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13 April 1994
Doc. 7068
1403-12/4/94-13-E
OPINION
on the protection and patentability
of material of human origin1
(Rapporteur: Mr BIRRAUX,
France, Group of the European people's party)
I. Introduction
First of all, the subject of discussion requires clarification in order to avoid any confusion and define the area under consideration. For a number years, public opinion has been preoccupied with a growing number of processes all deriving from the biological sciences, such as genetic engineering, biotechnologies and human genome analysis. Even though practical reasons have caused a tendency to examine all these activities under the generic term "bioethics", needless to say very marked shades of difference exist between the various types of process. The problems raised and the solutions proposed are not and cannot be the same for applications of biotechnologies to plants, animals and human beings respectively.
The first two applications have already been the subject of pronouncements in many different quarters, including the Parliamentary Assembly, having regard to their economic, social, legal, ecological and not least ethical implications. Biotechnologies applied to human beings, despite certain features in common with the above, undoubtedly display fundamental contrasts calling for separate examination and highly circumspect recommendations.
The report submitted by the Committee on Social, Health and Family Affairs to the Assembly and referred to us for opinion is confined to scientific research and its applications to humans. Although the title is not very explicit in this respect, the actual subject of the report is the patentability of human genes and DNA sequences, or of the human genome to use a broader term. The final title of the report will possibly be altered for a more accurate reflection of the real issue, for example "Protection and patentability of living matter of human origin".
The question demands a speedy reply not only because researchers cannot keep on working in a legal vacuum but also and above all because potentially enormous scientific, technological and commercial interests are involved. Europe cannot afford to be outstripped by the United States and Japan in a field which is at the leading edge of modern science. It must therefore find an avenue reconciling scientific progress with technological competitiveness while meeting the ethical demands of its public.
II. Scientific research concerning the human genome
A survey of scientific research on the human genome may aid comprehension of the possibilities available in this field as regards therapeutic, genetic, technological and other applications. Any legal and ethical treatment must be interpreted and assessed against this background.
Investigation into the material basis of genes and how they act has been one of the major focuses of biological research over the last half century. Studies of inheritance and of the dramatic effects of gene mutations foreshadowed two major discoveries, firstly the chemical basis of the gene is DNA and secondly that genes specify the synthesis of proteins. These crucial landmarks opened up the fields of molecular and biochemical genetics and led in turn to the development of novel recombinant DNA technologies which provided new approaches to many unsolved problems, such as the organisation of genetic information in eukaryotes, the regulation of embryonic development, differentiation, antibody production and vaccine development, as well as the molecular structure of proteins. Recombinant DNA techniques also permitted the production of proteins in prokaryotes and eukaroytes, the isolation, analysis and manipulation of individual genes, detection of genetic defects leading to heritable conditions, and ways of detecting an affected foetus or carriers at risk of producing an affected offspring. Indeed, a multibillion ecu biotechnology industry is emerging to exploit the potential of recombinant DNA.
As more and more genes were mapped and sequenced it became clear that a valuable resource was being generated that could have a major impact on basic research as well as health and disease. A programme to map, sequences and interpret proteins, and thereby to understand the genetic basis of homo sapiens, was thus conceived. The task is exciting, vast and will promote more in the way of co-ordinated national and international research collaboration than anything that has gone before. It is claimed that the human genome programme is the largest biological science venture of all time; the implications for mankind of understanding the human genetic blueprint will certainly be vast.
The human genome consists of some 3 thousand million bases on twenty-four distinct chromosomes; it is believed these compose some fifty to one hundred thousand genes. At present only 2% of the genes has been assigned specific chromosomal locations. The aim of the Human Genome Programme is to locate the position of all of the DNA and to decode the genetic information contained therein; this will of course include aberrant information present in disease genes. Strategies centre on construction of the genetic map, the physical map and ultimately the complete DNA sequence.
New research technologies developed as a consequence of the human genome programme will benefit research in many areas of biology and medicine, such as cell growth and organ development, morphogenesis and ageing. Gene sequence data will aid basic science through the design of drugs, receptors and diagnostic reagents, such as probes for genetic disorders and for blood or tissue identification. Industrial processes involving the use of bacteria, yeasts or fungi could be improved through the construction of improved strains, while both agriculture and animal husbandry could benefit from the development of species suited to particular environments (some countries express reservations over the ethics of such activities, however). The translation of DNA sequence into protein sequence and the understanding of protein structure and function will also advance more rapidly as a consequence of genome research. It is absolutely crucial that Europe has the opportunity to make a competitive contribution to these major scientific advances.
It is anticipated that the human genome programme will also aid the understanding of many of the genetic diseases that afflict man and will in turn facilitate their treatment. Of the four thousand or so single gene disorders now known, less than 10% are understood at the genetic level. A final scale human map will permit localisation of disease genes, while their sequences will ultimately reveal function. Data generated by the project will also facilitate complete understanding of diseases that are not primarily due to genetic disorders, since it is the protein products of genes which are involved in pathogenesis, defence mechanisms and normal development. The end point of genome research is also worth stressing, for this will encompass both the generation of information for counselling on severe genetic disorders and the production of screening kits for those diseases, and only those diseases, where a clear health benefit can be perceived. Health services must be prepared for the implementation of these applications.
The human genome analysis programme will rapidly increase our knowledge of the chromosomal location of defective single disease genes. Amongst those already identified are the genes for cystic fibrosis (chromosome 7) Duchenne muscular dystrophy (chromosome X), polycystic kidney disease (chromosome 16), Huntington's disease (chromosome 4), retinoblastoma (chromosome 13) and familial Alzheimer's disease (chromosome 21); many of these can now be detected during pregnancy. The ability to detect individuals who are carriers for specific gene defects will also facilitate epidemiological studies of the risks associated with environmental or occupational factors. Problems of susceptibility to cadiovascular heart disease, "essential" hypertension, some forms of cancer, diabetes, schizophrenia, multiple sclerosis and mental retardation will be resolved more easily and may well benefit from international co-operative efforts.
Opportunities opened up as a consequence of human genome analysis include:
i. better risk detection and diagnosis either through the techniques of molecular genetics, or through use of biochemical, immunochemical, histochemical and other techniques to detect phenotypic abnormality in genetically determined disorders;
ii. identification and better knowledge of gene products, with opportunities for improvements in diagnosis, better drug design and gene therapy where there is a clear health benefit;
iii. better understanding of disease, which will not only contribute to more precise diagnosis and more satisfactory treatments, but also offer potential opportunities for identifying methods for prevention and/or avoiding the serious complications of established diseases. There may be considerable opportunities in relation to those common disorders in which genetic factors play a role.
The informatics requirements of the initiative will lead to the development of new hardware, software, networks, robotics, database management and information retrieval systems that will have far reaching applications beyond genetics and disease. In terms of economic benefit, it might be possible to commission industrial companies to organise information generated by the genome programme and then offer the data for purchase by interested parties. Finally, since a considerable amount of the routine work inherent to the programme can be undertaken by non-academics, there are attractive opportunities in terms of long term employment for skilled and unskilled labour. There are areas that Europe cannot afford to neglect.2
III. The international situation
Eight countries in all have human genome analysis programmes, some more ambitious than others: Denmark, France, Germany, Italy, Japan, Russia, United Kingdom, United States. The United States and the United Kingdom were long in the forefront of research. In other countries such as Australia, Canada, Sweden, South Korea, the Netherlands and Sweden, new programmes are being introduced (see Appendix I).
In order to co-ordinate research and assist international data exchange, the Human Genome Organisation (HUGO) has been set up with its headquarters in Geneva. In addition, the framework programme for Community research and technological development includes substantial amounts for genome analysis over the period 1994-98.
This programme makes provision for co-operation with the EFTA countries and also with those of central and eastern Europe (COST). Where the Community countries are concerned, the Commission's contribution will undoubtedly help match Europe's strength more equally with that of the United States and Japan, which spent ecu 150 million and ecu 30 million respectively on their national programmes in 1992.
On the other hand, the degree of co-ordination achieved in the United States has yet to be attained in Europe, where research definitely suffers from fragmentation and disparate legal and ethical contexts.
IV. Why the question of a patent?
In general, a patent follows the principle of a fair return for the R and D investment made. In other words, it constitutes recognition of an effort (intellectual property) and an economic incentive to research. The dictionary definition reads "a grant from a government [or nowadays an international organisation] to a person or persons conferring for a certain definite time the exclusive privilege of making, using or selling some new invention".3 An intellectual process or a mathematical theory is not patentable.
The patentability of living matter had never come up since the occasion in 1873 when Louis Pasteur was granted a patent for a yeast free from organic germs. The early warning sign was the filing of an application in the United States in 1988, subsequently granted, to patent the "HARVARD" mouse, a transgenic mouse used in cancer research. This involved the case of an organism isolated and transformed by the inventor to perform a function which it did not have under natural conditions. The requirements of the Patent and Trademark Office USA and of the EPO (European Patent Office) were apparently satisfied.
Not long afterwards in 1991 and 1992, again in America, Dr Venter, who heads the national human genome project, filed on behalf of the National Institutes of Health (NIH) a patent application concerning a total of 2 400 ESTs (expressed sequence tags), which are DNA fragments from the human brain. Several applications were subsequently filed in Europe. Some 20 000 ESTs are now stored in databases. The patent applications say nothing about the specific use of the ESTs or of the corresponding genes, but make reference to hypothetical uses.4
At this point the complications start, firstly because application for a patent in respect of parts of the human body is a qualitative departure for which professional and public opinion is unprepared as yet, and secondly because ethical problems are raised by a patent application for a discovery of unknown practical utility and technical applicability. This verges on a crisis in scientific ethics, so that the EPO's extremely cautious approach to such cases is understandable and justified.5
The fact remains that the criteria set forth in the European Patent Convention of 5 October 1973 are becoming dated. Firstly, the distinction between the discovery of a substance present in nature and a technically applicable invention is now more imprecise than ever. Secondly, the staggering development of the sciences renders the former distinction between micro and macro-biology inoperative. Lastly, the reservations involving ordre public stated at the time are incomplete and no longer in line with ethical concerns and fears of chimera production, for instance, or embryo cloning.
V. Future action
It is for the very purpose of filling the gaps in the European Patent Convention that other initiatives are afoot: clauses of somewhat general purport in the draft European convention on bioethics in preparation at the Council of Europe; a draft directive under consideration by the European Community, on which the European Parliament has already given its opinion. As these two texts are closely and very thoroughly analysed in the report by Mr Monfils, we need only comment on the two essential points below:
1. The fundamental debate on technologies of living matter cannot be confined to the sphere of patent law. The Community directive is useful but insufficient. A draft protocol to the European Bioethics Convention must be put in hand in order to establish a regulatory and ethical framework for the debate.
This is the report's essential message, which we fully endorse. The reports before us necessarily constitute the intellectual basis for the future protocol. It is harder to go along with the claim made by Mr Monfils that it should rest with the legislator alone to determine society's current state of mind and prevailing morality. This extremely difficult undertaking requires a combined effort by all sectors of society, the media and the scientific community.
2. A distinction must be drawn between the human body as such, its complete genome and its parts and components such as cells, genes and gene sequences, the latter being patentable in certain cases.
In our opinion it would not be difficult to reach a consensus on this point, considering the outcry and the wave of reactions aroused by the news of hypothetical cloning of human beings.
The question of the patentability of the whole human genome is in any case hypothetical. The human genome contains an estimated 100 000 genes, but their aggregate length represents a mere fraction of the aggregate length of human DNA. Consequently, the present requirement is to establish the conditions under which genes and gene sequences may be patentable.
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The collapse of the conventional distinction between basic research and its applications, often referred to as technological developments, complicates the legislator's task. The dividing line between the principle of a research project's "public benefit" and its commercialisation has become very narrow. The "globalisation" occurring in all realms of life means that Europe cannot conduct its enquiry into the protection of the human body without reference to events in other parts of the world. We have learned caution from scientific experiments now buried in the past, such as eugenics. Conversely, European history also records cases of undue conservatism and hesitation retarding scientific and industrial progress.
The "bioethical" debate opened in Europe barely fifteen years ago is not yet sufficiently advanced to provide flawless theoretical insight. It is hoped that the European convention, most likely to be opened for signature in 1994, will constitute one of the foundations for such insight. Meanwhile, observance of certain criteria regarding the patentability of parts of the human body may represent a workable compromise.
The main consideration is the rule of establishing whether or not a "human inventive step"6 has been made. A joint statement recently adopted by the ESF7 and the European Molecular Research Centre (EMRC) bears this out:
"Work on human genome sequencing has great potential both for the advancement of the understanding of fundamental human biology and for advances in health care and prevention. The scientific and industrial communities and the public at large are best served when this potential can be realised through full international collaboration and a free flow of information. We take the view that progress would be greatly facilitated by an international agreement that no country should seek patents on genome sequences of unknown utility identified as a result of publicly funded research."8
The scope of the statement is limited to publicly funded research, for the simple reason that the jurisdiction of the international institutes forming the nucleus of the organisations in question does not extend to the private sector. This ethical stance displays wisdom and self-restraint. It should ideally be shared by scientific communities throughout the world.
In the light of the above, your Rapporteur for opinion would like to add the following comments:
—un der point 13 (iii) it is proposed that the drafting of the protocol to the convention be assigned to the "Steering Committee on Bioethics" (CDBI).Th
The Rapporteur feels here that, in view of the importance of the issues at stake, the representatives of the Parliamentary Assembly of the Council of Europe who, it should not be forgotten, shape legislation within their own parliaments, would wish to be closely involved in this work. This is the point of Amendment No. 1.
Similarly, the Rapporteur is moving Amendment No. 2, to point 14 of the draft recommendation, so that elected representatives may play a role in supervising applications for patents relating to living material processed by the European Patents Office. Clarification is also required as to the prohibitions listed as examples under point 13 of the draft recommendation. It should be made clear what, implicitly, is not authorised.
Generally speaking, the Rapporteur hopes that the work in progress will be considered in the light of the principles that have underpinned the Council of Europe since its founding in 1949: the respect and safeguarding of human rights. In view of its traditions and reputation, the Council of Europe must, in our view, exemplify the vigilance which must predominate in order to ensure respect for the rights of human beings at all stages of their development.
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Amendment No. 1
In the draft recommendation, under point 13, paragraph iii :
After the words: "assign the drafting of the protocol to its Steering Committee on Bioethics (CDBI) ...", add the words:
"— in which the Assembly should be represented and the work of which will be discussed by the Parliamentary Assembly of the Council of Europe —" leaving the rest unchanged.
Explanation
It is indispensable that elected representatives be closely involved in the decision-making process given the serious ethical issues at stake.
Amendment No. 2
In the draft recommendation, under point 14 :
After the words: "... annual report on decisions ...", add the words: "— with whose work the Parliamentary Assembly should be associated — ...", leaving the rest unchanged.
Explanation
Elected representatives must be closely involved in the processing by the European Patents Office of applications for patents relating to living material.
APPENDIX I
Bibliometric Analysis of Genome Research - Human
Histograms showing the percentage share of articles on genetic mapping published in European Community countries and all countries of the world.
APPENDIX II
The "normal" patent application on human genes: present situation9
The "normal" cases referred to above are those in which human genes or DNA sequences are used as means for expressing in a host certain useful products such as tPA, the interferons, interleukins, growth hormone, insulin or the relaxins. In these cases the respective gene has been identified to encode a certain useful protein and the invention relates to the technical use of this finding. The European Patent Office has developed a practice with regard to these kind of cases which is to allow claims to human genes or DNA sequences in the genomic form or in the form of cDNA because they are an integral part of the overall invention yielding useful products. It is not at present considered appropriate for the purpose of patentability to distinguish between cDNA, genomic DNA and complete genes because all of these forms of DNA are equally suitable for obtaining the desired proteins in conventional methods of recombinant gene technology. Moreover, in some cases as in the one of alpha-interferon the genomic and cDNA are identical and a distinction would not be meaningful.
The European Patent Office never considered it necessary in the past to apply ethical considerations with regard to claims for human genes or DNA sequences of the above type. The prime reason for this is that patents can only be granted in relation to technical inventions and the effect of a patent on human genes or DNA sequences is restricted to the exclusion of others from using the genes or DNA sequences in an industrial process. Moreover, the personality of human beings is not affected at all if human genes are protected by a patent for a technical purpose. Quite to the contrary it could be argued that it would be immoral to prohibit patent protection on human genes or DNA sequences because there would be less incentive for the provision of valuable medicaments which in large amounts are available only with methods of genetic engineering.
One argument against the patenting of human genes is the alleged possibility that a proprietor of such a patent could inhibit further technical use of these genes in another technical field, particularly somatic gene therapy, and that in such a case the proprietor would have to be compensated without any contribution. This argument is not convincing because the identification of the gene may be considered a first contribution even for somatic gene therapy. The latter may not be possible without the findings of the first invention. Moreover, dependent patents exist in all technical fields and it has been the political intention of the legislator to provide for these. Otherwise the legislator would have introduced use-restricted rather than absolute product protection and, to a large extent, would have avoided the alleged problem. This has not been done.
Another argument against the patenting of human genes is that the gene is a discovery and therefore not eligible to patent protection in accordance with Article 52.2.a EPC. In this regard the practice of the European Patent Office is as follows: The finding of a substance freely occurring in nature is a mere discovery and therefore unpatentable. However, if a substance found in nature has first to be isolated from its surroundings and can be properly characterised and is "new" in the absolute sense of having no previously recognised existence, then the substance per se may be patentable provided a technical use has been found for it. Exactly this is the case with regard to the type of inventions referred to above.
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Reporting committee: Social, Health and Family Affairs Committee.
Committee for opinion: Committee on Science and Technology.
Reference to committee: Doc. 6661 and Reference No. 1804 of 30 September 1992.
Opinion: approved by the committee on 12 April 1994.
2 1European Science Foundation: Report on Genome Research 1991.
3 1The Shorter Oxford Dictionary.
4 2Dr Christian Gugerell, Director, EPO, statement at the 2nd European Symposium on Bioethics, Strasbourg, 1993.
5 3Appendix II contains a summary of current EPO practice as to the grant of patents covering human genes.
6 1Dr José Elizalde, Directorate DGXII of the Commission of the European Communities. Document presented at the Council of Europe Symposium on Bioethics, Strasbourg, December 1993.
7 2European Science Foundation.
8 3ESF/EMRC Statement on the patentability of the human genome, 13 December 1993.
9 1European Patent Office: Excerpt from the document presented at the Symposium on Bioethics, Strasbourg, December 1993.