are resistant to moist heat, and were used to monitor sterilisation by wet (superheated steam) and dry heat. Both these bacteria are more resistant to sterilisation conditions than are the normal run of bacteria to be expected as the "bioburden" on material to be sterilised, and their spores are much more resistant. Thus to kill a comparatively small number of spores of these bacteria is a good indicator that substantial numbers of the bacteria normally encountered will have been killed.

  9. Incubation of a test strip carrying spores of these bacteria after exposure to sterilisation conditions would at the priority date take a day or more. As I understand it, although any surviving spore would have germinated within an hour or so, and cell division would have commenced, the test consists of a visual inspection of a liquid growth medium into which the test strip was placed. For a single cell to have multiplied into numbers sufficient to create a clouding of the medium ("turbidity") would take some time. So the test was slow. It should be noted that the test could be substantially speeded up if there were a visual test for the existence of the products of cell metabolism which would produce an indication (as for example a colour change) before there were sufficient cells to produce turbidity to the naked eye. There is no doubt that the slowness of the test was generally perceived to be a serious drawback, and that at the priority date there was considerable commercial pressure to produce some sterilisation test which gave its indication more quickly.

  10. Because sterilisation of bacteria by heat is a time-dependent phenomenon, the initial number of spores on a test strip has to be prescribed. The nominal number on the spore strips used before the priority date was 1 million. When the spore strips are sampled and tested (since the quality assurance for the strips must itself be based on a statistical evaluation) the probability of there being a surviving organism on a spore strip should be less than 10-6 (the SAL) for an initial cell population of one million. To some extent this is an arbitrary criterion, but it is commonly used. It can be viewed notionally as requiring a sterilisation time 12 times longer than that required to reduce the population of microoganisms by a factor of 10.

  11. Thus, if one starts with a spore strip which has one million organisms on it, and all are dead at the conclusion of the sterilisation cycle, one cannot say that the sterilisation cycle is successful unless one is satisfied that there is a lower than one in a million chance that the spore strip would give a false negative. One would look also at the conditions under which the sterilisation process had operated (temperature, time and pressure, for example) and from a knowledge of these conditions and with the confidence that there is a less than one-in-a-million chance that the spore strip would give a false negative satisfy oneself that the articles were in fact sterile. From this it is obvious that one only sterilises things that are already clean: a substantial bioburden could not be guaranteed to be sterilised within a reasonable time frame.

  12. Of course, this is not the only test which must be undertaken. The sterilisation equipment must itself be monitored so that the operator can be satisfied that it has followed its prescribed cycle. The parameters of the cycle (temperature, pressure, time) are absolute, and perhaps the best primary indication that the sterilisation cycle has been performed correctly. But a biological indicator is the standard in the United States (it is not in the United Kingdom) and anyway gives additional reassurance.

  13. There were also chemical indicators. There is not much evidence about them but what there is suggests that they were unsatisfactory.

    3. THE PATENT IN SUIT

  14. The patent in suit describes the field of the invention in the following words.

    The present invention relates to a rapid method for determining the efficacy of a sterilization cycle. In particular, the present invention employs an enzyme whose activity can be correlated with the viability of at least one microorganism commonly used to monitor sterilization efficacy, hereinafter referred to as a "test microorganism". The enzyme, following a sterilization cycle which is sublethal to the test microorganism, remains sufficiently active to react with an enzyme substrate in a relatively short period of time, e.g., normally eight hours or less. However, the enzyme is inactivated or appreciably reduced in activity following a sterilization cycle which is lethal to the test microorganism.

    The invention is said to be based on a discovery which is described as follows (page 3 line 42)

    1)  

    that certain enzymes remain active following a sterilization cycle which is marginally sufficient to kill the test microorganism whose viability correlates with the enzyme’s activity; and

    2)

    the enzyme activity following the marginal sterilization cycle is sufficient to convert a substrate system for that enzyme to a detectable concentration of product within a relatively short period of time, e.g., generally less than about eight hours.

    Where a test microorganism is used along with, or as the source of, the enzyme, very low numbers of the test microorganism can survive the marginal sterilization cycle. However, there is sufficient enzyme activity associated with the inactivated microorganisms to indicate a sterilization failure.

    The enzyme detection method of the present invention acts as a failsafe in marginal sterilization cycles because the enzymes of the present invention are more resistant to sterilization conditions than the test microorganism. In less complete sterilization cycles the existence of detectable enzyme-modified product, and, hence, the existence of enzyme activity can be used to predict the survival or viability of the test microorganism if it were subjected to the same sterilization conditions and incubated with nutrient medium for at least twenty-four hours.

  15. Enzymes are proteins (polypeptides) and there are a vast number of different ones. The function of enzymes is to catalyse the chemical reactions upon which the functioning of the organism depends. Some enzymes are highly specific, catalysing one particular reaction. Others are much more general in their abilities. For example, some enzymes are capable of decomposing a variety of different proteins into their component amino acids. Every enzyme molecule has one or more active sites. These active sites are designed to receive the molecule or molecules upon which the enzyme is to operate (called the substrate(s)) precisely orientated in such a way that certain of the groups of atoms in the molecule of enzyme exercise a particular chemical influence on the target groups of atoms in the substrate(s). As the catalysed reaction proceeds, chemical bonds are formed between the atoms of the substrate(s) and of the enzyme and are broken, so that the desired chemical reaction takes place.

  16. The effect of heat on an enzyme is to "denature" it. As a result of heat, the enzyme loses its shape and thus its ability to catalyse the chemical reaction for which it is designed. All proteins denature in response to a rise in temperature: a familiar example is the hardening of white of egg as the egg is boiled.

  17. As substrate concentration increases, the rate of an enzyme-catalysed reaction tends towards a maximum value—intuitively, this is when all the molecules of enzyme present are fully employed in catalysis. This is quite different from the behaviour of an ordinary reaction in which rate is proportional to the concentration of reagents. Thus, if it is desired to detect the presence of an enzyme, use of an excess of substrate should result in a reaction in which the concentration of product is proportional to time. It is then possible, in principle, to devise an assay in which some measurable property of the product of the enzyme-substrate reaction that is proportional to its concentration can be measured from time to time, so giving an indication of the amount of enzyme present. Furthermore, limits may be set, so that a concentration of product less than some predetermined level after a prescribed period of time can be used to indicate enzyme activity below some acceptable threshold.

  18. The specification continues (page 2 line 45) with a description of the claimed invention which follows claim 1:

    Accordingly the present invention provides a method for rapidly determining the effectiveness of a sterilization cycle, characterized by the steps of

    A.

    subjecting to said sterilization cycle a source of active enzyme which provides a detectable amount of said enzyme, said enzyme having sufficient activity following a sterilization cycle which is sublethal to at least one test microorganism commonly used to monitor sterilization, to react with an effective amount of a substrate system for said enzyme to produce a detectable enzyme-modified product within less than twenty-four hours, yet said enzyme following a sterilization cycle which is lethal to said test microorganism, being inactivated or having is activity reduced,

    B.

    incubating said enzyme, following the completion of said sterilization cycle, with an effective amount of said enzyme substrate system for a time period and under conditions sufficient to promote reaction of any enzyme remaining active with said substrate.

    The reaction mixture is then evaluated in e.g. a fluorometer [sic] or a colorimeter, to determine the presence of any enzyme-modified product. The existence of detectable enzyme-modified product above background within an established period of time (dependent upon the identity of the enzyme and the substrate, the concentration of each, and the incubation conditions) indicates a sterilization failure. The lack of detectable enzyme-modified product within the established period of time indicates a sterilization cycle which has been lethal to the test organism and is therefor adequate.

  19. It seems to me that this passage does not positively require that the effect of the sterilisation treatment be to destroy all the activity of the chosen enzyme. While step B can be read as an instruction to look for any surviving enzyme activity at all, the emphasis on an established period of time in the passage immediately following seems to me to disclose the possibility that not all enzyme activity needs to be destroyed, but that it be sufficiently impaired that levels of product below a threshold of detectability are all that it is capable of producing in the period of time allowed.

  20. The next passage is important:

    The source of active enzyme may be the purified enzyme isolated from an organism, or may be a microorganism which may itself be one commonly used to monitor sterilization, such as Bacillus stearothermophilus or Bacillus subtilis. When such a microorganism is used as the enzyme source, the method of the present invention may include the step

    C.

    incubating any of the microorganisms which remain viable, following the completion of the sterilization cycle, with an aqueous nutrient medium capable, with incubation, of promoting growth of viable microorganisms and a detector material capable of undergoing a detectable change in response to growth of the microorganisms, under conditions suitable to promote growth of viable microorganisms.

    Here, the patentee is suggesting what are really two different embodiments of the invention. In the first form (isolated enzyme) the skilled man has enzyme alone as his sensitive material. In the second, he uses enzyme of which the "source" is a microorganism "commonly used to monitor sterilization". B stearothermophilus is a spore-forming bacterium which was common used at the priority date on test strips for use in heat sterilisation in autoclaves, for example, and B subtilis was used for sterilisation processes in which the target material is exposed to ethylene oxide gas. This raises the principal point on construction: is the claim limited to enzymes present in the microorganisms at the end of the sterilisation cycle, but before any further treatment, or does it cover a method in which the enzyme is generated by the surviving microorganisms (if any) in the early stages of germination and which therefore acts to flag the existence of survivors? The question is important since it affects the scope of the attack of obviousness and might lead to an objection of anticipation.

  21. Some light is thrown on this problem by certain passages in the section of the specification entitled "Detailed description of the invention". First, there is the description of suitable enzymes (page 4 line 19):

    The enzymes useful in the practice of the present invention are enzymes including extracellular and intracellular enzymes, whose activity correlates with the viability of at least one microorganism commonly used to monitor sterilization efficacy, hereinafter referred to as a "test" microorganism. By "correlates" it is meant that the enzyme activity, over background, can be used to predict future growth of the test microorganism. The enzyme must be one which following a sterilization cycle which is sublethal to the test microorganism, remains sufficiently active to react with a substrate system for the enzyme, within twenty-four hours .... yet be inactivated or appreciably reduced in activity following a sterilization cycle which would be lethal to the test microorganism.

    This passage is obviously concerned with enzyme which is present at the beginning of the sterilisation cycle. While it is true that the presence of enzymes resulting from germination or outgrowth of the surviving spores can be used to predict future growth of the microorganism, the requirement that the enzyme "remain" active seems to exclude enzymes produced during the process of outgrowth. The whole flavour of the passage is that the test enzyme is itself exposed to sterilisation conditions. It is clear that the results recorded in the specification are not consistent with enzyme produced at germination being the enzyme of interest, and taking the specification as a whole I am satisfied that the idea was that the enzyme should be used to mimic the survival of spores through the sterilisation cycle.

  22. NAMSA suggest that it is not possible to distinguish between enzyme produced by germination and enzyme which has survived the sterilisation. Even if this were true (and Professor Perham’s evidence under cross-examination suggested that it would be possible to distinguish between enzyme produced on germination and pre-existing enzyme) I do not think it matters. If any enzymatic activity is present at all, the test has failed. What NAMSA wished to show was that as a matter of construction, the claim covered techniques in which enzymatic activity was used as an indicator of germination and outgrowth of surviving spores. Such a test was undoubtedly old, or obvious, at the date. The distinction is therefore a fine one when the source of the enzyme tested for is, in effect, a surviving organism. NAMSA’s own work showed that the detection of outgrowth using enzyme tests was easy enough, but that it was difficult to fine tune the test to give the sensitivity required within a reasonably rapid time. The position is quite different with isolated enzyme. On the whole, I consider that in failing to distinguish between isolated enzyme and enzyme whose source is a microorganism the claim is talking about pre-existing enzyme only.

  23. The notion of correlation with which this passage is also concerned is important. It is clear that correlation is a loose concept. There is some inconsistency in the specification’s description of its nature. In feature A of the claim quoted in paragraph 18 above, the reference to inactivation is inconsistent with the suggested "failsafe" nature of the invention. This latter feature can be summarised by saying that the enzyme to pick is one that denatures not at the same speed as the test organisms are killed, but more slowly. This makes sense, because an enzyme which denatured more quickly, or has a shorter half-life, than the organism would be useless as a predictor of sterility, and one that denatured at the same rate would allow no margin of safety. Again, it is necessary to remember that the behaviour of the organisms and the enzyme can only be discussed statistically. The user must be confident to the appropriate level of confidence that the enzyme will not denature more quickly that the organism, and this necessarily involves a longer half-life. Second, the criterion does not have to be the presence or absence of the product of the enzyme-catalysed reaction with the substrate, because the essential feature of the enzyme-catalysed reaction which can be exploited is its rate, for the reasons which I set out in paragraph 17 above. There is obviously a relationship between the method used to detect surviving enzyme and the level of enzyme which can be permitted to remain after a successful cycle. The reaction used to detect surviving enzyme can be arranged so that it is immune to what the specification calls background. For example, it might be arranged so that if the detecting reaction gives no result within a particular period of time it indicates a successful cycle. I accept, therefore, NAMSA’s contention that in fact the only criterion is that less enzyme survives after a lethal cycle than survives after a sublethal cycle, and that the latter be detectable before 24 hours.

  24. The selection of an enzyme suitable for use in the method of the invention is described as follows (page 4 line 27):

    The following test has proven useful in identifying those enzymes having the requisite characteristics to be used in the sterilization monitoring devices and methods of the present invention. The enzyme when subjected to sterilization conditions which would be just sufficient to decrease the population of 1´ 106 test microorganisms by about 6 logs has residual enzyme activity which is equal to "background" as measured by reaction with a substrate system for the enzyme; however the enzyme upon being subjected to sterilization conditions sufficient only to decrease the population of 1´ 106 test microorganisms by at least 1 log, but less than 6 logs, has enzyme activity greater than "background" as measured by reaction with the enzyme substrate system. The enzyme substrate system is a substance, or mixture of substances, which is acted upon by the enzyme to produce a detectable, e.g., fluorescent or colored, enzyme-modified product. The enzyme activity is measured by the amount of detectable enzyme-modified product produced. Preferably, the enzyme is one which has sufficient activity, following sterilization conditions insufficient to decrease the population of the test microorganism by 6 logs, to react with the enzyme substrate system and produce a detectable amount of enzyme-modified product within 24 hours, preferably within eight or less hours, and most preferably within two or less hours.

    Preferably, the activity of the enzyme after sterilization conditions insufficient to decrease the microorganism population by 6 logs, is at least 2 percent greater, and more preferably at least 5 percent greater, than background, and most preferably is at least 10 percent above background. It is understood that the residual enzyme activity level which is defined as "background" for purposes of this invention, may be higher than that achieved by the spontaneous conversion of enzyme substrate after the enzyme has been totally and irreversibly inactivated.

  25. Three potential sources of enzyme are identified:

    1. purified isolated enzyme derived from an appropriate microorganism;

    2. a microorganism to which the enzyme is indigenous or added by genetic engineering; and

    3. a microorganism to which the enzyme has been added during sporulation or growth in such a manner as to incorporate it in the vegetative microorganism.

    This case is primarily about purified isolated enzymes, which is what NAMSA uses. The specification suggests that a mixture of enzymes may be used, and sets out a number of techniques of testing for enzymatic activity. Nothing turns on these techniques, which were well-known to enzymologists.

  26. A container for the test materials suitable for insertion in an autoclave is also described. The claim to this container (claims 13-15) gave rise to the only substantial argument on infringement, which I should consider here. The described container is for use with a system in which the source of enzyme is a microorganism, and the device also contains nutrient for the microorganism and substrate and indicator for the enzyme. The idea is that after exposure to the sterilisation cycle, an internal glass ampoule with the liquid medium, substrate and indicator is crushed by manual pressure on the cap of the container so as to expose the microorganism to these materials. A dual test (enzymatic, fairly quickly, and microorganism growth, rather more slowly) is conducted in the same container. So as to ensure contact of the microorganism with the sterilising agent, which may be steam, dry air or ethylene oxide, the container must be porous. But obviously the ingress of microorganisms is not desired, since they may give a false result. The claim requires that there be a "gas transmissive, bacteria impermeable" means covering the opening of the container, even though this claim relates to a container containing an isolated enzyme alone, claim 14 relating to a container with a source of enzyme. The defendants say that their container is not impermeable to bacteria, and in any event they are not concerned about the odd bacterium getting in because they use very large quantities of enzyme and rely upon the detection reaction to distinguish between lethal and marginally lethal sterilisation cycles. In my judgment, the words "bacteria impermeable" cannot be used literally to refer to a cover which is also gas-transmissive. As is not uncommon, the defendants have seized upon a phrase which is superficially absolute in its meaning, but any such phrase must be construed in its context and having regard to the purpose of the feature it describes in the invention as a whole. Of course any cover which is adequate for its purpose is all that would be required. In some cases, no doubt, such a cover would need to be very resistant to the passage of bacteria, and in others not at all. It all depends upon the detection system which is used. To apply the principles of construction set out in Catnic v Hill & Smith [1982] RPC 183 and in Improver Corp v Remington Consumer Products Ltd [1990] FSR 181 at 189 as explained in Kastner v Rizla Ltd [1995] RPC 585, to use a cover sufficiently obstructive to bacteria that the test is unaffected has no effect upon the way the invention works; that fact would certainly be apparent to the skilled man at the priority date, and there is nothing in the specification to suggest that the patentee sought to exclude such a possibility. So I would construe "bacteria impermeable" as meaning "sufficiently obstructive to the ingress of bacteria to prevent their having any effect upon the test".

    4. INFRINGEMENT

  27. The only outstanding issue is the question of the meaning of the phrase "gas-impermeable" in claim 13, and for the reasons I have given it has a meaning which means that NAMSA’s product infringes. I shall return to the details of this product when I consider the objections to validity.

    5. VALIDITY: GENERAL

  28. The attack on the specification is two-pronged. It can be summarised by saying that the idea of using enzymes as sterilisation detectors is obvious, but that its implementation, at least so far as isolated enzymes are concerned, is very difficult, and the specification is insufficient on this point. 3M say that the history of the NAMSA development show that the invention is not obvious, and they go further and say that NAMSA only developed a usable product when they read the specification of the patent in suit, after a long period of frustrating failure. NAMSA rely upon their own development to support the allegation of insufficiency. I shall deal with the allegations of obviousness based on the documents first, and then that on the basis of common general knowledge alone, to which the NAMSA development is relevant. The NAMSA development is relevant only to the objection based on common general knowledge alone because it is not shown that NAMSA’s scientists were aware of the cited prior art.

    6. THE ADDRESSEE OF THE SPECIFICATION

  29. The question of the addressee of the specification is unusually difficult in this case. Before the date of the patent, it seems that the persons principally concerned with sterilisation indicators were, unsurprisingly, microbiologists. Mr Hurrell says that in 1988 he was unaware of any research looking at enzymes present in microorganisms as a direct means of assessing the success of a sterilisation cycle. (Such work had in fact been proposed in the cited Senkpiel II paper, to which I shall return.) The patentees say that the inventive step lay in the discovery that some enzymes present in bacteria (or bacterial spores) commonly used to test for sterilisation can survive (in the sense of still being active after) a sterilisation cycle which kills the microorganism. The defendants say that this is obvious to any enzymologist, who would know that there must be some enzymes which survive up to the end of the bacterial life and beyond, and that accordingly if a greater quantity of enzyme is present than would be present in the 106 spores which are present on the test strip, there is a better chance that the enzyme will survive, and, of course, enzyme assays are an extremely well understood and researched area. Furthermore, they say that since the enzyme is to a certain extent protected in the bacterium or spore, it is appropriate, if using isolated enzyme, to protect it also. So, in essence, the defendant’s position is that it is all obvious to an enzymologist, a view which received enthusiastic endorsement from the very distinguished enzymologist who gave evidence on behalf of the defendants, Professor Perham FRS.

  30. It seems to me that as a matter of principle invention cannot lie in bringing into a notional team working on a particular problem a new notional member with different skills from those of the existing notional team. The specification necessarily describes the attributes of the team to which it is addressed. Here, the team consists (notionally) of a microbiologist and an enzymologist. There was some suggestion that the patent is addressed to a microbiologist alone, who would have sufficient knowledge of enzymology to put the invention into effect but insufficient insight to appreciate the significance of enzymes in the survival of bacteria or of their spores. I reject this suggestion. The addressee of a specification is the person likely to have practical interest in an invention: here, it is the maker and seller of sterilisation indicators who wishes to make an indicator following the directions of the patent, and I am satisfied that for this purpose he employs a microbiologist with interests in the relevant area and an enzymologist who can carry out the directions of the specification. The notional team will also have a good knowledge of the relevant standards existing in 1988, and will be aware of the simple statistical assumptions which underlie sterilisation detectors.

    7. THE WITNESSES

  31. The claimant’s expert, Mr Hurrell was a well qualified expert on sterilisation techniques. He has a BSc degree in Microbiology and Chemistry from the CNAA, and a Master’s degree from the school of Pharmacy at the University of Bath on the effect of alkylating agents on bacterial endospores. Mr Hurrell’s degree was obtained after he had started work at the Department of Health, and he has always been concerned with sterilisation techniques and their validation. He has worked on the acceleration of germination and outgrowth in spores for use in test strips. He was a careful witness. Professor Eisenthal is an enzymologist also from the University of Bath. He gave evidence on the sufficiency of the specification, which was also relevant to the allegation of obviousness. For NAMSA, Professor Perham FRS gave evidence as an expert enzymologist. Whilst he was of course completely authoritative on the enzymological aspects of the case, he was hindered by a lack of experience in the area of sterilisation indicators. Dr Hegeman has been for the past 7 years Senior Fellow of the Institute for Molecular and Cellular Biology at Indiana University. He too lacked experience of sterilisation indicators. All the experts gave their evidence fairly. 3M submitted that neither of the NAMSA witnesses was "in a position to give evidence which could properly support the Defendants’ case on obviousness." It is also said that Dr Hegeman was "not in a position to give assistance to the Court having regard to his lack of experience in relation to sterility indicators". These submissions overlook the function of expert evidence. Of course these gentlemen could give relevant evidence. They knew about the science of what was being discussed. I accept entirely that Mr Hurrell had a perspective which the others could not approach, but I found the evidence of all of them helpful. Indeed, my impression was that the problem of the sterility indicator was comparatively easily stated by reference to the relevant standards, and what mattered in this case was the knowledge which the skilled man brought to the problem.

    8. OBVIOUSNESS IN THE LIGHT OF COMMON GENERAL KNOWLEDGE

  32. NAMSA attack the patent on the footing that the invention is obvious in the light of the common general knowledge alone, and upon the basis of the citations to which I shall come. I shall deal with the allegation of obviousness in the light of common general knowledge first, since the evidence throws light on the attainments of the skilled man in the art at the date. Allegations of obviousness in the light of common general knowledge have to be approached with caution. They are particularly prone to be tainted by hindsight. This is a well known risk against which there are many warnings in the cases, the best-known perhaps being that of Lord Moulton in British Westinghouse v Braulik (1910) 27 RPC 209, repeated in Technograph Printed Circuits v Mills & Rockley [1972] RPC 363 and restated in Beloit v Valmet [1997] RPC 489. I should just add to this well-known list of warnings one small caution more. As Aldous LJ indicates in the last of the cases to which I have referred, any allegation of obviousness involves the use of a kind of hindsight. The investigation of this "jury type question" is an objective investigation. It is not an attempt to second-guess the persons working in the art at the material time. It involves the identification of a legal fiction, the notional addressee of the specification or the skilled man in the art, and the attribution to him of that knowledge which as a matter of fact it is fair to attribute to him as the legal representative of the real workers in the art, not perhaps as the lowest common denominator but as a fair common denominator. Thus, the activities of those skilled in the art may throw light on what a skilled man would have done, but (for example) the fact that all those at work in the art followed a course different from that pursued by the inventor is only indicative of non-obviousness and cannot be determinative. Only one obvious course of action can be followed at a time, and it may be the case that a particular team of workers did not possess all the skills and knowledge which are to be attributed to the skilled man in the art. Put bluntly, the fact that any particular worker in the art had fewer attainments, more limited funds or was more stupid than the notional skilled man cannot turn something that is obvious to the latter into an invention. The same remarks can be made in respect of obviousness in the light of particular publications or prior uses, but in these cases the history of those actually skilled in the art at the material time (and the court usually gets to see only what the patentee and the defendant were doing) is of less interest unless they can be shown to have been aware of the relevant information. It is for this reason that the time and money spent investigating what particular groups were doing at a particular time may be disproportionate to the usefulness of the evidence obtained: see Molnlycke v P&G [1994] RPC 49.

  33. A good and frequently applied and approved approach to answering the question "obvious or not?" is set out in the judgment of the Court of Appeal in Windsurfing International v Tabur Marine [1985] RPC 59. This approach breaks the question into a number of steps, which can be summarised as follows:

    1. Identify the inventive concept embodied in the patent in suit;

    2. Assume the mantle of the normally skilled but unimaginative addressee in the art at the priority date and impute to him what was, at that date, common general knowledge in the art;

    3. Identify what, if any, differences exist between the matter cited as being made available to the public and the alleged invention;

    4. Determine whether, viewed without any knowledge of the alleged invention, those differences constitute steps which would have been obvious to the skilled man or whether they required any degree of invention.

    The inventive concept is normally what is set out in claim 1 of the patent. Because it is the law that anything obvious falling within the claim will invalidate the patent, it is usually incorrect to attempt to generalise from the claim’s express terms, at least unless it contains arbitrary or meaningless limitations. In the present case, the specification itself describes the discovery underlying the claim in the passage quoted in paragraph 14 above. If one accepts that this passage is a general description of the inventive concept, I think that there is force in the contention that the concept consists of the discovery that certain enzymes are better survivors of a sterilisation cycle than the microorganisms currently used; and the appreciation that those enzymes may be used to indicate (rather than predict) whether the standard test microorganisms exposed to the same sterilisation cycle would have survivors or not, and with the necessary degree of confidence. I have preferred to use the word "indicate" rather than "predict" because the latter is better reserved for results of a test which are going to be obtained in the future, rather than the results which would have been obtained had the test been performed.

  34. The patentees suggest that the realisation that the surviving enzyme can be detected by a test with a shorter period than is required to incubate the microorganisms is also a part of the inventive concept. This I do not accept. Any interest in enzymes will necessarily be conditional upon there being a usable reaction with some substrate. That is the reason for using an enzyme in the first place, and is inherent in its use. It is not a separate appreciation. Put another way, enzymes will be investigated in the hope that one will be found present in sufficient quantity for its reaction with its substrate to be detectable within a useful (or competitive) time.

  35. Of the claims other than claim 1 alleged to be infringed, claims 3, 10, 11, 12 and 13 are said to be valid. The inventive concept of claim 3 is said to be the use of isolated enzyme, that is, enzyme which is not contained within the spores or bacteria on a test strip. This claim raises different questions from claim 1, because the factors affecting correlation and testing for the presence of surviving enzyme are different. In the case of surviving enzyme, it is not necessary to test for the presence of surviving enzyme "above background". A great excess of enzyme can be used, and the differences in amount remaining active to be expected after a lethal cycle as opposed to a marginal cycle can be exploited with knowledge of the rate of the enzyme catalysed reaction. One waits for a result from the enzyme catalysed reaction within a particular time period: if the result is obtained, the cycle failed, and if not obtained the cycle passed. But if one waited for longer, one would obtain the result anyway. This is what NAMSA say they do, and it is relevant to obviousness.

  36. I must now turn to the technical common general knowledge. I should start with a few statements of the obvious. Bacteria differ widely in their susceptibility to heat. They can be broadly classed as thermophilic, mesophilic and psychrophilic. Certain bacteria live in the most hostile conditions (for example, around superheated steam vents accompanied by high concentrations of sulphur on the floors of the oceans) and, as Mr Hacon said, if one wanted a thermophile you could go and look in geysers. The skilled man would be aware of bacteria which survived in extreme conditions (Mr Hurrell called them extremophiles) and some of them have remarkable properties, including growth at temperatures above that of boiling water. In fact, the principal thermophile used in test strips was Bacillus stearothermophilus. As Mr Hurrell said, the use of a vegetative bacterium on a test strip is problematic because of the need for stability, and for this purpose a spore is vastly preferable. Finally, there was by 1988 considerable interest in extremophile bacteria because of industry’s need to have high temperature enzymes available for such mundane purposes as washing powders. NAMSA submit that the following was accepted by Mr Hurrell as being within the common general knowledge of the skilled microbiologist in 1988:

    1. A cell may be killed by denaturing an essential enzyme, leaving others active, in the sense that they would react with a substrate. Mr Hurrell accepted this.

    2. That isolated enzymes can be stabilised against heat, as for example by drying them according to the method of Warth, whose work on enzymes in spores was by then well-known. Warth had established that enzymes in spores appeared to be stabilised by the effects of drying rather than by the presence of stabilising substances. Mr Hurrell accepted that Warth formed part of the common general knowledge of the skilled man. It is sometimes necessary to be satisfied that the witness understands what it meant by this phrase, but I am sure that Mr Hurrell did understand it.

    3. Warth had also described a method of stabilising enzymes by "drying" them, and his enzymes were more stable than the spore in the natural state. He was working on a mesophile, and one might reasonable suppose that enzymes from a thermophile would be capable of being made even more stable.

    4. Thermophilic bacteria were an obvious choice for heat-resistant enzymes.

    5. The temperatures at which various thermophiles live could be easily looked up.

    6. Furthermore, there were existing examples of heat-stable enzymes already known to the skilled man: an example is DNA polymerase from Thermus aquaticus used for that essential reaction of modern biochemistry, the polymerase chain reaction.

    7. Even in a microorganism living at 110° C, some enzymes were bound to be more stable than others (lack of stability could be compensated for by a higher rate of production within the cell): the more stable enzymes could be distinguished by a thermostability experiment.

    8. Spore germination can take place within 40 minutes, and the time taken to activation and initiation is correspondingly much less. Furthermore, a spore can be thermally shocked into activation.

    9. Enzymes inside a spore would react if exposed to a substrate.

  37. I think that NAMSA are justified in treating this material as part of the common general knowledge, arising as it does largely from Mr Hurrell’s concession that Warth represented the common general knowledge. But there is more to it than that. Professor Perham, for his part, accepted that B. stearothermophilus was of unusual stability, and that in fact little work had been done on the heat stability of enzymes. Certainly, there was no general knowledge as to the heat stability of various enzymes. While he had a rule of thumb that an enzyme had to be stable 20° above the optimum growing temperature for the organism, he recognised that some enzymes denatured over a rather narrow temperature range. My feeling was that this was not a well worked-over field, but that a great deal of work remained to be done.

  38. NAMSA’s case of obviousness in the light of common general knowledge is not primarily directed at the obviousness of relying on bacterial or spore enzyme, but on the use of isolated enzyme. The difference between the state of the art and the invention is the use of isolated enzyme rather than the organism. It was accepted by Mr Hurrell that enzyme detection was obvious at the date for the purpose of the early detection of germination of spores, an event at which quantities of enzymes would be released. Thus, in order to detect germination early, attempts were being made to detect the enzyme which the spores would produce on germination and in early vegetative growth so as to obtain as early an indication as possible. So far as Mr Hurrell was aware, this course of investigation, although obvious, had not in fact been undertaken by the priority date.

  39. The question came down to rather a short one. Would the skilled man have thought of using enzymes at all? I was left with the feeling that he should have done, but that I could not be confident that what appears with hindsight to be such an obvious step would have appeared in that light to him at the date. My reason is simple. It does not require much insight to realise that cells can only survive because their enzymes survive. Accordingly there are present compounds which are capable of surviving at the temperatures with which we are concerned, but which are known to denature at those temperatures, and to denature more slowly. One cannot help thinking that all he needed to do was to put two and two together. However, it has to be borne in mind that the context of the work which is being done by the skilled man is a field in which there are two principal methods of determining the success of the sterilisation cycle: either watch the parameters, or test with a previously validated spore strip, or both. In this context, the well acknowledged disadvantage of the spore strip is its slowness. So the obvious thing to do is to use the techniques of enzymology to detect the germination and outgrowth of the spores before they become visible to the naked eye in a turbid suspension and, if possible, to accelerate that process. But the standard is written around the spores, and against this background I am not sure that the skilled man would think merely of watching enzymes, rather than the spores themselves.

  40. 3M also rely upon the history of NAMSA’s own development. For the reasons I have given I do not regard this as of central importance, but I should set out my findings.

    9. NAMSA'S OWN DEVELOPMENT

  41. In January 1987, NAMSA had a meeting with the Medical College of Ohio ("MCO") with the purpose of identifying possible avenues for a more rapid detection system for use in determining the effectiveness of a sterilisation cycle. This initial brainstorming session was attended by Dr Wallin (among others) from NAMSA and Professor Burnham (among others) from MCO. Both these men gave evidence before me and I should record that I consider them both to be truthful witnesses. This is necessary because it was suggested by Mr Waugh QC on behalf of 3M that NAMSA and MCO had only arrived at the product of which complaint is made in these proceedings as a result of having read the patent in suit, a contention which Professor Burnham denied and which is not made out.

  42. I should add that I consider that it is desirable that allegations of copying of this sort should in future be pleaded. In order to rebut the allegation of copying evidence may have to be given which could not be relevant to the principal issues in a patent action. It may be that a suggestion of copying can only be made after disclosure has taken place, but that is no reason not to plead it. It may also change the scope of standard disclosure. Copying is anyway equivocal on the issue of validity. If a defendant forms the view that what is in the patent is obvious, why should he not copy? In the present case, the relevance of the allegation is further diminished by the fact that the 3M and NAMSA products are very different. The NAMSA product depends upon the use of isolated enzyme alone, which the 3M product does not: the 3M product provides a spore indicator as well as the enzyme indicator, the enzyme indicator depending, as I understand it, on the surviving enzyme in the spores, in the manner which forms the major part of the disclosure of the patent.

  43. At the meeting in January 1987, a number of proposals were advanced. The first (and the one that was proceeded with) was to use substrate in media that is converted to a coloured form by protease released by vegetative outgrowth. It is suggested that a strain of bacterium with optimal protease production be identified and that trait transferred to the indicator mechanism, no doubt by genetic engineering. The other techniques proposed were either different germination detection mechanisms or the use of a recombinant technique perhaps involving RNA on filter paper. Thus the proposals at this meeting mirror Mr Hurrell’s belief that the skilled man at the date was chiefly interested in detecting the outgrowth of any surviving spores at the earliest possible moment. The RNA on filter paper suggestion does show that other techniques, not constrained by the biological spore standards, were also considered.

  44. The original grant proposal describes the first proposal concisely as follows:

    This project is designed to develop a biological detection system that will allow verification of the sterility of health related products. Available biological sterility indicators utilize a 2 to 7 day incubation period to insure sterility. This project should expedite sterility verification by providing for

    (a)

    completion and results within one shift time period (8 hours);

    (b)

    the utilization of personnel with minimal training to achieve reliable results;

    (c)

    more practical and efficient means of marketing and utilizing sterile products produced by the health care, pharmaceutical and medical device industry.

    The project will initially assay strains of Bacillus stearothermophilus (for heat sterilization) and Bacillus subtilis (for ethylene oxide sterilization) to find strains that produce optimal amounts of protease during germination, and develop methods for the measurement of the proteases released. An assay will be developed to detect the release of these proteases and alternatively, calcium, during germination of bacterial spores that survive steam heat (autoclaving) or ethylene oxide sterilization.

    The methodology to be investigated will involve both the use of chromogenic dyes that can be liberated from a dye-protein substrate following the action of proteases, and the use of a reporter enzyme-protein system that amplifies the initial proteolytic reaction by liberating the reporter enzyme to initiate easily detectable reactions within the test system. In addition spore viability will be investigated by the detection of calcium liberated from germinating spores by either direct chemical methodology or by detecting an enzymatic reaction catalyzed by calcium. In order to increase the sensitivity (reaction time) and thermostability of the aforementioned protease and calcium reactions non-aqueous enzyme technology will be investigated.

  45. The work appears to have proceeded fairly slowly. NAMSA imposed some reasonably stringent requirements. The indicator was to produce a read-out in less than eight hours with no instrumentation. It had to be robust and easily manufactured. It had to use spores, since, as Mr Wallin put it, they wanted the product to be considered as a biological indicator. It goes without saying that it had to be consistent and repeatable. The work on the indicator was certainly not the only work being done at MCO. Moreover, it appears to have been conducted on a very modest scale: NAMSA paid about $50,000 in cash and kind, and the State paid as much again, under a programme called the Edison Program. So all the work was being done within a budget of about $100,000 in cash and supplies.

  46. In broad outline, what happened is that detection systems were developed for the detection of the product of protease enzyme-catalysed reactions, the proteases having been produced during bacterial outgrowth. In December 1989, a patent application was filed in which proteases produced during spore germination and outgrowth are detected by the fact that they convert certain proteins of a supplied protein substrate to amino acids. The amino acids are detected by an indicator called ninhydrin which gives a pronounced blue colour with amino acids. The development to that date is described in a report also produced in December 1989, which refers to another detection method involving what is referred to as "reporter enzyme-substrate technology". This involves the use of proenzymes that will be activated by the spore enzymes so as to act as additional proteases. In this way the effect of the proteases produced on germination and outgrowth is amplified.

  47. A number of amplification systems for B stearothermophilus were contemplated, based on B-galactosidase, aryl sulphatase and alkaline phosphatase. Note that these are enzymes mentioned in the patent in suit, but employed merely for the purpose of amplification. But six months after the patent application it was recognised that the thermal stability of the reporter enzyme system would itself be a problem if the reporter enzyme system were itself to be exposed to the sterilisation process. So the reporter enzymes were stabilised by various techniques obtained from a reading of "stabilisation of enzymes against Thermal Inactivation" by Klibanov (1986). This publication points out that there are only two ways of getting hold of heat-stable enzymes: go for extreme thermophiles or stabilise or protect more susceptible molecules. One of the ways of protecting them he mentions is to dry them: that is, use what MCO referred to as a non-aqueous system.

  48. In February 1991 NAMSA became aware of a press release announcing the 3M product. This contains the sentence "The enzyme activity parallels the survival of the organism therefore the detection of the enzyme indicates a sterilisation failure". They persist with the ninhydrin detection system with amplification. In May 1991, Professor Burnham read the 3M patent application as published. By December 1991 the gloss has come off ninhydrin, but MCO continued to work to stabilise an alkaline phosphatase amplification system which produces another dye. Then somebody realised that if they had an amplification system which was sufficiently stable to temperature that it survived the death of the spores whose survival it was detecting, they could throw away the spores, and just use the amplification system. If it survived, the spores might have survived. If it did not survive, the spores would not have survived. The alkaline phosphatase system contained three enzymes, but a different, 2-enzyme, system was ultimately adopted.

  49. I am bound to say that I consider that the defendant’s development was ingenious. The ingenuity lay in appreciating that once the enzyme-based amplification system was sufficiently stable to heat it was no longer necessary to use it to detect the difference between total death of all the spores and the survival of one. Professor Burnham did not think that he had used the information in the 3M specification to arrive at this point, and I can see no reason not to believe him. The striking feature of the case is the successful attempt to stabilise the alkaline phosphatase system originally proposed as an amplification system. The teaching of the patent in suit is certainly not to go for an enzyme from a mesophile (his alkaline phosphatase was bought in, and came from chickens) and there is no teaching of stabilisation. The only example of an isolated enzyme is given in example 10 in which A-glucosidase is extracted from B stearothermophilus spores. So if there was copying, it was of the concept only. What this history does suggest is that stabilisation is a problem easily solved, using Warth’s common general knowledge techniques.

  50. In fact the defendants’ history throws only limited light on the inventiveness of the patent in suit. It does confirm Mr Hurrell’s views that what the skilled man was looking at was acceleration of the purely biological test. Professor Burnham did abandon the spores, but only when he had an enzyme system which did not need them any longer. It was not obvious to him to jump straight to the isolated enzymes. On the whole, I think it comes down in favour of the view that it was not obvious to go for enzymes alone. It follows that I do not consider that the invention is obvious in the light of the common general knowledge.

  51. I confess that I have wavered on this point. I was for some time attracted by Mr Hacon’s submission that the only issue that determines whether a biological indicator based on isolated enzymes was obvious was whether the skilled man would have embarked on a search for such enzymes with a reasonable expectation of success knowing that he could protect them or stabilise them if necessary so as to mimic the behaviour of the spore, since the principle would be known or obvious to him. But in the end I am not satisfied that the principle was obvious from his common general knowledge alone.

    10. OBVIOUSNESS: DOCUMENTS

  52. While a number of the documents relied on were relevant to the defendants’ contention that the measurement of enzyme produced during germination and outgrowth was covered by the claim (they included their published grant applications, for example, in relation to the ninhydrin work) the only document which matters to this part of the case is the document known as Senkpiel 2.

    11. SENKPIEL 2

  53. Senkpiel 2 is an article entitled "Kinetics of Destroying Microorganisms and Damaging Selected Bacterial Enzymes by Heat and Chemical Agents. It was published in a 1986 publication in the German Democratic Republic. It is concerned with B subtilis vegetative cells and spores exposed to moist heat at temperatures up to about 105° C. Two enzymes (creatine kinase and aminopeptidase) were assayed after exposing the spores to temperatures from 85° C to 105° C and mechanically disrupting the spores in a ball mill. It is worth setting out the conclusions of the paper in full:

    The destruction of microorganisms, when viewed as a whole, is generally explained by coagulation or denaturation of protein parts and nucleic acids of the cell. These are irreversible changes of cytoplasmic components. The present investigation focussed on the role of proteins as highly specific enzymes in the spore and vegetative cell. The difference found for creatine kinase – in contrast to aminopeptidase – with respect to the temperature optimum of the enzymatic performance after extraction from vegetative cells and spores of B. subtilis indicates that creatine kinase is subject to higher intramolecular stabilization in the spores than in the vegetative cells.

    Without entering further into the molecular and morphological causes and conditions of intrinsic thermostability and thermoresistance (e.g. amino acid sequence, tertiary and quaternary structure of the enzyme, metal ion content, substrate concentration, degree of hydration, ionic strength, pH value, ionogenic and hydrophobic interaction as well as endogenic and exogenic factors in cultivation, exposure and recultivation of microorganisms) .... their characteristics, measured as specific enzyme activity at different temperatures and as reaction rate constant 1/D were compared in B subtilis spores. After determining the specific enzyme activities (As) of the spore, linear equations 2 and 3 an be used to calculate the corresponding reaction rate constants of the destruction of the bacteria (1/D).

    Thus, it is possible to show "bacterial destruction by heat" – here shown for B subtilis and its spores– not only by the loss of the availability to recultivate but also by characterizing it through biochemical methods (inhibition of enzyme activities) – here shown for aminopeptidase and creatine kinase.

    This characterization permits a relatively simple and fast comparison of microbicidal methods and the evaluation of different parameter combination for new and continued developments.

    It is certainly still premature to comprehensive evaluate when this additional method is indicated for determining the value of sterilization procedures and disinfectants (see III Communication) especially since the method can be further developed, for instance by selecting other bacterial enzymes or enzyme systems.

    When the "III communication" is examined, it is concerned only with disinfectants, and is open to a number of serious criticisms.

  54. On the face of it, this is a clear pointer in the direction of using the denaturing of spore enzymes to model the destruction of the bacteria by heat. Indeed, nothing could be clearer. Mr Hurrell expressed the view that the results of the paper suggested that both creatine kinase and aminopeptidase would be denatured under normal sterilisation conditions well within 15 minutes, and would therefore be of no interest to the skilled man. He also said that the paper suggested that the enzymes were less resistant to heat than the intact spores. Under cross-examination, he accepted that the opposite was the case. He also acknowledged that Senkpiel’s extraction of enzyme was to obtain material to determine the properties of the enzyme.

  55. At 100° C, the curves suggest that aminopeptidase has a half-life of about 6 minutes, since 15 minutes exposure gives a decrease in activity of 80%. This means that about 10% activity will be remaining after 21 minutes. This is correlated with bacterial counts achieved by incubating the spores which are shown in Figure 4. Senkpiel thus demonstrates that his enzymes are more resistant to heat than the spores.

  56. 3M suggest that Mr Hurrell’s conclusion that Senkpiel was of no interest to the skilled man was not cross-examined to. In my judgment, the cogency of his conclusion, and the reasons which Mr Hurrell gave for it, was seriously undermined by his failure to appreciate that Senkpiel showed the opposite of what he had said in chief that it did. In my judgment, if the basic discovery of the invention of the patent in suit is that there are enzymes which survive their cells under sterilization conditions then the difference between the invention of claim 1 is that Senkpiel has not identified a suitable microorganism to use for this purpose. But in the final paragraph of the paper he gives clear indication that this is the direction in which to go. In fact, we know from the patent in suit that for B stearothermophilus the denaturing of the aminopeptidases do in fact function as required. Senkpiel provides the push which was lacking when the problem is viewed from the perspective of the common general knowledge alone. My clear conclusion is that the invention of claim 1 is obvious in the light of Senkpiel.

  57. So far as claim 3 is concerned, the enzymes of Senkpiel are exposed to heat in the spore. Furthermore, it has to be accepted that the article does not provide a practical method which can be used in the real world. This brings us back to the question whether it is obvious to extract the enzyme from the microorganism and use it in isolated form, having now been given clear instructions to do so. In my view, this is obvious once the clear indication has been given to examine the denaturing of the bacterial enzymes. Senkpiel gives a clear indication that for the mesophile B subtilis there is correlation between spore death and aminopeptidase, and the skilled man would look first at aminopeptidase in any thermophile he examined. I conclude that once the connection is shown between death of the relevant thermophile, B subtilis, the skilled man would look at the activity of aminopeptidase to mirror the death of the organism. I suspect that the one thing that does give a difficulty in using an isolated enzyme is the difficulty of satisfying oneself that it does, in truth, track the behaviour of the organism. It is far easier to use the organism’s own enzyme, as do the patentees in their commercial device. Be that as it may, I am satisfied that once the pointer is given in the direction of correlation between enzymatic denaturing and spore death, the whole invention, including isolated enzymes, becomes obvious.

    12. OBVIOUSNESS: SNYDER 2

  58. For this purpose, it is necessary to remember that the claim is not restricted to spores, but covers vegetative cells as sources of the relevant enzyme. It is also necessary to remember that the patent permits a cell population in excess of 100,000 to be counted a failure while a cell population between 10 and 100,000 to be counted a success: see the passage quoted in paragraph 24 above.

  59. Snyder 2 discloses a method of showing the existence of surviving organisms in the bioburden, but Mr Hurrell expressed the view that since the limit of detection was about 360 organisms, the limit would still require spore outgrowth for detection.

  60. This leads to one of the features of these tests to which I have not previously referred. In a conventional sterilisation assurance standard of 10-6, (that is, a chance of one in a million that a single organism has survived) the sterilisation cycle lasts for a time twice that required for a population of one million to be reduced to a single microorganism. Sampling techniques can then satisfy one of the degree of confidence the user has that the failure of any organism to survive indicates a successful cycle. But what if one starts with a far larger population, as for example NAMSA do in the alleged infringement, and rely upon the test to distinguish numbers of survivors characteristic of a successful cycle from those characteristic of a failed cycle. In other words what if the criterion for failure is not one single organism? If the criterion for failure is not a simple yes/no answer as it is with a spore strip, then it seems to me that Snyder 2 is directly in point. The real problem with Snyder is that the paper nowhere suggests its usability for verifying sterilisation, and, indeed, Mr Hurrell’s suggestion that it is not a practical method was not challenged. Of course, practicability would not matter if it were otherwise within the claim: but there is no suggestion that the particular enzymes used by Snyder would, in fact shadow the death of the cell in sterilisation. So to rely on Snyder assumes that the essential concept underlying the invention is known to the skilled man, but if that is the case he does not need to use Snyder. I reject the case on obviousness based on this publication.

    13. CONCLUSIONS ON OBVIOUSNESS

  61. Claims 1 and 3 of the patent are obvious in the light of Senkpiel 2 and common general knowledge. They are not obvious in the light of common general knowledge alone, and they are not obvious in the light of Snyder. In view of the construction I place on claim 1, the other citations do not need to be considered.

    14. INSUFFICIENCY

  62. This objection can be quickly dealt with. The pleaded case related only to the isolated enzyme case, and relies upon the defendants’ own development. The evidence of sufficiency was given by Mr Hurrell and Professor Eisenthal and was not challenged in cross examination. I conclude that the skilled man can make a workable device using the invention of the patent in suit without undue effort and experimentation and without the exercise of ingenuity. The patent in suit does give a single instance (Example 10) of the use of an isolated enzyme. In a ruling made shortly before trial, I refused to permit insufficiency of Example 10 to be raised unless the point was properly pleaded. It was not. Thus Example 10 must also be accepted as being sufficient.

  63. The only other matter is a so-called "Biogen insufficiency" based on the speech of Lord Hoffmann in Biogen v Medeva [1997] RPC 1. Biogen is concerned with the relationship between support for the claim and insufficiency: insufficiency of the description followed from the fact that the claim lacked support. What the patent in the present case teaches is that one can anticipate the behaviour of the test organism by watching the denaturing of an enzyme. This is precisely what the NAMSA product does, albeit that the product was arrived at by a different series of deductions from that described by the patent. The realisation that the defendants could use their amplification system without the spores is the point at which the teaching of the patent is used. It is important that when Lord Hoffmann speaks about the claim covering ways of delivering the goods which owe nothing to the teaching of the patent or any principle which it disclosed, he is talking about a claim which is not supported by the specification since it claims (as in that case) an obvious desideratum. He is not talking about a case in which there are ways of arriving at a device within the claim which themselves involved invention. The Defendant’s work did not point up an insufficiency in the disclosure of the patent in suit.

    15. CONCLUSIONS

  64. In the result, claims 1 and 3 of the patent are invalid and must be revoked. Claims 10, 11 and 12 are merely claims to obviously nice things to have, but the underlying concept being obvious are themselves invalid. No features of the packaging claim is pointed out as having independent inventive subject matter. It follows that the patent must be revoked. The allegation of insufficiency, however fails. The patent, if valid, would have been infringed.


Cases

Catnic v Hill & Smith [1982] RPC 183; Improver Corp v Remington Consumer Products Ltd [1990] FSR 181; Kastner v Rizla Ltd [1995] RPC 585; British Westinghouse v Braulik (1910) 27 RPC 209; Technograph Printed Circuits v Mills & Rockley [1972] RPC 363; Beloit v Valmet [1997] RPC 489; Molnlycke v P&G [1994] RPC 49; Windsurfing International v Tabur Marine [1985] RPC 59; Biogen v Medeva [1997] RPC 1

Authors and other references

Senkpiel 2: "Kinetics of Destroying Microorganisms and Damaging Selected Bacterial Enzymes by Heat and Chemical Agents", published 1986

Representations

Andrew Waugh QC and Thomas Mitcheson for the Claimant

Richard Hacon and Heather Lawrence for the Defendant


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