Asahi Medical Co Ltd v Macopharma (UK) Ltd [CAEW]

www.ipsofactoJ.com/international/index.htm [2003] Part 1 Case 2 [CAEW]

Coram

Asahi Medical Co Ltd

- vs -

Macopharma (UK) Ltd

LORD JUSTICE ALDOUS

LORD JUSTICE TUCKEY

LORD JUSTICE JONATHAN PARKER

16 APRIL 2002

Background

(i) Blood and its components

As its title indicates, the patent is concerned with apparatus used in connection with blood transfusion services. Blood is a complex product. For many purposes it is convenient to consider it to be made up of four types of component as follows; First there are red blood cells, or “erythrocytes”. They contain a protein called haemoglobin which enables them to carry oxygen from the lungs to all parts of the body. Second, there are white blood cells, or “leukocytes”. This is a mixture of cells known as neutrophils, lymphocytes, monocytes, eosinphils and basophils. They all play major parts in the body’s defence mechanism against viral and bacterial infection. The third component consists of small cells called “platelets”. Their principal function is to work in conjunction with blood clotting factors to plug small gaps in blood vessels and prevent bleeding. The fourth component consists of “plasma”. It is a pale yellowish liquid used to carry the first 3 types of components. It comprises a number of electrolytes and proteins and it transports blood cells to where they are needed, transports other key chemical substances around the body and regulates the balance in the blood between acidity and alkalinity.

(ii) Transfusion of blood and its components

Originally, all blood collected from donors was transfused in an unmodified state into recipients. This is known as whole blood transfusion. This still accounts for about 5% of transfusions in developed countries. During World War II, large-scale fractionation of plasma was initiated and was further enabled by the introduction of plastic bags. From then on there was general agreement that the efficient and economical use of blood implies that patients be transfused only with the specific components of blood required. The result has been that most transfusions over at least the last two decades have been of components rather than whole blood. Transfusions of red cells are used to help patients lacking haemoglobin due to blood loss or depressed bone marrow function (where most red blood cells in the adult are made). When used in this manner, the red cells are packed together and are known as red cell concentrates or “RCC”. Platelets are given to patients where there is depressed bone marrow function due to haematological diseases or cancer treatment. As plasma contains the essential clotting factors, plasma transfusions are given to patients such as haemophiliacs with clotting factor deficiencies. Plasma has also been used to make clotting factors for administration to such patients. Finally, leukocytes have been transfused into patients with depressed bone marrow function and overwhelming bacterial infection. However this is exceptional. For reasons explained below, there are well recognised advantages in excluding leucocytes from blood components to be transfused.

(ii) Methods of separating blood into its components

5.	Because the various components within blood have different densities, they will tend to sediment out if left standing for long enough, assuming that an anti-coagulating agent is present to prevent clotting. However although this is a cheap method of separation it is slow and inefficient in that it does not divide the components from each other very well. From at least the 1950’s, the major method for separation has consisted of various forms of centrifugation. The blood is put in a centrifuge and spun. The most dense components will be forced to the bottom of the centrifugation vessel while the less dense will lie above them. In fact two types of centrifugation were conventionally employed. The first, less vigorous than the second, is called soft centrifugation. It produces two components. The bottom one is rich in red blood cells. It is RCC. It contains leucocytes as well. The top layer contains plasma, platelets and leucocytes it is called platelet rich plasma or “PRP”. The second method is referred to as hard centrifugation. It results in the production of three layers. Once again the bottom layer is RCC. The top layer is cell free plasma. In between is another layer, called the “buffy coat”, consisting mainly of white blood cells and platelets.
6.	Well before the priority date it had become conventional to collect blood in plastic bags. The centrifugal separation referred to above could be achieved conveniently by centrifuging the bag in which the whole blood had been collected. Where soft centrifugation was used, the contents of the bag would contain the two layers described above. The top layer, the PRP containing platelets and plasma (and leucocytes) could then be expressed into what was called a “satellite bag” connected to the main bag. In fact the satellite bag could then itself be centrifuged so as to create a bottom layer of platelet concentrate (“PC”) and an upper layer of plasma. Again the plasma could be syphoned off into another satellite bag. This sequence is illustrated in the following drawing in which (1) is the main bag and (2) and (3) are satellite bags. During centrifugation, the connecting tubes between bags can be sealed. They are opened when contents have to be passed from one bag to another: Figure 1:
7.	The hard centrifuge method only requires one centrifugation stage. One convenient way of putting it into operation is called the bottom and top method (“BAT”). In this case the main bag has two satellite bags connected to it, one at the top and one at the bottom. After centrifugation, the plasma and the RCC can be passed to different bags. This is illustrated below: Figure 2:
8.	In practice, frequently more satellite bags are used than this. For example, if most of the plasma is removed from the RCC, the resulting mass of red cells will be quite ‘sticky’. It is therefore normal to add what is called an optimal additive solution (such as SAG-M - a water solution of saline, adenine, glucose and mannitol) to the red cells. This performs two functions. First it supplies nutrition to the red cells thereby ensuring their viability during storage. Second, it provides a fluid to give the cell suspension a sufficiently low viscosity for easy flow at a transfusion. Therefore the type of arrangement illustrated in Figure 2 might well have an additional satellite bag attached, as illustrated below:
9.	Another method used for separating out some of the components of blood consists of a technique known as apheresis. This may be thought of as an in situ form of centrifugation. The donor’s or patient’s blood is collected through a needle and immediately mixed with simultaneously flowing anticoagulant. The blood is passed through a machine in an integral vein to vein extracorporeal (outside the body) circuit which subjects the blood to a centrifugation. This separates the blood into its component parts. The platelets and plasma can be taken off and the remaining blood components are immediately returned to the donor.
10.	There are and were other, non-centrifugal, methods of separating blood components. Of particular importance to this case is the use of filters. However in relation to this technique, there appears to be no dispute of substance between the parties. As Dr. Pietersz stated in her expert report: “The removal of leukocytes from blood by the use of a nylon wool filter was first described in 1962. These experiments were done in test tubes. In the early 1970s Fenwal developed a filter for whole blood made of nylon (Leukopak). Later filters were developed using first cotton wool and subsequently the cotton wool was replaced by cellulose acetate. This cellulose acetate filter was first marketed by [the Central Laboratory of the Netherlands Red Cross Blood Transfusion Service] around 1975 as Cellselect in the Netherlands and internationally as Erypur (by Organon Teknika, The Netherlands). In 1978 another filter (Imugard-IG 500, Terumo, Japan), made of cotton wool, was marketed. These filters could be used either at the bedside by placing them in the transfusion set or in the blood bank. The filters were expensive but compared to other leukocyte-removing methods highly effective and easy to perform. Both filters consisted of a hard column filled with the filter material (and could be manufactured with connected tubing and bags). Because the volume of the column was 20 to 30 ml about 10 to 15% of the red cells were lost in the filter. Rinsing the filter with an isotonic solution reduced this loss. The filters could be used for whole blood, but generally only red cell concentrates were filtered, and only for a selected group of patients.”
11.	Much the same thing is said by Asahi. For example, Mr. Thorley’s opening skeleton argument states that the removal of leukocytes by filtering was well known, and it was usually the centrifuged components which were filtered. Filtration to remove leucocytes was known at least as far back as 1962.
12.	Finally, there were other techniques for separating red blood cells from leucocytes. In particular, there were processes which involved the manual or automated washing of the red cells with the aid of a blood cell separator and there were also freeze thawing processes. However these were of variable efficiency and cost. Dr Pietersz says that the most effective were also more laborious and expensive. They were all carried out in an open system (as to which, see below).

(iii) Storage of blood components - open and closed systems

13.	Blood taken from a donor will tend to coagulate rapidly unless it is mixed with an anticoagulant. The use of such agents has been common for very many years, but even anti-coagulated blood has a limited shelf life. Obviously there are strong incentives to ensure that blood and its components can be kept in a useable state for as long as possible. Any of this material which is not used before the expiry of its shelf life must be thrown away. The process of taking blood from a donor involves puncturing the donor’s skin with a cannula. This involves some risk of bacteria entering the blood being collected. For this reason, the process of taking blood is carried out in as sterile conditions as possible. Whole blood which has been collected in this manner and is kept under suitable sterile conditions may be useable, at least as a source of viable red cells, for up to three weeks. When a pre-prepared bag of a substance for transfusion, such as blood, saline and the like, is to be connected to another piece of equipment, for example in a hospital, this is usually done by use of plastic tubing. At the end of the tubing there is a needle or “spike” which is pushed into the container or device to which it is making a connection. This breaks the sterile seal of the perforated container and there is then an increased risk of bacteria entering the previously sterile interior of the container. Any system of storing or handling blood or its components where there is interconnection by spikes creates such a risk of outside bacterial contamination and is said to be “open”. There are well established rules of practice which require blood or components to be administered to a recipient within a few hours once the system becomes open.
14.	To ensure that blood or its components can be stored for longer periods, they have to be handled in what are called “closed” systems. That means systems where there is no risk of bacterial contamination (other than that inherent in inserting a cannula in the donor and, on transfusion, in the recipient). If blood is separated into components in a closed system, the permissible shelf life of each of them is increased. No longer is it necessary to use them within 24 hours or so. Thus RCC transfusions made in a closed system and kept at an appropriate temperature have a shelf life of about 6 weeks. Similarly platelets from a closed system have a shelf life of 5 days while plasma can be frozen and then has a shelf life of a year. It follows that if blood components are to be stored they must be separated and kept in closed equipment.
15.	For many years, manufacturers have sold pre-assembled (i.e. closed and pre-sterilised) blood bag sets to be used at the donation site to take blood from a donor. These bags are constructed so as to correspond to the methodology to be used for preparing the components: e.g. they have built-in needles, satellite bags for separation, allow for addition of anticoagulant and red cell preservative and have sealable and cuttable tubing. Thus various bag configurations are made available in closed condition. The bag manufacturers make pre-assembled bag sets in accordance with the functional requirements asked of them.
16.	While on the subject of the manufacture of sterile blood handling systems, I should mention the Sterile Connection Device (“SCD”). This was manufactured by DuPont and made available in 1986 or 1987. It enabled anyone to make a sterile connection between two pieces of plastic tubing. For example, if a blood bank had a bag filled with blood, it could make up the bag set illustrated in Figure 1 by joining it to separate sterile bags (2) and (3). Prior to this, interconnection of bags at the site of use would have involved using spikes to puncture sterile seals on the bags. That would have led to the equipment becoming open. With the arrival of SCD it was no longer necessary to ask a manufacturer to make up a pre-assembled sterile bag set. It could be done on site when required. There is little doubt that some in the art learned of SCDs before the priority date. I suspect that all bag manufacturers would have been aware of them before that time. However no evidence was called from anyone in the bag manufacturing industry. As far as potential users were concerned, Dr. Pamphilon accepted that SCDs and their trade literature were available on the market before the priority date. What he and Dr. Pietersz were unable to say was that these devices were common general knowledge. On the evidence before me it has not been proved that they were.

(iv) Problems with the transfusion of blood or components containing leucocytes.

17.	As Dr. Pamphilon states, by the priority date it was recognised that there was a need in some cases for blood and blood components to be “leukocyte depleted”, that is to say, have a reduced white cell content. As he puts it, this has arisen because of the adverse effects which have long been known to be associated with transfusion of leucocytes. They were certainly well recognised by 1988. Dr. Pamphilon describes these adverse effects. They include the following. First there are what are called febrile transfusion reactions. They were described as early as the mid 1950s. When white cells are included within a transfusion, the recipient can suffer from increases in temperature, shivering, headache and a feeling of general malaise. The mechanism which caused these adverse symptoms was not fully understood in the 1980s. The second involved passing on transmissible diseases in leucocytes. Dr. Pamphilon explains this as follows: There are a number of infectious agents, particularly viruses such as human immunodeficiency virus (HIV)-1, Hepatitis B virus (HBV), Hepatitis C virus (HCV), cytomegalovirus (CMV) and human T-cell leukaemia/lymphoma virus (HTLV)-1, that may be transmitted via transfused blood and blood components. Some of these agents are present in white cells, particularly CMV and HTLV-1. There was enthusiasm for developing protocols for white cell depletion of blood and blood components for transfusion to prevent viral infections. A report in 1984 by Okochi indicated that whilst 69% of patients who received blood from donors who had been infected with the HTLV-1 virus as evidenced by the presence of antibodies to the virus (i.e. anti-HTLV-1) that became themselves infected with the virus, none of 52 recipients of plasma stored frozen and then thawed prior to infusion did so. The process of freezing and thawing plasma disrupts and destroys leucocytes and since the HTLV virus lives in leucocytes it was inferred that such disruption would prevent it from being transfused. This report would have been widely known at the time of its publication. Subsequently when red cell concentrates were filtered using a newly developed filter containing polyester fibres (Sepacell R500, Asahi) leucocyte removal was 96.1 - 99.9% and lymphocytes present in the filtrate of blood from HTLV-1 carriers did not survive more than 3 days in culture. On the basis of these findings, it was thought at the time (1988) that filtration would prevent HTLV-1 transmission. … At the same time it had been shown that washing red cells to remove approximately 90% of the leucocyte content or transfusion of frozen and thawed red cells, which removes 94 - 98% of the leucocytes, prevented CMV infection in neonates, and renal dialysis and bone marrow transplant patients. This led to a belief that since CMV was predominantly contained within white cells, their removal would be clinically useful in prevention of CMV transmission. … it is still accepted practice to remove leucocytes from blood and blood components as an effective way of preventing CMV infection…
18.	Third, it is and was believed that transfusion of blood components containing significant quantities of white cells could cause immunosuppression, that is to say a reduction in the ability of the recipient to fight infection.
19.	The fourth, and potentially most important, adverse effect is referred to as alloimmunisation. When a recipient receives a series of transfusions containing white cells, his own immune system will learn to recognise some of the proteins on them to be allogenic (i.e. foreign). These proteins are called human leucocyte antigens (HLA). The recipient will build up antibodies to these proteins with the result that the immune system will attack and destroy subsequent incoming white cells. Platelets in the incoming transfusion also carry HLA. Apparently, if platelets are transfused by themselves, they will not induce the production of anti-HLA antibodies in the recipient. Presumably this is because in such cases the amount of HLA present is too small, that is to say it is below the immunogenic dose. However if sufficient leucocytes are present an anti-HLA immune response is triggered and this will result in the recipient’s immune system attacking and destroying both incoming white cells and platelets. This is clinically significant as Dr. Pietersz explains: In blood transfusion, which is a special case of transplantation, it became obvious that the reason why 80-90% of patients with leukaemia, and who frequently needed transfusions with red cell and platelet suspensions, developed HLA antibodies was because the blood products contained leukocytes. This was disastrous for the supportive therapy with platelets necessary during the bone marrow dip. Platelets have HLA groups attached and are destroyed within a few minutes when they enter the blood stream of patients with HLA antibodies (as these antibodies attack the HLA groups on the platelets). These patients are called refractory to platelet transfusions; they cannot be treated with chemotherapy any more and their cause of death is often bleeding. This could only be avoided by ensuring the blood products given to them were either HLA compatible or leukocyte- depleted. To match donor and patient for HLA is labour intensive and very costly, therefore it was not (and still is not) done routinely prior to each blood transfusion. The best way to prevent HLA antibody formation in patients with haematological diseases or in organ transplant candidates is instead to transfuse leukocyte depleted blood products, from which leukocytes should be removed to below a critical immunogenic dose.
20.	The methods of reducing the number of leucocytes in blood or its components have been touched upon above. They include the use of filters, hard spinning to create a buffy coat, washing and freeze thawing. As mentioned, leucocytes in plasma are destroyed by freezing.

The present invention relates to a method for separating blood into blood components aseptically in a closed system which is useful for separately collecting leukocyte-removed blood components, particularly leukocyte-removed erythrocytes, leukocyte-removed plasma, leukocyte-removed platelets etc from the whole blood of a healthy human. The present invention is also concerned with a blood components separator unit, which can advantageously be used in practice of the above-mentioned method.

The present inventors have made extensive and intensive studies with a view toward developing a method and a unit for separating blood into blood components aseptically, which are free from the above-mentioned drawbacks. As a result, it has been found that when whole blood is first filtered by filter means for removing leukocytes to collect the leukocyte-removed blood in a primary bag and the primary bag is then aseptically disconnected from the filter means and subjected to centrifugation. Blood components, such as plasma, erythrocytes and platelets in leukocytes-free form can be aseptically and readily obtained without the danger of damage to the filter means and the primary bag. Based on the above-mentioned finding, the present invention has been completed.

21.	The patent is quite a lengthy document. However its core teaching is simple to understand. It can be explained by reference to its first drawing which is set out below:
22.	In this arrangement all the connections are by cuttable and sealable tubing. In other words it is a closed system. Blood is collected directly from the donor into the collector bag (1). It is then passed through a filter (2). The filter can either be a filter which filters out leucocytes only or one which filters out leucocytes and platelets. The leucodepleted blood then passes into primary bag (3) which is described in the specification as the primary bag. The connection to the filter (2) can then be sealed and aseptically separated. The remaining bags are centrifuged so that the contents of primary bag (3) are separated into discrete fractions. The top fraction can then be passed to satellite bag (4). Again the interconnecting tube (10) can then be sealed and aseptically severed. The result will be that the leucodepleted blood will be separated into two components retained separately in bags (3) and (4). If the filter is one which filters out both platelets and leucocytes, then what is left after the filter (2) consists only of plasma and erythrocytes. After centrifugation, bag (3) will contain RCC and bag (4) will contain plasma. Because they have been made in a closed system, they can be stored.
23.	If the filter (2) only removes leucocytes, then what passes into satellite bag (3) consists of red cells, platelets and plasma. This can be split into its three components by a double centrifugation step. This is illustrated by another drawing in the patent set out below:
24.	In this case the leucodepleted blood in main bag (3) can be centrifuged a first time to split it into two components: RCC and a mixture of plasma and platelets. The latter can then be passed to satellite bag (4) where there is a second centrifugation. This splits the contents of the bag into two components: a platelet concentrate and plasma. These can then be separated. For example the plasma can be decanted into satellite bag (5). This arrangement can be re-drawn in the style of figure 1 above:
25.	These figures illustrate essential features of the invention, namely (a) that the method involves filtering the whole blood before it undergoes further separation by centrifugation and (b) the whole method is carried out in a closed system. These features are central to the claims still in issue.

Claim 1:

A method for separating blood into blood components, comprising the steps of;

(a)	providing blood collector means (1) fluid-tightly connected to filter means (2) for removing leukocytes or removing leukocytes and platelets from whole blood, said filter means (2) being fluid-tightly connected to a primary bag (3) through sealable, cuttable conduit means (9);
(b)	collecting, from a donor, whole blood comprising plasma, erythrocytes, leukocytes and platelets;
(c)	passing the whole blood through said filter means (2) to produce a filtered blood containing the plasma, the erythrocytes, and the platelets or containing the plasma and the erythrocytes;
(d)	discharging the filtered blood from said filter means (2) into said primary bag (3) through said conduit means (9);
(e)	sealing said conduit means at least at one portion intermediate ends thereof;
(f)	cutting said conduit means (9) portion to separate said conduit means (9) into a filter means-side unsealed or sealed conduit portion and a primary bag-side sealed conduit portion to thereby disconnect from said filter means (2) said primary bag (3) containing the filtered blood, said disconnected primary bag (3) being sealed by virtue of said primary bag-side sealed conduit portion connected to said primary bag (3); and
(g)	centrifuging the filtered blood in said primary bag (3).

Claim 4:

The method according to claim 1, wherein in step (c) the whole blood is passed through said filter means (2) for removing leukocytes and platelets, and in step (g), the filtered blood is separated into the erythrocytes and the plasma.

Claim 8:

A blood components separator unit comprising:

means for collecting blood (1);

filter means (2) for removing leukocytes or removing leukocytes and platelets, said filter means (2) having a filtrate outlet (23);

first conduit means (8) for connecting the means for collecting blood (1) to the filter means;

a primary bag (3);

second conduit means (9) for connecting the filtrate outlet (23) of said filter means (2) to said primary bag (3), said second conduit means being sealable and cuttable;

a satellite bag system; and

additional conduit means (10, 11) for connecting the satellite bag system to said primary bag (3), the additional conduit means (10) being sealable and cuttable, wherein said first conduit means (8) is fixedly connected at both ends thereof to said means for collecting blood (1) and said filter means (2), respectively; said second conduit means (9) is fixedly connected at both ends thereof to said filtrate outlet (23) and said primary bag (3), respectively; and said additional conduit means (10, 11) is fixedly connected at both ends thereof to said primary bag (3) and said satellite bag system, respectively, so that a substantially closed system of the blood components separator unit is provided, thereby enabling whole blood to be aseptically separated into leukocyte-containing blood components and leukocyte-free blood components.

... There is no requirement that the blood be separated into multiple components. It is enough, for example, that the method and apparatus can produce RCC. What is at the heart of the invention is the idea of passing whole blood through a filter in a closed system. As Dr. Pamphilon accepted, everything that happens after the filtration step is absolutely standard blood processing.

154.

There are, we think, four steps which require to be taken in answering the jury question. The first is to identify the inventive concept embodied in the patent in suit. Thereafter, the court has to assume the mantle of the normally skilled but unimaginative addressee in the art at the priority date and to impute to him what was, at that date, common general knowledge in the art in question. The third step is to identify what, if any, differences exist between the matter cited as [forming part of the state of the art] and the alleged invention. Finally, the court has to ask itself whether, viewed without any knowledge of the alleged invention, those differences constitute steps which would have been obvious to the skilled man or whether they require any degree of invention

45.	In my view, none of this undermines Macopharma’s case. It would have been nothing more than a workshop variation to make the Frey-Wettstein apparatus in a fully closed system by asking one of the existing specialist manufacturers to use standard procedures to pre-assemble the parts in the factory in sterile conditions. Furthermore Frey-Wettstein points in that direction. It emphasises the good storage characteristics of the filtered components and states that one of its objectives is to prolong shelf life (see paragraph 39 above). By 1988 it would not have been permissible to store the Frey-Wettstein RCC for three weeks and then use it for transfusing into patients. The standards imposed on blood banks to avoid the risk of contamination would have required the RCC to be used within 24 hours. But it would be apparent to anyone in the art that suitability for storage could be regained and enhanced by making and using the apparatus in the standard closed condition.
46.	Furthermore it is not legitimate to approach Frey-Wettstein, as Mr. Thorley does, by asking whether anyone in practice would have thought of implementing it at all. The notional skilled addressee comes to the prior art with a practical interest in the design, manufacture and use of blood component separators. He is taken to be interested in removing leukocytes at least from some blood products. He is taken to have read Frey-Wettstein and to be interested in its contents. For reasons set out above, he would have considered the manufacture and operation of a closed version of Frey-Wettstein to be no more than a workshop variation of what the authors describe.
47.	In addition, even if Mr. Thorley’s approach was permissible as a matter of law, I accept Dr Pietersz’ evidence that Frey-Wettstein would have been thought of as very interesting in 1988. Even if the notional addressee in the art is assumed to have settled into thinking of always using filters just before transfusion, this article would have told him that filtering the whole blood first would result in leucocyte depleted components which could then be stored and that at least one blood bank had done this.

We agree, of course, that one must not assume that the skilled man, casting his experienced eye over Darby [the prior art], would at once be fired with knowledge that here was something which had a great commercial future which he must bend every effort to develop and improve, but he must at least be assumed to appreciate and understand the free-save concept taught by Darby and to consider, in the light of his knowledge and experience, whether it would work and how it will work.

If Peter Chilvers had adopted, as part of his device, the conventional wishbone boom in place of the more primitive straight split boom which he in fact used, it would, we should have thought, have been quite unarguable that this would not have been an anticipation under sub-paragraph (e), for the notion behind anticipation is, as we understand it, that it would be wrong to enable the patentee to prevent a man from doing what he has lawfully done before the patent was granted. No doubt, the philosophy behind sub-paragraph (f) [obviousness] is different to this extent, that a patent is granted only for an invention and that which is obvious is not inventive, but it also must, we think, take into account the same concept as anticipation, namely that it would be wrong to prevent a man from doing something which is merely an obvious extension of what he has been doing or of what was known in the art before the priority date of the patent granted. This emerges perhaps most clearly from the following passages from the speech of Lord Moulton in Gillette Safety Razor Co. Ltd v Anglo-American Trading Co. Ltd (1913) 30 RPC 465 at 480:

“But he” – a prior inventor – “has shown the world how to make a safety razor by clamping a blade in the way which I have described … The knowledge so communicated applies to blades of any section. After the public has been shown how thus to clamp a blade, one cannot make a novel invention by saying that, instead of clamping a thick blade, one will clamp a thin one … If the claims of such a patent were so wide as to include it, the patent would be bad, because it would include something which differed by no patentable difference from that which was already in possession of the public. Such a patent would be bad for want of novelty … from the point of view of the public it is important that this method of viewing their rights should not be overlooked. In practical life it is often the only safeguard to the manufacturers. It is impossible for an ordinary member of the public to keep watch on all the numerous patents which are taken out and to ascertain the validity and scope of their claims. But he is entitled to feel secure if he knows that that which he is doing differs from that which has been done of old only in non-patentable variations, such as the substitution of mechanical equivalents or changes of material shape or size.

Mr. Chilvers, of course, and indeed, any of the persons who witnessed or copied his aquatic feats, are members of the public and one asks then on what principle should such persons, who clearly cannot be prevented from doing exactly that which they did before, be prevented from doing that which is no more than an obvious variant of what they did before?

Before a step from the prior art can be held to be obvious there must be some reason why the man skilled in the art would wish to take it. If he has a problem and the step would occur to him as a solution to it, then he has a reason. But there is no requirement that it be demonstrated that the step would have been expected to produce significant commercial advantages. The problem might be very small. The courts will assume that he may just want an alternative way of achieving essentially the same result as in the prior art. Thus were workshop modifications, none of which would be expected to produce significant technical or commercial benefits are still obvious. To adopt an example sometimes given by Jacob J., if it is known to make a 5-inch plate, it is obvious to make a 5¼ -inch plate. Technicians and businessmen frequently want to make trivial variations in established or known products. Similarly if the prior art discloses two wooden parts held together by screws it would be obvious to glue them, even if so doing would not be expected to advance the industry. The notional addressee is likely to want to use materials readily at hand to make essentially the same thing as is disclosed in the prior art. That is sufficient motivation and the use of those materials is, accordingly, obvious. When the defendants argue that Hingorani or any of his readers is entitled to use any "natural extension" or "obvious variant" of his concept, they are correct if by that they mean the type of workshop modification or alternative discussed above. But it was not and could not be suggested by any witness that changing the medium from aqueous to organic and changing the resin was a mere workshop variant of what is set out in Hingorani.

124.

That statement of the law was, I expect, apt on the facts of that case, but should not be followed generally. A step from the prior art, albeit made without reason, can still be obvious. The judge categorises such a step as workshop modifications and, in so doing, introduces a test not in the statute, namely whether the step from the prior art was a workshop modification. The statutory test is obviousness and any modification which is obvious will not be patentable, whereas one which is not obvious will be. The true test, as made clear in Windsurfing, is to ask whether the invention was obvious. Whether or not there is a reason for taking the step from the prior art may well be an important consideration, but that does not mean that it is an essential requirement of a conclusion of obviousness.

A simple method is described for the preparation of leukocyte-poor red cell concentrates from fresh and stored CPD blood. Warm normal CPD blood is passed through a nylon wool filter. After centrifugation at 1,5000g for 3 min, the plasma, the buffy coat and the top 30 ml of the red cell concentrate are eliminated. The average removal of leukocytes is better than 97%, the relation of remaining lymphocytes and granulocytes being 1:1. Red cell loss ranges around 20%. Advantages and disadvantages are discussed.

38.

The main text of the paper starts by recording the increasing demand for leucocyte depleted blood for patients with febrile transfusion reactions (see paragraph 17 above) and the need for simple and economic methods of getting rid of the HLA covered leucocytes and platelets (see paragraph 19 above). The introductory section ends with the following:

With a view to diminishing the leukocyte content of the filtrate and to prolong the shelf life of the leukocyte-poor red cell concentrate, we have attempted to process blood collected into standard CPD plastic bags.

39.

The method, described by the authors as their “routine”, consists of taking either recently collected or stored blood and filtering it through the then-available Leukopak filter material so as to produce leucodepleted whole blood in standard plastic bags. This is then centrifuged so as to produce different layers. The supernatant plasma, the buffy coat and the top 30 ml of the red cell sediment are then decanted into a satellite bag. The result is leucodepleted RCC. The authors assert that the advantages of their system include the fact that it can be carried out with commercially available equipment by any blood bank technician and is fast. They also say:

It has the advantage of being performed in an almost closed system with only minimal possibilities of contamination when filter and transfer packs are connected. Preliminary sterility tests showed that leukocyte-poor CPD blood remains sterile even after a 21-day storage period.

40.

As described, the equipment, when assembled, would have the layout illustrated in Figure 4 above. The difference between that (which is one of the embodiments falling within the claims) and the Frey-Wettstein arrangement is that the former is a closed system – that is to say it is made in a factory with all the bags and connecting tubes pre-assembled in sterile conditions, or made in situ with SCD apparatus – whereas the Frey-Wettstein paper describes a piece of apparatus which is put together on an as-required basis using the equipment then available. In practice this means that it involved the assembly of discrete pieces of equipment using spikes to connect them together, thereby creating an increased risk of contamination. It should be remembered that SCD equipment was not available in 1974. It is because the equipment was assembled in this way that the authors refer to it as being “almost closed”.

41.

Macopharma argues that it was obvious in June 1988 that equipment suitable for use in the Frey-Wettstein system could be made in a closed condition. Frey-Wettstein teaches that the blood products produced by its methodology are so nearly closed that they have enhanced storage characteristics. It would be obvious that those characteristics could be further enhanced in 1988 by making the apparatus in a truly closed condition and the obvious way to achieve that would be to ask a manufacturer to pre-assemble the apparatus in sterile conditions. It is not suggested that there would have been any difficulty in 1988 in making such a request or having it fulfilled. Furthermore, even without Frey-Wettstein’s encouragement in that direction, by 1988 a skilled worker in the art would have appreciated the advantages in making the equipment in a closed, as opposed to an almost closed, condition. Unless the equipment is closed, the RCC produced would have to be used within 24 hours, leading to increased wastage. Furthermore Dr. Pietersz says that in 1988 it would have been obvious and desirable not to jettison the mixture of red cells, buffy coat and plasma which are decanted from above the RCC. She says that that would have been wasteful. That material would have been subjected to a further centrifugation so as to produce cell-free plasma. The result would have been to produce a closed system which is indistinguishable from the layout depicted in Figure 5 above.

An object of the present invention is to provide a filter medium useful for a filter for selectively removing leucocytes, which is capable of efficiently removing leucocytes while holding down the loss of platelets to a minimum and which is useful in a platelet transfusion and an extracorporeal circulation leucocyte removal therapy.

The present invention relates to a fibrous filter medium for selectively removing leucocytes. More particularly, the present invention is concerned with a filter medium for selectively removing leucocytes, which is capable of efficiently removing leucocytes, with little loss of platelets from a cell-containing suspension containing both platelets and leucocytes, represented by blood.

…

In the field of blood transfusion, platelet transfusion for improving the bleeding condition of a patient fills an important position. Platelet transfusion includes fresh whole blood transfusion, fresh concentrated red cells transfusion, platelet rich plasma transfusion and platelet concentrate transfusion, and in each type of such transfusions, the blood product usually contains a considerable amount of leucocytes. If a patient repeatedly receives transfusion of blood containing leucocytes, anti-leucocyte antibodies are likely to be produced in the patient.

52.

These passages indicate that the filters of the invention can be applied either to whole blood or to one of its separated components. This is confirmed by the rest of the specification. In particular, example 8 describes how two litres of bovine whole blood was passed through the filter. Clearly, this is for the purpose of demonstrating how the novel devices can be used for filtering whole blood. The result of use of this type of filter is therefore to produce blood which has leucocytes removed but all the other, useful, ingredients largely left intact. Dr. Pietersz’ evidence was that this was a very interesting disclosure. She said that if she had seen it in June 1988 she would have thought of employing it in a closed system with collection bag containing anticoagulant, filter, and outlet conduit leading to a satellite bag system all connected by sealable cuttable tubing. She said that one would naturally arrive at something falling within the scope of claim 1. This really was not challenged in cross examination. In fact the only relevant piece of the transcript appears to be as follows:

Q	[The ‘286 specification] it is teaching you nothing about the strategy to be adopted in filtering blood.
A	That is correct.
Q	Are you able to assist my Lord, having looked at 286, as to whether or not those filters would be cheaper or more expensive than the Erypur-type of filter?
A	I really would not know. It is up to the manufacturers to make up the prices. I cannot say that. I do not know how expensive these fibres are and to make the filter.
Q	[The authors] are certainly not telling that you it is going to be a cheap product.
A	I do not think so. None of the filters were cheap, so I do not expect it. We would hope for it.

53.

For reasons already given, the fact that cost may drive one away from adopting a technically obvious course does not stop it being obvious. In my view Dr. Pietersz was right in saying that ‘286 would have led you to think of using a closed system falling with the scope of claim 1 (and the other claims in issue). Once a highly selective filter had been described, it was technically obvious to use it to filter whole blood. Indeed this was one of the suggestions made in ‘286. The alternative would be to use separate filters to filter each component of the blood once it had been separated from the others. Thus the choice was between use of a single filters or multiple filters. There was nothing inventive in choosing the former just as there was nothing inventive in proposing that the filter should be used in a closed system. The claims in suit are obvious over ‘286 as well. I should only add a reference to Dr. Pamphilon’s cross-examination in relation to this document. He accepted that the disclosure of ‘286 taken as a whole contained a proposal to filter whole blood through a familiar type of filter in order to remove just leukocytes. He accepted that it would have struck him as something novel because it removes only the least desired of the four major components of whole blood. He also accepted that if you filtered whole blood, you would then centrifuge it. However he refused to accept that it would have led one to thinking of making human blood components by filtering whole blood at the priority date or that it would have been used in a closed system. I did not find Dr. Pamphilon’s evidence in relation to this issue convincing. It is somewhat inconsistent with the statement in his report that before the priority date there was “enthusiasm for developing protocols for white cell depletion of blood and blood components for transfusion” (emphasis added, see paragraph 17 above). Although he appeared to retreat from this evidence under cross-examination, I think his report was accurate in this respect. This is one of those areas in which I prefer and accept the evidence of Dr. Pietersz.