Gene patents not dead yet

Dr Nina White, Partner, Boult Wade Tennant

This article first appeared in the MIP Life Sciences IP Focus 2009. Click here to read this article in PDF format.

Recent case law developments in the field of gene patenting, both before national courts and the EPO Technical Boards, have emphasised the importance of adequate functional charracterisation of a novel gene, or rather the protein it encodes, in order to cross the boundary from non-patentable discovery to patentable invention. Here we report on a number of key decisions that illustrate how the characterisation of "function" is essential to meeting the requirements for industrial application and inventive step.

Industrial application (Article 57 EPC)
For many years, instances of a European patent being revoked, or an application refused, for lack of industrial application (Article 57 EPC) were rare. In the case of gene patents, this all changed following the introduction of Rule 29(E) EPC, which expressly requires that the industrial application of a sequence or partial sequence of a gene must be disclosed in the patent application.  Rule 29(3) EPC is itself derived from Article 5(3) of the Biotechnology Directive (Directive 98/44/EC).

Recitals (23) and (24) of the biotechnology Directive indicate that adequate characterisation of the "function" of a gene is key to crossing the boundary between non-patentable discovery and patentable invention:

(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.

EPO case law on "function"
A number of EPO Technical Board of Appeal decisions address the question of what constitutes an adequate indication of function to satisfy the requirements of Artile 57 and Rule 29(3).

Case T 870/04, concerning the novel protein phosphatase BDP1, confirmed that merely because a novel substance (the BDP1 polypeptide) can be made, it does not necessarily mean that the requirements of Article 57 are fulfilled, unless there is also some profitable use for which the substance can be employed. Critically, use of the protein as a "research tool" to find out more about the specific function of the protein, and how this function might be translated to a profitable use, could not itself satisfy the requirements of Article 57. Case T 898/05, concerning a novel hematopoietic receptor, also confirmed that an "immediate concrete benefit" (of a novel gene product) must be derivable from the patent application without need for a research programme. There must be a real prospect of exploitation derivable directly from the specification.

In T 898/05 the Technical Board of Appeal noted that the "function" of a protein can be assessed at various levels, namely molecular function, cellular function and broad biological function. For the purposes of Rule 29(3), none of these levels of "function" was considered more important than the others. Nevertheless, the function that is described in the patent application must lead immediately to practical exploitation in industry without extensive further resarch, if this is not already obvious from the nature of the invention or the background art. By way of example, in case T 604/04, concerning a platelet factor 4 superfamily receptor, industrial applicability was acknowledged for novel protein assigned (on the basis of homology) to a class of cytokine receptor proteins with broadly defined well known biological function, even though the specific molecular function of the novel family member had not been confirmed in teh patent. In this case the "utility" of the protein was held to follow from its identification as a family member.

Thus, when determining if the requirements of ARticle 57/Rule 29(3) are met, it seems one needs to ask how far down the road from "interesting research result" to "immediate concrete benefit" the applicant/patentee had progressed before filing the patent application, and whether the disclosure in the patent application allows one skilled in the art to derive a real prospect of exploitation in industry, if this is not apparent from the nature of the invention and/or the background art. This is necessarily a subjective test, and in inter partes proceedings the outcome may well depend on the quality of experimental evidence supplied by the parties, including post-filing date evidence of the "true" function of the protein in question. In this regard, the use of traditional wet biology to confirm function is not necessarily essential; T 898/05 and T 604/04 indicate that bioinformatics (and homology to know proteins) can be used to assign function to a novel protein, provided the practical use of the protein is then immediately apparent without further research.

UK national law
The issue of industrial applicability in gene patents has also been considered by the UK High Court, in Eli Lilly v Human Genome Sciences ([2008] EWHC 1903). The case concerned an application for revocation of the UK national part of Human Genome Sciences' European patent (EP-B-0 939 804) with claims to the TNF ligand superfamily protein neutrokein-a.

HGS found neutrokine-a using bioinformatics, and identified it as a putative member of the TNF ligand superfamily. The patent included a long list of predicted biological functions and proposed uses of neutrokine-a relating to B cell and T cell function and an unspecified role in regulating immune and inflammatory response, but contained little in the way of experimental support. Eli Lilly claimed that the proposed uses were speculative, and that HGS had filed claims to the neutrokine-a polypeptide without knowing its "true" biological function. The specific function of neutrokine-a as a TN ligand family member in relation to B cells, and the theraputic potential of antibodies to neutrokine-a in the treatment of B celld isorders, was not determined until after the filing date of the patent.

In revoking the patent for lack of industrial application (S1(1)(c) Patent Act 1977), Mr Justice Kitchin held that the patent did not disclose a practical way of exploiting neutrokine-a beyond speculation, nor was this immediately apparent from the nature of the invention or the background art. In contrast to T 604/04, identifying neutrokine-a as a novel member of the TNF ligand family did not allow one to immediately derive a specific function for neturokine-a, nor provide a solution to a specific technical problem. Thus, while it might have been reasonable to assume that any new TNF ligand superfamily would find some practical exploitation in industry, Kitchin has set the bar rather higher; requiring that the specific way in which neutrokine-a can be exploited should have been disclosed i the patent. In simple terms, at the time the patent was filed HGS had not progressed sufficiently far down the road from interesting result to concrete benefit and too much further research was needed before the pharmaceutical relevance of neutrokine-a, or rather antibodies to it, became apparent.

Questions to be answered
It is now clearly established that patent applications with claims to novel proteins must contain adequate functional characterisation to meet the requirements of Article 57, and the equivalent provisions of national law (at least in the UK). Industrial application is also now a useful weapon in the armoury of those seeking to invalidate unduly speculative gene patents, particularly those granted before the biotechnology Directive provisions were introduced into the EPC.

Several questions remain to be answered. In particular, it is not clear whether the requirements of Article 57 must be met at the priority date or the European filing date. Also, it is unclear what the legal situation will be if the "function" claimed for a particular protein on filing is later shown to be incorrect.

Inventive step (Article 56 EPC)
Inventive stop is one of the basic requirements for patentability in biotechnology, as it is in every other area of technology.
 Across all technical disciplines, EPO examiners are expected to apply the probelm-and-solution approach to assessing inventive step.

In applying this approach it is necessary first to identify the closest prior art in the same technical field as the invention. One must then formulate the ojective technical problem to be solved based on the disclosure of the patent application and the closest prior art. Finally, one must decide whether a person of ordinary skill in the art would (not could) have arrived at the claimed solution from the closest prior art (alone or in combination with general knowledge or with another piece of prior art).

In the case of gene patents, application of the probelm-solution approach can lead to claims to genes encoding novel proteins, and the proteins themselves, being held to lack inventive step due to inadequate functional characterisation.

This principle is illustrated by the EPO opposition proceedings on EP-B-0 939 804 - the Human Genome Sciences patent on neutrokine-a which forms the basis of the Lilly v HGS judgement discussed above. At the same time as bringing the UK revocation action, Lilly (and others) also filed an opposition against the grant of the patent centrally at the EPO.

In opposing the patent Lilly argued that claims to the neutrokine-a polypeptide, and the polynucleotide that encoded it, lacked inventive stop in view of known TNF superfamily members.

Lilly argued that the closest prior art had to be a document describing other members of the TNF ligand superfamily. According to Lilly, the technical disclosure in the patent was insufficient to demonstrate that neutrokine-a was, in fact, a member of the TNF ligand sueprfamily, or to demonstrate the particular function of neutrokine-a. It followed that the "problem to be solved" was the provision of a new protein with structural motifs characteristic of the TNF ligand superfamily. The neutrokine-a protein was simply an arbitrary solution to this problem, since the patent failed to demonstrate a particular function for the protein.

The Opposition Division (OD) found that claims to neutrokine-a lacked inventive step, based on an assessment of the "technical contribution to the art" provided by the patent. According to the OD< the only contribution to the art was the provision of a putative further member of the TNF ligand superfamily which was "devoid of any useful properties which might justify the acknowledgement of an inventive activity".

It is not entirely clear whether the OD conisdered the "problem" of providing a noel TNF ligand superfamily member to have been solved or not, based ont he technical evidence in the patent. Nevertheless, this may have been irrelevant for the outcome before the OD. If the "technical problem to be solved" was viewed simply as providing a novel member of the TNF ligand superfamily, then claims to neutrokine-a may have been considered bovious, even if the problem were solved. Since the TNF ligand superfamily was so well known at the priority date, it may well have been obvious to a person of ordinary skill to clone new members of the family, and later characterise their particular properties and biological roles. The outcome may depend on whether a person of ordinary skill in the art would have had a reasonable expectation of success in cloning neutrokine-a using techniques available at the priority date.

In order of the OD to have found neutrokine-a inventive under the problem-solution approach, it might perhaps have been necessary to set the "problem to be solved" as more challenging: providing a TNF sueprfamily member with a particular biological function. The OD seemingly considered that limited technical data in the patent was insufficient to allow a skilled person even to determine what this more challenging problem should be, let alone demonstrate that the problem had plausibly been solved. It should be noted, however, that this decision is under appeal.

Old patents on shaky ground
It is very clear that, in the biotech field, claims to a novel protein (and the gene which encodes it) will be judged patentable or not based on the "technical contribution to the art" which the protein provides. Adequate characterisation of the "function" of the protein at the molecular, cellular or biological level is essential to meeting the requirements for patentability in Europe. Claims to proteins with inadequate, or unduly speculative, functional characterisation are likely to be held invalid for lack of industrial application and/or lack of inventive step.

While reports of the demise of gene patents in Europe may be premature, there may well be old gene patents standing on somewhat shaky ground in view of the standards being set by the recent case law.

Dr Nina White, Boult Wade Tennant, nwhite@boult.com