Stem cells have several applications with the potential for commercialisation. These range from unique services for customers (eg, a cell-based platform for drug cardiotoxicity testing for a pharmaceutical company) to a stem cell-based drug which is sold as an actual product (eg, a bottle of heart cells to be used as a treatment for a failing heart). However, despite significant investment in R&D, no marketable stem-cell product has yet appeared.
James Thomson first isolated human embryonic stem cells in 1998, sparking a surge of interest in the commercialisation of stem-cell technologies. Many scientists around the world filed patent applications for inventions relating to derivation, differentiation or applications of stem cells, from human embryonic stem cell lines, induced pluripotent stem cell lines or adult progenitor stem cells. The applicants often intended to found their own companies to make use of the protected knowledge. One early example of a scientist-initiated start-up stem-cell company is that of Thomson himself, who founded Cellular Dynamics, which focuses on developing human model systems based on stem cells to test for drug toxicity.
Several other stem-cell companies – such as Geron, Advanced Cell Technologies, NovaCell, CellArtis and Stem Cell Sciences – were founded either to develop stem cell-based therapies for a variety of diseases or to exploit pluripotent stem cells in order to develop models for human diseases or specific cell types as screening systems for testing drug toxicity (so-called ‘safety pharmacology’). Many of these companies were founded between 2002 and 2005. However, given that therapies in particular have turned out to be further off than originally believed, several of these companies no longer exist. As the opportunities for safety pharmacology become clearer and some therapies in unexpected areas do seem feasible (eg, to treat the eye disease macular degeneration), a new wave of stem cell-based biotech companies has emerged.
The legal and patent issues in this area are far from clear, in part because of a network of patent claims from the early companies which may or may not protect intellectual property from use by others. The complexity is in part due to different opinions around the world on what it is morally acceptable to grant patents for. Patenting the production and use of adult stem cells has been relatively straightforward compared to pluripotent cell lines derived from human embryos, since there are fewer perceived ethical issues. By contrast, patent protection for methods to obtain or use induced pluripotent stem cells is an area of emerging legal complexity, in part because of differences in opinion as to who discovered what first. Such issues have the potential to make or break the stem-cell promise. Without patent protection, companies are unlikely to invest in the production of stem cells for therapy; while most hospitals do not themselves have access to the technology, infrastructure and expertise to produce a complex stem-cell product for medical purposes.
Many legal battles over stem-cell patent rights have already taken place and many more are expected to arise as potential applications are realised. The stakes are high and extremely broad claims are being made in the most basic patents as a result. For example, with respect to induced pluripotent stem cells (iPS cells) – that is, pluripotent stem cells generated from adult cells – the question has arisen as to whether the method for deriving mouse iPS cells was the actual invention and that for obtaining human iPS cells a logical consequence of this – or whether the method for deriving the first human iPS cell line was the invention that should be patented. To complicate things further, papers on the establishment of iPS cell lines were published simultaneously by American and Japanese stem cell groups, but described different methods. Are the two methods eligible for separate patents or did one come first? And would either patent be entitled to a scope that would also cover the other technology?
Considering the complexity of reprogramming and the amount of trial and error involved in any of the successful approaches, it seems likely that the individual methods for producing iPS will both be considered patentable. Taking the present efforts to generate transgene-free iPS cells as an example, it is clear that the various methods to generate such transgene-free iPS are not simple alternatives to one another. Using adenovirus vectors, only liver cells appeared to be reprogrammable and these frequently gave rise to tetraploid iPS. With plasmid vectors, repeated transfections of foetal fibroblasts were necessary and even then resultant iPS in many cases contained stably integrated transgenic DNA. Transfection of the episomally replicated plasmids based on the Epstein-Barr virus yielded iPS from human fibroblasts, albeit that additional factors were required. Other approaches that rely on the active removal of integrated transgenes after their use has expired have been more successful. Removal of the integrated genes using the site-specific recombinase technology of the Cre-lox system and recently using a transposon/transposase system have yielded efficient transgene-free iPS. These latter approaches benefit from the experience gained with stably modified iPS and have the added bonus that the transgene-free iPS contain a genetic footprint. The footprints might solve the paradox that the closer the iPS cells get to embryonic stem cells, the less likely they are to be separately patentable. It is one of the hallmarks of the patent system that only novel subject matter can be patented. For successful patent protection, the iPS cell must have something unique that distinguishes it from the classical stem-cell cultures derived from early-stage embryos. The footprints could possibly be such a unique feature. Mobile elements transposing via DNA intermediates often leave small rearrangements or footprints at sites where they excise. The Cre-lox system leaves one of the lox sites.
Biotechnology Directive and European Patent Convention
Europe has generally shown greater concern towards ethical issues than the United States with respect to the patentability of biotechnological inventions and has implemented means to address this within the European Patent Convention (EPC). From its inception, the EPC has excluded, for example, “morally offensive subject-matter” from patent protection.
In 1999 the EPC was amended to incorporate provisions from the EU Biotechnology Directive (98/44/EC). These rules provide guidance on how to interpret the concept of morality in the field of biotechnology. The new rules included Rule 28(c) EPC, which states that European patents shall not be granted for biotech inventions that involve “uses of human embryos for industrial or commercial purposes”.
While the United States has granted a range of patents covering the generation and culture of human embryonic stem cells, the European Patent Office (EPO) has put the grant of patents with such claims on hold, pending a decision by the Enlarged Board of Appeal on this issue. The Enlarged Board of Appeal was asked to decide on this issue in appeal proceedings in the context of a patent application filed by the Wisconsin Alumni Research Foundation (WARF). The invention covered by this application was directed to cell culture of primate embryonic stem cells which are capable of in vivo proliferation (eg, after implantation into an embryo).
In its Decision G2/06, the Enlarged Board of Appeal decided that the EPC prohibits the patenting of claims on human embryonic stem cell cultures which, as described in the application, at the filing date can be prepared only by a method which necessarily involves the destruction of the human embryos from which the cultures are derived. This is also true when the destruction of the embryos themselves is not part of the claim. The Enlarged Board of Appeal further considered that it is irrelevant whether, at a later date, a technique is developed through which a cell line can be produced without destroying a human embryo. The EPO subsequently rejected WARF’s application.
National courts and European Court of Justice
Although the EPO Enlarged Board of Appeal has the final word in the interpretation of the EPC, the practice before the EPO is generally harmonised with the national patent law of EU member states. In this respect, it is interesting that in a case between Oliver Brüstle and Greenpeace, the German Federal Supreme Court referred a number of questions on embryonic stem cell patenting to the European Court of Justice (ECJ). One of these specifically addressed whether, under the Biotech Directive, a technical procedure is patentable if the destruction of human embryos is necessary for the application of that procedure, even though the use and destruction of the embryo do not actually form part of the procedure.
In Decision C-34/10 the ECJ decided that the Biotech Directive excludes an invention from patentability when it requires the prior destruction of human embryos or their use as a base material, whatever the stage at which that takes place and even if the description of the technical teaching claimed does not refer to the use of human embryos. With specific reference to stem-cell lines, the ECJ considered that it is irrelevant that destruction may have occurred at a stage long before the invention, as was the case with stem-cell lines at the time the patent application was filed. Subsequent to the ECJ decision, the German Federal Supreme Court decided that, at least in Germany, cell cultures that do not directly involve the destruction of blastocysts are capable of being patented. This decision appears to deviate somewhat from the approaches followed by the ECJ and the EPO.
Meanwhile, back at the EPO…
Since the EPO Enlarged Board of Appeal issued its decision in WARF (G2/06), several other stem-cell cases have been decided by the EPO boards of appeal. For instance, in T522/04 and T329/06 the claims were found to violate Rule 28(c) of the EPC, since the applications described only the preparation of the embryonic stem cells through a method involving the destruction of early-stage embryos. However, claims expressly disclaiming human embryonic stem cells were allowed. As one can imagine, such a disclaimer significantly reduces the commercial relevance of a patent.
By focusing the decision on the destruction of embryos, the Enlarged Board of Appeal provided no direction as to whether stem cells prepared using methods in which the embryos remain viable would be allowed. Recently, techniques have been reported which appear to generate embryonic stem cells from human embryos without embryo destruction. This usually involves removing one of the cells at the eight-cell stage, much as would be done for prenatal genetic diagnosis. Instead of using that one cell to search for disease-causing mutations, it is used to derive a cell line. The remaining seven-cell embryo can in principle develop normally if transferred to the uterus of a recipient mother. Of course, this raises the question of “what mother would let her embryo be used for this purpose?”, but the issue is at present one of principle.
Another way to patent inventions with respect to human embryonic stem cells without actually referring to the use of a human embryo would be by referring to established stem-cell lines. The test for this case was Application EP1554373 of the Technion Research Foundation. The application claimed methods for maintaining stem cells in culture and specifically mentioned stem-cell lines as a source for these stem cells. The central issue was whether the stem-cell lines mentioned in the application were available to the public. The examining division refused the application because there was no evidence that the cell lines mentioned in the application were in fact publicly available. A skilled person trying to carry out the invention would therefore have to resort to methods that would lead to the destruction of an embryo. In the subsequent appeal (T2221/10), the Boards of Appeal confirmed the decision and clarified that cell lines available at the time of filing had all been derived from embryos that were destroyed in the process, and that this was not allowed. This decision was followed by a preliminary opinion from the Boards of Appeal in the European Brüstle patent, which corresponds to the German national patent that was the subject of ECJ Decision C-34/10 (EP1040185, to be decided on February 26 2015 as T1808/13).
In another recent decision (T1441/13) the boards of appeal established January 10 2008 as the cut-off date from which it was possible to obtain human embryonic stem cells from human blastocytes without destroying the human embryo. This date is based on the publication by Chung et al (Cell Stem Cell. 2: 113-117, 2008) setting out the so-called single blastomere biopsy (SBB) process. Thus, patent applications filed after this date may avoid objections under Article 53(a) and Rule 28(c) of the EPC, provided that they describe how human embryonic stem cells can be obtained without destroying human embryos.
Embryonic stem cells versus pluripotent cells
In a dispute between the International Stem Cell Corporation and the comptroller general of patents, designs and trademarks (effectively the UK patent office), the English High Court has referred questions to the ECJ regarding the patentability of parthenotes. These are human ova whose division and further development have been stimulated by parthenogenesis rather than fertilisation. Parthenogenesis is a method by which unfertilised ova are induced to develop by applying chemical and electrical stimulation. However, due to absence of fertilisation, parthenotes lack paternal DNA, which means that human parthenotes can never develop into human beings.
On December 18 2014 the ECJ handed down its decision (C-364/13) stipulating that in order to be classified as a human embryo, a non-fertilised human ovum must have the inherent capacity to develop into a human being. Consequently, the mere fact that a parthenogenetically activated human ovum commences a process of development is insufficient for it to be regarded as a human embryo. The ECJ thus appears to have followed the opinion of the advocate-general that parthenotes differ from human embryonic stem cells in that they are not totipotent, but only pluripotent, in that they are capable of developing into different cell types or tissues.
The ECJ’s decision in C-364/13 further stresses the difference between the patentability of pluripotent stem cells and that of embryonic stem cells. While the term ‘pluripotent stem cell’ arguably encompasses embryonic stem cells, other methods which are not contrary to morality can be used to produce such cells. Therefore, it would seem better to claim pluripotent rather than embryonic stem cell subject matter in a patent application, and to include in the patent various methods and sources for obtaining stem cells. In any case, the best advice is to try, if possible, to disclose inventions in a manner that includes non-controversial uses or methods of preparation.
This article first appeared in IAM magazine. For further information please visit www.iam-magazine.com.