February 17, 2016

Introduction

CRISPR-Cas9 technology is a revolutionary method of modifying genomic sequences. Although genomic modification has been possible for many years, CRISPR technology is cheaper, easier and more accurate than the modification tools preceding it.

CRISPR technology has its basis in a naturally occurring bacterial defence system against viruses. This system has been modified in such a way that it can be deployed in mammals. CRISPR technology tools comprise an RNA sequence which is constructed so as to hybridise to a target DNA sequence and a bacterial protein, Cas9, which cleaves and in certain instances, modifies, target DNA sequences.

The tool has a wide array of potential applications, not least the treatment of human diseases by, for example, correcting faulty genes. In this regard, an important distinction needs to be made between somatic and germ line cells. From an ethical standpoint, changes to human germ line cells, which pass on genetic information from parent to offspring are considered to be far more problematic than changes to human somatic cells, which are not involved in the reproductive process. Although CRISPR is not the first gene editing tool that makes it possible to modify human germ line cells, the wide dissemination and use of the technology has sparked a renewed and vigorous debate on whether it should be permissible to modify the human germ line.

Recent developments

In January 2015, a group of interested stakeholders, including scientists at the forefront of CRISPR developments, called for a voluntary moratorium on germline genome modification for clinical application in humans while the societal, environmental and ethical implications of such activity are discussed.[1] In spite of this, research relating to modification of the human germline has proceeded at pace.

In April 2015, a Chinese research team (Liang et al.) published a paper[2] which described the use of CRISPR technology to modify human embryos.  Although the embryos in question were stated not to be viable, due to the fact that they had an extra set of male chromosomes, this work sparked a renewed debate about the potential use of CRISPR to modify the human germ line. More recently, a team from London’s Francis Crick Institute announced on 1 February 2016[3] that the Human Fertilisation and Embryology Authority, which licenses all research involving human embryos in the UK, approved its proposal to modify the genomes of human embryos using CRISPR technology for research purposes (editing the human germ line for therapeutic purposes is not permitted in the UK).

From an ethical and regulatory perspective, debate is needed on whether human germ line genetic modification is permissible for therapeutic purposes. A separate but related question, is whether the use of CRIPSR technology to modify the human germ line is patentable and if so, under what circumstances.

Patentability

In Europe, the patentability of biotechnological inventions is governed by the provisions of Directive 98/44/EC on the legal protection of biotechnological inventions (the “Directive”). Article 6(1) of the Directive provides that inventions are not patentable “where their commercial exploitation would be contrary to ordre public or morality”. The meaning of ordre public is open to interpretation in different member states. However, the Directive sets a minimum standard for ordre public and morality by stipulating certain biotechnological inventions that are excluded from patentability on these grounds. These include:

• “processes for modifying the germ line genetic identity of human beings” (Article 6(2)(b)); and
• “uses of human embryos for industrial or commercial purposes” (Article 6(2)(c)).

Interestingly, with regard to one of the first European patents granted in relation to the application of CRISPR technology in eukaryotic cells (EP2771468), the examiner added a proviso to a subset of the claims concerning the use of the claimed CRISPR composition, with a view to bringing the claim into compliance with Rule 28(b) EPC (which incorporates Article 6(2)(b) of the Directive). The proviso was that the use claimed is not a process for modifying the germ line genetic identity of human beings.

Unlike Article 6(2)(c), which is the subject of two CJEU judgments regarding the meaning of “human embryo”, Article 6(2)(b) has not been the subject of any significant judicial discussion. The UKIPO’s current manual of patent practice (dated July 2015) does not discuss the provision in any detail, nor do the Guidelines for Examination in the EPO (dated November 2014). Although it is likely to be many years before the CRISPR technology might be considered feasible for use in human germ line gene therapy due to ethical and regulatory concerns, Article 6(2)(b) is beginning to come into play as the first CRISPR patents are applied for and granted.

One of the difficulties with Article 6(2)(b) is that there is no definition in the Directive of “germ line”. The Directive does not leave the interpretation of the term to national courts and it is therefore likely to be a matter for the CJEU to provide guidance on.

In the scientific world, references to ‘germ line’ include, at the very least, sperm or egg cells, or their precursor cells. It would therefore appear that inventions which comprise processes for modifying those types of human cells have the potential to fall within the exclusion in Article 6(2)(b) of the Directive.

However, it is not clear how the words “genetic identity” and “modifying” might be interpreted. Take for example, the correction of a single base pair (or letter in the DNA sequence) of a single gene in order to render it functional. Would that be enough to modify the “germ line genetic identity of a human being”? Or are there distinctions to be drawn, for example, between correcting existing but malfunctioning genes and inserting new genes that were never part of a cell’s original genetic complement? Recital 40 of the Directive talks of “interventions in the human germ line” as being contrary to ordre public and morality and, therefore, it might be expected that processes for any type of modification to the DNA of a human germ line cell will fall within Article 6(2)(b).  This would be in line with the CJEU’s rather expansive interpretation of “human embryo” in Oliver Brüstle v Greenpeace (case C-34/10) (see below), although difficult to reconcile with the practice of the EPO which is to construe exceptions to patentability narrowly.

The position with regard to patentability of certain aspects of CRISPR technology is further complicated by the fact that debates on germ line genetic identity are not restricted to modification of gametes (sperm and egg cells). The scientists who have called for a moratorium on human germline genome modification for clinical applications refer to the possibility of using CRISPR to modify embryos, “thereby altering the genetic makeup of every differentiated cell in an organism and so ensuring the changes will be passed on to the organism’s progeny”.  Many of the developments which have caused debate (including those described above) concern embryos or embryo-like cells rather than gametes or their precursors. Would the application of the Directive be different in relation to these types of developments?

By way of example, the research by Liang et al. was performed on “human triplonuclear zygotes” (egg cells that had been fertilised by two separate sperm cells and were considered by the scientists to be ‘non-viable’). These cells have been fertilised and would therefore, appear to have at least many of the characteristics of human embryos. As stated above, the provision of the Directive that is most relevant to human embryos is Article 6(2)(c).

In Brüstle, the CJEU ruled that the term ‘human embryo’ is to be understood “in a wide sense” and that “any human ovum must, as soon as fertilised, be regarded as a ‘human embryo’ within the meaning and for the purposes of the application of Article 6(2)(c) of the Directive, since that fertilisation is such as to commence the process of development of a human being.” The zygotes used by Liang et al. were intended to serve as an alternative for studies of normal human zygotes and presumably shared many of their characteristics. The CJEU’s ruling in Brüstle, read in isolation, suggests that human triplonuclear zygotes would fall within the definition of human embryo.

However, in a later judgment (International Stem Cell Corporation v Comptroller General of Patents, Designs and Trade Marks, (case C-364/13)), the CJEU clarified the meaning of the words “capable of commencing the process of development of a human being”, albeit not in relation to fertilised egg cells but in relation to parthenotes (eggs cells that are stimulated to undergo a process of cell division that is analogous to normal fertilised human embryos). Despite the fact that the CJEU had earlier ruled (in Brüstle) that parthenotes were human embryos, in International Stem Cell Corporation the CJEU found that a parthenote is not a ‘human embryo’ “if in the light of current scientific knowledge, it does not, in itself, have the inherent capacity of developing into a human being”. The CJEU distinguished Brüstle on the basis that in that case, submissions made to the Court indicated that parthenotes were capable of developing into human beings.

If one applies the CJEU’s reasoning in International Stem Cell Corporation to a human triplonuclear zygote (from the point at which it has been fertilised by a second sperm cell and loses its inherent ability to develop into a human being), it suggests that such a zygote would not be considered to be a human embryo within the meaning of the Directive.  On this basis, Article 6(2)(c) may not pose a block to the patentability of inventions relating to the use of CRISPR technology in relation to human triplonucelar zygotes or other embryo-like structures that do not have the inherent capability of developing into a human being.

The same reasoning would not apply to embryos used by the UK research team at the Francis Crick Institute (who intend to use embryos that are surplus to IVF treatment) on the assumption that such embryos have the inherent capacity to develop into human beings.

In circumstances where Article 6(2)(c) does not apply, Article 6(2)(b) may still pose a block to the patentability of inventions relating to the use of CRISPR technology to modify the human germ line. Taking human triplonuclear zygotes as an example, if as a result of applying the test set out in International Stem Cell Corporation, these do not fall within the definition of “human embryo” and do not therefore fall within the exclusion in Article 6(2)(c), it could still be argued that processes for modifying the genomes of such zygotes fall within the exclusion in Article 6(2)(b). Alternatively, it is arguable that Article 6(2)(b) should not apply to processes for modifying human triplonuclear zygotes on the basis that they are incapable of developing into human beings and transmitting genetically modified DNA to offspring.

Finally, it should be noted that under Article 6(1) of the Directive, member states can go further than the specific exclusions set out in Article 6(2) and exclude from patentability any inventions that are contrary to ordre public in that member state.

Conclusion

While this ‘shifting sands’ approach does provide the flexibility for patent law to be developed in a way that is consistent with scientific, ethical and regulatory developments, it causes difficulty for entities investing in CRISPR technology. At the point of filing a patent application, the patentability of any claims relating to use of the technology in human embryo-like structures and human reproductive cells is far from certain. This uncertainty also causes issues for those who wish to avoid infringing claims covering CRISPR technology, particularly where the claims have been limited by reference to wording from the Directive which is open to interpretation.

Published with minor amendments on 12 November 2015 in Life Science Intellectual Property Review

 

[1] Baltimore D, Berg P, Botchan M, et al. A prudent path forward for genomic engineering and germline gene modification. Science. 2015;348(6230):36–38.

[2] Liang P, Xu Y, Zhang X, Ding C, Huang R, Zhang Z, et al. CRISPR/Cas9-mediated gene editing in human tripronuclear zygotes. Protein Cell. 2015;6:363–72.

[3] https://www.crick.ac.uk/news/science-news/2016/02/01/hfea-decision/