Human Genome Sciences Inc. v Eli Lilly and Company

Heard on 18, 19 and 20 July 2011

This appeal is concerned with the validity of a patent which claims the nucleotide sequence of the gene which encodes for a novel protein (and which has further associated claims). Although there is an insufficiency issue, which I will consider at the end of this judgment, the primary issue on this appeal raises a difficult question, namely the way in which the requirement of industrial applicability in Articles 52 and 57 of the European Patent Convention ("the EPC") extends to a patent for biological material.

While this issue can be said to raise an important question of principle, its resolution is inevitably fact-sensitive, and therefore any answer may be of limited value in other cases. Further, the issue arises in the context of a fast-developing field, which requires a court to approach it with caution. The need for caution is reinforced by the fact that the answer may give rise to potentially far-reaching consequences for scientific research, the biotech industry, and human health. On the other hand, for those very reasons, it is particularly important that the law in this area is as clear, consistent and certain as possible.

The patent in suit ("the Patent") is European Patent (UK) 0,939,804. It describes the encoding nucleotide, the amino acid sequence, and certain antibodies, of a novel human protein, which it calls Neutrokine-a, and includes contentions as to its biological properties and therapeutic activities, as well as those of its antibodies. These contentions are predictions, which are substantially based on the proposition that Neutrokine-a is a member of the TNF ligand superfamily.

The application for the Patent was filed by Human Genome Sciences Ltd ("HGS") on 25 October 1996, and it was granted by the Examining Division of the European Patent Office ("the EPO") to HGS on 17 August 2005. Accordingly, the Patent's validity is to be judged as at October 1996.

For present purposes, it is unnecessary to go into the claims or the description of the Patent in much detail. The claims, although not in their final form as allowed by the Technical Board of Appeal of the European Patent Office, are set out in an appendix to the judgment of Kitchin J at first instance, [2008] EWHC 1903 (Pat), [2008] RPC 29. The centrally important claim for present purposes is Claim 1, which essentially extends to the encoding nucleotides of the gene of Neutrokine-a.

The specification, or description, of the Patent is well summarised by Kitchin J at [2008] RPC 29, paras 100–133. It is confusingly long, diffuse, and widely expressed, running to over 25 closely typed pages, and nearly 200 paragraphs of descriptive text, and a further twelve pages of sequences of polypeptide amino acids and DNA nucleotides. Also, as Kitchin J said, the specification "contains extravagant and sometimes contradictory claims"— [2008] RPC 29, para 134. Perhaps rather more tolerantly, the Technical Board of Appeal of the European Patent Office ("the Board") referred to the Patent as having been drafted on a "boiler-plate" basis, which it described as "a practice used by patentees"- T 0018/09 Neutrokine/Human Genome Sciences, para 27.

The specification begins by explaining that Neutrokine-a is a new protein, and a member of the TNF ligand superfamily of cytokines, which are proteins which act as inter-cellular mediators in inflammation and other immune responses. It states that all the known members of that superfamily "are involved in regulation of cell proliferation, activation and differentiation, including control of cell survival or death by apoptosis or cytotoxicity…". The specification also explains that the first identified member of the superfamily is known as TNF-a, which was isolated in 1975 and whose encoding gene was sequenced in 1985. By 1996, it was clear that TNF-a had a variety of effects on different cell types, which the specification describes as including "immunoregulatory actions including activation of T-cells, B-cells, monocytes, [and] thymocytes…". Accordingly, it is claimed, "there is a need to provide cytokines similar to [TNF-a] that are involved in pathological conditions".

The specification goes on to reveal the existence and structure of Neutrokine-a, to claim it as a member of the superfamily, and to explain that it is "expressed…in neutrophils…in kidney, lung, peripheral leukocyte, bone marrow, T-cell lymphoma, B-cell lymphoma, activated T-cells, stomach cancer, smooth muscle, macrophages and cord blood tissue." The specification then describes the claimed invention as potentially useful for the diagnosis, prevention, or treatment of an extraordinarily large and disparate number of, sometimes widely expressed, categories of disorders of the immune system, and other conditions and actions, either through Neutrokine-a itself or through its antagonists. However, nowhere in the Patent is there any data or any suggestion of in vitro or in vivo studies, so there is no experimental evidence to support any of those suggestions.

Among its many contentions, the specification states that, "[l]ike other members of TNF family, Neutrokine-a exhibits activity on leukocytes including for example monocytes, lymphocytes and neutrophils", and so "is active in directing the proliferation, differentiation and migration of these cell types". These activities are said to be "useful for immune enhancement or suppression, myeloprotection, stem cell mobilization…and treatment of leukemia". The specification also discusses the tissues in which Neutrokine-a is expressed, and goes on to state that, because Neutrokine-a belongs to the TNF superfamily, "it will have a wide range of anti-inflammatory activities" and "may be suitable to be employed as an anti-neovascularizing agent to treat solid tumors by stimulating the invasion and activation of host defense cells, e.g., cytotoxic T-cells…". It is also said that Neutrokine-a may be "suitable to be employed to enhance host defenses against resistant chronic and acute infections" and also "to inhibit T-cell proliferation" or "for the treatment of T-cell mediated auto-immune diseases and lymphocytic leukemias".

In very summary terms, the disclosure of the Patent thus includes the following features: (i) the existence and amino acid sequence of Neutrokine-a, (ii) the nucleotide sequence of the gene encoding for Neutrokine-a, (iii) the tissue distribution of Neutrokine-a, (iv) the expression of Neutrokine-a by its mRNA (the encoding gene) in T-cell and B-cell lymphomas, and (v) the information that Neutrokine-a is a member of the TNF ligand superfamily.

The teaching in the specification must, of course, be read through the eyes of the notional addressee (or "the person skilled in the art"), an appropriately skilled person or group of persons, as at October 1996. In that connection, the Judge said this at [2008] RPC 29, paras 30 and 32:

"30. The Patent is directed to a team of people with about two years of post doctoral experience. It would include a molecular biologist familiar with routine techniques of cloning, expression and sequencing of genes and proteins; a biochemist to make and purify recombinant proteins; and a biologist or immunologist with experience of the TNF superfamily and with the skills necessary to generate and test antibodies. I am also satisfied that any team interested in identifying a new member of the TNF superfamily would carry out a literature search to gather as much knowledge as possible about the existing members.

…

32.…[T]he skilled team looking for a new member of the TNF superfamily would have been aware that the science of bioinformatics could provide assistance in the search and, if a bioinformaticist was not already a member of the team, would have considered it worthwhile to consult such a person."

Accordingly, particularly in the light of the last sentence of the first of those two paragraphs, recourse must be had not only to the common general knowledge as at October 1996, but also to the results of any research into the literature which such notional addressees could be expected to carry out as at that time.

While a fuller explanation of the background and technique of bioinformatics, referred to in the passage quoted in para 11 above, was provided by the Judge at [2008] RPC 29, paras 78–99, I shall attempt a very brief explanation in the ensuing five paragraphs.

DNA molecules are found in virtually every human and mammalian cell. They consist of a long chain of units called nucleotides, many of which encode, via a related molecule called RNA, for proteins through specific regions known as genes. A gene is a stretch of DNA, which normally includes non-coding regions as well as protein-encoding regions. RNA is made from DNA, and the non-coding regions are removed as the RNA is processed into mature messenger RNA (mRNA). mRNA thus contains the protein encoding regions of a gene. mRNA is unstable outside the cell so it is copied in the laboratory to produce the more stable cDNA.

Proteins consist of a chain (or sometimes linked chains) of amino acids, and, in mammals, they perform many essential functions in the body; they include, for instance, insulin and erythropoietin. There are four different nucleotides, and contiguous groups of three specific nucleotides in DNA encode either for a specific amino acid or to indicate...