- Email: [email protected]
Brüstle Decision Is Unhelpful, but Not Catastrophic
Cell Stem Cell
Letters Court ruling on EU companies will vary depending on their specific circumstances. Companies that would have faced a freedom to operate problem because of hESC patents held by others may now be more likely to start, or continue, hESC research programs because the Court’s ruling renders such patents unenforceable. Companies working on the ‘‘improvement’’ of hESC related-technologies, for instance, which would have faced patent infringement litigation or would have had to pay royalties, may find themselves more incentivized to perform hESC research in the EU following the Court’s ruling. By contrast, companies holding foundational hESC inventions might be incentivized to work in jurisdictions that offer patent protection for hESC inventions (e.g., the USA). Despite the Court ruling we believe that sponsors of hESC-based therapies will locate trials in Europe for a number of reasons. Companies developing hESC therapies will ultimately desire to sell their products on the European market. The EMA may require data from European clinical trials before it approves of any future hESC-derived therapy. Moreover, recent studies suggest that over 50% of products headed for FDA approval are in clinical trials that involve foreign study sites (Levinson, 2010). Finally the possibility that some companies could be attracted to Europe
because of this decision cannot be discounted. Although the Court ruling does not directly impact the patentability of hESC inventions in the U.S., it will have a ripple effect there. American companies facing a freedom to operate problem because of U.S. patents held by others may now reconsider their business plans. Moving their research operations to Europe becomes a more attractive option because the EU counterparts of those patents are no longer enforceable. These companies will balance the benefit afforded by the new EU patent landscape against the protection that the Hatch Waxman Act provides for certain research activities in the U.S. and the significant costs of moving an already established and ongoing research operation. A cost differential that disfavors the U.S. as an alternative to the EU may incentivize companies to consider moving their trials and preclinical efforts to places such as India or China. As Yogi Berra once said, ‘‘It’s tough to make predictions, especially about the future.’’ Everyone will need to wait and see how various stakeholders in the research community actually respond to the Court’s ruling. Nevertheless, we are confident that the reaction will be dependent on many individual variables. As a result, we expect that some of the currently critical hESC research and development in the EU will continue to flourish.
REFERENCES Court of Justice of the European Union (2011). Oliver Bru¨stle v Greenpeace eV. Judgment of the Court (Grand Chamber) of 18 October 2011. Case C-34/10. http://eur-lex.europa.eu/LexUriServ/ LexUriServ.do?uri=CELEX:62010CJ0034:EN:HTML. European Union (2004). Directive 2004/27/EC of the European parliament and of the Council of 31 March 2004 amending Directive 2001/83/EC of the Community Code relating to Medicinal Products for Human Use, Official Journal of the European Union, L 136/34. http://ec.europa.eu/health/files/ eudralex/vol-1/dir_2004_27/dir_2004_27_en.pdf. Fung, R.K., and Kerridge, I.H. (2011). Bioethics 2011, 4. Levinson, D.R. (2010). Challenges to FDA’s ability to monitor and inspect foreign clinical trials. Report of the Office of Inspector General, Department of Health and Human Services. June 2010, OEI-0108-00510. http://oig.hhs.gov/oei/reports/oei-0108-00510.pdf. Naik, G. (2011). Patent ruling sets back EU stemcell scientists. Wall Street Journal: Health Industry, October 19, 2011. http://online.wsj.com/article/ SB10001424052970204346104576639010759884 794.html. Rai, A., Graham, S., and Doms, M. (2010). Patent reform: unleashing innovation, promoting economic growth & producing high-paying jobs. A White Paper from the U.S. Department of Commerce, April 13, 2010. http://www.commerce.gov/sites/ default/files/documents/migrated/Patent_Reformpaper.pdf. Smith, K.P., Luong, M.X., and Stein, G.S. (2009). J. Cell. Physiol. 220, 21–29. Tam, J.W.Y. (2010). Georgetown Law J. 98, 535–536.
Bru¨stle Decision Is Unhelpful, but Not Catastrophic James Lawford Davies1,2,* and Alex Denoon2 1Institute
of Genetic Medicine, International Centre for Life, Newcastle University, Newcastle upon Tyne, NE1 3BZ, UK Davies Denoon, 14a Clerkenwell Green, London, EC1R 0DP, UK *Correspondence: [email protected] DOI 10.1016/j.stem.2011.11.007 2Lawford
On October 18, 2011, the Court of Justice of the European Union (CJEU) issued its much anticipated and controversial decision in the case of Bru¨stle v. Greenpeace (Court of Justice of the European Union, 2011). The Court ruled that inventions involving human embryonic stem cells
(hESCs) are unpatentable. While this decision is unhelpful for the field, its impact may be more limited and nuanced than others have suggested. In brief, the case related to a patent filed by Professor Oliver Bru¨stle in 1997 that described and claimed the isolation and
500 Cell Stem Cell 9, December 2, 2011 ª2011 Elsevier Inc.
purification of precursor cells generated from hESCs. Greenpeace argued in proceedings launched initially in Germany in 2004 that this patent breached Article 6(2)(c) of the EU Biotechnology Directive, which states that inventions involving the ‘‘use of human embryos for industrial or
Cell Stem Cell
Letters commercial purposes’’ are unpatentable in EU Member States (European Union, 1998). Greenpeace was partially successful at the first instance, but eventually Germany’s highest court stayed the action and referred certain questions on the meaning of Article 6(2)(c) to the CJEU in November 2009. The questions referred were complicated, but may be condensed to the following: (1) are inventions involving hESCs unpatentable because the hESCs constitute an ‘‘embryo’’ and thus fall within the patentability exclusion of Article 6(2)(c)? And (2) are inventions involving hESCs for use in scientific research also excluded from patentability? In March 2011, the Advocate General of the CJEU, Yves Bots, produced an opinion to assist the Court that concluded that if a technical process for which a patent is filed necessitates the prior destruction of an embryo, then even if the patent description does not contain any reference to the use of embryos or the source of the cells, the invention must be excluded from patentability. The Advocate General also stated that the expression ‘‘embryo’’ required a Community-wide interpretation to prevent each Member State from determining the patentability of biotechnology inventions using local definitions; something which Mr. Bots concluded would be antithetical to the purpose of the Directive. Because totipotent cells have the capacity to develop into a complete human body, the Advocate General took the novel view that they represent an embryo. Furthermore, according to Mr. Bots, because totipotent cells give way to blastocysts, a blastocyst is also an embryo for the purposes of patentability. The October 2011 decision of the CJEU largely adopted this opinion. The Court found that an invention is excluded from patentability if the process requires either the prior destruction of human embryos or their prior use as base material, even if the application does not refer to the use of human embryos. Furthermore, the CJEU concluded that scientific research entail-
ing the use of human embryos cannot access the protection of patent law. This decision is an unwelcome development for stem cell research, and it has generated widespread criticism from the scientific community, notably contrasted with broadly held support among those ideologically opposed to hESCs and embryo research. However, the impact of the judgment may be moderated for a number of reasons. First, it will be virtually impossible for a regulator to approve a generic (technically a biosimilar) stem cell therapy. Such therapies will typically be complex entities that would be challenging, if not impossible, to reproduce, and preclinical and clinical trials would be required to establish comparability. A high barrier to entry for an hESC biosimilar would offer greater regulatory protection for hESC-derived inventions, arguably liberating such therapies from the tyranny of limited patent life. Second, it is likely that many hESC therapies will be eligible for orphan drug designation. Therapies intended for the diagnosis, prevention, or treatment of a life-threatening or chronically debilitating condition affecting not more than 5 in 10,000 people ordinarily benefit from a 10-year period in which no European regulator will accept another application for a marketing authorization for the same therapeutic indication in respect of a similar product. Orphan drug designation can therefore deliver 10 years of market exclusivity. Third, it will still be possible to obtain patents such as that filed by Professor Bru¨stle in other jurisdictions (including the U.S., China, and India). Furthermore, other aspects of hESC therapies (such as biomarkers) may still be patentable in Europe. Inventors will inevitably continue to seek ways to obtain patents notwithstanding the decision. Finally, it is uncertain what effect the CJEU’s ruling will have on the approach of the European Patent Office (EPO) to hESC inventions. The sector has been grappling with similar issues for some time; opposition proceedings regarding
hESC lines came before the EPO over a decade ago, and the patent office’s Enlarged Board of Appeal (EBA) decided in 2008 that it is not possible to patent claims directed to products that, as described in the application at the filing date, could be prepared exclusively by a method that involved the destruction of an embryo, even where the method was not part of the claim (Enlarged Board of Appeal, 2008). However, the EPO would not look behind the patent application and would grant certain patents on the basis that the initial material could have been obtained from publicly available sources. We await further clarification from the EPO as to how they will interpret and apply the CJEU’s decision in the Bru¨stle case. As regards the specific patent filed by Professor Bru¨stle, the CJEU referred a basic question back to the German court, namely whether hESCs obtained from a human embryo at the blastocyst stage of development are capable of commencing the development of a human being in light of scientific advances. It seems clear from the CJEU’s ruling that the Court believes (like the Advocate General) that such hESCs will fall within the definition of a human ‘‘embryo.’’ If the German court agrees, as we believe is likely, then inventions involving such hESCs will not be patentable.
REFERENCES Court of Justice of the European Union. (2011). Oliver Bru¨stle v Greenpeace eV. Judgment of the Court (Grand Chamber) of 18 October 2011. Case C-34/10. http://eur-lex.europa.eu/LexUriServ/ LexUriServ.do?uri=CELEX:62010CJ0034:EN:HTML. Enlarged Board of Appeal. (2008). Decision of the Enlarged Board of Appeal dated 25 November 2008, G 2/06. Official Journal EPO, 2009. http://archive.epo.org/epo/pubs/oj009/05_09/ 05_3069.pdf. European Union. (1998). Directive 98/44/EC Of the European Parliament and of the Council of 6 July 1998 on the legal protection of biotechnological inventions, Official Journal of the European Communities, L 213/13. http://eur-lex.europa.eu/ LexUriServ/LexUriServ.do?uri=OJ:L:1998:213:0013: 0021:EN:PDF.
Cell Stem Cell 9, December 2, 2011 ª2011 Elsevier Inc. 501
Letters Court ruling on EU companies will vary depending on their specific circumstances. Companies that would have faced a freedom to operate problem because of hESC patents held by others may now be more likely to start, or continue, hESC research programs because the Court’s ruling renders such patents unenforceable. Companies working on the ‘‘improvement’’ of hESC related-technologies, for instance, which would have faced patent infringement litigation or would have had to pay royalties, may find themselves more incentivized to perform hESC research in the EU following the Court’s ruling. By contrast, companies holding foundational hESC inventions might be incentivized to work in jurisdictions that offer patent protection for hESC inventions (e.g., the USA). Despite the Court ruling we believe that sponsors of hESC-based therapies will locate trials in Europe for a number of reasons. Companies developing hESC therapies will ultimately desire to sell their products on the European market. The EMA may require data from European clinical trials before it approves of any future hESC-derived therapy. Moreover, recent studies suggest that over 50% of products headed for FDA approval are in clinical trials that involve foreign study sites (Levinson, 2010). Finally the possibility that some companies could be attracted to Europe
because of this decision cannot be discounted. Although the Court ruling does not directly impact the patentability of hESC inventions in the U.S., it will have a ripple effect there. American companies facing a freedom to operate problem because of U.S. patents held by others may now reconsider their business plans. Moving their research operations to Europe becomes a more attractive option because the EU counterparts of those patents are no longer enforceable. These companies will balance the benefit afforded by the new EU patent landscape against the protection that the Hatch Waxman Act provides for certain research activities in the U.S. and the significant costs of moving an already established and ongoing research operation. A cost differential that disfavors the U.S. as an alternative to the EU may incentivize companies to consider moving their trials and preclinical efforts to places such as India or China. As Yogi Berra once said, ‘‘It’s tough to make predictions, especially about the future.’’ Everyone will need to wait and see how various stakeholders in the research community actually respond to the Court’s ruling. Nevertheless, we are confident that the reaction will be dependent on many individual variables. As a result, we expect that some of the currently critical hESC research and development in the EU will continue to flourish.
REFERENCES Court of Justice of the European Union (2011). Oliver Bru¨stle v Greenpeace eV. Judgment of the Court (Grand Chamber) of 18 October 2011. Case C-34/10. http://eur-lex.europa.eu/LexUriServ/ LexUriServ.do?uri=CELEX:62010CJ0034:EN:HTML. European Union (2004). Directive 2004/27/EC of the European parliament and of the Council of 31 March 2004 amending Directive 2001/83/EC of the Community Code relating to Medicinal Products for Human Use, Official Journal of the European Union, L 136/34. http://ec.europa.eu/health/files/ eudralex/vol-1/dir_2004_27/dir_2004_27_en.pdf. Fung, R.K., and Kerridge, I.H. (2011). Bioethics 2011, 4. Levinson, D.R. (2010). Challenges to FDA’s ability to monitor and inspect foreign clinical trials. Report of the Office of Inspector General, Department of Health and Human Services. June 2010, OEI-0108-00510. http://oig.hhs.gov/oei/reports/oei-0108-00510.pdf. Naik, G. (2011). Patent ruling sets back EU stemcell scientists. Wall Street Journal: Health Industry, October 19, 2011. http://online.wsj.com/article/ SB10001424052970204346104576639010759884 794.html. Rai, A., Graham, S., and Doms, M. (2010). Patent reform: unleashing innovation, promoting economic growth & producing high-paying jobs. A White Paper from the U.S. Department of Commerce, April 13, 2010. http://www.commerce.gov/sites/ default/files/documents/migrated/Patent_Reformpaper.pdf. Smith, K.P., Luong, M.X., and Stein, G.S. (2009). J. Cell. Physiol. 220, 21–29. Tam, J.W.Y. (2010). Georgetown Law J. 98, 535–536.
Bru¨stle Decision Is Unhelpful, but Not Catastrophic James Lawford Davies1,2,* and Alex Denoon2 1Institute
of Genetic Medicine, International Centre for Life, Newcastle University, Newcastle upon Tyne, NE1 3BZ, UK Davies Denoon, 14a Clerkenwell Green, London, EC1R 0DP, UK *Correspondence: [email protected] DOI 10.1016/j.stem.2011.11.007 2Lawford
On October 18, 2011, the Court of Justice of the European Union (CJEU) issued its much anticipated and controversial decision in the case of Bru¨stle v. Greenpeace (Court of Justice of the European Union, 2011). The Court ruled that inventions involving human embryonic stem cells
(hESCs) are unpatentable. While this decision is unhelpful for the field, its impact may be more limited and nuanced than others have suggested. In brief, the case related to a patent filed by Professor Oliver Bru¨stle in 1997 that described and claimed the isolation and
500 Cell Stem Cell 9, December 2, 2011 ª2011 Elsevier Inc.
purification of precursor cells generated from hESCs. Greenpeace argued in proceedings launched initially in Germany in 2004 that this patent breached Article 6(2)(c) of the EU Biotechnology Directive, which states that inventions involving the ‘‘use of human embryos for industrial or
Cell Stem Cell
Letters commercial purposes’’ are unpatentable in EU Member States (European Union, 1998). Greenpeace was partially successful at the first instance, but eventually Germany’s highest court stayed the action and referred certain questions on the meaning of Article 6(2)(c) to the CJEU in November 2009. The questions referred were complicated, but may be condensed to the following: (1) are inventions involving hESCs unpatentable because the hESCs constitute an ‘‘embryo’’ and thus fall within the patentability exclusion of Article 6(2)(c)? And (2) are inventions involving hESCs for use in scientific research also excluded from patentability? In March 2011, the Advocate General of the CJEU, Yves Bots, produced an opinion to assist the Court that concluded that if a technical process for which a patent is filed necessitates the prior destruction of an embryo, then even if the patent description does not contain any reference to the use of embryos or the source of the cells, the invention must be excluded from patentability. The Advocate General also stated that the expression ‘‘embryo’’ required a Community-wide interpretation to prevent each Member State from determining the patentability of biotechnology inventions using local definitions; something which Mr. Bots concluded would be antithetical to the purpose of the Directive. Because totipotent cells have the capacity to develop into a complete human body, the Advocate General took the novel view that they represent an embryo. Furthermore, according to Mr. Bots, because totipotent cells give way to blastocysts, a blastocyst is also an embryo for the purposes of patentability. The October 2011 decision of the CJEU largely adopted this opinion. The Court found that an invention is excluded from patentability if the process requires either the prior destruction of human embryos or their prior use as base material, even if the application does not refer to the use of human embryos. Furthermore, the CJEU concluded that scientific research entail-
ing the use of human embryos cannot access the protection of patent law. This decision is an unwelcome development for stem cell research, and it has generated widespread criticism from the scientific community, notably contrasted with broadly held support among those ideologically opposed to hESCs and embryo research. However, the impact of the judgment may be moderated for a number of reasons. First, it will be virtually impossible for a regulator to approve a generic (technically a biosimilar) stem cell therapy. Such therapies will typically be complex entities that would be challenging, if not impossible, to reproduce, and preclinical and clinical trials would be required to establish comparability. A high barrier to entry for an hESC biosimilar would offer greater regulatory protection for hESC-derived inventions, arguably liberating such therapies from the tyranny of limited patent life. Second, it is likely that many hESC therapies will be eligible for orphan drug designation. Therapies intended for the diagnosis, prevention, or treatment of a life-threatening or chronically debilitating condition affecting not more than 5 in 10,000 people ordinarily benefit from a 10-year period in which no European regulator will accept another application for a marketing authorization for the same therapeutic indication in respect of a similar product. Orphan drug designation can therefore deliver 10 years of market exclusivity. Third, it will still be possible to obtain patents such as that filed by Professor Bru¨stle in other jurisdictions (including the U.S., China, and India). Furthermore, other aspects of hESC therapies (such as biomarkers) may still be patentable in Europe. Inventors will inevitably continue to seek ways to obtain patents notwithstanding the decision. Finally, it is uncertain what effect the CJEU’s ruling will have on the approach of the European Patent Office (EPO) to hESC inventions. The sector has been grappling with similar issues for some time; opposition proceedings regarding
hESC lines came before the EPO over a decade ago, and the patent office’s Enlarged Board of Appeal (EBA) decided in 2008 that it is not possible to patent claims directed to products that, as described in the application at the filing date, could be prepared exclusively by a method that involved the destruction of an embryo, even where the method was not part of the claim (Enlarged Board of Appeal, 2008). However, the EPO would not look behind the patent application and would grant certain patents on the basis that the initial material could have been obtained from publicly available sources. We await further clarification from the EPO as to how they will interpret and apply the CJEU’s decision in the Bru¨stle case. As regards the specific patent filed by Professor Bru¨stle, the CJEU referred a basic question back to the German court, namely whether hESCs obtained from a human embryo at the blastocyst stage of development are capable of commencing the development of a human being in light of scientific advances. It seems clear from the CJEU’s ruling that the Court believes (like the Advocate General) that such hESCs will fall within the definition of a human ‘‘embryo.’’ If the German court agrees, as we believe is likely, then inventions involving such hESCs will not be patentable.
REFERENCES Court of Justice of the European Union. (2011). Oliver Bru¨stle v Greenpeace eV. Judgment of the Court (Grand Chamber) of 18 October 2011. Case C-34/10. http://eur-lex.europa.eu/LexUriServ/ LexUriServ.do?uri=CELEX:62010CJ0034:EN:HTML. Enlarged Board of Appeal. (2008). Decision of the Enlarged Board of Appeal dated 25 November 2008, G 2/06. Official Journal EPO, 2009. http://archive.epo.org/epo/pubs/oj009/05_09/ 05_3069.pdf. European Union. (1998). Directive 98/44/EC Of the European Parliament and of the Council of 6 July 1998 on the legal protection of biotechnological inventions, Official Journal of the European Communities, L 213/13. http://eur-lex.europa.eu/ LexUriServ/LexUriServ.do?uri=OJ:L:1998:213:0013: 0021:EN:PDF.
Cell Stem Cell 9, December 2, 2011 ª2011 Elsevier Inc. 501