Ipsofactoj.com: International Cases [2001] Part 9 Case 8 [Ch.D]


CHANCERY DIVISION (PATENTS COURT)

Coram

Inhale Therapeutic

Systems Inc

- vs -

Quadrant Healthcare Plc

MR JUSTICE LADDIE

20 JUNE 2001


Judgment

Mr Justice Laddie

INTRODUCTION

  1. This is an action for infringement of European Patent (UK) 383 569 ("the Patent") brought by Inhale Therapeutic Systems Inc ("Inhale") against Quadrant Healthcare Plc ("Quadrant"). Quadrant does not admit infringement and claims that the Patent is invalid for lack of novelty, lack of inventive step and insufficiency. Mr Carr QC, who appears on its behalf, says that the allegations of insufficiency are principally relied upon as a squeeze between the prior art and the disclosure of the Patent. There is also an application to amend the Patent, which is opposed by Novo Nordisk A/S ("Novo") as well as by Quadrant. Novo has not been represented before me at the trial. However I was taken through its written objections to the amendments and it does not appear that they contain any point which is not covered by the arguments advanced by Mr Carr.

  2. The Patent has a priority date of 16 February 1989. It is entitled "Storage of materials" although its scope is rather narrower than this might suggest. It is concerned with products which have been made resistant to degradation and methods of making such products. Before considering the teaching of the Patent and its claims, it will be useful to describe some essential technical concepts all of which were known at the priority date, unless expressly stated to the contrary.

    TECHNICAL BACKGROUND

    (i) Degradation of unstable substances

  3. There are a number of ways in which a chemical or substance can be degraded with time. For present purposes it is only necessary to consider two of them.

    • First, the chemical may react with other chemicals in the environment in which it is kept and thereby be transformed into something else. For example, a piece of iron, if left in a moist atmosphere, will rust. At the molecular level, atoms of iron have reacted with molecules of oxygen in the presence of molecules of water to produce iron oxide. Many substances are subject to chemical degradation. As with any chemical reaction, the rate of degradation will be increased by an increase in temperature.

    • Second, some molecules exhibit beneficial characteristics which are determined, at least in part, by their shape. For example most proteins, including antibodies, enzymes, hormones and the like, need to be folded in a particular way in order to carry out their biological functions. If they unfold, they may lose all or most of their respective functions. Again this is a temperature-influenced degradation. The 3-dimensional shape of a protein is called its tertiary structure.

  4. For a long time people have tried to find better ways of preventing degradation. For example a piece of iron can be protected by covering it with a sacrificial layer of zinc (i e galvanizing) or by covering it with a lacquer to prevent contact with other reactive molecules (e g the process known as japanning). In many cases, degradation can be slowed by lowering the temperature at which the substance is stored. This is why foodstuffs are kept in a refrigerator or, for long term storage, in a freezer.

    (ii) Amorphous / Crystalline Physical States

  5. As the Primer agreed between the parties records, by the priority date of the Patent it was well known that solid substances can exist in two different physical states: as crystalline or amorphous solids. In crystalline solids, the building blocks (atoms, molecules or ions) exhibit a regular internal spatial relationship to each other, which is held together by consistent forces throughout the solid structure. In non-crystalline solids, i e amorphous materials, the molecules are randomly arranged and there is no long-range, ordered, repeat pattern.

    (iii) Glasses / Glass transition temperature

  6. A glass is an amorphous solid. It is not crystalline. If one heats up a solid crystalline substance, a temperature will be reached at which it turns into a liquid. In some cases, under certain conditions, a solid, on heating, will turn directly into a gas. This is called sublimation. When a material passes from a crystalline to a liquid phase it is said to melt and the change from one state to another is abrupt. For example, below 0 degrees C water is a crystalline solid, i e ice. Above that temperature it is a liquid. The changeover from one condition to another is at a sharply defined temperature. Glasses do not have such an abrupt melting point. Instead they have what is called a glass transition temperature (referred to by the symbol Tg). Below that temperature they are solids with very low molecular mobility, in which diffusive processes take place at extremely low rates. In this state, they are called glasses. Above the Tg they turn into flowable liquid. The Tg is not a specific temperature like the melting point of a crystalline solid. Rather, the glass transition takes place over a range of temperatures. In general terms, the Tg of any system will depend on the molecular weights and molecular complexities of the glass-forming substances of which it is made.

    (iv) Glass-forming substances

  7. If silica (with various additives) is melted and then cooled quickly to prevent crystallization, it forms the glass from which windows are made. It, like all other glasses, has a Tg and exhibits very low mobility. There are many substances which form glasses. Among those others, which are of particular significance in this case, are carbohydrates (such as sugars), certain derivatives of carbohydrates and synthetic polymers. Cane sugar, or sucrose (to give it its chemical name) can be crystallised. The granulated sugar one purchases in the shop is this form of solid sucrose. Sucrose (and other sugars, i e members of the same chemical family) can also be melted and then cooled without crystallisation to a transparent solid. This amorphous solid is a sugar glass. It is, with minor additions, the type of solid sugar which coats a toffee apple, from which barley sugar sweets are made and from which the ‘glass’ bottles so liberally used in fight scenes in cowboy films are sometimes made.

    (v) Differential Scanning Calorimetry

  8. It is possible to measure the amount of heat supplied to a substance against the rise in temperature of that substance. If the substance is one which, in the solid state, is a crystal, there will be a sharp change in the ‘heat flow v temperature’ curve at the melting point. As the Primer explains, because it is a characteristic of glasses that they have no sharp melting point but, on heating, transform from a solid to a flowable liquid over a range of temperature, the inflection in the ‘heat flow v temperature’ curve will be different. This curve can be obtained by use of a process called differential scanning calorimetry (‘DSC’).

  9. The analytical method of DSC has been known and used since at least the early 1970s. In short, it involves placing two small pans, one containing the composition to be tested and the other – being a blank reference pan – in an oven at a constant temperature well below the temperature of interest. The temperature of the oven, and therefore the pans, is then raised at a constant scanning rate until the temperature in the oven and the pans is above the temperature of interest. During the DSC ‘run’, the amount of energy needed to be supplied to each pan is monitored and compared by a computer. The computer draws a ‘trace’, showing the amount of energy needed to be supplied to the sample to raise the temperature of the pan containing the sample at the same rate as the blank reference pan. An improved form of DSC, known as modulated DSC (‘MDSC’) was first used in the 1990s, ie after the priority date of the Patent. It is not necessary to understand its mode of operation. It is sufficient to know that it makes it easier to identify a Tg in some cases.

    THE PATENT IN SUIT

  10. As mentioned already, the Patent is concerned with the storage of materials. It says that the principal envisaged application is with materials employed in the biochemical field and some pharmaceuticals (p 2 lines 3-4). It goes on to record, as has not been disputed, that a few biologically active materials (e g some proteins) are sufficiently stable that they can be isolated, purified and then stored in solution at room temperature, but for most materials this is not possible and some more elaborate form of stabilisation / storage procedure must be used. The specification then lists what it describes as a repertoire of known techniques. Once again, it is not suggested that anything in this list was not known at the priority date. There are six techniques referred to. The first is the use of high concentrations of chemical ‘stabilizers’. The other 5 all use cooling or freezing in one way or another. They include what is described as the commonest method for the stabilisation of isolated protein preparations, namely freeze-drying: which involves taking an aqueous isolate of the material to be stored, together with certain additives, and freezing it to a low temperature. It is then placed under vacuum which has the effect of pulling off much of the water. In fact, at the low temperatures involved the water turns from solid (i e ice) to gas without first melting. That is to say it sublimes (see paragraph 6 above). Residual moisture is then removed by a process called desorption while the temperature is allowed to rise. The Patent states that a complete freeze-drying cycle may take several days and is costly in capital and energy and in some cases the product so made may still suffer significant degradation, if kept at ambient temperature. All of the known processes are said to suffer disadvantages and the Patent states (p 2 lines 43 – 45):

    It will thus be apparent that a stabilisation/storage process which enabled storage at ambient temperature would be very desirable, since it would avoid the need for low temperature storage entailed by existing processes. Hitherto, however, storage at ambient temperature has been impossible for many materials.

  11. The discovery which underpins the Patent is described as follows (p 3(a) lines 1 – 5):

    We have found, surprisingly, that materials which are not stable when isolated and held in solution at room temperature can nevertheless be successfully incorporated into a glass formed from a water-soluble or water-swellable substance, and can later be recovered. While in the glass the material is immobilised and stable.

  12. This discovery is said to be of wide application. As noted above, the title to the Patent relates to storage of "materials" and that width is consistent with the description in the specification. Although, as mentioned in paragraph 10, the principal envisaged field of application is with materials employed in the biochemical field and some pharmaceuticals, this is not a limitation. The width of application is emphasised further on in the specification. For example, under the heading "Material Stored", it says: (p 3(a) lines 26 to 36)

    The material(s) stabilized for storage may potentially be any of a wide range of materials which are ordinarily liable to undergo a chemical reaction which is dependent on diffusion of reacting species.

    One category of materials to which the invention is applicable is proteins and peptides, including derivatives thereof such as glycoproteins. Such proteins and peptides may be any of: enzymes, transport proteins, e g haemoglobin, immunoglobulins, hormones, blood clotting factors and pharmacologically active proteins or peptides.

    Another category of materials to which the invention is applicable comprises nucleosides, nucleotides, dinucleotides, oligonucleotides (say containing up to four nucleotides) and also enzyme cofactors, whether or not these are nucleotides. Enzyme substrates in general are materials to which the invention may be applied.

  13. The same message of broad application is found throughout the Patent and is reflected in the claims. As far as the stored materials are concerned there appears to be only one express exclusion, at least prior to the application to amend, namely that they must be water-soluble. This restriction is expressed as follows (p 3(a) lines 40 to 41):

    The material will need to be soluble in aqueous solution, at least to the extent of forming a dilute solution which can be used for incorporation into the glass forming substance.

  14. The specification also makes it clear that a wide variety of glass forming materials can be used as the storage medium. They must display certain physical characteristics. First they must be hydrophilic – i e they attract water – being either water-soluble or water-swellable (p 4 lines 11 to 17). Furthermore they must have a suitable Tg. This is described as follows:

    For this invention it will generally be necessary that the glass forming substance, when anhydrous or nearly so, displays a glass transition temperature Tg in a range from 20 to 150 degrees C, preferably 25 to 70 degrees C. If Tg is towards the higher end of the range, a lower Tg can be achieved by adding water which can be removed after the material which is to be stored has been incorporated into the glass. Mixtures of glass forming substances may be used if the components are miscible as a solid solution. If so, material(s) of lower Tg serve as plasticiser(s) for material(s) of higher Tg.

    If Tg of the final composition is sufficiently high, storage can be at room temperature. However, if Tg of the composition is close to or below room temperature it may be necessary or desirable to refrigerate the glassy composition if storage is for a prolonged period. This is less convenient but still is more economical than freeze-drying.

    If the composition is heated above its Tg during storage, it will change to its rubbery state. Even in this condition stored materials are stable for a considerable period of time. Consequently, it may well do no harm if the temperature of the stored material is allowed to go above Tg for a limited time, such as during transportation.

    If a composition is maintained above its Tg (and therefore in a rubbery condition) the storage life will be limited but still considerable and the benefit of the invention will be obtained to a reduced extent.

    Conversely, if Tg of the composition is well above room temperature, the composition is better able to withstand storage at an elevated temperature, eg in a hot climate.

  15. At this stage there are two points in this passage which are worth addressing. First, the main thrust of this passage is that the mixture containing the material to be protected should have a Tg of 20 degrees C or above. As Professor MacKenzie, one of the expert witnesses called by Quadrant, said, to scientists, room temperature is taken to be about 20 degrees C. One of the purposes of the invention is to ensure that the mixture should have a Tg above room temperature. Therefore, in a country with a temperate climate, the mixture would be expected to be in a solid amorphous, or glassy, state in normal conditions. Needless to say, if normal storage temperature is likely to exceed 20 degrees C for much of the time, it will be necessary to choose ingredients which give a mixture with a higher Tg.

  16. Second, the meaning of the last two sentences of the first paragraph in the passage quoted in the previous paragraph is quite simple. It will be recalled that at paragraph 6 above it is stated that, in general terms, the Tg of any system will depend on the molecular weights and molecular complexities of the glass forming substances of which it is made. If a substance with a Tg of, say, 20 degrees C is combined with another substance with a Tg of, say, 200 degrees C, the former acts as a plasticiser or ‘softener’ for the latter. In other words the low Tg component pushes down the Tg of the other component. More simply, in such a case the Tg of the combined system is somewhere between 20 degrees C and 200 degrees C, the precise Tg depending, amongst other things, on the relative quantities of the two or more components of which it is made. This is a principle of some significance when understanding the prior art in this case.

  17. The specification indicates that many substances can be used to form glasses. Among the families of chemicals specifically referred to are carbohydrates and their derivatives and water-soluble or water-swellable synthetic polymers. Specifically mentioned glass-forming substances include glucose, sucrose, maltose (all of which are sugars) and sorbitol (which is a sugar alcohol). It is pointed out that the glass forming substance should be sufficiently inert to the material which is to be incorporated in it (p 4 lines 39 – 40).

  18. The specification also indicates how the stabilisation is achieved. For reasons which will become apparent below, this explanation may be important. It says (p 4 lines 3 to 8):

    A glass is defined as an undercooled liquid with a very high viscosity, ....Normally a glass presents the appearance of a homogeneous, transparent, brittle solid which can be ground or milled to a powder. In a glass, diffusive processes take place at extremely low rates, such as microns per year. Chemical or biochemical changes including more than one reacting moiety are practically inhibited.

  19. This is consistent with the passages quoted at paragraphs 11 and 12 above. The degradable material is embedded in an amorphous matrix (the glass) which immobilises it and slows down diffusion. The reduction of diffusion prevents the material from coming into contact with other substances which will degrade it. As Mr Carr puts it, the degradable material can be visualised as a fly caught in amber. Similarly the Patent refers to "locking in" of the labile material (p 5 line 18). This is also consistent with the passage in the specification set out at paragraph 14 above. As the specification explains, as the temperature moves up past the Tg, the viscosity drops rapidly and the glass turns into a rubber, then into a deformable plastic which at even higher temperatures turns into a fluid (p 4 lines 9 – 10). In the rubbery state the combination has the consistency of a dough which can be rolled out into a sheet. So, although in the rubbery state the combination has a lower viscosity than when it was a glass, it is still very viscous and this slows down the mobility of the molecules more than when the system is a fluid and, of course, more than when the molecules are in an aqueous solution at room temperature. The immobilising effect is only fully achieved in the glassy state.

  20. Although in the trial it has been suggested that there may be other factors at play as well, the accuracy of the immobilisation explanation has not been seriously challenged. Once the degradable molecules are locked inside the solid amorphous matrix they cannot get into trouble.

  21. The specification also suggests ways in which the glassy stabilised products can be made. Various means for bringing the labile substance and the glass-forming material together are described. Since water depresses Tg and in some cases too much water may be present to give a Tg above 20 degrees C, methods of drying are described using heat or vacuum or both (p. 5 lines 41 to 46):

    Vacuum applied to assist the removal of water from the rubbery composition [ie labile compound + glass-forming substance above the Tg] need not be particularly hard. Suitably it is less than 90% of normal atmospheric pressure. A pressure which is 80% of normal atmospheric pressure has been found adequate. A harder vacuum may be employed, however, if this is found convenient.

    Heating of the doughy mixture to remove moisture may be at a temperature not above 80 degrees, and for a protein is preferably not above 60 degrees C. Heating may not be necessary: evaporation of moisture under reduced pressure may proceed to a sufficiently low moisture content even at room temperature of around 20 degrees C, but of course heat accelerates the evaporation.

  22. The specification describes (p 5 lines 8 to 14) how the mixture can be turned into a rubbery mass, meaning with a Tg which is too low, in which case it has the consistency of dough. This can be rolled out into a thin sheet which can then be subject to a reduced pressure and possibly increased temperature so as to remove most of the moisture. This increases the Tg so that the product is a glass at room temperature. This can then be kept in the form of a transparent film, or ground into a fine powder or compressed into tablet form.

    THE CLAIMS

  23. Although a number of claims are said to be independently valid over the cited prior art, most of the issues in this case can be resolved by concentrating on the main product claim, Claim 1, and the main method claim, Claim 9, each in its proposed amended form. I consider first the product claims.

  24. Claim 1:

    A non-freeze dried composition which is storage stable at 20 degrees C comprising

    (i)

    a carrier substance which is water-soluble or water-swellable and is in a glassy amorphous state;

    (ii)

    at least one material to be stored, which is unstable in aqueous solution at room temperature of 20 degrees C and which is dissolved in the said amorphous carrier substance said composition displaying a glass transition temperature of at least 20 degrees C so as to exist in a glassy state at 20 degrees C

  25. The points which I have made about the breadth of the Patent is reflected in this claim. Any carrier substance can be used, as long as it is in a glassy amorphous state in the composition. Similarly, but subject to a point I will discuss in a moment, any substance can be stored, as long as it is unstable in aqueous solution at 20 degrees C. Thus the claim covers unstable organic and inorganic substances. As far as the former are concerned, the range is unqualified. Not only does the claim cover the pharmaceutical and biochemical substances to which the invention is principally directed, it covers much more as well. For example it includes foodstuffs. It should also be noticed that the storage stable compositions can be made by any process save for freeze-drying. This is of importance in this case because the defendant’s allegedly infringing products are made by a process known as spray-drying. It is not in dispute that this claim covers products made by that process. Subject to certain detailed arguments on construction which I will consider in a moment, it will be appreciated that this claim matches the width of the principle claimed to have been invented by the inventor and referred to in paragraph 11 above. Any material which is unstable at room temperature in an aqueous solution which, as the Patent confirms, includes all but a few biologically-active organic substances, can be turned into a stable product by embedding it in a carrier material to produce a composition which is a glass at room temperature. The latter feature is of significance because it is the state of the final composition, not that of the ingredients, which is determinative of success. Thus it is the Tg of the final composition which has to be 20 degrees C or above, not the Tg of the carrier material by itself or of the other ingredients in the composition taken by themselves. This is consistent with the comments made at paragraph 16 above about the Tg of a system involving two or more components each of which has a different Tg. Finally the provision in the claim that the composition must display a glass transition temperature of at least 20 degrees C so as to exist in a glassy state at 20 degrees C is self explanatory. The stabilisation of the embedded molecules is achieved by immobilising them. Since one of the objectives of the patent is to enable labile molecules to be stored at room temperature, they must be immobilised at that temperature. In other words the composition in which they are embedded must be a glass at that temperature. Thus the Tg must be 20 degrees C or above.

  26. There are, however, two points of construction of this claim on which the parties appear to disagree. The first concerns the expression "storage stable". At one point it appeared that the parties could not agree as to how stability could or should be measured and to what extent the material to be stored had to be rendered more stable by its incorporation into the glassy composition. It appears to me that this dispute had largely disappeared by the end of the trial. Nevertheless, because it does have significance to the prior art relied on, the meaning of the words in the claim should be set out here. As I have already explained, the mechanism by means of which the patentee’s process and products work is not in dispute. The immobilisation of the target molecules results in them being rendered less prone to degradation. Embedding any molecule in a glass will render it immobile. However a molecule which is already stable will not be made more stable by doing this. Therefore the claim is limited to compositions where the embedded molecule is rendered more stable by being made immobile. Furthermore there is now no dispute between the parties as to what degree of increased stability is required. Mr Waugh relied upon and agreed with the way it was put by Professor Mackenzie, one of the Quadrant’s witnesses;

    I would take the term storage stable to mean that the substance stored in the glass should retain higher activity than the same substance which had not been stored in a glass.

  27. I agree that that is what the words in this claim mean.

  28. The other point of construction on which there continues to be a dispute is the reference in the claim to the material to be stored being "dissolved in the said amorphous carrier substance". As Mr Waugh concedes, it is common ground amongst the experts that the primary acontextual meaning of "dissolved" is "molecularly dispersed". One of the allegedly infringing products consists of a killed virus embedded in a glassy composition. There is no dispute that a killed virus is not a single molecule but is a structured assembly of molecules. Once again, Mr Waugh concedes that a killed virus cannot be regarded as dissolved in the carrier, if dissolution is given its normal meaning. However he argues that "dissolved" should be construed purposively, so as to embrace a dispersion of an assembly of molecules, such as a virus in the carrier. In support of this he refers to the fact that it is impossible in practice to draw a distinct line between a true molecular solution at one extreme, a colloidal suspension in the middle and a suspension at the other extreme, since the three states are in a continuum. He says that a skilled person, speaking a little loosely, might easily describe a dispersion of viruses in the carrier as being "dissolved" in it. He then says that the variant makes no material difference to the way in which the invention works, which is to immobilise the dispersed material to be stored in a glassy matrix and this would be obvious to the skilled person. Furthermore he says that there is nothing in the specification to indicate that the patentee regarded strict compliance with the primary meaning as essential.

  29. I agree with the first two of these points. It is clear that the way in which the invention works is by immobilisation of the dispersed material and that a killed virus would be immobilised in the glassy matrix. I also accept that this would be obvious to a skilled person. However I do not accept his last point. In particular, I do not accept Mr Waugh’s underlying argument that because there is a continuum between a true molecular solution at one extreme and a true suspension at the other, it is legitimate to ignore the patentee’s expressed desire to limit his claims to cases in which the stored material is dissolved. The same argument could be used where, say, a patentee refers to an ingredient being "large". Because there is no clear distinction between large, medium and small, a reference in a claim to "large" could be read to include things which are small if Mr Waugh’s argument were correct. For better or worse, the patentee has concentrated on solubility being an important part of his claimed invention. The material to be protected must be both soluble in water for the purpose of determining its instability and soluble in the glassy matrix to give it protection from degradation. There is nothing in the patent which suggests that these limitations are other than essential. A killed virus is neither soluble in water nor soluble in the glassy matrix. I have come to the conclusion that the requirement in the claims that the material to be protected is dissolved in the carrier cannot be ignored.

  30. The only other product claims which are said to be independently valid are claims 2 and 3. The former is substantially identical in scope to claim 1 save that the final product must have a Tg of at least 30 degrees C rather than 20 degrees C. No additional point of construction arises on this claim which is clearly directed to products which are in a solid glassy state at higher ambient temperatures. Mr Waugh does not dispute that if claim 1 fails for obviousness, this claim will fail also, for the same reason. However he says that if the attack of obviousness against claim 1 fails but an attack of anticipation succeeds, then this claim should survive. Claim 3 is dependent on claims 1 or 2 and limits the material to be stored to

    proteins, peptides, nucleosides, nucleotides, dimers or oligomers of nucleosides or nucleotides, enzyme cofactors and derivatives from any of the foregoing having one or more additional moieties bound thereto.

  31. The major method claim is as follows:

    Claim 9:

    A method of rendering a material storage stable at 20 degrees C; which material is unstable in aqueous solution at room temperature of 20 degrees C, comprising dissolving the material in a carrier substance which is water-soluble or water-swellable, or in a solution thereof, so that the material is dissolved in said carrier substance, and evaporating water from the resulting mixture without freeze-drying, thereby forming the resulting mixture into a glassy amorphous state, said mixture displaying a glass transition temperature of at least 20 degrees C so as to exist in a glassy state at 20 degrees C ....

  32. No separate point of construction arises in relation to this. However it should be noticed that the method claimed involves a drying step. Although it does not require the target material to be dissolved in an aqueous solution prior to combining it with the carrier, it is clear that the combination is assumed to be wet. Water depresses the Tg of a high Tg system. This claim is particularly directed at a process where the combined target material and carrier has its Tg raised to a useful level (i e 20 degrees C or above) by drying. There is no equivalent requirement in the product claims that a drying step was involved in reaching the required Tg.

  33. Although a number of other process claims are put forward as being independently valid (nos. 11, 14, 15 and 16) only one of these needs to be specifically referred to. That is claim 11 which provides:

    A method according to claim 9 or claim 10 wherein forming the said mixture into an amorphous state is effected by evaporation under subatmospheric pressure.

    Mr Waugh says that even if it the process of claim 9, including the drying step, is obvious, it is not obvious to dry under reduced pressure.

  34. I can now turn to the major attacks on validity, namely anticipation and obviousness. The prior art relied on consists of 8 publications as follows:

    1. US Patent 1 855 591 ("Wallerstein") published on 26 April 1932.

    2. US Patent No. 2 457 036 ("Epstein") published on 21 December 1948

    3. "Preservation of the enzymatic activity of Rennin during spray drying and during storage, and the effect of sugars and certain other additives" by M J van de Beek and S Y Gerlsma ("van de Beek") published on pages 46-54 of Neth. Milk Dairy J. 23 (1969).

    4. Laid-open Patent Application No. JP-S-57-21315 ("Miyake") published on 4 February 1982.

    5. Laid-open Patent Application No. JP-A-60/244288 ("Ishida") published on 4 December 1985.

    6. PCT Application No. WO 87/00196 ("Roser") published on 15 January 1987.

    7. "Use of lyoprotectants in the freeze-drying of a model protein Ribonuclease A" by M W Townsend and P P DeLuca ("Townsend and DeLuca") published on pages 190-199 of the Journal of Parenteral Science and Technology Vol. 42 No 6 (1988).

    8. "The glassy state and survival of anhydrous biological systems" by M J Burke ("Burke") published on pages 358-363 of "Membranes, metabolism and dry organisms" (1986) ed C Leopold.

  35. All except Burke are relied on as anticipations. All are relied on for obviousness. In respect of van de Beek and Ishida, Quadrant carried out experiments to prove anticipation by inevitable result. This, as usual, resulted in an enormous amount of evidence. Before turning to each of these pieces of prior art there are some issues of law which I should consider.

    MAN SKILLED IN THE ART AND COMMON GENERAL KNOWLEDGE

  36. The issue of obviousness has to be considered from the point of view of the notional uninventive man skilled in the art. He is supposed to have read the pleaded prior art and to consider it in the light of common general knowledge. The identity of the common general knowledge is, of course, related to the presumed experience and knowledge of the notional man skilled in the art. One would have hoped that there would by now be no difficulty in determining the characteristics of the man skilled in the art and the factors which determine the scope of common general knowledge. These are topics which have been considered at length both in the High Court and above in many cases. However in this case a considerable and important dispute has arisen in relation to both questions.

  37. Quadrant argues as follows. Two known methods of stabilizing organic molecules are freeze drying and spray drying. The notional person skilled in the art would include those having expertise in either or both of those techniques. Insofar as the notional person was a freeze-dryer he would bring to the consideration of the prior art a familiarity with all that material which would be common general knowledge in that field. Similarly, insofar as the notional person was a spray-dryer, he would read the art with a familiarity with the common general knowledge in his field. Consistent with this, Quadrant produced evidence from experts in each field; Professor Mackenzie being expert in freeze-drying and Professor Lee being expert in spray-drying.

  38. Mr Waugh argued for a notional skilled man in the art of more limited abilities and experience. He gets there by the following steps. He says that Mr Carr is really arguing for a notional team of skilled men in the art including both freeze-dryers and spray-dryers. He says that that is not a safe starting point. He points to the fact that the principal envisaged field of application of the invention is the stable storage of biochemical and pharmaceutical materials. He says that in that area freeze-drying is a far more widely used technique than spray-drying. Therefore the person skilled in the art would only have a slight acquaintance with spray-drying. He would have much more experience of freeze-drying. Furthermore he says that it is not legitimate to think in terms of a team because the person skilled in the art may well be an individual. In relation to this he relies upon the recent judgment in Quadrant Holdings Cambridge Ltd v. Quadrant Research Foundation (27 November 1998) in which Pumfrey J said (paragraph 55):

    The patent in suit is clearly addressed to a reader who is interested in the preservation of the activity of biological macromolecules after drying. As the patent itself makes clear, the potential field of application of the invention is very wide. The addressee of this specification will nonetheless have to possess sufficient skills to be able to perform the examples and carry them into effect. Professor Perham identified such a person as being of Ph D level, having a background in biochemistry or in biology or physical chemistry applied to biology. If Professor Perham had to place a small ad for the addressee it would include the words ‘experience in freeze-drying an advantage’. He was not challenged in this assessment and I consider it to be correct.

  39. Mr Waugh says that the reference to "a" person in this passage emphasises that in some cases it may only be permissible to consider the perception of a notional skilled individual, rather than a group of individuals. He says that those principles apply here and that the task of considering a solution to stability problems would be the responsibility of one individual. Because of the greater popularity of freeze-drying, he would be an expert in that field and none other.

  40. These arguments then lead on to Mr Waugh’s submission in relation to common general knowledge. He says that to the extent that it is necessary to consider a notional skilled person with expertise in different arts (i e a team), the common general knowledge is only what is common to persons with all those different backgrounds.

  41. Consistent with these submissions, Mr Waugh says that less attention can be paid to prior art from the spray drying field. Further, he criticizes Quadrant for having called Professor Lee as an expert, because his area of expertise is spray-drying, which is claimed to be substantially irrelevant. Mr Waugh says that although his client has adduced evidence from a spray-drying expert (Professor Kerkhof), he was called primarily to deal with Quadrant’s experiments and not because he is put forward as an addressee of the Patent.

  42. These submissions lead to some startling consequences. First, although the monopoly covered by the claims of the Patent exclude products made by freeze-drying but include products made by spray-drying (such as Quadrant’s), the question of obviousness has to be asked of a skilled person in the freeze-drying, not the spray-drying, field. So, even if the products made by Quadrant were at all material times obvious to persons in the spray-drying field, the claims are not invalid unless they are obvious to the notional skilled addressee in the freeze-drying field to which the claims do not apply. Second, the broader the scope of the claims, and therefore the greater the number of areas of application and expertise covered, the narrower the area of common general knowledge. This may be called the smallest common denominator approach.

  43. In my view these arguments are misconceived. In some cases a patent claim may cover a wide field so that some parts of it will be obvious to the notional skilled person in one field and other parts will be obvious to the notional skilled person in another. This is not unfair to the patentee, as Mr Waugh suggests, but simply a reflection of the fact that the scope of protection sought is wide. I accept, of course, that in some cases there will be invention in marrying together concepts from two unrelated arts, but that is not what Mr Carr is arguing for here. He says that the notional skilled worker in the art, whether he comes from the freeze-drying field or the spray-drying field, would find it obvious to work within the wide limits of the claim. When considering what would be obvious to the notional uninventive but skilled spray-dryer one must have in mind what would be common general knowledge in that field. Likewise when one is considering what is obvious to the notional uninventive but skilled freeze-dryer. I should only add that in my view there is nothing in what Pumfrey J said in Quadrant Holdings Cambridge Ltd v Quadrant Research Foundation which supports Mr Waugh’s submissions on these points.

    ANTICIPATION

  44. A claim can be anticipated in two ways. First, if the prior art describes something falling within its scope then, assuming that the description is enabling, the claim is anticipated. In such a case it is not necessary to carry out any experiments, or give evidence of what would have happened if the prior art were put into practice, because it already describes what it achieves. Expert evidence may be needed to explain the terminology used because the prior art may be written in technical language which is different to that used in the patent. The patentee may decide that the only way to avoid anticipation, other than by amendment of his claims, is to demonstrate that, notwithstanding its disclosure, the prior art is not enabling. He can do this by proving that what is described could not be achieved on the basis of the disclosure. Such proof would be secured by expert testimony, perhaps supported in some cases by experiments.

  45. The second way of proving anticipation is by showing that the inevitable result of carrying out what is described in the prior art would be a product or process falling within the scope of the claim. The classic statement on this issue is contained in the judgment Sachs LJ in General Tire & Rubber v. Firestone Tyre and Rubber [1972] RPC 457, 485 (p 458):

    .... if carrying out the directions contained in the prior inventor’s publication will inevitably result in something being made or done which, if the patentee’s patent were valid, would constitute an infringement of the patentee’s claim, this circumstance demonstrates that the patentee’s claim has in fact been anticipated.

    If, on the other hand, the prior publication contains a direction which is capable of being carried out in a manner which would infringe the patentee’s claim, but would be at least as likely to be carried out in a way which would not do so, the patentee’s claim will not have been anticipated, although it may fail on the ground of obviousness. To anticipate the patentee’s claim the prior publication must contain clear and unmistakable directions to do what the patentee claims to have invented: Flour Oxidizing Co. Ltd . Carr & Co Ltd ((1908) 25 RPC 428 at 457, line 34, approved in BTH Co Ltd v Metropolitan Vickers Electrical C. Ltd (1928) 45 RPC 1 at 24, line 1). A signpost, however clear, upon the road to the patentee’s invention will not suffice, the prior inventor must be clearly shown to have planted his flag at the precise destination before the patentee.

  46. The second paragraph in this quotation points out the difficulty faced by someone trying to prove anticipation by this route. A disclosure which is "capable" of being carried out in a manner which does not fall within the claim, does not anticipate – although it may be a basis for an obviousness attack. Frequently this type of allegation is supported by one or more experiments which are designed to show that something within the claim is produced by following the recipe in the prior art. The riposte of the patentee is nearly always either to say that the instructions in the prior art were not carried out exactly so that there is no proof of inevitable result, or to show that other ways of carrying out the instructions would not have produced something within the claim. The former of these has been deployed in a particularly extreme form in this case. As I have mentioned, Quadrant has carried out experiments in relation to van de Beek and Ishida. This was to prove inevitable result. The response of Inhale was to instruct its expert, Professor Kerkhof, to list every single difference between the way in which those experiments were conducted and what was described in those pieces of prior art. This he did, although it was apparent that some of the differences listed in his evidence would have no effect on the issue of whether the resultant product fell within the scope of the claims in issue. During his cross-examination the Professor explained that he listed all the differences only because that was what he was asked to do, not because he thought they were all significant which, in at least some cases, they clearly were not. This subject was considered in Evans Medical Ltd’s Patent [1998] RPC 517, 567-8 and 571-2. I reiterate what I said there, subject to one modification. I said that if the attacker can demonstrate that an experiment "well within the general teaching" of the prior art will produce something within the scope of the claim under attack, that proves anticipation. I think that was wrong. Showing that some types of implementation of a general teaching will produce a product within a subsequent claim may show that that subsequent claim is invalid for obviousness. By itself it does not prove anticipation.

    OBVIOUSNESS

  47. The relevant law does not appear to be in dispute. It was set out by Aldous J, as he then was, in Hallen v Brabantia [1989] RPC 307 (p. 327):

    The word "obvious" in section 3 is I believe directed to whether or not an advance is technically or practically obvious and not to whether it is commercially obvious. Although the law is encapsulated in section 3 of the Patents Act 1977, the law on obviousness goes back many hundreds of years. The basis of the law is that the public are entitled to manufacture that which has been published, in the sense of made available to the public, with obvious modifications. By "obvious modifications" are meant those which technically or practically would be obvious to the unimaginative skilled addressee in the art. Such a skilled man should be assured that his actions will not be covered by any monopoly granted to another if he does that which is part of the state of the art with modifications which are workshop modifications or otherwise technically or practically obvious alterations. He does not and should not have to look further and consider whether the step he is taking is obvious or not for commercial reasons. The prize for a good commercial decision or idea is a head start on the competition and not a monopoly for twenty years.

  48. However there is one issue which is of significance to one of the pieces of prior art relied on in this action. A fiction in patent law is that the notional uninventive skilled man in the art is deemed to have read and assimilated any piece of prior art pleaded by the party attacking the patent claim. If the invention is obvious to that person in the light of a particular piece of prior art, the claim is invalid. It is no answer to say that in real life the prior art would never have come to the attention of a worker in the field, for example because it was tucked away on the top shelf of a public library or because it was in a language which nobody in the art knew. The notional skilled person is assumed to have read and understood the contents of the prior art. However that does not mean that all prior art will be considered equally interesting. The notional skilled person is assumed to be interested in the field of technology covered by the patent in suit, but he is not assumed to know or suspect in advance of reading it that any particular piece of prior art has the answer to a problem he faces or is relevant to it. He comes to the prior art without any preconceptions and, in particular, without any expectation that it offers him a solution to any problem he has in mind. Some pieces of prior art will be much more interesting than others. A document directed at solving the particular problem at issue will be seized upon by the skilled addressee. Its very contents may suggest that it is a worthwhile starting point for further development. But the same may not be the case where a document comes, say, from a distant and unrelated field. For example, in theory a notional skilled person engaged in trying to improve the operation of an internal combustion engine is assumed to know, have read and assimilated the contents of all published material including those, say, in the baking field. It may be that a document in the latter field discloses something which, if applied to the internal combustion art, would produce a marked improvement in performance. However the person skilled in the art is not deemed to read the baking document in the knowledge, or even with a suspicion, that it is of significance to the problems he has to deal with. It may be that it is written in such a way that, although he understands it, the skilled person will dismiss it as irrelevant to his work. The more distant a prior art document is from the field of technology covered by the patent, the greater the chance that an intelligent but uninventive person skilled in the art will fail to make the jump to the solution found by the patentee.

    THE WITNESS

  49. Before turning to consider the prior art relied upon, it is necessary to say something about the expert witnesses called to give evidence. Inhale called Professor Pikal (freeze-drying), Professor Kerkhof (spray-drying, primarily called to give evidence relating to the experiments, not on obviousness) and Dr Sasieni (statistics). Quadrant called Professor Mackenzie (freeze-drying), Professor Lee (spray-drying) and Professor MacRae (statistics). It was apparent from his cross-examination and submissions that Mr Carr directs some criticism at what he suggests is the lack of balance in the evidence given by Inhale’s witnesses, particularly Professors Pikal and Kerkhof. However the stance taken by Mr Waugh is rather more extreme. He strongly criticizes Quadrant’s witnesses. In substance he accuses all three experts of being so partisan that their evidence should be largely ignored. In the case of Professors Mackenzie and MacRae he appears to me to get close to accusing them of outright dishonesty. Certainly he accused Professor Mackenzie in cross examination of doctoring his evidence in a disreputable and deceitful manner.

  50. The criticism of Professors Mackenzie arises in large part out of a comparison of the evidence he has given in this action and the evidence he gave in the Quadrant Holdings Cambridge Ltd v Quadrant Research Foundation case referred to above. That was an action in which the claimant was the owner of the Roser patent (i e one of the documents relied on as prior art in this action) and the defendant was the corporate embodiment of the inventor of the Roser patent. The defendant attacked the validity of the patent for his own invention. Professor Mackenzie was called as a witness for the claimant, which I assume was an associate company of the defendant in this action. His evidence was to the effect that the Roser patent was inventive. It is clear that the expert report in this action has been based upon the expert report in that action. Mr Waugh points to the fact that certain passages in the latter have been deleted. He suggests that that was to give a different and inconsistent slant to the evidence. He suggests that at least one false document has been exhibited to one of the Professor’s expert reports. He says that Professor Mackenzie’s evidence to the effect that the Roser patent was inventive is impossible to reconcile with the evidence given here that the Patent in suit is obvious. He says that, taken as a whole, the only explanation for Professor Mackenzie’s evidence in this action and in the previous proceedings is that he conceived it his function to support the case for Quadrant and to act as an advocate on its behalf. In these circumstances, he says that no reliance can be placed upon his evidence, save where it is adverse to Quadrant.

  51. A very similar, though briefer, criticism is made of Professor MacRae. He had given evidence in an entirely unrelated action which I heard; Lilly-Icos v Pfizer (the Viagra case). Mr Waugh says that the evidence given in that action, particularly in relation to the permissibility or otherwise of adding together different experimental results for the purpose of making a statistical analysis, is irreconcilable with the evidence given here. It is said that Professor MacRae conceived it to be his function to act as an advocate for Quadrant and that his evidence should be discredited on this account.

  52. In my view these criticisms, and particularly the suggestions of dishonesty inherent in them, are unjustified. I had and have no reason to doubt the honesty of any of the witnesses called on either side. As far as Professor Mackenzie is concerned, in the earlier proceedings he was concerned with the validity of a patent which was of far narrower scope than the Patent here. Of greater significance is the fact that none of the prior art in this action was relied on in that action. Whether that was because it was not found or not considered relevant, or because the attacking defendant, being the inventor, was not enthusiastic about attacking his own patent, is not possible to say. Pumfrey J’s finding of validity was based upon the material put before him. The Professor was only called on to consider the prior art in that action. The differences between the expert report in that action and the expert reports here are so apparent that both the Professor and Quadrant’s lawyers would have had to be foolish in the extreme to have made the changes so as to distort the evidence given in the expectation that the changes would not have been noticed. I accept the Professor’s evidence that the deletions from his earlier expert reports in the preparation of his evidence for this case were done for no other reason than to concentrate on the issues relevant to this case. I reject out of hand the suggestion that he deliberately exhibited a false document. The document at issue was a draft or retyped version of a court document relied on in the United States. How the former was substituted for the latter is not clear. I have no reason to believe it was knowingly done by either the Professor or the English lawyers. It appears to me that it is likely to have been done by accident. The suggestion that one document was deliberately substituted for the other might have had some mileage if there was any significant benefit which could have been secured by the substitution. I fail to see any such benefit here.

  53. I reject also the allegations against Professor MacRae. As he made clear here, the data he was relying on was all that was available. He was trying to make bricks with small quantities of straw. He did not suggest that that was very satisfactory and, in this it appears to me that the evidence he gave in this case was not inconsistent with that given in the Lilly case. Again, I have no reason to doubt the honesty of the evidence he gave.

  54. As far as Professor Lee is concerned, I am a loss to understand how serious allegations of bias could be made against him. The impression he left with me was that he was both knowledgeable and fair in the evidence he gave.

  55. This is not an end to the issue of the experts’ evidence. For the reasons set out above, I reject the strong allegations made against Quadrant’s experts. However some of the evidence given on either side did betray the slant which sometimes occurs when experts are called by parties. In particular both Professor Pikal and Professor Mackenzie struck me as very knowledgeable men who had fixed views on some of the major issues in this case and were not willing to abandon them even when another view was possible or even preferable. Each was no doubt selected by his party because of those firm views. This does not mean or imply any dishonesty or bias but it does mean that when assessing the evidence I do not necessarily accept that all experts in their arts would necessarily give the same or as firm views as they did on some issues. Furthermore it is only right to point out that on at least one point, namely the issue of drying when applied to the Epstein disclosure, Professor Mackenzie appears to have been less than thorough in checking the evidence he gave. I can now turn to the individual pieces of prior art, taking them in chronological order.

    PRIOR ART

    (a) Wallerstein

  56. This patent is concerned with the a method for making a stable preparation of an enzyme (i e a protein) known as invertase which causes a particular type of chemical change (called inversion) to some sugars. The patentee records that invertase has usually been used in the form of an aqueous solution. It then states (column 1 lines 17 to 20):

    Such solutions are, however, highly sensitive to deterioration when exposed to temperatures, say, of above 50 degreesC and they have the further disadvantage that they are subject to attack by micro-organic growths, and, as a result, to decomposition from such attack.

  57. It then says that these problems have been addressed by the incorporation of preservatives but these are objectionable for various reasons. It then says that it has been found (column 1 lines 27 to 31);

    .... that it is possible to produce invertase preparation in a dry or powdered form by incorporating with the invertase a protective sugar and that such preparation can be standardized.

  58. These dry preparations are said to exhibit marked resistance to deterioration by heat and to bacterial decomposition. An example, described as illustrative, is also set out. It suggests the use of a sugar which is not converted by invertase. That is to say a sugar which does not significantly react with the invertase. This is the same warning against using a carrier medium which reacts with the molecule to be stored as is contained in the Patent and is referred to at paragraph 17 above. Two particular sugars, dextrose and lactose are suggested. The sugar is added to a concentrated solution of the invertase to form a comparatively stiff dough (column 1 lines 40 to 44). This mirrors what is described in the Patent and is referred to at paragraphs 20 to 22 above. This is then dried at a temperature not exceeding 50 degrees C and preferably around 40 degrees C. The specification states that (Column 2 lines 57 to 64);

    This dry preparation containing the protective sugar is exceedingly stable, can be used at temperatures above 50 degreesC without deterioration, and has various advantages from the point of view of shipment and ease of handling over the solutions heretofore generally used.

  59. Quadrant’s argument is that this is clearly describing a process for stabilising a labile protein, invertase, by embedding it in sugar. A glass must have been formed although it is not described and it must have had a Tg above 20 degrees C. The method of preparation mirrors that in the Patent save that there is no reference to drying under reduced pressure. For these reasons claims 1 and 9 must be anticipated and, in any event, they are obvious as are the other claims. Inhale disputes this. It says that, insofar as stability is concerned, it asserts that no information is given as to whether invertase would be unstable in aqueous solution at 20 degrees C and that Quadrant has conducted no experiments to prove inevitable result. Furthermore, the fact that there may be a chance, even a "very good chance" that a glass might be obtained is not an inevitable result within the test of General Tire.

  60. First I should consider the question of anticipation. For this purpose it is necessary to distinguish between the scientific facts and the argument. No one has suggested that the disclosure in Wallerstein is not enabling. That is to say it is not suggested that the results claimed by the inventor could not be achieved by following his instructions nor that what he describes as happening does not happen. It is, of course, true that Wallerstein does not describe the formation of a glassy state. All he describes is making a dry product from a dough with certain ingredients and the stability exhibited by it. The question is what, on the evidence, is the nature of the product he has obtained, no matter how he describes it.

  61. First I should say something about the ingredients used in Wallerstein. Invertase is an enzyme. Wallerstein states that it is "highly" sensitive to deterioration above 50 degrees C. Mr Waugh says that this does not prove it is sensitive to deterioration at 20 degrees C. However all the evidence produced shows that invertase is sensitive to degradation at the lower temperature as well, it is just much more sensitive at higher temperatures – a fact which would be expected because the rate of chemical degradation increases with temperature. But there is more than this. As Professor Pikal stated in his expert report, proteins are particularly difficult to store due to conformational instability and the multitude of chemical degradation pathways, and even with freeze-dried proteins it was and still is common to keep them refrigerated to prevent degradation. Invertase is a protein. Under cross-examination, the Professor said that he had no reason to doubt that invertase would be unstable (Transcript p 230). Similarly Professor Mackenzie said that he would expect it to denature in aqueous solution at a room temperature of 20 degrees C. Furthermore invertase is stored at 2-8 degrees C even in the powder form and Professor Pikal accepted under cross examination that this was a "pretty good indication" of instability at 20 degrees C. He also accepted it would be likely to be even more unstable in aqueous solution. It seems to me that Mr Waugh is correct when he says that what counts is not the absolute stability of a particular molecule at 20 degrees C but rather whether it will be rendered significantly more stable by embedding it in an amorphous matrix. On that, there can be no reasonable ground for disputing that the product described in Wallerstein has far greater stability once it is turned into a dry product.

  62. As I have said, there is no express statement that the Wallerstein product had a Tg of above 20 degrees C. However there is much in the document which indicates what the Tg would be if it was a glass. It is not in dispute that of the two sugars expressly mentioned, namely dextrose and lactose, the former has a Tg of about 75 degrees C and the latter has a Tg of about 108 degrees C. It is not in dispute that proteins themselves have a notional Tg of about 120 degrees C. It follows that a glassy product made of a protein and, say, dextrose would have a Tg of somewhere between 75 degrees C and 120 degrees C in the dry state, depending upon the relative quantities of dextrose to protein. All of these would therefore have a Tg far above the minimum required by either claim 1 or claim 2. The presence of water would depress the Tg, but Wallerstein describes his product as being dried. This gave rise to a prolonged debate between the parties. Once again, it does not appear now to be in dispute that the water content would need to be in excess of 10% for there to be any chance of the Tg dropping as low as 20 degrees C. Furthermore Wallerstein describes his product as being made from a dough into a dry powder. The fact that it is a dry powder reinforces the view that it was turned into a solid, not rubbery composition. The parties disagreed as to how dry Wallerstein’s product would have been. At the end of the day there was little doubt that a person in the art repeating Wallerstein would have ensured that the product was dry by checking that the moisture level was below 4% and probably down at a 1% level. Either of these levels would have resulted in a Tg of well above 20 degrees C or 30 degrees C. It seems to me that on the evidence, it is likely that if a glass was present, it would have had a Tg above the limit set in claims 1 or 2.

  63. Mr Waugh argues that it cannot be assumed that Wallerstein actually produced a glass. It is not described as a glass, only as a dry powder. As I understand it there are really only two possibilities. Either he had achieved an amorphous solid, that is to say a glass, or else there was a phase shift and what he had was a mixture of invertase particles and particles of crystallised sugar mixed together. However it could not have been the latter. No one has suggested that what Wallerstein had was crystalline sugar nor has it been suggested that the stability undoubtedly claimed by him could have been achieved in any other way than by the existence of a glassy product in which the invertase was embedded. Furthermore, as Professor Mackenzie said and Professor Pikal did not seriously contest, the chances of there being phase separation in this type of system, where very small sugar molecules are used, is remote. The process described by Wallerstein was one which is in all material respects the same as the process contemplated in the Patent, using ingredients as covered by the Patent. On a balance of probabilities Wallerstein obtained same type of product as is described by the Patent, namely a glassy one, which is the only one which could have produced the results claimed.

  64. How do these findings impact on the case of anticipation? With one possible exception it has been proved that the product of Wallerstein has all the features of claim 1. The only caveat relates to Tg. As I have said, it is extremely likely that the glassy substance formed by Wallerstein and described in his patent would have had a Tg above the limit set in claims 1 or 2. On the repetition of Wallerstein, on the evidence, it is likely that such a product would have been produced. Indeed, in view of the compelling evidence given before me of the known desire to reduce the moisture content of proteins which are being prepared for storage, I think there is a strong likelihood that a moisture content would have been used or would be used on a repetition which would put the Tg well above 30 degrees C. However, the fact that products made in accordance with the Wallerstein teaching are likely to fall within the claims is not sufficient to succeed on anticipation. For this reason the anticipation allegation against claims 1 and 2 fails. For the same reasons the anticipation allegations against claims 3, 9, 10, 14, 15 and 16 also fail. There was no allegation of anticipation levelled at claim 11, concerned with drying at subatmospheric temperatures.

  65. On the other hand it appears to me that the obviousness allegation must succeed. There is no suggestion that at the priority date the relevant man skilled in the art would have found this disclosure other than extremely interesting. He would have been tempted to try it out. In doing so he would have tried to keep moisture levels low and almost certainly at 4% or less. He would have achieved a glass, whether he knew it or not. He would also have appreciated that the teaching was quite general so far as the carrier material is concerned. Although the specification refers to dextrose and lactose specifically, it makes it clear that these are only illustrative. Other sugars could be used. Furthermore, although the specification is only concerned with the stabilisation of one particular protein, invertase, it is likely that a man skilled in the art would have realised that it was worth trying to apply the Wallerstein teaching to other proteins. In relation to this, there is nothing in the disclosure which suggests that the enhanced stability is achieved by chemical interaction between the sugar and the invertase. On the contrary, the teaching is against using a sugar which reacts in some way with invertase. It seems to me that the skilled person in the art would have thought it at least likely that the same or similar stability could have been achieved with other proteins. It would have been worth taking the simple steps necessary to test out whether that was so.

  66. In the light of these conclusions, claims 1, 2, 3, 9, 10, 14, 15 and 16 all fail for obviousness. This only leaves claim 11, namely drying under subatmospheric pressure, for consideration.

  67. Quadrant argues that once it is known or obvious to dry a product, it must be obvious to do so under subatmospheric pressure. Inhale argues that the evidence did not show that it would be obvious to apply reduced pressure but concern over "splattering" would deter the skilled person from applying vacuum at above zero temperatures. Splattering is, in substance, what happens when something boils too fast. Therefore if it occurs, it tends to occur if a high vacuum is used.

  68. In fact the evidence does not support Inhale’s suggestion that the risk of splattering would deter a skilled person from applying a vacuum. The highest that the point was put was in the following passage in Professor Pikal’s expert report:

    5.8

    I also note that in relation to each Roser, Wallerstein and Epstein, Professor MacKenzie considers that it would have been an obvious step to repeat the disclosures using reduced pressure. If we were to assume that reduction of water content were a desirable outcome, someone with engineering expertise would be likely to recognise that the use of reduced pressure might accelerate the drying process. However, it was also recognized that reduced pressure might well cause boiling with " splattering". Splattering is generally recognized as undesirable and likely unacceptable, so one would proceed with the use of reduced pressure with extreme caution.

  69. Even if that were taken as an accurate reflection of the attitude of a non inventive man skilled in the art, it would not mean that he would be deterred from using reduced pressure, only that he would work with caution. However I do not accept that this gives a balanced view of the attitude which a man in the art would adopt. I accept the accuracy of the following passage in the evidence of Professor Mackenzie;

    It was well known at the priority date of the Patent that a reduction in pressure would lead to quicker drying of a composition and so I believe that if a skilled person wished to obtain a dry product more quickly, he/she would choose to dry at reduced pressure ....

  70. In my view this was not seriously disputed by Professor Pikal as the following extract from his cross-examination demonstrates (Transcript pp 282 – 284);

    Q

    .... It was well known at the priority date that a reduction in pressure could lead to quicker drying of the composition. Correct?

    A

    By some certainly.

    Q

    I would like you to undertake a slightly artificial exercise. Imagine that somebody told you about the method of claim 9. All right? Do you remember claim 9?

    A

    OK, right.

    Q

    We are in 1989 and I tell you that, OK.

    A

    Yes.

    Q

    Then you are asked, you know that method, would it be inventive to use that method and evaporate at subatmospheric pressure? Do you understand what I am asking?

    A

    I think I understand what you are asking and it is difficult for me to be certain. We have, for example, Roser claiming a year or two earlier that the optimum condition is air drying, that is drying at atmospheric pressure. I do recognize that drying in a liquid system at subatmosphere runs the risk of rather gross splattering of the product. For example, what I am envisaging here is the product in a vial or a container and you have it in a partial vacuum and the system may well boil and splatter the material around. You would have that issue to deal with. Simply from a mass-transfer point of view, as long as what is limiting is mass transfer in the vapour state then, carrying on that process at reduced pressure, I would have recognized -- I think any engineer would have recognized -- would have sped up the process.

    Q

    If you were concerned about spattering at subatmospheric pressure you would have the same concern having read the Inhale patent because the Inhale patent has this claim to drying at subatmospheric pressure?

    A

    That is right.

    Q

    But it does not tell you how to avoid the spattering problem?

    A

    That is correct, it does not.

  71. That water can be driven off faster and more completely in a drying process by application of a vacuum is school-level physics. Once it has been determined that drying of a medium should be undertaken, it is a mere workshop modification to try and speed it up by use of subatmospheric pressure. The risk of splattering would be known but would not act as a deterrent. It would only result in the worker proceeding with care. Claim 11 is obvious also. It follows that on the basis of Wallerstein, all the claims asserted to be independently valid fail. Nevertheless, because this case is likely to go further, it is desirable to consider the other prior art relied on.

    (b) Epstein

  72. This is a patent for making storage stable coffee powder. The inventor states that coffee concentrates, that is to say water soluble coffee extracts, are subject to certain shortcomings namely (column 1 lines 19 to 25):

    .... loss of volatile aromatic and flavour components resulting from exposure to air whenever the coffee extract container is opened; and absorption of atmospheric moisture because of the hygroscopicity of the coffee extract which causes deterioration of the coffee extract and promotes rancidity of the fatty constituents

  73. The objectives of the invention include (Column 1 lines 26 to 34);

    .... a water soluble coffee concentrate whose cup-coffee producing potency and flavor is fully preserved, and the possibility of deterioration from exposure to the air is reduced to a minimum.

    A further general object is a water soluble concentrate containing the coffee extractives in a form and in a manner so that they will not be chemically altered in time or upon exposure.

  74. Further objectives are stated to be (column 1 lines 35 to column 2 line 2):

    .... the preparation of a coffee concentrate the essential principles of which are completely sealed in, thus protecting them from loss of potency, aroma, volatilization and chemical change due to atmospheric action; this being accomplished by means of a water soluble comestible base, with which the coffee extractives are homogeneously fused; and more particularly a comestible water soluble base, with a melting point below 100 degrees C.

    .... a vitrified coffee concentrate; .... a non-hygroscopic solid vitrified coffee concentrate.

    .... a coffee concentrate having the additional characteristic or a melting point, which is well above room temperature so that the coffee concentrate may be kept and stored at ordinary temperatures.

  75. The discovery underlying the patent is described generally in the following short passage (column 2 lines 3 to 10);

    The attainment of the foregoing and other objects .... evolved from the novel concepts of sealing-in the coffee extractives by fusing them into a molten comestible base and of employing for that purpose a comestible base which will cause the resulting fused volume to solidify to a vitrified mass.

  76. The coffee powder is "completely sealed in" in a "homogeneously fused" product so as to protect if from, inter alia, "chemical change" by fusing it with sorbitol (a sugar alcohol). Epstein explains that he uses sorbitol because it "vitrifies on cooling, that vitrification occurring quickly upon a drop in temperature" and because in its "solid or vitrified form" it is non-hygroscopic. Epstein says that he was also attracted to use sorbitol because of (column 2 lines 25 to 35):

    .... its capability in molten state to dissolve or fuse an amount of coffee extractives several times, by weight, that of the base itself, this amount of extractives fusing homogeneously throughout the base without residue or trace of the extractives in their original powdered form; it vitrifies upon cooling, even when containing this large amount of fused coffee extractives; it retains it characteristic of rapid vitrification without caramelization even with this large content of fused extractive ....

  77. The patent explains that the "vitrification point" varies depending upon the proportion of coffee extract to sorbitol and points out that just above the vitrification point the mass is sufficiently malleable that it can be worked into units of predetermined shape and weight. There are numerous other references to vitrification and vitrification point. Three examples of the method of preparing the vitrified mass are then set out. For present purposes it is only necessary to refer to the first one. 1 lb of sorbitol is fused with 3 lbs of coffee extracts, the fused mass is then cooled to a temperature above its ‘vitrification point’ at which it is still malleable. It is then shaped into tablets or other shapes and then cooled below the vitrification point. The vitrification point in this case is said to be 63 degrees C. One of the claimed benefits of the product made in accordance with this example is that it can be kept at ordinary temperatures without softening.

  78. Quadrant argues that this anticipates all the product claims in the Patent. It says that the product contains a water soluble carrier substance, namely sorbitol, and at least one substance to be stored, namely coffee powder. The latter is unstable in aqueous solution, as Epstein describes. It says that Epstein achieves much increased stability by embedding the labile coffee powder in a vitrified, that is to say glassy, matrix. The vitrification point, that is to say the Tg, of the product is 63 degrees C, which is well above 20 degrees C (claim 1 of the Patent) and 30 degrees C (claim 2). Professor MacKenzie supported this approach by reference to the terminology used by Epstein. He noted that the author explicitly use the word "vitrification" which, he says, means and meant in 1948 to form a material in a glassy. Further his evidence was that the "vitrification point" referred to by Epstein was obvious a reference to the Tg. Although I have re-read the transcript of the Professor’s cross-examination, it does not appear that this evidence was seriously challenged, at least in relation to what the terminology used in Epstein would mean to a person skilled in the art.

  79. However, Inhale argues that Epstein does not unequivocally disclose a product falling within the claims of the Patent. It says that Professor Mackenzie’s reading of the document is not a scientifically sound approach and is not justified. In particular "vitrification" and "vitrification point" do not mean what Professor Mackenzie says they mean.

  80. There is no doubt that Professor Mackenzie’s interpretation of these expressions accords with common usage. Under cross-examination, Professor Pikal said (Transcript p 263);

    Q

    You remember Epstein, which is the coffee extracts prior art and you considered it and you have drawn attention to the fact it uses the term vitrification?

    A

    Yes.

    Q

    The normal use of the term vitrification is as a reference to glass formation, is it not?

    A

    That is correct.

    Q

    The normal use of the term vitrification point is as a reference to glass transition temperature?

    A

    Not necessarily that which you measure by DSC, but, yes, as a rough approximation, yes.

  81. Furthermore the Professor accepted that Epstein was talking about making a glassy composition "if you take the word vitrification literally" (Transcript p 265). However Inhale says that these expressions cannot have their normal or literal meaning. This is based upon the following passage in Professor Pikal’s report (paragraphs 10.14 and 10.15):

    It is not clear from this publication whether ‘vitrification’ bears any relation to stability. I understand vitrification in this context to mean a consistency which is too stiff to be malleable and the "vitrification point" referred to here is probably a temperature which is well above the Tg of the composition. In my opinion, the object of Epstein is to try and get a solid at room temperature which will be able to melt in boiling water to enable the aroma which is trapped in the "vitrified" matrix to be released. This is a different issue from that concerned in the Patent which is concerned with the stability and storage of "unstable" molecules.

    Reduced loss of aroma could be related to low diffusion coefficient of the aromatic components in the system and/or reduced surface area and increased particle size in the sorbitol: coffee extract system relative to the coffee extract alone. It is unlikely that a molecular dispersion of the aroma components in a glassy sorbitol matrix is the major effect. After all, sorbitol is the minor component; it is not the matrix. Further, sorbitol has a very low glass transition temperature (about 2 degrees C). Thus, in my view, it is not at all obvious how (or if) superior stability is achieved.

  82. In substance the Professor was taking two points. First, that Epstein had nothing to do with rendering the coffee powder stable, but only with preventing aromatics from coming off. Second, he suggests that the use of sorbitol makes it unlikely that a suitable glass was formed. I am not certain that the first of these points is still pursued by Inhale. It was not referred to in Mr Waugh’s closing argument or skeleton submissions. In any event, it is clearly wrong. Epstein expressly states that one of the things he is concerned to prevent is the fats in the coffee going rancid. As Professor Pikal explained, a fat goes rancid as a result of an oxidation process. That is to say it is a chemical degradation – the fat equivalent of the rusting of a piece of iron. Furthermore Epstein says in terms, as set out at paragraph 72 above, that he is concerned to prevent chemical degradation. I do not accept that on this point Professor Pikal has accurately or fairly read Epstein. It is not the way that an ordinary skilled person in the art would read or understand this publication.

  83. The second point is still relied on by Mr Waugh. Essentially it is as follows; pure sorbitol has a Tg of –2 degrees C, therefore it is not likely that it could have made a glass composition with a Tg of more than 20 degrees C, in particular of 63 degrees C, as Epstein claims. This might be thought of as a surprising submission since sorbitol is expressly mentioned in Inhale’s own Patent as a suitable carrier material. In relation to this Professor Pikal said that he thought the Patent was giving very bad advice. However he did not say that sorbitol would not work. On the contrary he explained that it could be made to work in the patented process (Transcript p 263);

    A

    This particular teaching [in the Patent in suit] I regard as very bad advice. I would not recommend using sorbitol because of its low Tg.

    Q

    You could not think of a way of ----

    A

    It is possible if you only had a little bit of sorbitol and a lot of the system to be stabilized that the composite system could have a glass transition temperature high enough for you to use, but because the glass transition temperature would be relatively low, it certainly would not be a good choice.

  84. The fact that something is not a good choice, does not mean that it will not work. It can mean, and in my view does mean here, that other things will work better. In the latter extract from the transcript, the explanation given by the Professor for how sorbitol could be made to work is consistent with the rest of the evidence given in this action. As mentioned already, the Tg of a composite will lie somewhere between the Tgs of its individual ingredients. If, say, sorbitol with a Tg of –2.0 degrees C is mixed with a protein with a notional Tg of 120 degrees C, the resultant product will have a Tg between –2.0 degrees C and + 120 degrees C. The less sorbitol there is present, the higher the Tg. If that is then applied to the teaching of Epstein, it will be recalled that in example 1, the majority of the composition was taken up with coffee powder. Sorbitol was indeed the smaller ingredient. The Tg of the resultant product would therefore be expected to be closer to the virtual Tg of the coffee than the sorbitol. In my view this was, in effect, accepted by the Professor in another part of his cross-examination (Transcript pp 265 –266);

    Q

    This appears to be reporting the same effect as the patent with one of the carbohydrates specified for this purpose in the patent, does it not?

    A

    Superficially it would appear that he is forming a material which is a glass at room temperature. It does appear that he believed that is what he was doing.

    Q

    You believe that this could not be happening because of the low Tg of sorbitol.

    A

    I would not go quite so far as to be that dogmatic about it. Given the fact that you are using 1/3 of the .... well basically a one to three, it would be 25% of the total system being a material of very, very low glass transition temperature, given how the material was actually produced, the drying is certainly not going to be optimal. There is apt to be a fair amount of residual moisture. Taking all of those things into consideration, I am somewhat sceptical that in fact the glass transition temperature was much above 30 degrees C or, let us say, above 30 degrees C.

    Q

    Why do you say ----

    A

    I cannot know for sure.

    Q

    Why do you say that drying was not optimal? What do you mean by that?

    A

    As I see this, he is fusing all of this together and he is drying it somehow, and it does not say exactly how. If you were to create very small particles and dry small particles, that would be an attempt at optimizing the drying. I did not see that he was doing that. It may be I missed something.

    Q

    I see. I suppose your concerns about the use of sorbitol in this disclosure are the same as your concerns about the use of sorbitol in the patent. You will remember you told me it was bad advice?

    A

    I think from what he was trying to do here it might have made sense. One of the primary problems with quality of the coffee is loss of volatiles and if in fact by making this mass you reduce the specific surface area, you are going to, just by that in itself, decrease the volatility. He talks about rendering something which is hygroscopic and non-hygroscopic. In reality he does not do that. He might well change the rate of vapour transfer because of the surface area effect. The sorbitol here might be rather clever. He does say that he needs to have something that fuses at a modest temperature, 93 degrees C I guess, and sorbitol serves him well for that. However, I still maintain it is not a good material to use for the patent.

  85. In my view Professor Pikal’s evidence does not discredit the disclosure in Epstein. At its strongest it appears that the Professor doubts that Epstein really got to a Tg of 63 degrees C. He thinks it is more likely that it was not much above 30 degrees C. Even if that was so, it would still fall within the scope of claims 1 and 2 of the Patent. Professor Mackenzie also explained that the mixing of the components would raise the Tg of the resulting product above the Tg of the sorbitol (Transcript p 736).

  86. There is another reason for rejecting Inhale’s approach to this piece of prior art. Where, as here, a piece of prior art describes in clear, readily understandable language a process or product, it is not enough for the patentee to hint that it might not work or have the properties asserted for it. That is particularly so where, as here, the reason for the suggestion of inutility is the use in the prior art of an ingredient which the patentee, in his own patent, has said will work. If it is to be asserted that a piece of technical prior art is in error in its description of what it has produced, it is for the party asserting the error to prove it.

  87. Having read the Epstein disclosure and the evidence of Professors Pikal and Mackenzie again, I have come to the conclusion it does describe a product consisting of a labile composition embedded in a carrier in the form of a glass with a Tg above 30 degrees C. There is nothing to support the suggestion that Epstein did not achieve what he describes or that a reader of the document would be unable to do so, or would misunderstand what the author was claiming to have achieved. In my view this document discloses a product having all the features of claims 1 and 2 of the Patent. Furthermore the protected ingredient, coffee extract, clearly contains a number of different organic ingredients. There is nothing in this document which suggests that the embedding technique is ineffective for any of them. On balance I think that a man in the art seeking to find a convenient way of stabilising organic molecules would think it worth trying the Epstein process on other candidates. It follows that claim 3 is invalid for obviousness.

  88. In his expert report, Professor Pikal said (paragraph 6.4);

    It is the concept that one may expect stabilization of a reactive molecule by placing that molecule in a matrix of some carrier that will remain glassy under storage conditions of interest that is the key disclosure in the Patent that was not appreciated prior to February 1989. That is degradation requires molecular mobility, and one stabilizes by conferring the limited mobility of the glassy carrier matrix on the dispersed labile molecule and thereby limiting the degradation rate.

    and (paragraph 8.7)

    Essentially, the Patent discloses that you need to store the labile material by dispersing it in a glassy carrier and that if you do so you are likely to obtain a significant improvement in stability compared to the same material in aqueous solution. In my opinion the skilled person would then be able to practice the invention without any further information.

  89. I agree with the Professor’s analysis of the essential teaching of the Patent. However it appears to me that the same teaching is expressly to be found in Epstein.

  90. Epstein does not anticipate or render obvious any of the method claims of the Patent. All of them involve taking wet ingredients and drying the product until its Tg rises above 20 degrees C or 30 degrees C. Epstein only describes a process which involves blending together and then fusing dry powders, namely sorbitol and coffee extracts. He does not require or refer to a drying step and I see no basis upon which it can be said that the notional skilled person in the art would have thought of adding such a step to his process.

    (c) Van de Beek

  91. As the second paragraph of the main text of this document explains, van de Beek is concerned with the preservation of the biological activities of enzymes. To exemplify its proposed technique it uses, as an example, rennin. That is an enzyme which is used in the manufacture of cheese. The paper is concerned particularly with the use of spray-drying techniques and, according to its title, the process described achieves preservation of the enzymatic activity of the enzyme not only during drying but also during storage.

  92. Van de Beek states that rennin is on the market as an aqueous solution known as rennet. It also points out that, for preservation purposes, such solutions contain 20% common salt and 1% sodium benzoate. There is no serious doubt that rennin solution degrades with time, hence the need for preservatives. An alternative known method of preservation, vacuum drying at low temperature, is also mentioned. The method deployed by van de Beek consists essentially of spray drying a solution of rennin containing a sugar. Two sugars, lactose and sucrose, are specifically mentioned although the abstract refers to sugars generally and the main body of the text refers to the addition of "sucrose, lactose etc" (p 52 last full paragraph). The sugar is said to act as a preservative in two ways. First, it helps preserve the rennin during the spray-drying process. Second, it is said to ensure preservation during storage. As far as the latter is concerned, the paper says that products made by the process exhibit no loss of biological activity, i e are not degraded, after 250 days (p 49 first paragraph).

  93. Although spray-drying is not as widely used as freeze-drying, as Professor Mackenzie has explained in his expert report, it is a well known technique which has been used for many years in a number of fields. A description of how spray-drying works is included in an agreed primer prepared by the parties for this action. It consists of the transformation of a "feed" preparation, which can be a solution, suspension, emulsion or paste, into a dried particulate form by spraying the feed into a hot drying gaseous medium. Spray-drying therefore involves both particle formation and drying in a single step. The resulting dried product is composed of particles, granules or agglomerates. Spray-drying involves atomisation of the feed into a spray of small droplets and contact between the spray and the drying medium (usually hot air) resulting in moisture evaporation. The drying of the spray yields particles that are then recovered from the air. Evaporation is rapid, owing to the very large specific surface area of the spray. Spray dryers are commercially available in a number of different constructions and sizes, including internal geometries.

  94. Van de Beek offers some tentative explanations for the increased stability of the products he achieves. In particular it suggests that the stabilizing effect of the sugars can be explained by a reduction of the ability of the medium to break certain chemical bonds. There is no hint that the claimed results are attributable to glass formation.

  95. Quadrant argues that what van de Beek is doing is to produce, and to describe the production of, a storage stable material in which the degradation-prone enzyme is embedded in a sugar. The product is a powder and is stored at room temperature. On the basis of the material before the court it appears that there are three possible ways of attacking the validity of the Patent on the basis of van de Beek. First it can be argued that the document describes something which is in fact a product and process falling within the claims of the Patent and it is invalid for anticipation accordingly. Second, it can be said that van de Beek describes a process which inevitably would produce a product falling within the claims. This again is an allegation of anticipation. Third, it can be said that the document renders it obvious to carry out a process which will produce products falling within the claims. As I understand it, Mr Carr advances all of these arguments. In relation to the allegation of inevitable result, Quadrant carried out certain experiments. Mr Carr says that those results confirm the conclusion arrived at by Professor Mackenzie and Professor Lee that van de Beek describes something which falls within the claims. It is convenient to start with a consideration of the question of obviousness.

  96. By the end of the trial, there was no real dispute that rennin is unstable at room temperature in aqueous solution. Not only is this inherent in the disclosure in van de Beek, but there was other evidence which showed this to be true. The commercially available solution bears instructions that it be stored between 0 degrees C and 8 degrees C. Professor Pikal accepted that this was a good indication that it was unstable at 20 degrees C. The Professor said he had no reason to believe that rennin was stable in aqueous solution at that temperature. It is also not in doubt that one of the aims of van de Beek is to produce rennin in a form which is stable for storage. The specific sugars mentioned, sucrose and lactose, have respective Tgs of 78 degrees C and 108 degrees C in the dry state. Rennin, being a protein, has a notional Tg of about 120 degrees C in the dry state. During his cross-examination in relation to another piece of prior art, Professor Pikal gave the following evidence (Transcript p 161);

    Q

    [Putting a passage in Professor Pikal’s expert report to him] "Secondly, as the level of protein relative to sucrose increases, the Tg of the dried material will increase."

    A

    Correct.

    Q

    What I am asking you is would that also be true of a system with protein and trehalose?

    A

    No, not necessarily.

    Q

    Why not?

    A

    Because the Tg of the protein itself is much higher than the Tg of the sucrose, and when you mix the two you get a result that then moves up as the fraction of protein is increased ....

  97. This evidence, which was consistent with others, is to the effect that a glass containing lactose and rennin will have a Tg above 108 degrees C and if it contains sucrose and rennin it will have a Tg above 78 degrees C, in each case assuming that a glass is formed and there is nothing else, such as water, present to force the Tg down too far.

  98. As far as drying is concerned, there is no doubt that van de Beek teaches that his product should be dry. Not only does he use spray-drying for production, but he says that the product is stored over a dessicator. As far as the level of dryness is concerned, again there does not appear to be any serious dispute between the parties. As a rule of thumb, at the priority date, if a man skilled in the art was trying to make a product dry for storage purposes he would be looking to achieve a moisture level of about 1%. As Professor Pikal said, he would certainly go for a moisture level below 5%. If a man in the art were to follow the van de Beek teaching it would be obvious to try to make a product with less than 5% water. Assuming he produced a glass, that would be bound to have a Tg well above 30 degrees C, even if he did not know it.

  99. The question is, then, whether the process taught by van de Beek would produce a glass. On the evidence, there can be little doubt that it would. The paper claims that it achieves very substantial stabilisation of the rennin. No explanation has been offered for how this could have been achieved except by glass formation. On the basis of current knowledge, glass would have had to have been formed, even if, at the time, van de Beek or any skilled worker would have been oblivious of the fact that that was happening. In fact the process of spray drying is one which strongly favours the creation of a glass. There are only two possible forms in which the sugar-containing solid composition can be – either crystalline or as an amorphous glass. However it takes time for a system to crystallise. The molecules and atoms have to arrange themselves in the ordered pattern in order for the crystal lattice to form. If there is insufficient time, the dried product will be amorphous. Furthermore crystallisation involves nucleation. That is to say that there has to be a nucleus around which the crystals grow. The evidence was to the effect that fast drying would make it unlikely that crystals would grow. Furthermore drying of very small droplets makes nucleation unlikely. Thus spray drying would be expected to produce an amorphous, not a crystalline, product.

  100. It seems to me that on the evidence, a man skilled in the art would have operated van de Beek in a way which would in most, if not all, cases have produced an amorphous glassy product with a Tg above 30 degrees C. If he failed to do so, he would not have achieved the stability which van de Beek promises. It follows that claims 1, 2 and 3 fail for obviousness as do claims 9, 10, 14, 15 and 16. As far as claim 11 is concerned, namely drying under subatmospheric pressure, this is a matter I have dealt with already in relation to Wallerstein. For the same reasons, this claim fails for obviousness as well.

  101. In the light of this finding, it is not strictly necessary to consider the allegations of anticipation. However, in view of the extensiveness of the submissions put to me and the fact that this case may go further, I will deal with the arguments on this subject as briefly as possible.

  102. First I can deal with the argument that, whether he or any reader knew it or not, what van de Beek is describing is a product which falls within the scope of the claims. This is the ‘rose by any other name’ point. Mirroring the points made above in relation to obviousness, it is said that the dry product described by van de Beek must have been a stabilised glassy product with a Tg above 20 degrees C. This was the view arrived at by Professors Mackenzie and Lee. Mr Waugh says that this is not right. His argument is as follows. First he refers to the explanation given by van de Beek for the achievement of enhanced stability, namely the possible interference with the rupturing of hydrogen bonds in the protein. Then he says there is no appreciation of whether a glass was formed and if so whether that had any implication for storage stability.

  103. It appears to me that these arguments do not meet Quadrant’s attack. The issue is not whether the author of the prior art or any reader of it would have appreciated why stability was achieved or the presence of glass. The only issue is whether what was described did in fact have the necessary stability and was in fact a glass. Just as it is no defence to infringement for the infringer to say that he did not know that he had the features of the claim in his product, so it is no answer to an allegation of anticipation that no one would have realised that the article or process described in or obtained from the prior art had the features of the claim.

  104. Mirroring the points made above in relation to obviousness, on the evidence what van de Beek describes is a product and a method of making a product which is a stable dry solid containing rennin and lactose or sucrose and in which enhanced storage stability against degradation is bestowed on the rennin. The product will be in an amorphous glassy form. Furthermore, the moisture level will necessarily be low enough to ensure that the product achieves the enhanced storage stability and is solid at the temperature at which it is to be kept. This means that it is extremely likely that the Tg of the composition will be 20 degrees C or above since the latter temperature is what, by convention, is normally taken to be room temperature and, at page 49, the document refers to storage at room temperature. However, I do not think that that is enough to demonstrate anticipation. Although it is extremely likely that van de Beek was describing a product which was in a glassy state at 20 degrees C, anticipation is dependent upon showing that van de Beek definitely made or described something falling within the claims. Something with a Tg of 19.5 degrees C would not do although that might have been enough for van de Beek to describe it as stable at room temperature. In the terminology of General Tire, van de Beek must be shown to have planted his flag at the precise destination before the patentee. That has not be proved. The teaching is a clear signpost, hence the finding of obviousness, but it does not anticipate.

  105. I can therefore turn to the case on inevitable result. As I have said, in relation to this issue experiments were performed. This has produced a very large amount of evidence. Inhale has identified every single difference between the description of the process and apparatus in van de Beek and that used in Quadrant’s experiments and argues that the latter are neither a repetition of van de Beek nor do they prove that a product within the claims of the Patent would inevitably be made. Each of the points taken by Inhale has been addressed by Quadrant. However it is not necessary to go through each of them because, for the reasons set out in the last preceding paragraph, it has not been proved that repetition of the teaching in the document would inevitably have produced something with a Tg above 20 degrees C. Once again, it is overwhelmingly likely that such a Tg would have been achieved, but that is not enough for the purpose of anticipation.

  106. There is only one factual issue in relation to the experiments which I should touch upon in view of the possibility of this case going further. One of the objections taken by Inhale was that the van de Beek experiment produced a black deposit in the spray dryer which demonstrated that it had not been conducted properly. This was asserted by Professor Kerkhof. There was a lively dispute on this issue. Quadrant produced oral evidence to the effect that there was no significant deposit and suggesting that what Professor Kerkhof claimed to have seen, if it existed, did not show that the experiment was run other than properly. It may have been an artefact created as a result of washing the equipment after the run had been completed. There were photographs of the inside of the dryer taken at the time of the repeat. Quadrant says that they do not show the presence of any significant deposit. Professor Kerkhof says that the photographs are not sufficiently clear to undermine his clear recollection, noted in his notebook at the time, that there was a deposit.

  107. If this point was to be taken, it was incumbent upon Inhale to take it as soon as possible. As Professor Kerkhof said, it would have been very easy to have taken a sample of the deposit immediately after it had been seen. It would then have been easy to analyse it to identify what it was and to draw conclusions as to how it was formed. This was not done. Professor Kerkhof told me that he notified members of his team immediately of his observation. Unfortunately no one mentioned this to Quadrant’s team at the time nor for many weeks thereafter. No suggestion was made to collect a sample. By the time the issue was raised, the possibility of obtaining a sample had disappeared and the parties were left to argue and speculate. In these circumstances I have come to the conclusion that Inhale has failed to prove that a deposit indicating incorrect operation was produced on the repeat of the van de Beek experiment.

    (d) Miyake

  108. Miyake is, in many respects, similar to van de Beek. It describes the creation of a stable solid product containing a pharmacologically active protein called cytochrome C. The author claims that he achieves stabilisation by dispersing the cytochrome C and coating it in "dried dextran in a solid form". Dextran is a sugar. The author says that his solid formulations maintain the activity of the cytochrome C over a long period. He explains that cytochrome C can be reduced due to oxygen or light in the atmosphere, that is to say it is subject to degradation. He then lists various ways in which this instability has been tackled in the past. He refers to the fact that aqueous solutions of cytochrome C have been stabilised by adding reducing agents, amino acids or proteins such as albumin.

  109. This confirms, and it was not in dispute, that cytochrome C in aqueous solution is unstable and needs additives to stop or slow down degradation. Miyake claims that his product maintains at least 90% of the cytochrome C activity over lengthy periods even under severe conditions and it includes an illustrative table showing the stability of the cytochrome C in his products over lengthy periods compared with its stability in the absence of the solid dextran coating.

  110. Two processes for making the protein/sugar product are described and exemplified. One involves freeze-drying a solution containing the two ingredients. Since the claims of the Patent exclude freeze-drying processes and products made by them, this part of Miyake can be ignored. The other process involves spray-drying such a solution.

  111. The arguments in relation to obviousness and anticipation are essentially the same as those discussed above in relation to van de Beek. Once again Inhale relies on the fact that the explanation given by Miyake for the protective effect of the dextran is the provision of a protective coating. It says that this is not the solution provided by the Patent which requires that the resulting composition be in the glassy amorphous state. It also relies on the fact that there is no reference to obtaining the glassy state or the significance of the glass transition temperature. For reasons already given, this does not address the issue of anticipation or obviousness.

  112. The evidence at the trial was that the Tg of dextran was between 150 degrees C and 200 degrees C. Again, if the product is a glass, the Tg must have been above 30 degrees C unless well over 10% water is present. For reasons already given, at the priority date any person skilled in the art would have ensured a moisture content of below 5% and, probably, in the 1% region. Again, for the same reasons as have been set out in relation to van de Beek, Miyake must have achieved the manufacture of a glass. There is no other explanation which has been proffered for the increased stability achieved. Extensive and compelling evidence on these subjects is given by Professor Lee who came to the conclusion that, when put into practice, a glass would have had to have been formed. I accept that evidence. For reasons which track those given in relation to van de Beek, all the claims fail for obviousness.

  113. No experiments were conducted in relation to this piece of prior art. Although he suggests that there is anticipation, Mr Carr does not appear to push the argument and rightly in my view. The process details in Miyake are not precise and there is no explicit claim to have produced a product which is solid at 20 degrees C. As with van de Beek, it is likely that the author had a product in a glassy state within the scope of the claims of the Patent but not inevitably so, nor is it shown that operating with such process details as are given would inevitably fall within the scope of the claims. Anticipation fails.

    (e) Ishida

  114. This is yet another document teaching the manufacture of a product which has storage stability. In this case the exemplified active ingredient is an enzyme which is used clinically for its anti-inflammatory effect, serrapeptidase. In this case the enzyme is stabilised by incorporating it into an aqueous solution of lactose, dextran, dextrin or mannitol. This is then spray dried to produce a solid substance which maintains quality and stability over a long period. The author states that the stability is achieved as a result of the "coating" of the protein with the carrier.

  115. The Tgs of lactose and dextran have already been discussed above. Professor Lee says, and it has not been disputed, that lactose, dextran, dextrin and mannitol are all glass forming substances. For the reasons given in relation to van de Beek and Miyake, it is highly likely that Ishida did produce glassy substances falling within the claim. Professors Lee and Pikal both expected a glass to be formed. However, notwithstanding the evidence produced and the experiments carried out, and with considerable misgivings, I have come to the conclusion that Quadrant have failed to prove anticipation. In this case there is a reason for coming to this conclusion additional to that referred to in relation to van de Beek and Miyake. The only protein exemplified as being protected by the Ishida process is serrapeptidase. There is no doubt that Ishida claims that he bestows on it long term storage stability. It is likely, because it is a biologically active protein, that it would be more unstable in aqueous solution at room temperature. However it is not proved that this is so. Mr Carr relies on the fact that most proteins are unstable in aqueous solutions and that Professor Pikal was not able to say from his own knowledge that serrapeptidase was storage stable in aqueous solution at room temperature. In my view this is not enough. The onus is on Quadrant to prove that serrapeptidase is unstable in aqueous solution at 20 degrees C and that stability is improved by following the Ishida process. This should have been an easy matter to prove, but it has failed to do so.

  116. For the reasons given in relation to the other prior art it would be obvious to a man skilled in the art to follow the teaching of Ishida and make a product with a low water content which would take the form of a glass. However, to the extent that following the instructions of Ishida would have involved making storage stable serrapeptidase, again it has not been proved that such a product would fall within the claims of the Patent because it is not proved that it has the necessary instability in aqueous solution at 20%. But that is not the end of the story. Ishida bears the title "a method of manufacturing stable serrapeptidase powder" and it concentrates on that protein. On its second page it describes the method of stabilisation it is promoting. There is points out that "enzymes such as serrapeptidase" are thought to be unstable when heated, Ishida has discovered that stability could be maintained "in the above enzymes" by the disclosed process. It seems to me that the teaching of Ishida goes beyond the stabilisation of serrapeptidase alone and would have been so read by a man skilled in the art. Since it promises long term storage stability, it is likely that a man skilled in the art in 1989 would have taken this as an encouragement to try the same process on other enzymes including those which are unstable in aqueous solutions at 20 degrees C. It will be recalled that the Patent itself confirms that only a few biologically active materials are stable enough to be stored in solution at room temperature (see paragraph 10 above). It follows that the findings of obviousness in relation to the other prior art applies similarly here. On this basis, Ishida invalidates all the claims in the Patent.

    (f) Roser

  117. This is the patent which was the subject of the action before Pumfrey J to which I have referred already. The Quadrant products and processes of which complaint is made in these proceedings are claimed to fall within its scope and to be made under its protection but no s. 64 point is taken. Although the arguments based on Roser largely follow those advanced in relation to the other prior art, it deserves to be looked at afresh because of the extent of its disclosure. In essence Mr Carr argues that it discloses the use of a particular sugar, trehalose, to stabilise labile molecules. The method for producing the stabilised products is said to be indistinguishable from the method used in the Patent in suit, namely drying a solution. Furthermore, although Roser admits that he does not know for certain why the trehalose stabilises the sensitive molecules, he suggests that the mechanism involves immobilising them. Mr Carr says that what Roser is doing is teaching the same thing as the Patent teaches to achieve the same result. The only difference is that the Patent identifies that the immobility is achieved by the presence of a glassy state, whereas Roser does not expressly identify that. But what Roser teaches falls within the scope of the Patent claims, whether or not Roser or anyone else appreciated that a glass is present. Against the background of these submissions, I can consider the detailed disclosure in Roser.

  118. The whole of Roser’s teaching is directed to making proteins and other macromolecules in the dry state. It is concerned to protect them during the drying process itself so as to generate products which have long term storage stability. To achieve this objective, it proposes and describes drying a variety of substances in the presence of trehalose, a sugar which is found in, amongst other things, the resurrection plant, bakers’ yeast and brine shrimps, life forms which are famous for being able to survive prolonged periods of extreme dehydration (bakers’ yeast can be purchased as a dry powder). The disclosure is supported by the description of 13 experiments carried out on different target molecules or macromolecules. Many of these are clearly unstable at room temperature in aqueous medium. For example, the author explains the application of his discovery to preserving a protein fraction, called complement, which is found in blood serum (pp 6-7);

    Serum itself contains about 70—75 mg/rnl of proteins of which only about 2 mg/ml comprise the complement fraction. Serum containing complement (or a purified complement fraction derived from it) cannot be dried, it has to be stored under very low temperature conditions (—70 degrees  to 196 degrees C). It can be lyophylised, but even this technique destroys some of the activity. Thus, for example, lyophylised complement cannot be used in lymphocyte cytotoxicity assays. Most surprisingly, we find that complement can be completely preserved according to the present invention by drying in air at room temperature. The dried material can be stored at, say, 37 degrees C for weeks and can be reconstituted with its activity retained.

  119. Similarly the author says (at p 9) that his technique can be applied to vaccines. He says that previously these had to be stored "under cool, hydrated conditions, or under deep freeze conditions" but, by using his process, dried vaccines are possible. This indicates that in the wet state, the vaccines tend to denature, hence the requirement for storage under cool conditions or frozen.

  120. A particularly interesting description of the efficacy of Roser’s technique is given in relation to a type of protein called R Phycoerythrin. He says as follows (pp 11 and 12):

    R Phycoerythrin is a phycobiliprotein which .... is brilliantly fluorescent .... Its bright fluorescence and high quantum yield are dependent upon the spatial distribution and configuration of the phycourobilin and phycoerythrobilirin chromophores in the molecule ....

    A serious drawback to the use of this reagent is its susceptibility to fluorescence fading in aqueous solution This gives the fluorescence a very short half life. It is thought to be due to damage to the phycoerythrin molecule due to the creation of free radicals in the aqueous solvent when illuminated with the exciting wavelength for fluorescence. Drying the molecule prevents creation of free radicals and therefore the fading but destroys more than 90% of the fluorescence because the three dimensional structure of this large protein (240 Kd), upon which its fluorescent properties depend, collapses when dried.

    We have found that this molecule can be dried completely in the presence of trehalose without loss of its fluorescent properties. This means that this protein can now be used in assays which require prolonged or repeated exposure to high intensities of exciting light without fading and with complete retention of its intense fluorescence. Fading can be reestablished by washing away the trehalose and irradiating the molecule in an aqueous solvent.

  121. This is describing a protein which is highly labile in aqueous solution but which can be dried and then rendered stable. This general statement is supported by four of the examples. Example 1 shows how the protein can be protected from denaturation during the drying process. To this end it is dried with and without trehalose. In the latter case, unlike the former, it retained its ability to fluoresce (i e it was not denatured) even though "it was completely dry" (p 15). The drying process is not described. Example 6 also relates to R Phycoerythrin. In this case it is said that the protein was dried at 37 degrees C on filter paper. In the absence of trehalose, more than 90% of the ability to fluoresce was lost, whereas it was not lost in the presence of trehalose. Furthermore the trehalose containing product was stored for 10 months without losing fluorescence, that is to say it achieved long term stability. Example 7 also uses R Phycoerythrin. In this case, a wet but non-trehalose containing sample lost its ability to fluoresce within 30 seconds. A preparation containing trehalose and dried at room temperature did not lose any significant ability to fluoresce over a period of 3 days.

  122. The final R Phycoerythrin example, is example 8. This is concerned with the use of the protein as a marker in a process known as fluorescence microscopy. Again the author points out that this is inefficient because the fluorescence of the protein fades "in aqueous mountants", that is to say in an aqueous medium. However drying with trehalose "preserves virtually all of the fluorescence intensity" and this is preserved "for prolonged periods". The extent of the difference is marked. The wet sample without trehalose lost most of its fluorescence within 20 to 30 seconds, but the sample dried with trehalose retained its fluorescence without detectable fading over several weeks. This example is followed by a passage of general teaching (p 29):

    Thus trehalose preserves completely several widely divergent and very labile properties of protein molecules even when they are completely dried. These properties (fluorescence and antigen binding) depend completely on the preservation of an intact tertiary structure of the molecules.

    This phenomenon means that the functions and structures of proteins can now be completely preserved in the dry state. Thus proteins of scientific or medical interest can be preserved without the requirements for freezing or freeze-drying.

  123. Roser does not contain an extensive description of the drying techniques to be used. In an introductory passage he says (p 5):

    The drying process may be achieved by simple air drying of aqueous systems containing the protein and trehalose on a suitable surface, e.g a glass or plastic plate, or dish, a film of plastic or nitrocellulose or a porous support such as a paper. The drying is preferably at atmospheric pressure.

  124. The drying regimes contemplated include drying at 37 degrees C (many of the examples), at any convenient ambient temperature (p 12) or under a stream of dry air at room temperature overnight (example 10). In all cases the product is said to be dry or completely dry. In addition, as indicated above, Roser says that his products can be stored for lengthy periods. This includes storage "at, say, 37 degrees C for weeks" (p 7), "at room temperature indefinitely" and "at 37 degrees C for 2 months" (both example 3) or for 7 days or various periods at 37 degrees C (example 5).

  125. Finally, Roser offers a suggestion as to how his results are achieved. Although he does not state that a glass has been formed, it is apparent that he thinks that the target molecules are effectively frozen so as to be immobile. This appears from the following paragraphs (p 13);

    While we do not wish to be bound by theory, it seems likely that the unique properties of trehalose in preserving the structure and function of proteins and other macromolecules in the dry state is due to hydrogen bonding of trehalose molecules via their hydroxyl groups to appropriate groups on the macromolecule. In this way trehalose takes the place of structural (bound) water molecules so that there is no collapse of macromolecular structure upon drying. The trehalose acts as a dry scaffold maintaining the structural integrity of the macromolecule.

    Many macromolecular functions require mobility of the macromolecule e g antibodies have to physically move into close proximity to their antigen in order for binding to occur through electrostatic and hydrophobic interactions. The same is true of enzymes binding their substrates. Minor molecular motion is also required for other macromolecular functions. Thus haemoglobin undergoes rotation and movement of certain amino acids during the reversible binding of oxygen and carbon dioxide. None of this molecular mobility is observed in the dry state. Thus we have dried haemoglobin in the oxy and carboxy forms, and these molecules retain their spectral properties when dried in the presence of trehalose.

  126. Professor Mackenzie’s evidence was that this piece of prior art discloses products and processes covered by the Patent in suit and that the latter "merely provides an explanation for the effect which Dr. Roser had observed and patented". He also said (First report paragraph 88):

    Although Dr Roser did not mention glass formation, the fact that a glass had been formed .... was evident to me when I first saw a copy of Roser in 1989.

  127. This passage was not challenged. I have no reason to doubt its accuracy. Professor Mackenzie remained firmly of the view that Roser had fairly planted his flag in the middle of the territory claimed in Inhale’s patent, even if he did not use the same language. His evidence was that the products disclosed in the Roser document would have exhibited the necessary glassy structure and Tg and that operating the processes described in it to achieve the stability Roser promises would inevitably have produced product and processes within the claims. Consistent with this, he also said that it would have been obvious to implement its teaching in a way which would have resulted in the production of products within the claims of the Patent.

  128. Professor Pikal’s written evidence in relation to this disclosure is interesting more for what it does not say, than what it does. In his first report, he comments that there is no discussion with regard to keeping the trehalose / protein composition in a "glassy state" or with regard to measuring the Tg of the composition, or that the Tg should be above room temperature (or the temperature at which the material is to be stored). From this he goes on to say that it does not disclose the invention but suggests an alternative solution to the problem. Interestingly he says nothing about whether or not the products and processes in Roser in fact are the same as those covered by the Patent. Nor does he address the issue of obviousness. In his second report he says, amongst other things, the following (Second Report paragraph 5.2);

    [In relation to Roser, Wallerstein and Epstein] I do agree with Professor MacKenzie that in most if not all cases it is possible that glassy composition might have been produced. Moreover, one can say that it is more likely in some cases than in others. In particular, it is more likely that a glassy composition would be produced if the prior art document uses a carrier that has a high Tg than if the prior art document uses a carrier that has a low Tg. Thus one can say that, disregarding all other factors, it is more likely that a glassy composition would be produced by a skilled person seeking to reproduce Wallerstein, Miyake, Ishida and Roser, which employ carriers with relatively high Tg such as lactose, dextran and trehalose than it would be a person seeking to reproduce van de Beek, where sucrose which has a lower Tg is used, and least likely that it would be by a person seeking to reproduce Epstein, since sorbitol has the lowest Tg of any of the carriers I have mentioned.

  129. This evidence was refined, or its emphasis shifted, under cross-examination. The Professor was asked what his view was now, rather than in 1989, of what Roser was producing. His evidence was (Transcript p 176):

    A

    OK. What I would guess now is that the most probable explanation would be that you did indeed form a glassy system. I use the term probability because what we do not know is what the level of instability of this particular preparation really was in solution or in fact how precise the assay is and are we going to have ambiguous results due to, let us say, fluctuations in assay? So there are some caveats, but my expectation would be that it probably .... It was stable because it was a glass, again with some possible reservations, but ----

    Q

    I understand. Indeed, a glass with a Tg of above 20 degrees C?

    A

    Correct.

    Q

    And a glass indeed with a Tg of above 30 degrees C?

    A

    Correct.

  130. Mr Carr then took the point further (Transcript p 177-8);

    Q

    .... Do you remember we have discussed, let me ask you again, the object, there is a loft examples in Roser, of each of them is to dry in the presence of trehalose in order to stabilize unstable materials?

    A

    Correct.

    Q

    And bearing in mind we are talking about trehalose with various different proteins, that effect, stabilizing unstable materials, bearing in mind what you know now, can only happen as a result of formation of glassy compositions.

    A

    The statement is too strong.

    Q

    Right.

    A

    I cannot agree with it the way you have stated it.

    Q

    Perhaps you would like to express it in your own terms. If you say it is too strong ----

    A

    I would say that this whole concept of stabilization by immobilization in a glass is a very valuable and useful concept, and it is what I regard as a first order approximation. What we have learned over the years, what we are still learning, is that the situation is actually a bit more complex than that. There is the possibility of other mechanisms having some importance which do not necessarily have anything directly to do with the formation of the glass. I would perhaps use the word "probable" here rather than the certainty that you have implied.

  131. By this evidence I understood the Professor to be accepting that glass was formed. His argument was that a full scientific explanation of what was going on might involved additional concepts. Mr Carr’s fly-in-amber analogy might be too simple.

  132. Even if this evidence is ignored, most of the Professor’s reluctance to accept that glasses were present in the Roser products appears to have centered on a vestigial concern that Roser may not have dried his products enough. If the residual moisture level in those products was about 10%, then it was possible that glasses with Tgs above 20 degrees C might not have been formed. I must confess that I found this part of the Professor’s evidence difficult to accept. Roser refers to his product being completely dry. Furthermore if, as Professor Pikal suggests as an outside possibility, there was so much moisture present that the Tg would have been below 20 degrees C, the products would have failed to exhibit storage stability because it is the immobilisation of the molecules which prevents degradation and above the Tg of the composition they are not immobile. In relation to this, it must be remembered that Roser expressly describes products which are dried and stored at 37 degrees C for weeks or months without loss of activity.

  133. It may be that Professor Pikal’s hesitation to accept what the Roser patent says about dryness or whether it is describing products which were in a glassy state is attributable to the fact that he knew the author personally and had views as to his abilities and understanding as a result of conversations with him. For example, in relation to the issue of dryness, he said under cross-examination (Transcript p 184):

    Roser by his own admission, was not a particularly astute physical scientist. He was not necessarily an individual who would come up with well-engineered drying processes.

    and in relation to whether a glassy compound was produced he said (Transcript p 175):

    Q

    If in the system we have just looked at the antibodies after drying in the presence of trehalose could be stored at 37 degrees C for two months without loss of activity, that would be as a result of glass formation, would it not?

    A

    Not necessarily because Roser in fact claims that trehalose has unique properties and really does not mention glasses. If I really believe everything Roser says in the patent here, and in fact as well as believe what he told me personally a number of years ago during this time period, I would conclude that the stability had nothing whatsoever to do with glass formation, but rather had to do with the unique, almost magical properties of the molecule trehalose.

  134. In any event, Mr Carr put to the Professor the passage in Roser concerning the mobility of molecules (see paragraph 11 above) and then proceeded (Transcript pp 188-189);

    Q

    The Inhale patent teaches that glass formation results in immobility and immobility achieves storage stability. Correct?

    A

    Yes.

    Q

    Assume with me for a moment that the passage I have just read to you is in fact saying that if you dry in the presence of trehalose, the result is molecular immobility. Applying your knowledge, that molecular immobility must have been as a result of glass formation, must it not?

    A

    With your premise, I think so, yes.

  135. In my view Mr Carr is correct in his submission that, although the terminology is different, what Roser describes are products which have the necessary glassy structure and Tgs to fall within the product claims of the Patent. They are therefore anticipated. Furthermore if that is so, the process claims, with the exception of claim 11, also fail for anticipation. As far as the latter claim is concerned, although there is no express example of use of sub-atmospheric pressure, Roser does say that drying is "preferably at atmospheric pressure". Inherent in this is the suggestion that it is possible to use sub-atmospheric pressure. Claim 11 would fail for obviousness for that reason and for the reasons set out at paragraph 66 et seq above.

  136. Finally, even were Inhale to overcome the attack of anticipation, all the claims would fail for obviousness. The only serious argument against the submission that it would be obvious to follow the teaching of Roser in a way which would have created compounds within the scope of the Patent claims is that the moisture level might not have been kept low enough by Roser, and therefore by anyone following his teaching. On this point the evidence and logic all point one way. Roser keeps telling his reader to make the product dry or completely dry. It would have been clear to any person skilled in that art that this encouraged the use of very low moisture levels and, in particular, levels much below 10%. As Professor Pikal put it, for most proteins, the drier the better. That was the obvious thing to do and it would produce compounds within the claims of the Patent.

    (g) Townsend and DeLuca

  137. This is concerned with making freeze-dried stabilised products. Since the proposed amendments to the claims of the Patent exclude freeze-drying and freeze-dried products and this case has proceeded on the basis of the claims in that form, this disclosure is irrelevant. Mr Carr made it clear that he only kept this document in the case against the possibility that Inhale might abandon or be forced to abandon its proposed amendments. He does not assert an obviousness case based upon this disclosure. In these circumstances it is not necessary to consider this further.

    (h) Burke

  138. This document is only relied on in support of an obviousness attack. It is an Appendix in a publication entitled "Membranes, Metabolisms and Dry Organisms". Consistent with this its teaching is directed at issues of biology and living cells. This is emphasised in its own title "The Glassy State and Survival of Anhydrous Biological Systems". It contains two statements upon which Mr Carr relies. On the first page the author states;

    Glasses are exceedingly viscous and should stop all chemical reactions that require molecular diffusion. In so doing they may assure dormancy and stability over time.

  139. Secondly, towards the end, under a heading "Glasses and protection from severe dehydration" the author says:

    Some sugars that form high-temperature aqueous glasses can replace "bound" water and protect macromolecules, and membranes from denaturation (chapter 11). These include trehalose, sorbitol, fructose, sucrose and glucose, all of which form high-temperature aqueous glasses, some stable up to 90 degrees C. As such they may stabilize hydrophobic bonding, prevent salting out, and attenuate adverse effects of pH changes. In addition, reduced diffusion of even small molecules in a glass at warm temperatures (50 degrees C) must stop essentially all chemical reactions and ensure complete dormancy. Finally, glasses have no thermal transitions below Tg and thereby could provide protection from temperatures between 0 degrees K and +90 degrees C.

  140. Taken out of context, and looking back from the a knowledge of the importance of glass formation in the stabilisation of isolated molecules, these passages look impressive. But I am not persuaded that they would have inspired the imagination of a notional skilled but uninventive man in the art at the priority date. Burke’s teaching is directed to living systems. That is why in the first extract above he talks of ‘dormancy’ and why the heading to the second refers to protection from severe hydration. Many other passages in the document also emphasise Burke’s interest in how living organisms survive in arid conditions. There is nothing in this article which suggests to a skilled reader who is looking for a way of making proteins and other macromolecules stable enough to withstand storage that it has an answer. As mentioned above, the skilled man comes to the prior art without the knowledge or a suspicion that it is of significance to the problems he has to deal with. In some cases its very terms may be such as to excite hopes of a lead. In others it may be perceived as irrelevant. The Burke article falls into the latter category. None of the claims are invalid over it.

    COMMON GENERAL KNOWLEDGE

  141. Mr Carr also argues that the claims in the Patent are invalid in the light of common general knowledge. This was, in large part, dependent on Professor Mackenzie’s evidence that it was well known to all in the art at the priority date that in existing stabilised dry systems, the sugar carriers were present as glasses and that it was this which bestowed resistance to degradation on the product. It is in relation to this issue in particular that Mr Waugh most strongly criticized the Professor. As I have said, I do not accept that the Professor was trying to mislead the court. However I do accept that he may well see the underlying technology with a greater clarity now than would have been the case in 1989. In any event, I am not persuaded that his realisation of the presence and function of glasses in the preparation of stable compounds reflects what would have been common general knowledge at the priority date. This argument fails.

  142. This then only leaves the issues of insufficiency, infringement and amendment. They can be disposed of briefly.

  143. Insufficiency is only raised as a squeeze. The primary argument is that there is difficulty in knowing what the Tg of a composition is because of defects in the known DSC technology. This fails on the facts. It is clear that all in the art knew and know what a glass transition temperature is. The fact that it may be an imprecise figure and difficult to measure does not detract from the fact that it is well understood and a recognised and defining characteristic of a glass. The imprecision of the claim is not a fault of the patentee but a reflection of the imprecision of the physical phenomenon to which the invention is tied.

  144. The objection in relation to amendment of the claims is that they should not be allowed because they do not cure invalidity. That point succeeds but adds nothing to the findings of anticipation and obviousness above.

  145. As far as infringement is concerned, only two points of substance arise.

    • First, it is said that Quadrant’s products which do not utilise proteins in solution can not infringe. Since I have held that the claims are limited to cases where the target molecule is in solution, this defence succeeds.

    • Second, it is said that there is a defence of experimental use. This fails on the facts. None of the exploitation of the products or technology complained of was conducted by Quadrant for its own experimental purposes. In all cases Quadrant was trying to exploit and sell its technology to third parties. This is not experimental use.

  146. For the reasons set out above, I find the Patent invalid.


Cases

Quadrant Holdings Cambridge Ltd v. Quadrant Research Foundation (27 November 1998); General Tire & Rubber v. Firestone Tyre and Rubber [1972] RPC 457; Evans Medical Ltd’s Patent [1998] RPC 517; Hallen v Brabantia [1989] RPC 307; Lilly-Icos v Pfizer

Authors and other references

US Patent 1 855 591 ("Wallerstein") published on 26 April 1932.

US Patent No. 2 457 036 ("Epstein") published on 21 December 1948

"Preservation of the enzymatic activity of Rennin during spray drying and during storage, and the effect of sugars and certain other additives" by M J van de Beek and S Y Gerlsma ("van de Beek") published on pages 46-54 of Neth. Milk Dairy J. 23 (1969).

Laid-open Patent Application No. JP-S-57-21315 ("Miyake") published on 4 February 1982.

Laid-open Patent Application No. JP-A-60/244288 ("Ishida") published on 4 December 1985.

PCT Application No. WO 87/00196 ("Roser") published on 15 January 1987.

"Use of lyoprotectants in the freeze-drying of a model protein Ribonuclease A" by M W Townsend and P P DeLuca ("Townsend and DeLuca") published on pages 190-199 of the Journal of Parenteral Science and Technology Vol. 42 No 6 (1988).

"The glassy state and survival of anhydrous biological systems" by M J Burke ("Burke") published on pages 358-363 of "Membranes, metabolism and dry organisms" (1986) ed C Leopold.

Representations

Mr Andrew Waugh QC and Mr Richard Arnold QC (instructed by

Simmons & Simmons for the Claimant)

Mr Henry Carr QC and Mr Piers Acland (instructed by Bristows for the Defendant)


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