Norms of international law in the field of application of the results of scientific research in the field of biotechnology (on the example of therapeutic and reproductive cloning and editing of the human genome) and their patent protection

Akhmadova Maryam Abdurakhmanovna ORCID: 0000-0003-1423-7044 PhD in Law Lecturer; Department of Business and Corporate Law; O.E. Kutafin Moscow State Law University (MGUA) Head of the Legal Support Department; GBU 'Small Business of Moscow' 14/4 Tatyanin Park str., Moscow, 119618, Russia 4ernijkvadrat95@gmail.com Other publications by this author

To date, some breakthrough achievements in the field of biotechnology are moving from the stage of basic research to clinical trials and therefore require adequate regulatory regulation, since innovative technologies in medicine, along with obvious advantages, usually carry the risk of occurrence and devastating consequences for the entire human population. In this regard, the possibility of negating the fruits of progressive development by the very fact of attempts to change the human essence as a result of research manipulations by geneticists and physicians has been rightly noted ^[22].

For example, the discovery of the CRISP/Cas9 technology, which, according to some experts, became the flagship of the biotechnological revolution ^[42], made it possible to treat genetically determined diseases by editing the genome of human somatic cells in "in vitro" conditions ^[6]. To date, states (for example, in Russia - Article 4 of Federal Law No. 61-FZ dated April 12, 2010 "On the Circulation of Medicines" ^[34]) allow the introduction of exclusively non-inherited changes into the human genetic apparatus, while recent achievements in this field determine the question of the admissibility of inherited genome modifications, i.e. editing the embryo genome ^[16] (for example, Russian molecular biologist Denis Rebrikov, upon receiving permission from the Ministry of Health, is ready to try to edit the embryo of a child of parents with hereditary deafness ^[1]).

The use of the CRISP/Cas9 technology causes certain concerns among scientists, who, recognizing its importance, conditionally identify two groups of ethical problems associated with carrying out embryo gene editing procedures. The first group includes technical problems caused by the imperfection of a new and therefore little-studied technology, when during an experiment a specialist by mistake or accident can cut DNA in the wrong place, which can lead to unpredictable mutations. The second group of ethical problems is associated with mutations, including inherited ones, which may be endowed with a child with an edited genome ^[39].

It should also be noted that biotechnology products capable of changing the entire paradigm of the modern therapeutic and diagnostic process are being developed by scientific teams from different countries at the same time, and some of them conduct very ambiguous experiments and clinical studies to test new technologies. In addition, the legal map of the world regulating the designated area of legal relations has a mosaic character, since the ban established in one State can be easily overcome in the jurisdiction of another. All this points to the need to create a layer of international legal acts designed to regulate relations in the field of biomedicine in general, by defining the boundaries of what is permissible for the entire world scientific community, where the main postulate should be to maintain a balance of potential benefits and the risk of unintended harm ^[40].

For this reason, we have chosen international acts regulating issues related to the use of therapeutic cloning, genomic editing and bioprinting technologies in practical medicine to one degree or another as the subject of our research. We have previously considered these issues from the perspective of the national intellectual property legislation of the BRICS countries. At the same time, the focus of the author's attention will be on the issue of extending the patent legal regime to the named innovative medical technologies.

To begin with, we note that stable economic growth of the BRICS countries is not possible in isolation from the proportional growth of their contribution to the global stock of knowledge, and therefore in recent years, on the sidelines of annual summits, special attention has been paid to the development of dialogue between partner countries in the field of science, technology and innovation, where biotechnology is one of the priorities. The commitment of the BRICS countries to the idea of developing multilateral cooperation in a number of strategic scientific areas, including in the field of medicine and biotechnology (Article 3), was reflected in the Memorandum on Cooperation in the field of science, technology and Innovation between the governments of the BRICS countries in 2015 ^[20], which was adopted following a meeting of representatives of the ministries of science, technology and innovation. The provisions of the named memorandum are detailed in the annual declarations adopted following the meeting of the heads of relevant ministries in the field of science and innovation of the BRICS countries (e.g., the Kampin Declaration of Ministers of Science, Technology and Innovation 2019 ^[38]), as well as in the BRICS Work Plan in the field of science, technology and innovation for 2019-2022 ^[21].

In turn, the patentability of biotechnologies as inventions is the main driver of the development of this industry, since scientific research and subsequent commercialization of the results require large financial investments. Thus, due to the wide scope of patent protection provided in the 1980s, the USA and Japan were able to become world leaders in the chemical and biological industries ^[41].

In turn, the BRICS countries (with the exception of China) have modest achievements in terms of the number of patented inventions in the global biotechnology market (see Figure 1). According to domestic experts, the reason for this is the limited capabilities of the BRICS countries due to the subject composition of key players in the national biotechnology markets, which are mainly represented by government agencies (research institutes, universities, etc.) ^[33].

Fig.1 BRICS patent activity in the field of biotechnology

Source: Streltsova E. The biotechnology race. URL: http://bricsmagazine.com/ru/articles/gonka-biotehnologiy (accessed 05/27/2020).

The scientific doctrine notes different positions on the possibility of patenting technologies for therapeutic cloning, genomic editing and bioprinting, and therefore research in this direction is relevant ^{[14, 22]}.

Proponents of depriving such objects of patentability point to the need to limit the monopoly on the part of the world's leading biotechnology companies, since free competition between research teams and laboratories working on the same scientific issues should serve as a serious incentive for such research. As a result, this will affect the cost and quality of the "products" being created, which will make innovative technologies for the diagnosis and treatment of various diseases more accessible to the population ^[25]. In turn, the antagonists of this approach mainly appeal to the loss of attractiveness of financing such scientific research for private investors, which can have negative consequences for science as a whole.

At the same time, the approaches chosen by the legislator to regulate the designated area of legal relations, as well as law enforcement practice, are strongly influenced by changing trends caused, first of all, by the permanent development of scientific progress in this area. The validity of this thesis can be easily illustrated by the example of a landmark court case in the United States in the lawsuit "Association for Molecular Pathology vs Myriad Genetics" ^[37], in which the U.S. Supreme Court issued a decision contradicting the previously adopted procedure for granting patents based on the results of human gene research.

By discovering the sequence of cancer-causing genes and patenting these results, Myriad Genetics became the owner of the exclusive right to isolate and study the BRCA1 and BRCA2 genes, which gave it the opportunity to create special methods for detecting mutations in these genes in specific people ^[12].

In connection with this course of events, the Association of Molecular Pathology filed a lawsuit to invalidate the patents granted on the basis of Section 101 of the America Inventions Act 2013, since DNA fragments created by nature cannot be patented on the grounds that they are isolated from the human body. The US Supreme Court recognized the plaintiff's claims as justified, noting that the discovery of the gene did not meet the criteria for patentability of the invention. Consequently, other laboratories are free to study open combinations of human DNA without fear of prosecution by patent holders, which in the future may reduce the cost of diagnosis and treatment. At the same time, Judge John Salk (Jonas Salk), in the framework of the aforementioned court case, stated that the discovery of the sequence of the BRCA1 and BRCA2 genes could not be patented, just as it could not be done with respect to the polio vaccine, since it belonged to all mankind.

Recognizing the validity of this approach, in our opinion, it is necessary to note the negative consequences of the practice of limiting patent protection in the field of biotechnology, expressed in the loss of interest of private investors to finance this kind of scientific research, which, of course, will slow down scientific progress. These concerns are shared by representatives of the scientific community. For example, the famous jurist R. Notta noted at the end of the last century that denying the possibility of patenting a method aimed at curing a significant part of hereditary diseases is short-sighted ^[44].

Before proceeding to the direct study of international acts designed to regulate relations in the field under study, it should be noted that among those acts of soft law prevail ("soft law"). This situation has developed, firstly, because of the specifics of the scope of their application, which is in its infancy, and, secondly, any public relations that acquire a cross-border character tend to receive a political coloring.

In this regard, one of the main (but not the only) instruments of international legal regulation of the field of biotechnology are acts of "soft law", which do not limit the sovereignty of States and represent legally non-binding rules of conduct created unilaterally by an international organization or agreed upon by subjects of international law (political agreement) ^[35]. In our case, these are declarations. Other acts are conventions.

The Convention on the Protection of Human Rights and Dignity in Connection with the Application of Advances in Biology and Medicine: The Convention on Human Rights and Biomedicine (Oviedo, 1997) (hereinafter referred to as the Oviedo Convention) ^[15] is currently the only and unique by virtue of the binding nature of its provisions for the countries that have joined the international treaty regulating the use of new genetic and biological technologies in relation to humans, which was developed under the auspices of the Council of Europe. Despite the duration of the existence of the named document, not all member States of the Council of Europe, including Russia, have signed and ratified the Oviedo Convention, as well as its additional protocols on human organ and tissue transplantation ^[11], genetic testing for medical purposes ^[10], human cloning ^[9] and biomedical research ^[8], which are designed to specify the convention in relation to various branches of knowledge and practice.

This situation indicates the lack of consensus between countries at the global and regional levels regarding the rules established by this convention, when some countries adhere to a conservative position on the issues under study, while others are concerned about the possible limitation of the convention to strategically important scientific research in modern conditions ^[13].

The BRICS countries are not parties to the Oviedo Convention, but it deserves our attention because the principles underlying it serve as a guideline for global norms and aspirations.

In general, this approach is reflected in one of the definitions of the Constitutional Court of the Russian Federation concerning issues of Russian legislation on transplantation, where the court noted that not joining the Oviedo Convention does not exclude the possibility of taking into account and using its provisions in the formation of domestic legislation in the relevant field of public relations ^[23].

The Oviedo Convention and its Additional Protocols formulate a number of extremely important principles aimed at protecting the fundamental rights and freedoms of the individual from abuse related to the use of biomedical achievements, which directly relate to the subject of research and therefore deserve our close attention.

So, firstly, the prohibition of human cloning is established in the Additional Protocol to the Oviedo Convention (12.01. 1998) and has an absolute character. By cloning, Article 1 of the protocol means the creation of a being genetically identical to another (living or dead) being with an identical set of genes of the cell nucleus. Secondly, this international act does not limit cloning for therapeutic purposes, performed in various ways: separation of the zygote, somatic (asexual) cells, transplantation of the nucleus of a somatic cell into a nucleoless egg of a donor ^[30]. Therapeutic cloning is ultimately aimed at obtaining stem cells capable of transformation and development into different tissues of the human body ^[2]. Modification of the human genome is recognized as permissible for the purposes of therapy, prevention or diagnosis, provided that this change is not inherited (Article 13 of the Oviedo Convention). That is, there is a ban on interference during the embryonic stage of human development ^[16].

Regulation of the issue of conducting research on embryos in "in vitro" conditions, provided that the creation of human embryos for research purposes is strictly prohibited, the authors of the convention purposefully withdraw from the scope of the international act. In turn, if the state permits such research, then adequate protection of embryos must be provided at the legislative level (Article 18).

It is also worth noting some of the principles reflected in this convention, which, although indirectly related to the area under consideration, seem to be basic in the implementation of any genetic research and gene therapy, namely:

- the permissibility of carrying out tests that allow predicting the presence or predisposition to one of the genetic diseases, only for medical reasons or for scientific purposes (Article 12) in order to avoid possible provocations and abuses by employers and insurance companies;

- the inadmissibility of using specific technologies used by medicine for childbirth with the intention to choose or change the sex of the unborn child, except in situations in which this choice is due to the desire to avoid a severe hereditary disease related to the sex of the unborn child (Article 14), otherwise a gender imbalance may arise in the structure of the country's population ^{[39, 5]}.

And finally, thirdly, bioprinting technology is not mentioned at all in the Oviedo Convention. It seems that this state of affairs is due to the specifics of this field of biotechnology, which is still in its infancy. At the same time, one should agree with the opinion of D.S. Ksenofontova, who noted the possibility of extrapolating to the sphere of creation and use of bioprinted organs the principles on the removal of organs and (or) human tissues enshrined in the convention under consideration.

In this sense, the principles specified in the convention are assumed as follows: (1) exclusivity, allowing the removal of organs from living donors only if they are absent from deceased donors and if other methods of treatment are impossible (art. 19); (2) inadmissibility of the removal of organs or tissues from living donors in the absence of their consent, expressed explicitly and specifically (Articles 19, 20); (3) the inadmissibility of trading in the human body and its parts for monetary gain (Articles 21), etc. ^[17].

At the same time, according to the author of this approach, in cases where the recipient's own cellular material is used to print an organ, referring to the listed principles is not so relevant, since potential risks are minimized, however, the opposite situation develops when using cells of a third party (donor), when the risks of committing bioprimes are extremely high.

D.S. Ksenofontova's reflections on the issue of regulating relations related to the use of 3D bioprinting in the context of the Oviedo Convention seem fair. At the same time, in our opinion, the rapid development of medical technologies in this area determines the need for more detailed coverage of this issue through the development of special principles in the form of an additional protocol to the named convention.

The issue of patentability of medical technologies, which are the focus of the author's attention, is not reflected either in the text of the convention or in the provisions of the additional protocols thereto. For this reason, as civilists who tend to think in line with the general legal principle "what is not prohibited by law is allowed", it seems possible for us to patent technologies for bioprinting, genomic editing and therapeutic cloning, subject to compliance with the requirements and restrictions set out in the Oviedo Convention.

Next, we will consider the main acts of "soft law" in the field under consideration, which for the most part were developed under the auspices of UNESCO, as a specialized UN agency designed to organize substantive cooperation between countries on bioethics and biomedicine at a universal level. Thus, at the international level, the regulation of the legal relations under study is based on the following documents (declarations):

· UNESCO Universal Declaration on Bioethics and Human Rights 2005 ^[3],

· The 2005 UN Declaration on Human Cloning ^[7],

· UNESCO International Declaration on Human Genetic Data 2003 ^[19],

· The UNESCO Universal Declaration on the Human Genome and Human Rights of 1997 ^[4] hereinafter referred to as the 1997 Declaration), in which guarantees of respect for human rights and freedoms are fairly well balanced with the freedom to conduct scientific research aimed at ensuring the health of individuals and the population as a whole. Article 1 formulates the concept according to which the human genome is the common heritage of mankind, and by analogy, for example, with nuclear technologies and resources, it is jointly owned and does not belong to any state ^[24]. The legal doctrine considers the concept of the common heritage of mankind as an ethical provision of justice between different generations of people ^[45].

Such an approach to regulating the object of research, in our opinion, seems justified and justified, since "the nature of the human genome has been determined collectively for many centuries through generations of human evolution" ^[43], for this reason, the process of genome formation is objective, and therefore is the heritage of the entire world community and cannot belong to an individual the state.

The 1997 Declaration reflected the main components of the concept of the common heritage of mankind, which are based on the joint extraction of preferences from the use of the genome through the creation of an international management system based on independent actions by States to implement this declaration "by all possible means" (section G). However, the provisions of the 1997 Declaration are rather general in nature, and therefore it is not possible to get more specific ideas about these preferences.

It should also be noted that the issues related to the permissibility of extending the patent legal regime to the genome, although not opposed by the developers of the declaration to the concept of the common heritage of mankind, were "taken beyond" the international act itself. At the same time, Article 4 of the 1997 Declaration establishes the provision according to which the human genome in its natural state should not serve as a source of income.

At the same time, comments on this declaration refer to the human genome in its natural state as a discovery, not an invention. The combination of the lack of legal definitions of the term "human genome" and the concept of its "natural state" leads to the recognition of the possibility of the "human genome" being in a different state (e.g., complementary DNA or cDNA), which creates difficulties for law enforcement practice, in particular to address the issue of patentability of the genome ^{[26, 18]}.

At the end of the last century, thanks to the efforts of scientists, the first cloned organism appeared - Dolly the sheep. After that, the international community was faced with the need to regulate relations in this area by adopting a special regulatory act in order to establish prohibitions for scientific research and indicate the limits of what is allowed. At the global level, for the first time, the 1997 Declaration established a ban on human reproductive cloning as a practice that contradicts human dignity (Article 11).

In turn, after long discussions, on March 8, 2005, the adoption of a special international document on this issue in the form of the UN Declaration on Human Cloning (hereinafter referred to as the Declaration on Cloning) finally took place.

In legal doctrine, the named declaration is called "toothless", since it was expected that the document would contain a number of mandatory prohibitions on human cloning, including a ban not only on reproductive, but also on therapeutic cloning. Such a draft declaration was prepared by several States at the initiative of the United States and submitted to the working group, but it was not supported by other participants. In the final draft of the declaration, the accents condemning cloning were noticeably softened, for example, the preamble only indicates concern about the ethical consequences of the application of certain achievements of biological sciences for all mankind ^[32].

Thus, the Declaration on Cloning does not contain a statement on the need to develop an international convention on the prohibition of cloning, its main provisions are reserved to the competence of States, which, in order to ensure the implementation of the Declaration, must promote the adoption and observance of national laws in their jurisdictions.

The above-mentioned acts and documents of international law, in fact, form a unified system of principles and standards, differing in the breadth of coverage of some aspects of regulated relations. Among such principles that States should be guided by in developing their legislative acts and policies in this area, the following should be noted:

· Respect for human dignity, human rights and fundamental freedoms (Articles 1, 2 of the 1997 Declaration, Articles 1, 3 of the 2003 Declaration, Article 3 of the 2005 Declaration, paragraph "c" of the 2005 declaration on cloning);

· Preliminary assessment of potential hazards and benefits (Articles 5 of the 1997 Declaration, Articles 15 of the 2003 Declaration, Articles 4 and 20 of the 2005 Declaration);

· The validity of the goals of scientific research (sections C, D of the 1997 Declaration, Article 5 of the 2003 Declaration, Articles 7, 18, 19 of the 2005 Declaration);

· The prior, free and explicit consent of the person concerned (Articles 5 of the 1997 Declaration, Articles 8-9 of the 2003 Declaration, Article 6 of the 2005 Declaration);

· Non-discrimination (Article 6 of the 1997 Declaration, Article 7 of the 2003 Declaration, Article 11 of the 2005 Declaration);

· Confidentiality (Article 7 of the 1997 Declaration, Article 14 of the 2003 Declaration, Article 9 of the 2005 Declaration);

· Ensuring universal access to scientific achievements and international cooperation (Articles 12 of the 1997 Declaration, Articles 18, 19 of the 2003 Declaration, Articles 15, 21, 24 of the 2005 Declaration);

· Prohibition of reproductive cloning (Article 11 of the 1997 Declaration, paragraph "b" of the 2005 declaration on cloning)

All the designated international acts provide for the freedom to conduct scientific research in relation to various biotechnologies that are applied and aimed at reducing the suffering of specific people and improving the health of all mankind. Of course, such innovative medical technologies as therapeutic cloning, genomic editing and organ printing technologies using a 3D printer that can create medicines designed for individual healing, or "print" a transplanted organ that is not rejected due to genetic identity - all this contributes to solving most medical problems, for example, caused by hereditary diseases.

The international regulatory framework governing various aspects of the subject of our study also includes a number of bilateral intergovernmental agreements on scientific and technical cooperation concluded by Russia with all BRICS member countries.

Based on our detailed analysis of the content of these bilateral agreements and additional protocols, it was found that all of them contain provisions enshrining the principle of the need to ensure adequate legal protection, both previous and created within the framework of joint research projects of intellectual property (e.g., Article 3 of the Intergovernmental Protocol on the Protection and Use of Rights intellectual Property Rights to the Agreement between Russia and India ^[28]; Article 4 of the Intergovernmental Protocol on the Principles of Protection and Distribution of Intellectual Property Rights to the Agreement between Russia and China ^[29], etc.). Protection of intellectual property results implies, inter alia, obtaining security documents in accordance with the procedure established by national legislation the countries where the joint project was directly implemented by contacting the national patent office. In some of the named agreements, the issue of determining the order of filing patent applications is consecrated (for example, Article 8 of the Intergovernmental Protocol on the Principles of Protection and Distribution of Intellectual Property Rights to the Agreement between Russia and China, etc.).

In turn, the lack of explicit permission to carry out scientific research in this field of biotechnology with the subsequent commercialization of results that can be patented as inventions hinders scientific progress. At the same time, the system of international principles and standards formed by the considered acts of soft law does not answer this question, except for the establishment of a ban on reproductive cloning, and, accordingly, patenting of such technologies is not possible.

Considering the fact that the considered international acts contain an appeal to States to ensure the implementation of the provisions of the declarations within the framework of national legislation, modern countries focused on the development of the studied branch of medicine are forced to create a legal foundation in the absence of a universal international treaty binding, as a result of which the legal map of the world acquires a rather mosaic character.

For this reason, as noted in the legal doctrine, innovative technologies in the field of medicine are distributed in countries with legislation loyal to scientific research, which are, in fact, "scientific offshore" ^[16].

Whereas countries that immediately opposed the permission of research in the field of, for example, genomic editing, due to the risk of being technological outsiders, are forced to lift such legislative prohibitions. The validity of this thesis can be illustrated by the example of how a group of scientists from the UK in 2016 received permission for the first time to conduct research in the field of editing the human embryo genome using the CRISPR/Cas9 method, after Chinese scientists published the results of successful research in this area in 2015 ^{[31, 46]}. The latest high-profile case of editing the human embryo genome using the CRISPR/Cas9 method was the work of Chinese scientist He Jiankui, aimed at the appearance (for the first time in the world) of twins after artificial editing of their genes in the direction of obtaining innate immunity to HIV ^[27].

Based on the above, it can be concluded that Russia, as well as all other BRICS countries, needs to modernize national legislation in order to fill in the gaps on the problems highlighted in this study. In addition, it seems advisable to work out the possibility of concluding a multilateral international agreement between partner countries on patenting innovative technologies in the field of biomedicine under study, since private business, acting as the main source of financing, will not invest in long-term projects with a high degree of risk until it receives legal guarantees of reliable protection of its developments from their use by competitors by obtaining security documents.

Otherwise, the BRICS countries risk becoming technological outsiders, and the citizens of these countries will be forced to engage in medical tourism with all its negative consequences in the foreseeable future.