Stem Cell Patents
Current Issues in Europe

Andrew R N Clements & George W Schlich

Stem cell research is a highly promising source of new therapeutic treatments for a number of diseases, and offers new insights into fundamental biological processes. Not surprisingly, stem cell research has also generated a large number of patent applications, as researchers and inventors seek protection for their inventions. A recent search of all US patents that use the terms "stem cell(s)", "progenitor cell(s)", "precursor cell(s)", "multipotent cell(s)", "pluripotent cell(s)" or "totipotent cell(s)" in their claims identified more than 1,400 patents (1). In Europe, more than 560 patent applications containing one or more of the same terms have been published in the last 24 months alone, and it is likely that many more such applications have been filed in the same period.

Where rights held by different parties overlap or complement one another (e.g. rights in respect of a particular type of stem cell and rights in respect of methods for deriving or expanding such stem cells) further work, particularly work directed to commercial ends, is likely to require licences to be granted and taken by multiple parties. It is also likely that, in future, the validity of many granted patents may be challenged to avoid the need to take such licences and avoid infringement.

However, significant litigation of stem cell patents has yet to be reported in Europe or the US. In Europe, the focus remains on the acquisition of patent rights and legal activity has focused on the prosecution of patent applications and the defence of granted patents in post-grant opposition proceedings. The legal arguments have frequently focussed on moral issues, especially in connection with embryonic stem (ES) cell-related inventions, and the consequent decisions of the Boards of Appeal of the European Patent Office (EPO) are likely to significantly influence the scope of protection available in Europe for stem cell-related inventions.

ES cell patents and the EPO

Of course, patent applications in respect of ES cell-related inventions must satisfy the same legal requirements as applications in respect of any other subject matter. However, certain legal provisions of the European Patent Convention (EPC) are particularly pertinent to ES cell-related inventions or have frequently been invoked in relation to such applications.

In particular, the EPO and third parties seeking to oppose stem cell-related patents have frequently invoked Article 53(a) EPC, which states that European patents shall not be granted in respect of:

• inventions, the publication or exploitation of which would be contrary to 'ordre public' or morality, provided that the exploitation shall not be deemed to be so contrary merely because it is prohibited by law or regulation in some or all of the Contracting States.

This provision has traditionally been interpreted narrowly, so as to exclude only inventions which, if published or exploited, would be so abhorrent to the public in general that the grant of patent rights would be inconceivable. Moreover, when there has been genuine divergence of opinion across the EPC member states, the morality provisions have generally not been applied. For example, the non-binding statement of the Opposition Division in the Relaxin case (2) was that "Only in those very limited cases in which there seems to be overwhelming consensus that the exploitation or publication of an invention would be immoral may an invention be excluded from patentability under Article 53(a)". However, this position seems to be subject to some movement when the subject matter relates to ES cells.

In addition, provisions originally provided in the Biotechnology Directive 98/44/EC were imported into the EPC in September 1999 as Rule 23d, which provides a non-exhaustive list of biotechnological inventions that are to be excluded under the morality provisions of Article 53(a) EPC. Notably, these exclusions include:

• (c) uses of human embryos for industrial or commercial purposes.

As will be seen below, this provision has frequently been invoked against ES cell-related patents and applications, whether or not the claimed invention explicitly requires the use of human embryos. This approach is perhaps best seen in relation to two specific cases: European patent no 0695351 ("the Edinburgh patent") and European patent application no 96903521 ("the WARF application").

The Edinburgh patent

European patent no 0695351 was granted by the EPO with claims directed to methods of isolating, enriching or selectively propagating animal stem cells present in a mixed population of cells, by means of the differential expression of a selectable marker gene in the stem cells of interest and other cell types. One application of this method is the isolation of ES cells, including human ES cells, from a mixed population of cells.

The patent was opposed by fourteen opponents, all of which cited the morality provisions of Article 53(a) EPC. The arguments focussed on whether the exclusion of uses of human embryos for industrial or commercial purposes under Rule 23d(c) covered only uses of human embryos as such, or whether it also covered cells retrieved from embryos using methods that require destruction of the embryos, i.e. human ES cells. The Opposition Division ruled that the latter interpretation of the exclusion was correct, and required amendment of the patent claims to exclude any methods covering the isolation or purification of human ES cells, although the claimed invention did not explicitly require any use of human embryos. This decision is currently under appeal.

It is noteworthy that the Opposition Division recognised that there was considerable divergence amongst EPC contracting states as to the moral acceptability and legality of human ES cell research. However, the Opposition Division's concern that, at the time of the original patent application, human ES cells were only obtainable using methods that involved the destruction of a human embryo was considered to be a significant factor. This ultimately led to a broad interpretation of Rule 23d(c) and application of the EPC's morality provisions, even in the absence of a moral consensus.

The WARF patent application

Similar concerns over the origins of human ES cells have influenced the prosecution of the WARF patent application, which includes claims directed to a cell culture containing primate (including human) ES cells. The application was refused by the Examining Division (3) under the morality provisions because the claimed human ES cells could not have been produced without destruction of human embryos when the application was filed, and this amounted to commercial use of human embryos. Furthermore, the Examining Division determined that the exclusion of Rule 23d(c) was not directed at the claimed subject matter, but the invention as a whole. Thus, according to the Examining Division, it was irrelevant whether the claims were directed to human ES cells as such or to methods for obtaining ES cells.

The applicant appealed this decision, and as a result of this appeal a number of legal questions were referred to the EPO's Enlarged Board of Appeal , the highest authority within the EPO, namely:

1. Does Rule 23d(c) EPC apply to an application filed before entry into force of the rule?
2. If the answer to question 1 is yes, does Rule 23d(c) EPC forbid the patenting of claims directed to products (here: human embryonic stem cell cultures) which - as described in the application - at the filing date could be prepared exclusively by a method which necessarily involved the destruction of the human embryos from which the said products are derived, if the said method is not part of the claims?
3. If the answer to question 1 or 2 is no, does Article 53(a) EPC forbid patenting such claims?
4. In the context of questions 2 and 3, is it of relevance that after the filing date the same products could be obtained without having to recur to a method necessarily involving the destruction of human embryos (here: e.g. derivation from available human embryonic cell lines)?

The arguments are likely to focus on questions 2 and 3, and it is clear from the large number of third party opinions submitted to the EPO (by individuals and political, legal, commercial, academic, environmental and religious organisations and institutions) that there are strongly held and diverging views on these questions. The submissions of the UK Patent Office (4) are noteworthy for their generally balanced and positive approach to these questions. For example, it favours a narrow interpretation of the exclusion of uses of human embryos for industrial or commercial purposes that does not extend to the products (e.g. human ES cells) because the exclusion of Rule 23d(c) EPC cannot have been intended to prevent the patenting of inventions in areas beyond the bounds of the limited moral consensus between legislators of different EU states when the Biotechnology Directive was drawn up. In addition, it has been submitted that there is no consensus that use of human ES cells is immoral because of their origins, and there is no reason to believe that the use of such cells (e.g. in research or therapy) would be regarded as contrary to conventionally accepted standards in European society as a whole. However, the EPO Enlarged Board has given no indication of its likely decision to date.

ES cell patents and the UK Patent Office

The submissions of the UK Patent Office in relation to the WARF appeal are indicative of a divergence of approach to stem cell-related patents between the EPO and the UK Patent Office. Thus, despite the substantial harmonisation of European patent laws, differences in interpretation may permit patent protection to be obtained in at least some European countries. It remains to be seen whether the current interpretive differences will persist in the longer term, particularly in light of the expected decision of the EPO Enlarged Board of Appeal in relation to the WARF patent application.

The UK's more positive attitude to stem cell patents is consistent with the generally supportive environment for ES cell research currently found in the UK. Thus, whilst the UK Patent Office will not grant patents with claims covering processes for obtaining stem cells directly from human embryos or to totipotent human cells (as such cells retain the potential to develop into an entire human body), it will grant patents with claims directed to human pluripotent cells, including ES cells. In particular, it is a matter of record that the Patent Office recognises the enormous potential of stem cell research and that the exploitation of inventions relating to human embryonic pluripotent stem cells would not be contrary to public policy or morality in the UK.

Outlook

The outcome of the WARF appeal is likely to have significant effect on the stem cell patent landscape in Europe. It would also seem probable that following this decision we will see a greater emphasis on exploitation and enforcement of stem cell patent rights. This may herald a period of increased litigation, especially if aggressive licensing policies are adopted or maintained by key holders of stem cell-related patents.

References

(1) Robert W Esmond, Robert A Schwartzman and Ted J Ebersole (2006). Intellectual Property and Technology Law Journal 18: 1-4

(2) Howard Florey Institute of Experimental Physiology and Medicine: Opposition Division Decision OJEPO (1995) 6: 388-407

(3) Interlocutory Decision of Technical Appeal Board T1374/04 re European patent application No 96903521.1, Wisconsin Alumni Research Foundation

(4) http://www.patent.gov.uk/warf.pdf

Correspondence

Andrew Clements
Schlich LLP
34 New Road, Littlehampton
West Sussex BN17 3AT, UK
Tel: +44 1903 717 001
Fax: +44 1903 717 002
Email: andrew.clements@schlich.co.uk