Revocation of European patent for neural progenitors highlights patent challenges for inventions relating to human embryonic stem cells

Abstract

Cells derived from human embryonic stem cells have great therapeutic potential. Patents are key to allowing companies that develop methods of generating such cells to recuperate their investment. However, in Europe, inventions relating to the use of human embryos for commercial purposes are excluded from patentability on moral grounds. The scope of this morality exclusion was recently tested before Germany's highest court and before the European Patent Office (EPO), with diverging results. The decision by the EPO's Opposition Division to revoke EP1040185 relating to neural precursors and methods for their generation has received a mixed reception. The decision has very recently been appealed, and the outcome of this Appeal should provide more definitive guidance on the scope of the morality exclusion.

Keywords::

• European Patent Office
• exclusion from patentability
• human embryonic stem cells
• morality
• neural progenitors
• patents

1. Introduction

The human nervous system appears to have a very limited regeneration potential, which represents a challenge in the treatment of nervous system diseases or injury. One promising therapeutic avenue is the transplantation of healthy neural precursors, which are cells that have the ability to develop into mature nervous system cells. Parkinson's disease is just one example of the many neurological disorders that could potentially benefit from such treatment.

There is, however, a shortage of suitable neural precursors. Brain tissue of aborted human foetuses may in principle be used, but this approach is severely hampered inter alia by the limited availability of such tissue. Genetic manipulation has been used to try to provide larger numbers of neural precursors, but this approach is unsatisfactory because of the associated risk of cancerous growths.

In 1997 and 1998, Professor Brüstle filed patent applications to seek protection for a method of generating neural precursor cells from human embryonic stem (hES) cells, as well as for the resulting neural precursor cells themselves. These patent applications appear to have been one of the earliest reports of the conditions under which hES cells can be coaxed into differentiating into neural precursor cells in vitro.

Brüstle obtained a granted German patent, DE19756864, and a granted European patent, EP1040185 [1,2]. However, both patents were challenged post-grant by third parties on moral grounds, because the claimed methods and products allegedly involved uses of human embryos for commercial purposes.

2. Legal background

The patentability of biotechnological inventions in the European Union (EU) is governed by European Directive 98/44/EC of 1998, known as the Biotech Directive, which has been implemented into national law by EU member states, as well as by the European Patent Office (EPO) [3,4]. The Biotech Directive states that inventions are not patentable where their commercial exploitation would be contrary to public order or morality, and it specifically prohibits the use of human embryos for commercial or industrial purposes. However, the Biotech Directive neither provides a definition of the term ‘human embryo', nor does it explain what acts constitute the ‘use of a human embryo'. This has created uncertainty surrounding the patentability of inventions relating to hES cells.

In a landmark case in 2008, the Enlarged Board of Appeal, the highest authority of the EPO, held that inventions which necessarily require the destruction of a human embryo are not patentable [5]. However, European patents could be obtained for inventions which from the filing date of the patent could be worked using an existing hES cell line. hES cell lines are in vitro cultures of hES cells that were originally derived from an embryo, but which are subsequently maintained and propagated in a laboratory to provide an essentially unlimited supply of hES cells.

However, in 2011, in response to questions referred to it by the German court handling DE19756864, the Court of Justice of the EU (CJEU) unsettled patent practice when it held that it is immaterial how far removed the destruction of a human embryo is from the invention [6]. Thus, according to the CJEU, the exclusion applies not only to those inventions that directly involve the destruction of an embryo but also to those requiring the use of an hES cell that was originally derived through the destruction of a human embryo. Consequently, any methods or products that involve as their base material cells taken from an established hES cell line which was originally obtained through the destruction of a human embryo are apparently excluded from patentability, no matter how long ago the hES cell line was originally established.

With regard to the meaning of the term ‘embryo', the CJEU held that this encompasses inter alia any fertilised egg from the moment of fertilisation and including all subsequent stages during the process of the development and formation of the human body, including the blastocyst stage from which embryonic stem cells are typically retrieved; as well as any other cell capable of commencing the process of development of a human being, such as a human egg into which the genetic material of an adult human cell has been introduced. However, the CJEU left it to the national courts to ascertain whether an hES cell itself should be considered to be a human embryo.

The CJEU's ruling is binding on all EU member states and, for example, the UK Patent Office issued a practice note reflecting the decision of the CJEU [7]. Although the EPO is not bound by the ruling, it too changed its practice accordingly [8]. Following the CJEU ruling, the validity of Brüstle's patents was considered by the German Federal Supreme Court (Bundesgerichtshof) and by the EPO respectively.

3. Maintenance of DE19756864 in amended form

In November 2012, the Bundesgerichtshof of Germany, having considered the ruling of the CJEU, held DE19756864 to be valid in amended form [9].

The Bundesgerichtshof ascertained that an hES cell that has been obtained from a human embryo should not be regarded as a human embryo.

It ruled that the exclusion from patentability under the morality provisions may be avoided by limiting patent claims such that precursors which were obtained from human embryonic stem cells obtained by destroying human embryos are not encompassed within the scope of the claims.

The Bundesgerichtshof accepted Brüstle's argument that the claimed invention could be carried out using human embryonic germ cells, that is, the cells that give rise to eggs or sperm, which may be isolated from aborted foetuses. It was therefore satisfied that it was possible at the filing date of the patent to carry out the method of the invention without destroying a human embryo.

The Bundesgerichtshof therefore allowed the granted claims to be amended to include provisos which set out that the claimed methods do not encompass the use of human embryonic stem cells obtained by destroying human embryos; and that the claimed products do not include precursor cells generated from human embryonic stem cells obtained by destroying human embryos. It ruled that the patent so amended does not contravene the morality provisions of German patent law.

4. Revocation of EP1040185

European Patent application number 98966817.3 granted as EP1040185 in 2006 after the claims were amended to included a proviso that the ‘method does not include the destruction of human embryos' to address objections raised under the morality provisions.

The patent was opposed inter alia for allegedly contravening the morality provisions of European patent law, extending beyond the scope of the application as filed and being insufficiently disclosed [4,10,11]. Brüstle requested the maintenance of the patent as granted. As an auxiliary request, a claim set with a slightly revised proviso was filed.

The Opposition Proceedings attracted a great deal of attention and observations were filed by a number of different parties, including Greenpeace, the European Patent Institute and the Dutch Biotechnology Association, some of which urged the EPO not to adopt a more restrictive interpretation of the morality provisions than the German Bundesgerichtshof had done [12]. However, in April 2013, the EPO revoked EP1040185 [13].

The EPO considers that a paper published in 2008 was the first report of a method of obtaining hES cells without destroying a human embryo, and that therefore at the filing date of the Brüstle patent (1998), no method of obtaining hES cells without destroying a human embryo was known [14]. Unlike the Bundesgerichtshof, the EPO rejected the argument that embryonic germ cells are equivalent to embryonic stem cells. Consequently, the Opposition Division ruled that at the filing date of the patent, it would not have been possible to work the invention without destroying a human embryo.

Technically, the Opposition Division's decision to revoke the patent was based on Article 123(2) (the so-called ‘added matter' provisions) of the European Patent Convention, under which patents may not be amended such that they extend beyond the scope of the application as filed. However, it is clear that the Opposition Division's decision was driven by a consideration of the morality provisions.

Brüstle has filed an appeal against the EPO's decision to revoke EP1040185. At the time of writing, the reasoned grounds of appeal had not yet been filed.

5. Expert opinion and discussion

Given that the German Bundesgerichtshof, which is bound by the ruling of the CJEU, decided to allow the patent in amended form, it is somewhat surprising that the EPO, which is under no obligation to follow the ruling of the CJEU, took a stricter line than the Bundesgerichtshof.

It appears that different definitions of hES cells may have played a pivotal role in these cases. The Brüstle patent asserts that the term ‘hES cells' includes human embryonic germ cells. This definition was accepted by the Bundesgerichtshof, satisfying it that at the filing date of the patent the skilled person was provided with at least one way of carrying out the claimed invention, namely by using human germ cells. By contrast, the EPO held that whilst it is permissible to a certain extent for patent applicants to write their own dictionary in a patent application, defining germ cells as embryonic stem cells goes too far. Consequently, the EPO did not accept that the invention could be worked by using germ cells. It remains to be seen whether the German decision hinges on the particular facts of this case, or whether similar patents that do not include any references to germ cells will also be allowable in Germany.

Questions are being raised as to whether the EPO was right to let the ruling of the CJEU prompt a change in the practice that had been established as a result of a ruling of the EPO's own Enlarged Appeal Board. It is expected that this and other issues pertaining to the scope of the morality provisions will in due course be considered by the EPO's Appeal Board for example as part as the appeal against the revocation of EP1040185. A further appeal relating to the patentability of inventions concerning hES cells is also currently pending before the EPO and there is hope that this issue will eventually be put to the EPO's Enlarged Board of Appeal for more definitive guidance and greater legal certainty [15].

In the meantime, it is important to appreciate that the EPO considers that a report published in February 2008 provides a method of isolating hES cells without destroying a human embryo [14]. Consequently, patent applications relating to hES cells filed since February 2008 are typically outside of the exclusion from patentability on moral grounds.

The determination by the German Court that hES cells do not constitute a ‘human embryo' has been welcomed, but the precise scope of the term ‘human embryo' remains a grey area. A recent further referral to the CJEU in this regard is likely to impact on future practice in this field [16].

It is also worth examining whether there is a risk that the laws which were introduced to implement the Biotech Directive may be taking on a direction that is not in line with the aims of the Directive. A key aim of the Biotech Directive was to harmonise biotech patent law across the EU and to clarify what subject matter is patentable and what is not. The divergent decisions of the German Bundesgerichtshof and the EPO signal that at least for now we are a long way off harmonisation of this issue across Europe.

Another key aim was to prevent the patenting of inventions which are contrary to morality and to exclude uses of human embryos for industrial or commercial purposes from patentability. In the author's opinion, this exclusion was never meant to prohibit the patenting of inventions that can be practiced by using hES cells from an established hES cell line. The laws of most EU member states governing stem cell research and funding therefore make a clear distinction between work that necessitates the use of a human embryo and work on hES cell lines; indeed, in many of these countries the use of cells from existing hES cell lines is encouraged to prevent the use of embryos [17]. It is a pity that the EPO's recent revision of the Guidelines and the revocation of EP1040185 signal that the EPO nevertheless considers the use of hES cell lines established prior to February 2008 to be contrary to morality. It remains to be seen whether these trends will be reinforced or reversed by the EPO's Appeal Boards.

The Brüstle cases have fanned the debate as to why European patent law includes any morality provisions at all. It would appear that the introduction of the morality provisions was at least in part motivated by a desire to avoid the patent system from being seen to endorse morally questionable inventions. However, it must be appreciated that a patent does not automatically give the patent owner the right to practice his invention. Instead, a patent is a negative right, which allows the patent holder to stop others from working the patented invention. Paradoxically, the morality provisions may arguably be at risk of increasing the amount of research that is carried out on human embryonic stem cells, because they weaken the patent barriers to such work. Perhaps it would have been more appropriate to try to educate the public about the rights afforded by a patent, and to leave the determination of what is morally acceptable to legislators in non-patent fields. However, the morality provisions are firmly enshrined in European patent law, so the challenge is to determine how these provisions should be interpreted and applied. It is the author's hope that European patent practice will develop to allow the patenting of inventions that can be practiced by using hES cells from any established hES cell line, but it remains to be seen what view the EPO's Appeal Boards and perhaps higher instances take on this matter.

Declaration of interest

B Rigby is employed at Dehns, Patent and Trademark Attorneys. The author states no conflict of interest and has received no payment in preparation of this manuscript.