Thursday, 16 May 2013

When is genetic material capable of (or susceptible of) industrial application?

Human Genome Sciences Inc v Eli Lilly and Co [2011] UKSC 51 is by no means a new case. However, it is the Supreme Court's first foray into patent law, which gives it some lasting importance, and it is noteworthy for the way Lord Neuberger, the Master of the Rolls, played such an influential part in a court which is not normally his preserve, such that the Supreme Court reversed judgments of two of the finest intellectual property lawyers (Kitchin J and Jacob LJ) of the era. This article (for such it is) was a long time in the writing, so long that the journal for which it was intended no longer considered it current enough to use. If it is insufficiently current for a printed journal, it is even less sufficiently current for a blog, but we are not deterred. It will still be useful to someone, and we hope it will also be at least a bit entertaining. It is not all my own work: it benefits from the co-authorship of Dr Yasmin Churcher, shortly-to-be-a-solicitor, who actually understands the science involved.


The unravelling of the human genome has led to many innovations, some of them in the patent system. For one thing, it has led to the formulation of rules that permit the grant of patents for what look to most people like excluded discoveries. Directive 99/44/EC confirms that a naturally occurring gene is patentable, but to overcome the objection that it is merely something that has been discovered the Directive goes on to insist that its industrial application be disclosed in the application. That might seem a bit of a statement of the obvious, simply reinforcing Article 52(1) of the European Patent Convention, but the key difference is that you can't get away with just hoping that some industrial application will turn up later, as many participants in the human genome patent rush seemed to be doing: it helps to ensure that the patent teaches how to solve a technical problem. Or, to put it another way: “However clever and inventive you may have been in discovering a gene sequence, you cannot have a patent for it or for the protein for which it encodes if you do not disclose how it can be used.” (Jacob LJ, [2010] RPC 14, [2010] EWCA Civ 33, para 57.)

Article 52(1) insists that you must have an invention that is susceptible of industrial application, and Article 57 expands on the meaning of this phrase, stating that the requirement will be satisfied if the invention can be made or used in any form of industry. Applying this to the fruits of biotechnology research, as the Supreme Court was called on to do in HGS v Eli Lilly, is not an easy matter.

The judgment does more than shed light on the difficult question of how to apply the industrial application rule. It is also intimately tied up with the equally important, perhaps even more important, issue of how national courts cope with the need to follow the case law of an institution with a very different approach to the doctrine of precedent.

The science and the patent

Readers more accustomed to reading complex legal material, whose eyes may glaze over (or skip over) scientific technicalities, may find the following summary of the science helpful. Those magical molecules so important to writers of detective fiction, deoxyribonucleic acid or DNA, are found in the nucleus of the cells that make up living organisms, such as us. Genes, sequences of nucleic acid, are regions located along those molecules, and they are said to code or encode (often with the redundant preposition “for”) proteins, determining how the organism will synthesise, or in the scientific vernacular “express”, the protein. Proteins have biological properties, including therapeutic ones, and so do their antibodies, which are another type of protein.
If a gene is involved in the regulation of cell proliferation, activation and differentiation, it might have applications in the field of cancer treatment, and knowing how it is expressed could be extremely valuable. Such was the case with European Patent (UK) 0,939,804, the application for which was filed by Human Genome Sciences Inc on 25 October 1996. The patent describes the encoding nucleotide, the amino acid sequence, and certain antibodies, of a novel human protein, Neutrokine-α (which for the sake of simplicity, readability, and ease of typing, is referred to in this piece as “the protein”). The patent includes what are referred to as “contentions” or predictions about its biological and therapeutic properties and those of its antibodies, but they are little more than educated guesses largely based on the proposition that the protein is a member of the group of proteins known as the tumour necrosis factor (or TNF) ligand superfamily (which, for the same reasons as set out above, is referred to in this piece as “the superfamily”). Members of superfamilies share certain properties, so the predictions were well-founded, but do those predictions show that the invention is susceptible of industrial application?

The history of the litigation

In the EPO, Eli Lilly opposed the grant, and the Opposition Division answered that question in the negative and revoked the patent. Eli Lilly also bought parallel proceedings in the High Court for revocation of the patent in the UK.
After the Opposition Division's decision, the High Court (Kitchin J) also revoked the patent on the grounds that a person skilled in the art would have concluded that the functions of the protein were too general and would provide nothing more than the basis of a research project ([2008] EWHC 1903 (Pat), [2008] RPC 29). There were further grounds for revocation based on insufficiency and obviousness. The High Court and the Opposition Division were in agreement, but then in October 2009 the Board of Appeal spoilt matters by reversing the Opposition Division's decision (on the basis, it should be noted, of more restricted claims) in T 0018/09. It held that the notional addressee would have appreciated that in the light of general knowledge of the superfamily the protein would have certain functions, and that was all that was needed.
In February 2010 the Court of Appeal unanimously upheld Kitchin J's decision on the industrial applicability point, maintaining the rift between Munich and London, and did not rule on the other issues ([2010] EWCA Civ 33, [2010] RPC 14). It dismissed the appeal on the basis that (even with the more restricted claims with which the Board of Appeal had been satisfied) the invention was not susceptible of industrial application. Conscious that its decision was contrary to that of the EPO, the Court of Appeal (in the judgment of Jacob LJ, with whom Lady Justice Hallet and Lewison J agreed) was at pains to explain and contrast the functions of the EPO and the Court of Appeal and the manner in which each reached its decision before concluding that:
157. ... The upshot of all this is that the Board, working on different evidence and using a different procedure came to a different conclusion on the facts. We are not bound to follow, or even give deference to, the Board’s findings of fact.158. For the above reasons I have come to the clear conclusion that the Judge was right to hold that the invention failed to comply with Art. 57.

The Supreme Court judgment

The Supreme Court which heard the appeal in July 2011 (giving judgment on 2 November) comprised Lord Hope (Deputy President), Lord Walker, Lord Neuberger MR, Lord Clarke, and Lord Collins. The leading judgments came from Lord Hope and, significantly, Cambridge chemistry graduate Lord Neuberger (the Master of the Rolls making, as it were, a guest appearance). Unsurprisingly, it was the judgment of the chemist (and former Patents Court judge) that was the more leading of the two.

While recognising the importance of deferring on matters of fact and value judgments to a court of first instance (especially when it had been upheld on appeal), the Supremes allowed the patentee's appeal. Lords Walker and Clarke went so far as to say that their default position had been not to interfere with the lower courts' decisions, but they had been persuaded by Lord Neuberger to allow the appeal. That they, against their instincts, should overturn the judgments of two heavyweight patents judges speaks volumes about Lord Neuberger's powers of persuasion. Some commentators have suggested that Lord Neuberger may be too influential and asked whether this situation is any different from the Hoffmann era.

The Supreme Court found little in the way of domestic authority on industrial application, particularly of biological material: the principles are found in the jurisprudence of the EPO's Board of Appeal, in what are sometimes, a little disparagingly, referred to as “T cases”. National courts are not obliged to follow the Board's reasoning in its decisions , but normally they should follow the EPO jurisprudence. This is especially so where the Board has adopted a consistent approach to an issue in several decisions, as the Supreme Court found was the case here – not that the Board's decisions all go one way.

The Supreme Court also identified good policy reasons for a consistent approach to patents in the biotechnology field: researchers need to be able to tell when they should file patent applications, and they need to be able to use patent protection to support their search for funding. These policy reasons surely extend to other areas of research too. The Justices were aided in their appreciation of this point by the intervention of the Bioindustries Association. See para 96 ff.

The patent contained wide-ranging and generalised suggestions about the uses of the protein it described and its antibodies: “[I]t contains an astonishing range of diseases and conditions which Neutrokine-α and antibodies to Neutrokine-α may be used to diagnose and treat and there is [sic] no data of any kind to support the claims made”: Kitchin J, at para 31. It did not however tell the reader anything specific: the only relevant guidance it gave came from its teaching about the tissue distribution of the protein, its expression in T-cell and B-cell lymphomas, and its membership of the superfamily. On the face of it, nothing about the invention's susceptibility to industrial application could be found in the patent. It neither revealed how the protein could be used to solve a particular problem, nor identified any disease or condition which it could be used to diagnose or treat.

So was the judge in the High Court right (or was he at least entitled) to conclude that Article 57 was not satisfied, that the inferences that (back in 1996) would have been drawn from the specification were insufficient?

The Supreme Court thought not, because this approach was not consistent with that of the Board in a series of cases, although the fact that both parties were able to derive support from the jurisprudence makes one wonder about the consistency of the Board's decisions.

Eli Lilly placed reliance on T 0870/04, Phosphatase/Max Planck where the Board held that it was not enough to describe the product, means and method for making it, and prospective use for basic scientific activities: the “application identifies no practical way of exploiting it in at least one field of industrial activity therefore not sufficient for industrial applicability”, and no function was identified. There was only a vague and speculative indication of possible objectives that might or might not be achievable by carrying out further research.

Shortly thereafter, the Board concluded in T 1329/04, the Tumour Growth Factor 9 (Factor-9/JOHN HOPKINS) case that because there was no functional characterisation and that a significant feature was not identical with the rest of the TGF superfamily there was an absence of applicability.

HGS sought assistance from T 0898/05 Hematopoietic receptor/Zymogenetics where the Board refused the patent application because the use of computer assisted sequence homology does not provide concrete conclusions about the actual function of the protein and therefore no inevitable therapeutic or diagnostic use, and because ZCytor1 was nothing more than a research tool and only the beginning of the process towards quest for industrial applicability.

In T 0604/04 PF4A receptors/Genentech the important point was that chemokines as a family were not only interesting but important for pharmaceutical industry irrespective of whether their role was clearly defined or not. It would therefore be reasonable to conclude that the claimed peptides exhibiting characteristics of receptors of PF4A family of cytokines would have been regarded as important to the pharmaceutical industry so the requirement for industrial applicability was automatically satisfied.

T 1452/06 Serine Protease/Bayer the application was refused due to lack of any experimental evidence in support of the claimed serine protease activity. Although the Board said that such support might be provided by computer assisted comparisons against known serine proteases and more particularly with the alleged closely related related sequence of Epithin, it pointed out that although Epithin is defined as a putative serine protease there was no experimental evidence to support that finding.

In T 1165/06 IL-17 related polypeptide/Schering 19 July 2007 the main issue was obviousness but the Board also considered the requirements of Article 57 and whether they had been addressed, and were decided that they had.

In light of the principles drawn from the jurisprudence of the Board, the Supremes considered that, taking common general knowledge into account, the disclosure of the existence and structure of the protein and its gene and of its membership of the superfamily sufficed to show that it was susceptible of industrial application. All known members of the superfamily were expressed on T-cells and could co-stimulate T-cell proliferation: the protein could be expected to display these properties too.

It made no difference that other properties found in superfamily members were not displayed by the new protein. Proteins in the superfamily were also known to have pleiotropic effects - multiple effects from a single gene, so members of a superfamily may be capable of driving multiple biological processes: but the Supreme Court considered this to be a red herring. given that the value of the new member of the superfamily lay in the features it had in common with all the other family members, and the skilled reader would have understood that not all its properties would be shared.

The patent was not well-drafted, but neither Kitchin J nor the Board had considered this would have diverted the person skilled in the art from their understanding of what the patent taught, given their common general knowledge and what they would have found in the literature. The Supreme Court considered that the lower courts had erred by concentrating on the speculative nature of some of the therapeutic uses of the protein which were disclosed in the patent, and on the extra effort that would be required to work out those uses: the known activities of the superfamily were enough in themselves to justify the grant of a patent for a novel molecule and its encoding gene.

The Supreme Court also rejected the argument that the specification was insufficient, for the same reasons. Kitchin J had, the Supreme Court decided, set a standard for susceptibility to industrial application that was higher, more exacting, than that set by the Board. He sought something that would show that a particular use for the protein had been demonstrated, when he should have been looking for something that showed that it could plausibly be used for research work. Reading between the lines of the Board's decision, the Supreme Court interpreted it as saying that this in itself amounted to an industrial activity.

After the Supreme Court reversed this decision, it remitted the case to the Court of Appeal, so that the question of insufficiency of three of the claims could be considered: two had been ruled insufficient at trial and HGS appealed, arguing that they weren't, while a third was ruled sufficient at trial and Eli Lilly appealed on the ground that it wasn't. But the insufficiency points are another, less important, story, not one we have time to tell here.

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