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England and Wales Court of Appeal (Civil Division) Decisions
You are here: BAILII >> Databases >> England and Wales Court of Appeal (Civil Division) Decisions >> Eli Lilly & Company v Human Genome Sciences Inc  EWCA Civ 33 (09 February 2010)
Cite as: (2010) 112 BMLR 161,  EWCA Civ 33,  RPC 14
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COURT OF APPEAL (CIVIL DIVISION)
ON APPEAL FROM THE CHANCERY DIVISION
The Hon Mr Justice Kitchin
HC 06 C02687
Strand, London, WC2A 2LL
B e f o r e :
THE RT HON LADY JUSTICE HALLETT
THE HON MR JUSTICE LEWISON
| Eli Lilly and Company
|- and -
|Human Genome Sciences Inc
WordWave International Limited
A Merrill Communications Company
165 Fleet Street, London EC4A 2DY
Tel No: 020 7404 1400, Fax No: 020 7404 1424
Official Shorthand Writers to the Court)
for the Appellant/Defendant
Andrew Waugh QC and Colin Birss QC (instructed by Messrs Howrey LLP)
for the Respondent/Claimant
Hearing dates: 8, 9, 11 and14 December 2009
Crown Copyright ©
Lord Justice Jacob:
Co-operation between the EPO and National Courts
The Issues on the Appeal
The nature of a first instance decision in England and Wales
The Nature of an Appeal in England and Wales
"The need for appellate caution in reversing the judge's evaluation of the facts is based upon much more solid grounds than professional courtesy. It is because specific findings of fact, even by the most meticulous judge, are inherently an incomplete statement of the impression which was made upon him by the primary evidence. His expressed findings are always surrounded by a penumbra of imprecision as to emphasis, relative weight, minor qualification and nuance (as Renan said, la vιritι est dans une nuance), of which time and language do not permit exact expression, but which may play an important part in the judge's overall evaluation. . Where the application of a legal standard such negligence or obviousness involves no question of principle but is simply a matter of degree, an appellate court should be very cautious in differing from the judge's evaluation".
The Nature of proceedings in the EPO
 There is still no European Patent Court. A European patent takes effect as a bundle of national patents over which the national courts have jurisdiction. It is therefore inevitable that they will occasionally give inconsistent decisions about the same patent. Sometimes this is because the evidence is different. In most continental jurisdictions, including the European Patent Office ("EPO"), cross-examination is limited or unknown. Sometimes one is dealing with questions of degree over which judges may legitimately differ. Obviousness is often in this category. But when the question is one of principle, it is desirable that so far as possible there should be uniformity in the way the national courts and the EPO interpret the European Patent Convention
The status of EPO and especially TBA decisions on questions of law in National (and especially UK) proceedings.
The Broad Context of the Invention
Susceptible of Industrial Application?
The Legislation: Art. 57 and the Biotech Directive
An invention shall be considered as susceptible of industrial application if it can be made or used in any kind of industry, including agriculture.
So if an invention does not comply with that requirement it not a patentable invention and the patent for it may (which in context means "must") be revoked (s.72(1) of the Patents Act 1977).
"1. The human body, at the various stages of its formation and development, and the simple discovery of one of its elements, including the sequence or partial sequence of a gene, cannot constitute patentable inventions.
2. An element isolated from the human body or otherwise produced by means of a technical process, including the sequence or partial sequence of a gene, may constitute a patentable invention, even if the structure of that element is identical to that of a natural element.
3. The industrial application of a sequence or partial sequence of a gene must be disclosed in the patent application."
22. . Whereas the industrial application of a sequence or partial sequence [of a gene] must be disclosed in the patent application as filed
23. Whereas a mere DNA sequence without indication of a function does not contain any technical information and is therefore not a patentable invention;
24. Whereas, in order to comply with the industrial application criterion it is necessary in cases where a sequence or partial sequence of a gene is used to produce a protein or part of a protein, to specify which protein or part of a protein is produced or what function it performs.
(1) The description shall
(f) indicate explicitly, where it is not obvious from the description or nature of the invention, the way in which the invention is industrially applicable.
The Rule itself is of course not the source of the law that depends and only depends on the true interpretation of Art. 57.
 In a nutshell, the industrial application of a gene must be disclosed in the application. If it encodes a protein then the protein or its function must be specified.
I agree with that, subject to the rider that what matters is a sufficient specification of the function of the protein. Just describing the existence of a protein and its structure is not enough. Nor is it enough to describe the function at a high level of generality e.g. that the compound must have a significant function biologically and so it (or its antibodies) may be usable to treat some sort of disease. You have to say what it is for with more particularity. What amounts to a sufficient specification of function will depend on the facts of the case and involves a question of degree.
The EPO Case Law on Art. 57
 In the board's judgment, although the present application describes a product (a polypeptide), means and methods for making it, and its prospective use thereof for basic science activities, it identifies no practical way of exploiting it in at least one field of industrial activity. In this respect, it is considered that a vague and speculative indication of possible objectives that might or might not be achievable by carrying out further research with the tool as described is not sufficient for fulfilment of the requirement of industrial applicability. The purpose of granting a patent is not to reserve an unexplored field of research for an applicant.
 In cases where a substance, naturally occurring in the human body, is identified, and possibly also structurally characterised and made available through some method, but either its function is not known or it is complex and incompletely understood, and no disease or condition has yet been identified as being attributable to an excess or deficiency of the substance, and no other practical use is suggested for the substance, then industrial applicability cannot be acknowledged. While the jurisprudence has tended to be generous to applicants, there must be a borderline between what can be accepted, and what can only be categorized as an interesting research result which per se does not yet allow a practical industrial application to be identified. Even though research results may be a scientific achievement of considerable merit, they are not necessarily an invention which can be applied industrially.
 Therefore, the issue here is rather how much weight can be given to speculations in the application in the framework of assessing inventive step, which assessment requires that facts be established before starting the relevant reasoning. In the board's judgment, enumerating any and all putative functions of a given compound is not the same as providing technical evidence as regard a specific one.
 Accordingly, as a significant structural feature fails to be identical in TGF-9 and the members of the TGF-ί superfamily, and no functional characterisation of TGF-9 is forthcoming in the application, it is concluded that the application does not sufficiently identify this factor as a member of this family i.e. that there is not enough evidence in the application to make at least plausible that a solution was found to the problem which was purportedly solved.
 The appellant filed post-published evidence . establishing that GDF-9 was indeed a growth differentiation factor. This cannot be regarded as supportive of an (sic) evidence which would have been given in the application as filed since there was not any. The said post-published documents are indeed the first disclosures going beyond speculation. For this reason, the post-published evidence may not be considered at all. Indeed, to do otherwise would imply that the recognition of a claimed subject-matter as a solution to a particular problem could vary as time went by. Here, for example, had the issue been examined before the publication date of the earliest relevant post-published document, GDF-9 would not have been seen as a plausible solution to the problem of finding a new member of the TGF-ί superfamily and inventive step would have had to be denied whereas, when examined thereafter, GDF-9 would have to be acknowledged as one such member. This approach would be in contradiction with the principle that inventive step, as all other criteria for patentability, must be ascertained as from the effective date of the patent. The definition of an invention as being a contribution to the art, i.e. as solving a technical problem and not merely putting forward one, requires that it is at least made plausible by the disclosure in the application that its teaching solves indeed the problem it purports to solve. Therefore, even if supplementary post-published evidence may in the proper circumstances also be taken into consideration, it may not serve as the sole basis to establish that the application solves indeed the problem it purports to solve.
 In summary, the patent in suit identifies applications for the claimed polypeptides which may ultimately lead to some profitable use. It provides a structural characterisation which enables their assignment to the category of receptors which bind members of the PF4A family of chemokines and, insofar, indicates what their function might be. Yet, in the absence of any characterisation of their ligands, this function remains at best incompletely understood.
 The board agrees with the criteria defined in T 870/04 and observes that, taken in isolation, the technical data provided in respect of the polypeptides of Figures 4 and 5 fall somewhat short of fulfilling them insofar as, as already above mentioned, there is no evidence available as to which ligands these polypeptides bind to. Yet, of course, each case has to be considered on its own merit (see eg. T 338/00 of 6 November 2002) and it is important here to take into account the common general knowledge at the priority date as well as the then prevalent attitude of the person skilled in the art as it may be inferred from the documents illustrating this common general knowledge.
[17 attractive targets for the development of new therapeutic agents. Inhibition of their activity may be an effective anti-inflammatory strategy and promoting that activity might enhance wound healing and tissue repair.
From that the Board reasoned:
 It is clear from this statement that chemokines as a family were considered not only to be interesting in fundamental research but also as important for the pharmaceutical industry irrespective of whether or not their role had been clearly defined. It follows that their receptors must have been considered equally important since the mode of action of chemokines is through their receptors. It is, thus, reasonable to conclude that the polypeptides of Figures 4 and 5 which exhibit the characteristics of receptors of members of the PF4A family of cytokines would have been regarded as important to the pharmaceutical industry, ie that industrial applicability may be acknowledged.
 the invention claimed must have such a sound and concrete technical basis that the skilled person can recognise that its contribution to the art could lead to practical exploitation in industry. It would be at odds with the purpose of the patent system to grant exclusive rights to prevent the commercial activities of others on the basis of a purely theoretical or speculative patent application. This would amount to granting a monopoly over an unexplored technical field.
 the need to disclose in definite technical terms the purpose of the invention and how it can be used in industrial practice to solve a given technical problem, this being the actual benefit or advantage of exploiting the invention. The essence of the requirement is that there must be at least a prospect of a real as opposed to a purely theoretical possibility of exploitation. Further, the use of the word "immediate" conveys the need for this to be derivable directly from the description, if it is not already obvious from the nature of the invention or from the background art. It should not be left to the skilled reader to find out how to exploit the invention by carrying out a research programme. Not only is this the essence of the requirements of Rules 23e(3) and 27(1)(f) EPC, it also corresponds to the requirements of Articles 56 (the need to provide a non-obvious solution to a technical problem), 57 (the need to indicate how to exploit the invention), and 83 EPC (the need to provide a sufficient disclosure of the claimed invention). All those provisions reflect the basic principle of the patent system that exclusive rights can only be granted in exchange for a full disclosure of the invention.
 Accordingly, a product whose structure is given (e.g. a nucleic acid sequence) but whose function is undetermined or obscure or only vaguely indicated might not fulfil the above criteria, in spite of the fact that the structure of the product per se can be reproduced (made) (cf. [Max Planck], point 10 infra). If a patent is granted therefor, it might prevent further research in that area, and/or give the patentee unjustified control over others who are actively investigating in that area and who might eventually find actual ways to exploit it.
 On the other hand, a product which is definitely described and plausibly shown to be usable, e.g. to cure a rare or orphan disease, might be considered to have a profitable use or concrete benefit, irrespective of whether it is actually intended for the pursuit of any trade at all. Thus, although no particular economic profit might be expected in the development of such products, nevertheless there is no doubt that it might be considered to display immediate concrete benefits.
 Although recognising that the predicted role of the protein Zcytor1 in proliferation, differentiation and/or activation of immune cells was "reasonably credible", the examining division denied the industrial applicability of the claimed invention on the basis of, essentially, the following two reasons: i) the use of a computer-assisted alignment as disclosed in the application did not allow any concrete conclusions to be made as to the actual specific function of the protein, because such studies provided only speculation of a vague nature and no specific therapeutic or diagnostic use could be ascertained therefrom; ii) the Zcytor1 receptor was only a research tool whose importance lay in establishing a research programme and whose disclosure was only the first step in the quest for industrially applicable matter.
 As seen above with reference to the case law of the boards of appeal, the disclosure of the function of a newly discovered protein is of utmost importance when examining the issue of "industrial applicability" as the function is the gateway to understanding the concrete benefits which may derive from exploiting the invention industrially. As shown by T 870/04 (supra [i.e. Max Planck]), the mere characterisation of the structure of a protein may not be enough to comply with Article 57 EPC if no profitable use of the protein is disclosed. On the other hand, T 338/00 and T 604/04 (supra) show that a positive answer can be given in spite of the absence of actual experimental data, if a profitable use can readily be identified on the basis of the description taking into account common general knowledge. This demonstrates that this matter can only be decided in each case on its own merits according to the particular technical circumstances (extent of disclosure, background art, post-published evidence etc).
 The fact that the putative function of the Zcytor1 receptor was assigned in the examples based on computer-assisted methods, rather than on the basis of traditional wet-lab techniques, does not mean that it has to be automatically disregarded or excluded from a careful and critical examination. There is no "all-encompassing" approach, and certainly not a "throw-into-the-bin" approach, for these in-silico examples. Their probative value has to be examined on a case-by-case basis regarding the nature of the invention and the prior art relating thereto. Such methods of analysis are increasingly becoming an integral part of scientific investigations and can often allow plausible conclusions to be made regarding the function of a product before it is actually tested.
 Whereas the structural characterization of a protein might be directly derived from the genome, its function cannot normally be derived in a straightforward manner therefrom. The function of a protein (and thus of the nucleic acid encoding it) can be seen at different levels. These include: i) the biochemical activity of the protein (protease, endonuclease, ion channel or pump, etc.), i.e. its molecular function; ii), the function of the protein in cellular processes (apoptosis, secretion pathway, etc.), i.e. its cellular function; and iii) the influence of those cellular processes within a multicellular organism, i.e. in a general and more complex network within a multicellular organism (cancer, inflammation, immune responses, etc.), this being its biological function in a broad sense. Each of these levels, particularly the cellular and biological function, may not be restricted to a very single (objective) function but may encompass multiple functions arising from all the different possible protein complexes (units of macromolecular organization) in which the protein might participate or contribute. In fact the latter is more the rule than the exception.
For the purpose of Article 57 EPC none of these levels is more fundamental, i.e. "more specific" or "less vague" in the words of the decision under appeal, than the other ones insofar as at least from one of these levels a practical application (a profitable use in a wider sense, cf. points 5 and 6 supra) is derivable in a straightforward manner.
 In the present case, the suggested role of the Zcytor1 receptor corresponds to the level of the biological function and the practical applications or the concrete technical benefits derived therefrom are clearly disclosed in the present application, namely the stimulation of cell-mediated immunity and of lymphocyte proliferation by agonist ligands of Zcytor1 and the suppression of the immune system by antagonists of the Zcytor1 receptor .
the (therapeutic) treatments directly derivable from the biological function identified by the computer-assisted method cannot be considered to be so "vaguely defined" that they do not suggest any therapeutic or diagnostic use. On the contrary, the treatments referred to in the application are specifically in relation to the function plausibly attributed to the molecule, and are in the areas of rheumatoid arthritis, multiple sclerosis, diabetes mellitus, etc.
 The board is convinced that the requirements of Article 57 EPC are fulfilled. The sequence information provided in the application with respect to the presence in IL-174 of the characteristic cysteine spacing of the IL-17 cytokine family makes it plausible that this polypeptide may belong to this family and have biological activities similar to those of the other family members known at the filing date, in particular CTLA-8. This is confirmed by post-published evidence filed by the appellant.
(i) The notion of industry must be construed broadly. It includes all manufacturing, extracting and processing activities of enterprises that are carried out continuously, independently and for commercial gain (Max-Planck).
(ii) However, it need not necessarily be conducted for profit (Chiron  RPC 535) and a product which is shown to be useful to cure a rare or orphan disease may be considered capable of industrial application even if it is not intended for use in any trade at all (ZymoGenetics).
(iii) The capability of industrial exploitation must be derivable by the skilled person from the description read with the benefit of the common general knowledge (Genentech).
(iv) The description, so read, must disclose a practical way of exploiting the invention in at least one field of industrial activity (/Max-Planck; Salk Institute T 338/00).
(v) More recently, this has been re-formulated as an enquiry as to whether there is a sound and concrete basis for recognising that the contribution could lead to practical application in industry. Nevertheless, there remains a need to disclose in definite technical terms the purpose of the invention and how it can be used to solve a given technical problem. Moreover, there must be a real prospect of exploitation which is derivable directly from the specification, if not already obvious from the nature of the invention or the background art (ZymoGenetics; Bayer T 1452/06).
(vi) Conversely, the requirement will not be satisfied if what is described is merely an interesting research result that might yield a yet to be identified industrial application (Salk Institute). A speculative indication of possible objectives that might or might not be achievable by carrying out research is not sufficient (Max-Planck). Similarly, it should not be left to the skilled reader to find out how to exploit the invention by carrying out a research programme (/ZymoGenetics).
(vii) It follows that the purpose of granting a patent is not to reserve an unexplored field of research for the applicant (Max-Planck) nor to give the patentee unjustified control over others who are actively investigating in that area and who might eventually find ways actually to exploit it (ZymoGenetics).
(viii) If a substance is disclosed and its function is essential for human health then the identification of the substance having that function will immediately suggest a practical application. If, on the other hand, the function of that substance is not known or is incompletely understood, and no disease has been identified which is attributable to an excess or a deficiency of it, and no other practical use is suggested for it, then the requirement of industrial applicability is not satisfied. This will be so even though the disclosure may be a scientific achievement of considerable merit (Max-Planck).
(xi) Using the claimed invention to find out more about its own activities is not in itself an industrial application (Max-Planck).
(x) Finally, it is no bar to patentability that the invention has been found by homology studies using bioinformatics techniques (ZymoGenetics) although this may have a bearing on how the skilled person would understand the disclosure.
It is thus clear that an application must show that an invention is useful to the public as disclosed in its current form, not that it may prove useful at some future date after further research. Simply put, to satisfy the "substantial" utility requirement, an asserted use must show that that claimed invention has a significant and presently available benefit to the public.
Thus, in addition to providing a "substantial" utility, an asserted use must also show that that claimed invention can be used to provide a well-defined and particular benefit to the public.
 So the application must show that the invention is useful to the public as disclosed, not at some future date after further research. The utility must be significant and presently available. It must also disclose a use which is well defined and not so vague as to be meaningless.
Of an argument, an idea, a statement, etc.: seeming reasonable, probable, or truthful; convincing, believable.
The Common General Knowledge
 Pulling these various strands together, I derive the following conclusions. I have no doubt that the details of all these publications did not form part of the common general knowledge of the ordinary skilled person in 1996. However, as the experts accepted, they would have been found by any researcher setting out to find or investigate the properties of a new member of the TNF ligand superfamily. Upon reading the publications any such researcher would have appreciated that the activities of the members of the superfamily are extremely complex and had been the subject of extensive research, as reflected in the forest of papers they reference. But some general points about the TNF ligand superfamily members would have emerged:
i) They were all expressed by activated T cells and some by other cells such as activated monocytes and macrophages.
ii) Their activities were mediated by binding to receptors, of which a number had been identified.
iii) They were known to have pleiotropic actions, that is to say a multitude of different effects on different cell types, driving multiple biological processes. Some of those activities were understood to be unique to particular TNF ligands and others were understood to be shared by some or all the other TNF ligands.
iv) They all played a role in the regulation of T cell proliferation and T cell mediated immune responses.
v) Some of the ligands played a role in the regulation of B-cell proliferation and antibody secretion and some took part in T cell dependent regulation of B cells.
vi) Some of the ligands had an ability to induce cell death by necrosis or apoptosis.
vii) TNF-a and TNF-ί were functionally linked as primary mediators of immune regulation and inflammatory response.
viii) It had been suggested that various ligands were associated with a very wide range of particular disease states such as septic shock, rheumatoid arthritis, inflammatory bowel disease, tissue rejection, HIV infection, and some adverse drug reactions. But no disease had been identified in which all the ligands were involved.
ix) TNF-a was the only ligand shown to have a therapeutic application; that being for the treatment of rheumatoid arthritis through the use of a specific monoclonal antibody. It was believed to operate in a particular way, namely by interrupting the cytokine cascade and by controlling the recruitment and trafficking of blood cells to the joint.
 Moreover, it was appreciated that further studies were both needed and desirable to identify further ligands in the TNF superfamily and, in relation to each ligand, to seek to identify its unique and redundant biological functions. There was undoubtedly an incentive to do so, because of their apparent roles in the regulation of the immune system and inflammatory response, their possible involvement in various different diseases and so also, in due course, their potential as therapeutic agents. The rewards were potentially very great.
The Patent in suit
i) to modulate angiogenesis;
ii) to inhibit immune cell functions and hence have a wide range of anti-inflammatory activities;
iii) to act as an anti-neovascularizing agent to treat solid tumours and other non-cancer indications where blood vessel proliferation is not wanted;
iv) to enhance host defences against resistant chronic and acute infections, for example, myobacterial infections via the attraction and activation of microbiocidal leukocytes;
v) to inhibit T-cell proliferation by the inhibition of IL-2 biosynthesis for the treatment of T-cell mediated auto-immune diseases and lymphocytic leukaemias;
vi) to stimulate wound healing, both via the recruitment of debris clearing and connective tissue promoting inflammatory cells;
vii) to treat other fibrotic disorders, including liver cirrhosis, osteoarthritis and pulmonary fibrosis.
viii) to increase the presence of eosinophils which have the distinctive function of killing the larvae of parasites that invade tissues, as in schistosomiasis, trichinosis and ascariasis;
ix) to regulate hematopoiesis, by regulating the activation and differentiation of various hematopoietic progenitor cells, for example, to release mature leukocytes from the bone marrow following chemotherapy, i.e., in stem cell mobilization; and
x) to treat sepsis.
i) the inhibition of Neutrokine-a;
ii) to inhibit the chemotaxis and activation of macrophages and their precursors, neutrophils, basophils, B lymphocytes and some T-cell subsets, eg activated and CD8 cytotoxic T cells and natural killer cells;
iii) in certain auto-immune and chronic inflammatory and infective diseases: examples of auto-immune diseases including multiple sclerosis and insulin-dependent diabetes; infectious diseases including silicosis, sarcoidosis, idiopathic pulmonary fibrosis;
iv) to treat idiopathic hyper-eosinophilic syndrome by preventing oesinophil production and migration;
v) to treat endotoxic shock by preventing the migration of macrophages;
vi) to treat atherosclerosis by preventing monocyte infiltration in the artery wall;
vii) to treat histamine-mediated allergic reactions and immunological disorders including late phase allergic reactions, chronic urticaria, and atopic dermatitis;
viii) to treat IgE-mediated allergic reactions such as allergic asthma, rhinitis, and eczema;
ix) to treat chronic and acute inflammation chronic and acute inflammatory pulmonary diseases;
x) to treat rheumatoid arthritis by preventing the attraction of monocytes into synovial fluid;
xi) to treat degenerative and inflammatory arthropathies;
xii) to prevent inflammation;
xiii) to inhibit prostaglandin-independent fever induced by chemokines;
xiv) to treat cases of bone marrow failure;
xv) to treat asthma and allergy by preventing oesinophil accumulation in the lung.
 Overall, the Patent contains extravagant and sometimes contradictory claims. By way of illustration, it suggests in paragraph  that Neutrokine-a inhibits immune cell function and in paragraph  that antagonists of Neutrokine-a also inhibit immune cell function. There is nothing by way of experimental evidence to support the claims made and I accept Professor Saklatvala's evidence that the idea that Neutrokine-a and antagonists to Neutrokinea could be used to treat the extraordinary range of diseases identified was fanciful. He found it hard to believe that anyone could seriously suggest on the basis of no experimental data at all that that Neutrokine-a was the answer to so many conditions, from treating cancer to treating worms. In my judgment the skilled person would come to the conclusion that the inventors had no idea as to the activity of Neutrokine-a when drafting the Patent. It teaches the skilled person nothing useful about its activity other than that Neutrokine-a is another member of the TNF ligand superfamily.
 In this case I am quite satisfied that the skilled person would consider the Patent does not of itself identify any industrial application other than by way of speculation. As is apparent from my review in paragraphs - of this judgment, it contains an astonishing range of diseases and conditions which Neutrokine-a and antibodies to Neutrokine-a may be used to diagnose and treat and there is no data of any kind to support the claims made. The skilled person would consider it totally far-fetched that Neutrokine-a could be used in relation to them all and, as I have found, would be driven to the conclusion that the authors had no clear idea what the activities of the protein were and so included every possibility. To have included such a range of applications was no better than to have included none at all.
 But that is not the end of the matter because the disclosure must be considered in the light of the common general knowledge which I have considered in paragraphs - of this judgment. The skilled person would have known that TNF was involved as a primary mediator in immune regulation and the inflammatory response and had an involvement in a wide range of diseases as septic shock, rheumatoid arthritis, inflammatory bowel disease, tissue rejection, HIV infection, and some adverse drug reactions. He would have known that all the members of the TNF ligand superfamily identified hitherto were expressed by T cells and played a role in the regulation of T cell proliferation and T cell mediated responses. Further, as Professor Saklatvala accepted, the skilled person would anticipate that the activities of Neutrokine-a might relate to T cells and, in particular, be expressed on T cells and be a co-stimulant of B cell production; that it might play a role in the immune response and in the control of tumours and malignant disease; that it might have an effect on B cell proliferation; and that it would have the same roles, to some degree, as those described in the Gruss paper.
 On the other hand, the skilled person would have also known that the members of the family had pleiotropic actions; that some of those activities were unique to particular TNF ligands and others were shared by some or all the other TNF ligands and that no disease had been identified in which they were all involved. Moreover, as explained in the Maini publication, the therapeutic application of TNF-a monoclonal antibody for the treatment of rheumatoid arthritis was believed to operate by interrupting the cytokine cascade and by controlling the recruitment and trafficking of blood cells to the joint a rather specific activity.
 Does that common general knowledge, taken as a whole, disclose a practical way of exploiting Neutrokine-a? Or does it provide a sound and concrete basis for recognising that Neutrokine-a could lead to practical application in industry? In my judgment it does not. The fact that Neutrokine-a might be expected to play a role in regulating the activities of B cells and T cells and play an unspecified role in regulating the immune and inflammatory response did not reveal how it could be used to solve any particular problem. Neither the Patent nor the common general knowledge identified any disease or condition which Neutrokine-a could be used to diagnose or treat. Its functions were, at best, a matter of expectation and then at far too high a level of generality to constitute a sound or concrete basis for anything except a research project.
It was plausible, based on the common general knowledge and the disclosure of the patent (including Gruss & Dower) that Neutrokine-... would, at the cellular level:
1) be expressed on activated T cells and co-stimulate T cell proliferation and hence be involved in regulation of T cell proliferation and T cell mediated immune responses;
2) co-stimulate B cell proliferation and be involved in the regulation of B cell proliferation and humoral B cell activity;
3) be expressed on B cell and T cell lymphomas;
plausibly leading to, at the biological level, application of Neutrokine-... and/or antagonists (including antibodies):
1) in the regulation of the immune and inflammatory responses and in the treatment and diagnosis of autoimmune diseases (e.g. RA) and inflammatory conditions;
2) in the control of tumours and malignant diseases, including B cell and T cell lymphomas.
Biologic activities related to T-cell-mediated immunity are a unique feature for all members of the TNF ligand superfamily. All ligands and receptors, without exception, are expressed on activated T cells (Table 4). Purified human T cells and T-cell clones show enhanced proliferation when stimulated with any recombinant TNF family ligand or crosslinked with antireceptor antibodies in the presence of anti-CD3 or other mitogens, such as phytohemagglutinin (PHA), phorbol myristate acetate (PMA), or ionomycin. Possible autocrine T-cell activation and growth control might be a common feature of this protein family. The induction of each ligand expression shows unique kinetics consistent with different roles for each of these ligands in the T-cell activation. For example, the induction of CD30L surface expression on activated T cells is slower in comparison to other TNF ligands such as TNF, CD27L, CD40L, and 4-1BBL (maximal expression, 24 hours v 6 hours, respectively). B-cell proliferation and Ig secretion is induced by at least TNF, LT(, and CD40L. Further, several members participate in T-cell-dependent help for B cells, which are known to express TNFR-I, TNFR-II, CD27, CD30, CD40, FAS and 4-1BB (Table 4). TNF, LT(, and CD40L are mitogenic to B cells.
In general, all TNF ligand superfamily members, including FASL and CD40L, are essential for T-cell costimulation and activation. It is of special interest that signals, at least through CD27L, CD40L, and 4-1BBL, can provide costimulation for activated peripheral blood (PB) T cells. Further studies need to be performed to see if other TNF ligand superfamily members are able to transduce a costimulatory signal.
Taken together, TNF superfamily ligands show for the immune response an involvement in the induction of cytokine secretion and the upregulation of adhesion molecules, activation antigens, and costimulatory proteins, all known to amplify stimulatory and regulatory signals. On the other hand, differences in the distribution, kinetics of induction, and requirements for induction support a defined role for each of the ligands for T-cell mediated immune responses. The shedding of members of the TNF receptor superfamily could limit the signals mediated by the corresponding ligands as a functional regulatory mechanism. Induction of cytotoxic cell death, observed for TNF, LT(, CD30L, CD95L, and 4-1BBL, is another common functional feature of this cytokine family. Further studies have to identify unique versus redundant biologic and physiologic functions for each of the TNF superfamily ligands.
Several TNFR superfamily members could be candidates for novel treatment protocols. Recombinant CD30L and CD40L could be by itself antitumorigenic for CD30+ ALCLs and CD40+ B-cell NHLs, respectively. Furthermore, CD30 and CD40 might be used for tumor targeting after conjugation with radioisotypes or cytostatic drugs for CD30+ and/or CD40+ HD and NHLs.
 The papers and work to which I have referred represent only a very small fraction of the work carried out on Neutrokine-a. Nevertheless, I believe the following general conclusions can be drawn from them and the expert evidence. From 1999 it became increasingly clear that Neutrokine-a is expressed by peripheral blood leukocytes, and in the spleen and lymph nodes. From that time it also became apparent that Neutrokine-a plays a significant and particular role in the proliferation and differentiation of B cells. Subsequently it has also been shown to play a part in the regulation of T cell proliferation and activation. As the activities of Neutrokine-a have gradually been elucidated, and particularly those relating to B cells, it has become increasingly recognised as a potential therapeutic target for diseases that are specifically associated with altered B cell function. Notable amongst these are autoimmune diseases such as rheumatoid arthritis and SLE and B cell malignancies such as lymphoma. Neutrokine-a has now been shown to have an important role in the development of autoimmune disease and B cell cancers; but, at the same time, much of its biology remains unclear and is the subject of continuing study by many different research centres. In my judgment the nature and extent of all this research work, the limited conclusions ultimately drawn and the amount of work that remains to be done point strongly to the conclusion that the therapeutic and diagnostic applications suggested in the Patent were indeed speculative.
 As pointed out in [Max Planck] (cf. in particular points 5 and 6 of the Reasons), in many cases the allocation of a newly found protein to a known protein family with known activities suffices to assign a specific function to the protein because normally the members of the family share a specific function. This may be a well-characterized and perfectly understood function which provides in a straightforward manner enough support for industrial applicability. In such cases, the "immediate concrete benefit" is manifest. In other cases, where the members of a protein family have different, pleiotropic effects which may even be opposite and neither completely characterized nor understood, no effect can be assigned to a new member without relying on some experimental data. Between these two extreme situations, a variety of other situations may arise for which a detailed examination of all the facts may be required. Indeed, this is the case for the TNF ligand superfamily.
I cannot support Professor Noelle's comment that one would expect Neutrokine-a to be useful in the same way as other members of the TNF ligand superfamily. By 1996 only TNF-a had been shown to be biomedically useful.
Prof Saklatvala was found to be "an outstandingly good witness" and his evidence "of very great assistance.". Prof. Noelle's evidence was less well received.
(l)ike other members of TNF family, Neutrokine-a exhibits activity on leukocytes including for example monocytes, lymphocytes and neutrophils. For this reason Neutrokine-a is active in directing the proliferation, differentiation and migration of these cell types.
Neutrokine-a may also be suitable to inhibit T-cell proliferation by the inhibition of IL-2 biosynthesis for the treatment of T-cell mediated auto-immune diseases and lymphocytic leukemias.
The contrast is remarkable, and surely supports Kitchin J's view that the Patent, even in relation to T-cell activity, is just too speculative to provide anything of practical value other than information upon which a research programme can be based.
When reading the patent specification, a skilled person would distinguish the positive technical information such as that mentioned above from other allegedly contradictory and broad statements found in the patent-in-suit, such as - in the respondent's view - the wide range of activities and conditions for which Neutrokine-a could be useful. This is because the skilled person realises that the description of the structure of Neutrokine-a, its structural assignment to the family of TNF ligands, and the reports about its tissue distribution and activity on leukocytes, are the first essential steps at the onset of research work on the newly found TNF ligand superfamily member.
Certainly there was no evidence from either side before Kitchin J that a skilled man would approach the patent with an ability to distinguish the kernel from the rest.
In the present case, the description of the patent delivers sufficient technical information, namely the effect of Neutrokine-a on T-cells and the tissue distribution of Neutrokine-a mRNA, to satisfy the requirement of disclosing the nature and purpose of the invention and how it can be used in industrial practice.
 In my judgment the skilled person would indeed have been able to identify or develop from his common general knowledge some assays with which to begin the study of the new ligand and start to assess at least some of its possible activities. But I am not satisfied that such studies would have produced informative results and I have no doubt that to carry out a comprehensive screening programme so as to identify the role of the ligand in the biology of any particular cell type would be an altogether more complex task, and one properly characterised as a research programme.
Lady Justice Hallett:
Mr Justice Lewison: