Ethical Considerations and Patenting in Europe Ordre Public & Morality vs. Patents – Complex Relationship

1. CASRIP 2002 High Technology Protection SummitSeattle, July 20, 2002Ethical Issues in Patent Law Biotechnology and Research Ethics- A European Perspective – Joseph Straus, Munich • Ethical Considerations and Patenting in Europe • Ordre Public & Morality vs. Patents – Complex Relationship • Agreement on Trade Related Aspects of IPR (TRIPS) (1994) the Controlling Rule • EU-Directive on the Legal Protection of Biotechnological Inventions 98/44/EC (1998) & Implementing Regulations to the EPC (1999) • Patenting of Human Stem Cells as Most Recent Example • Outlook

2. Ethical Considerations and Patenting in EuropeExclusionary Provisions in EPC & National Laws • Methods for treatment of the human or animal body by surgery or therapy and diagnostic methods practised on the human or animal body – not however products, i.e. substances or compositions, for use in any of these methods.* [Art. 52 (4) EPC] • Inventions the publication or exploitation of which would be contrary to „ordre public“** or morality*** - simple prohibitions of exploitation not sufficient [Art. 53 (a) EPC] * Thus methods employed and products used in and resulting from somatic gene therapy and somatic cell therapy patentable. ** To be construed as referring to the most fundamental rules of the relevant legal order. *** To be construed as embracing only high-ranking and generally accepted ethical principles.

3. Ordre Public & Morality vs. PatentsComplex Relationship • Ordre public and morality depending on: • Actual state of science and technology (e.g. feasibility, safety, etc.) • Social acceptance of technology at hand • Can be changed and adapted accordingly at will • Patents • Exclusive rights granted for 20 years • No license to use the patented invention • Once an invention becomes state of the art – no patent protection available • Traditionally – no specific exclusionary provisions, but general clauses only – ordre public and morality – allowing flexible response – specific exclusions – allow no flexible response – if removed – no retroactive effects

4. Controlling TRIPS Rules • Patents must be available for any inventions in all fields of technology, without discrimination as to the place of invention or to the place of production – if the usual patentability criteria are met. [Art. 27 (1)] • WTO Members may exclude from patentability inventions if their commercial exploitation would violate ordre public or morality (protection of human, animal or plant life or health or environment) mere prohibition of exploitation not sufficient – in any case, commercialisation of such inventions may not be allowed!!! [Art. 27 (2)]

5. Controlling TRIPS Rules continued • WTO Members may further exclude from patentability inventions of diagnostic, therapeutic and surgical methods for treatment of humans and animals, .... [Art. 27 (3 (a)] • These principles of TRIPS are explicitly acknowledged in the EU-Directive 98/44/EC [Recital 12, Art. 1 (2)]

6. EU-Directive on the Legal Protection of Biotechnological Inventions 98/44/EC of 1998 and Ethics • The Commission‘s European Group on Ethics in Science and Technology evaluates all ethical aspects of biotechnology. [Art. 7] • The Group maybe consulted only when biotechnology is to be evaluated at the level of basic ethical principles, including such patent law issues. [Art. 7 Recitals 19, 44]

7. EU-Directive on the Legal Protection of Biotechnological Inventions 98/44/EC of 1998Excluded from Patentability • The human body at various stages of its formation and development – principle of non-commercialisation of the human body Art. 5 (1)] • Inventions, the commercial exploitation of which would be contrary to ordre public or morality – mere prohibitions not sufficient - as such considered, in particular: • Processes for cloning human beings • Processes for modifying the germ line genetic identity of human beings • Uses of human embryos for industrial or commercial purposes • Processes for modifying the genetic identity of animals likely to cause them suffering without any substantial medical benefit to man or animal and the resulting animals [Art. 6 (1) (2)]

8. EU-Directive on the Legal Protection of Biotechnological Inventions 98/44/EC of 1998Excluded from Patentability continued • Generally accepted rule: Excluded only if this being the only possible (claimed) use • Ordre public and morality correspond in particular to ethical or moral principles recognized in a Member State [Recital 39] • Consensus exists that the cloning of human beings offends against ordre public and morality [Recital 40]

9. EU-Directive on the Legal Protection of Biotechnological Inventions 98/44/EC of 1998Excluded from Patentability continued • Process for cloning human beings – any process, including techniques of embryo splitting, designed to create a human being with the same nuclear genetic information as another living or deceased human being [Recital 41] • Inventions for therapeutic or diagnostic purposes applied to the h-embryo and useful to it – not affected by exclusions [Recital 42]

10. EU-Directive on the Legal Protection of Biotechnological Inventions 98/44/EC of 1998However patentable continued • Elements of the human body, including sequences or partial sequences of a gene – if isolated or otherwise technically produced even if structure identical to the natural one [Art. 5 (2)] • Prior free and informed consent of the donor, in accordance with national laws required [Recital 26]

11. European Court of Justice (ECJ) on EU-Directive 98/44/ECCase C-377/98 of October 9, 2001 • Confirmed the legality of the Directive • Observed that the „ordre public or morality“ rule in principle allows patent offices and courts of the Member States a wide scope for manoeuvre in applying this exclusion • Observed that that scope of manoeuvre necessary to take account of the particular difficulties to which the use of certain patents may give rise in the social and cultural context of each Member State, a context which the national legislative, administrative or court authorities are better placed to undertake than are the Community authorities

12. continued European Court of Justice (ECJ) on EU-Directive 98/44/EC Case C-377/98 of October 9, 2001 • The scope left to Member States not discretionary, its limits: • Prohibition of exploitation not sufficient • Four specific – mandatory – exclusions • Fundamental Rights to human dignity and integrity observed and guaranteed[Art. 5 (1) (2), Art. 6] • Observed that the prior free and informed consent of the donor and recipient outside the scope of the Directive and to be dealt by other laws • Clarified that the Directive does not preclude legal limitations and prohibitions applying to research into patentable products or the exploitation of patented products – i.e., research exemption

13. Opinion No. 15 of the EU Group on Ethics in Science and New Technologies (EGE) of November 2000 • EGE recommended as regards human stem cell research and its uses: • To set up a strict public control by centralized authorities, on human embryo research where it is allowed; • To take measures to prevent commercialisation of human embryos or cadaveric foetal tissue; • To ensure the respect of ethical principles through the control of public authorities, concerning import of human stem cells.

14. Opinion No. 16 of the EU Group on Ethics in Science and New Technologies (EGE) of May 2002 • EGE observed that it would be contrary to public (and especially patients) interests, if patenting of stem cells or stem cell lines would be forbidden • Isolated stem cells which have not been modified do not, as product, fulfil the legal requirements for patentability. Moreover, such cells are so close to the human body, to the foetus or to the embryo they have been isolated from, that their patenting may be considered as a form of commercialisation of the human body • Unmodified stem cell lines can hardly be considered as a patentable product. They do not have a specific use but a very large range of potential undescribed uses

15. continued Opinion No. 16 of the EU Group on Ethics in Science and New Technologies (EGE) of May 2002 • Stem cell lines which have been modified by in-vitro treatments, or genetically modified so that they have acquired characteristics for specific industrial application, fulfil the legal requirements for patentability • Processes involving human stem cells, whatever their source, patentable • Applicants for a patent involving human stem cells should declare which is the source of the stem cells • Patenting of inventions allowing the transformation of unmodified stem cells from human embryonic origin into genetically modified stem cell lines or specific differentiated stem cell lines for specific therapeutic or other uses – ethically acceptable

16. continued Opinion No. 16 of the EU Group on Ethics in Science and New Technologies (EGE) of May 2002 • Donors should be informed of the possibility of patenting and they are entitled to refuse such use • Apart from justified compensation, donors should not get a reward which could infringe the principle of non-commercialisation of the human body • In addition to the research exemption, it is essential to secure that patents on stem cell lines are not too broad • EGE-considers that there may be also a need to make ethical evaluations in the course of the examination of patent applications involving specific ethical dimensions

17. UK Human Fertilization and Embryology Act (HFE Act 1990) and German Embryo Protection Act (EPA 1990) – Two Extremes • HFE Act administered by Human Fertilisation and Embryology Authority (HFEA) • prohibits cloning involving "replacing the nucleus of a cell of an embryo with a nucleus taken from a cell of any person" • permits licensed research on human embryos of up to 14 days of development The following constitutes criminal offence: carry out any treatment using h-embryos outside the body • use donated gametes • store any oocytes, sperm or embryos, or • undertake any research on h-embryo without a license from the HFEA • Somatic Cell Nuclear Transfer (SCNT) involving nuclear substitution into an unfertilized egg - not an embryo - not covered

18. continued UK Human Fertilization and Embryology Act (HFE Act 1990) and German Embryo Protection Act (EPA 1990) – Two Extremes • Guidelines (DOH, MRC) exist for using pluripotent stem celllines (imported into or developed in the UK) • HFEA may license such research only if necessary or desirable for either of the following purposes: • promoting advances in the treatment of infertility • increasing knowledge about the causes of congenital disease • increasing knowledge about the causes of miscarriage • developing more effective contraception techniques • developing methods for detecting the presence of gene or chromosome abnormalities in embryo before implantation • other purposes as may be specified in regulations by the Secretary of State, e.g. • developing methods of therapy for mitochondrial diseases • developing methods of therapy for diseased or damaged tissues or organs

19. continued UK Human Fertilization and Embryology Act (HFE Act 1990) and German Embryo Protection Act (EPA 1990) – Two Extremes • German EPA – Basic Principles • The prohibitions aimed at safeguarding human dignity and protection of life from its inception • Embryo any fertilized egg (oocyte) capable of development, from the fusion of nuclei, i.e. the fusion of chromosomes of an oocyte and a sperm cell leading to the formation of a novel individual genome • As embryo considered also all totipotent cells removed from an embryo, which have the innate capacity to divide and develop into an individual being provided that suitable further requirements are met

20. continued UK Human Fertilization and Embryology Act (HFE Act 1990) and German Embryo Protection Act (EPA 1990) – Two Extremes • Cloning a criminal offence: artificial generation of a human embryo with the same genetic information as another embryo, foetus, or human being, whether living or dead • Interference with the development of an embryo permitted solely if it serves the welfare of the embryo • Prohibited: • the preparation of ES cells from blastocysts • nuclear transfer into enucleated oocytes because a totipotent cell is generated • Allowed: • the removal of primordial germ cells from dead foetuses for scientific, therapeutical, or diagnostic purposes [Sec. 6,8; DFG interpretation]

21. Patent DE 197 56 864 C1 of April 29, 1999Inventor: Dr. O. Brüstle Neural precursors, method of production and use for therapy of neural defects Claims: • Isolated, purified precursor cells with neuronal or glial characteristics from embryonic stem cells1)2) containing at most about 15% of primitive embryonic and non-neural cells, obtainable through the following steps: a) culturing of ES-cells to embryoid bodies b) .... 5. Cells according to one of the Claims 1-4, whereby the embryonic stem cells from oocytes are obtained after a nuclear transplantation

22. continued Patent DE 197 56 864 C1 of April 29, 1999Inventor: Dr. O. Brüstle • Cells according to one of the Claims 1-4, whereby the embryonic stem cells are obtained from embryonic germ cells • Cells according to one of the Claims 1-6, whereby the cells are mamalian cells • Cells according Claim 7, whereby the cells are from the group encompassing mice, rat, hamster, pig, beef, primates or human being were isolated ..... • Method for the production of purified precursor cells ...., encompassing the following steps: a) culturing of ES cells to embryoid bodies, ....

23. Patent DE 197 56 864 C1 of April 29, 1999Inventor: Dr. O. BrüstleDefinitions • ES-cells can be obtained, e.g. from very early embryos in the blastocyst stage. These are totipotent cells, which can be kept in undifferentiated stage through many passages, and which possess the ability to differentiate in all tissues and cell types [Specification p. 4 l. 33-36] • The term toti-, pluri-, multi- and bipotent cells stands for precursor cells which differenciate in all (totipotent), many different (pluri- or multipotent) or two (bipotent) mature cell types. [Specification p. 4 l. 53-55]

24. Patent DE 197 56 864 C1 of April 29, 1999Inventor: Dr. O. BrüstleInterpretation by the German Patent Office • Production of totipotent cells by nuclear transfer - not covered by Sec. 8 EPA, because neither a fertilisation takes place nor is a totipotent cell removed from an embryo • The point in time of accomplishment of reprogramming of nucleus corresponding to fusion of nuclei cannot be established - whether this has taken place can only be demonstrated by later development into a mature individual • This does not apply here because purified precursor cells with neural and glial properties are produced and no viable individuals

25. Patent DE 197 56 864 C1 of April 29, 1999Inventor: Dr. O. BrüstleInterpretation by the German Patent Office • The "totipotent" cells of the invention are actually not totipotent because they were removed from the inner cell mass (Embryoblast) which without foreign blastocyst cannot develop into a mature individual • Embryonal germ cells of the invention are cells of Embryoblasts, which can differentiate into all tissues and cell types, but cannot form Trophoblasts and have, thus, lost the capability to develop into an individual • Inventor is not obliged to strictly observe legal definitions. Decisive is the meaning which an expert can derive from the description and whether the expert can successfully repeat the invention

26. Perspectives of Ordre Public and Morality in Future European Practice in Biotech Area • Direct linking of patentability with specific prohibitions of exploitation based on ethical considerations – doubtful approach • Harmonized interpretation of Article 6 EU-Directive 98/44/EC and the respective national patent law provisions needed - otherwise the Directive cannot achieve its goals • This includes the interpretation of such terms as "cloning", "human being" and "embryo" according to a "European Standard" • Key role of the European Court of Justice in future setting of standards

27. continued Perspectives of Ordre Public and Morality in Future European Practice in Biotech Area • Since a patent not a license to use - national regulatory provisions will continue to control the use - exploitation of the technology - but should also be harmonized • To avoid, or at least, reduce negative economic impact resulting from possible future changes of regulatory provisions (deletion of prohibitory provisions), patent law exclusions should be interpreted narrowly • Stem cell technology should be used as an example why the legislator should refrain from specific exclusions from patentability