INTELLECTUAL PROPERTY CONSIDERATIONS IN THE DEVELOPMENT OF GENE-EDITING TECHNOLOGIES

ABSTRACT

Gene-editing technologies, such as CRISPR-Cas9, have sparked a revolution in biotechnology, promising breakthroughs in medicine, agriculture, and beyond. As scientists unlock the potential to precisely modify DNA, questions of ownership and protection of these innovations have become paramount. In this article, we explore the intricate landscape of intellectual property (IP) considerations in the development of gene-editing technologies, from patents that safeguard novel techniques to copyrights that protect innovative software. Understanding these IP principles is crucial for navigating the ethical, legal, and commercial aspects of this groundbreaking field.”

Keywords

Gene editing technologies, IPR, DNA, Genetic Resources (GR)

INTRODUCTION

The categorization of genetic and biological resources has undergone significant progress in recent times, primarily because of modern molecular characterization methods like genomic sequencing or genetic engineering. These methods, readily available for mapping transcriptomes, proteomes, or entire metabolomes of organisms, have been acknowledged as key catalysts for innovation centered on Genetic Resources (GR) across various fields and sectors utilizing GR. They are producing substantial volumes of biological characterization data at an unparalleled pace and magnitude.[1]

Gene editing refers to a form of genetic engineering where alterations are made to the DNA of a living organism by inserting, deleting, modifying, or substituting genetic material within its genome. In contrast to conventional methods that haphazardly introduce genetic material into a host genome, modern gene editing technologies focus on precise modifications to specific locations within the genome.[2]

Genome editing stands as a groundbreaking technology in the realm of molecular biology. While scientists are captivated by the boundless opportunities presented through deliberate and controlled modifications to DNA, and have eagerly embraced such tools for their research, there is often a gap in understanding the intellectual property (IP) implications associated with bringing products derived from genome editing to market. The significance of IP rights is progressively growing as innovation stemming from Genetic Resources (GRs) continues to emerge. The realms of IP law and practices relevant to GR-based innovation are broadening from traditional industrial property rights such as patents, trade secrets, and plant variety protection, to encompass copyright, and, where applicable, sui generis database protection, and regulatory data protection.[3]

Thanks to the innovation of genome editing, the period from the inception of a new product to its tangible existence can be quite brief; hence, understanding the intellectual property landscape surrounding the diverse methods of genome editing is pertinent.[4]

Zinc finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), and the clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 nuclease system are three prevalent gene editing methodologies. These technologies are extensively employed in genome engineering, facilitating a diverse array of mutations by prompting DNA breaks that initiate error-prone repair mechanisms such as homologous recombination (HR) or nonhomologous end joining (NHEJ). They effectively enable precise editing, alteration, and manipulation at specified genomic locations.[5]

OVERVIEW OF GENE-EDITING TECHNOLOGIES[6]

Zinc finger nucleases (ZFNs) are constructed from zinc finger proteins, which are a group of naturally occurring transcription factors fused with the endonuclease FokI3.

Originally, zinc finger nucleases were among the earliest enzymes used in targeted genome engineering. These are generated by combining a zinc finger with a restriction endonuclease, typically FokI3. Zinc finger domains have the ability to recognize three base pair sequences on DNA. When a series of linked zinc finger domains are combined, they can recognize longer DNA regions, providing the desired on-target specificity. The FokI endonuclease operates as a dimer, meaning that double-strand DNA cleavage only occurs at sites where two ZFNs bind to opposite DNA strands. To achieve this, two ZFNs are designed to recognize different closely positioned nucleotide sequences within the target site. This necessitates the simultaneous recognition and binding of both ZFNs, thereby naturally restricting off-target effects.

Nevertheless, the specificity of neighboring zinc fingers is also influenced by multiple zinc finger motifs aligned in an array. This complexity makes the design and selection of modified zinc finger arrays more challenging. Consequently, predicting the specificity of the final product can often be a daunting task.

Transcription activator-like effector nucleases (TALENs) are fusion proteins comprising a bacterial TALE protein and the FokI endonuclease.

Similar to ZFNs, the specificity of TALENs for their target sequences is achieved through the protein-DNA interaction. In the case of TALENs, each individual TALE motif recognizes a single nucleotide, and an array of TALEs can bind to a longer DNA sequence. The function of each TALE domain is limited to recognizing a single nucleotide, and this does not impact the binding specificity of neighboring TALEs. This characteristic makes the engineering of TALENs considerably simpler compared to ZFNs. Like ZFNs, TALE motifs are coupled with the FokI endonuclease, which requires dimerization to initiate cleavage. Consequently, the binding of two distinct TALENs on opposite strands in close proximity to the target DNA site is necessary.

The CRISPR-Cas9 (clustered regularly interspaced short palindromic repeats) system is derived from the bacterial immune system.

It consists of the Cas9 nuclease along with two types of RNAs: trans-activating crRNA (tracrRNA) and a single guide RNA (sgRNA). The sgRNA recognizes the target sequence through standard Watson-Crick base pairing and must be followed by a DNA motif known as a protospacer adjacent motif (PAM). Each Cas9 protein possesses a specific PAM sequence, for instance, the standard Cas9 PAM is 5’-NGG-3’. The Cas9 nuclease carries out DNA cleavage, resulting in a double-strand break with the wild-type enzyme, or a single-strand break when utilizing mutant Cas9 variants called nickases. The recognition of the DNA site in the CRISPR-Cas9 system is governed by RNA-DNA interactions.

This system presents numerous advantages over ZFNs and TALENs, including the ease of designing for various genomic targets, straightforward prediction of off-target sites, and the ability to modify multiple genomic sites simultaneously (multiplexing). Additionally, the recognition sequence of the sgRNA is small (20bp), simplifying the cloning process compared to traditional homologous repair designs.

PATENTS IN GENE EDITING

Genes do not act in isolation or serve a singular purpose. Genomes are not mere assemblages of independent elements that can be combined and recombined precisely without unintended consequences. Consequently, advocates argue that there are valid legal and scientific grounds for genes to be considered patentable subject matter when their functions are disclosed, such as their role in coding for a specific protein or their association with a disease. The primary rationale behind seeking patent protection is to safeguard one’s technology from imitation and to deter competitors’ patenting and application endeavors.

When DNA sequences are patented, it grants a monopoly not only over the sequence itself but also over any potential uses of that sequence. A gene patent provides exclusive rights over the gene for a period of 20 years. The owner has the authority to prohibit others from conducting research, running tests, or developing therapies related to that gene without acquiring a license and paying royalties.[7]

The introduction of CRISPR technology has had a notable impact on India’s patenting framework. The Indian Patent Office has encountered difficulties in determining the patent eligibility of CRISPR-related innovations due to the intricacies of the technology and the persistent patent disputes in other jurisdictions. In May 2020, the Indian Patent Office granted a patent application to ERS Genomics, a company co-founded by Dr. Emmanuelle Charpentier, the 2020 Nobel Prize laureate for gene editing. The patent was granted for “Methods and compositions for RNA directed target DNA modification and for RNA directed modulation of transcription.”

Furthermore, in 2020, India’s Council of Scientific and Industrial Research (CSIR) awarded a patent for CRISPR Cas-9 in India, marking a significant milestone for Indian researchers and enterprises. Nevertheless, India’s patent system continues to grapple with the intricacies of CRISPR technology and the ongoing patent disputes. Despite this, it seems that the Indian government is taking measures to encourage the advancement of CRISPR-based research and development within the nation. The emergence of gene editing technologies like CRISPR is inevitably expected to result in a rise in patent applications seeking protection for Genetically Modified Microorganisms (GMMs). [8]Top of Form

CASE LAWS[9]

Two recent rulings by the Supreme Court of the United States (SCOTUS) are of importance to the biotechnology industry since it invokes the dictum that “laws of nature, natural phenomena and abstract ideas” are not patentable.

Mayo Collaborative Services v. Prometheus Laboratories, Inc.[10]

In March 2012, the court delivered a ruling against Prometheus Laboratories in California, determining that it could not obtain a patent for using metabolite levels to guide drug dosing. The Supreme Court of the US stated that:

The application of a natural law is ineligible for patent protection if the steps involved in applying the natural law consist of well-understood, routine, conventional activities previously practiced by researchers in the relevant field.
Additional elements in a claimed invention that contribute nothing specific beyond what is already known about the laws of nature, natural phenomena, or abstract ideas, and merely involve routine, conventional activities previously undertaken by those in the field, do not render the claim eligible for a patent.

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Then, in June 2013, the court struck down a patent claim by Myriad Genetics of Utah that linked certain DNA sequences to female breast cancer

Association for Molecular Pathology v. Myriad Genetics[11]

While ethical and policy considerations played a significant role in the debate surrounding the case, the focus of the decision was primarily on the definitions outlined in two codes: the genetic code and the patent code. All nine Justices of the Court concurred that the segments of DNA constituting human genes do not qualify as patentable subject matter under section 101 of the Patent Act due to their natural origin. However, the Court determined that molecules created through reverse transcription from messenger RNA to remove intron sequences—referred to as complementary DNA, or cDNA—are indeed eligible for patent protection. Justice Thomas’s decisive statement in the ruling succinctly put it, “A naturally occurring DNA segment is a product of nature and not patent eligible merely because it has been isolated, but a cDNA is patent eligible as it is not naturally-occurring.”

Justice Thomas, in his deliberations on patents related to DNA sequences, sought to find a middle ground between the established principle that discoveries of natural phenomena are not eligible for patents and the conflicting idea that “all inventions to some extent … involve laws of nature, natural phenomena, or abstract ideas.” He achieved this by distinguishing between genomic DNA and cDNA. According to his analysis, the isolated DNA sequences were deemed unsuitable for patents because they were not “markedly different” from the sequences naturally occurring in nature. Their diagnostic usefulness, in fact, stemmed from their identical sequence to the naturally occurring ones.

This ruling adds to a series of recent Supreme Court decisions that are reshaping patent law, with significant implications for innovation within the life sciences sector. Thus to get a gene patent one will have to show that it is significantly different from any natural gene.

However, in an entirely opposite ruling, the Federal Court of Australia in

D’Arcy v Myriad Genetics Inc.[12]

The court unanimously rejected an appeal made by Yvonne D’Arcy aiming to invalidate Claim 1 of Australian Patent No. 686004, owned by Myriad Genetics Inc. The patent involves an isolated DNA sequence utilized for cancer diagnosis and was challenged for not being eligible as patentable subject matter.

The Court determined that the claim meets the criteria of being a “manner of manufacture” and is therefore deemed eligible for patent protection under section 6 of the Statute of Monopolies.

The Australian Court acknowledged that the Supreme Court of the United States denied the claim to the isolated DNA in the US Patent on the grounds of it being a “product of nature.” However, the Australian Court pointed out that such a principle does not exist in Australian patent law.

To say the least, this makes gene patenting a complex issue if such patents are sought in multiple countries.Top of Form

COPYRIGHT PROTECTION

Copyright pertains to the expressions of scientific or technical content, originally designed to safeguard literary and artistic creations. Copyright law explicitly excludes protection for “any idea, procedure, process, system, method of operation, concept, principle, or discovery, regardless of the form in which it is described…” The potential for copyright protection exists for the written representation of modified genetic material’s genetic sequence or genetic products such as proteins.

N. Boorstyn argues for the copyrightability of DNA sequences, while Sue Coke suggests that a DNA sequence could qualify for copyright protection when it involves a sufficient degree of skill, labor, and effort in elucidating the sequence. Advocates of gene copyright often draw parallels between genetic sequences and computer programs, viewing a DNA sequence as a series of instructions akin to a computer program. DNA molecules are recognized as both machines with functions and carriers of information. The chemical structure of a DNA sequence is generally distinct from the functions it performs due to the embedded information.

However, a crucial distinction between DNA sequences and computer programs lies in the fact that while programs can have multiple expressions to achieve a specific function, DNA sequences lack such alternative expressions. Consequently, the argument against copyright protection for DNA sequences stems from the concern that it may inadvertently protect the processes encoded by these sequences. Moreover, DNA sequences are not considered original works of humans, further complicating the application of copyright.

Recently, Willem P. C. Stemmer proposed a novel approach suggesting that DNA sequences could indeed be protected by copyright. Under Stemmer’s proposal, genomics companies could release their sequences to the public while retaining certain Intellectual Property Rights (IPRs). These companies would convert their existing DNA sequences into a ‘music file’ format, such as an mp3 file, making them accessible to external database users. These users could copy the music file, transfer the copy, and then re-convert it back into DNA sequences using a specialized program. Although the resulting back-translated DNA sequences would not themselves be protected by copyright, the act of accessing a DNA sequence without copying the copyrighted music file could constitute copyright infringement.

The advantage of this ‘music file’ approach is that it enables genomics companies to publish their DNA sequences while still retaining IPRs for these published sequences. Publishing DNA sequences traditionally could potentially hinder the possibility of obtaining a patent for them. As a result, many genomics companies are hesitant to make their sequences publicly accessible, keeping them largely inaccessible to the scientific community. Stemmer’s proposal offers a workaround by allowing companies to publish their sequences in a protected manner, preventing unauthorized copying of the ‘music file’ and maintaining control over their intellectual property.[13]Top of Form

ETHICAL DILEMMA FOR USING GENE EDITING TECHNOLOGIES

Genome editing holds the potential to encroach upon human rights in diverse ways. There are apprehensions that genome editing might pave the way for the creation of “designer babies” or the selection of specific traits, raising concerns about a new form of eugenics and potential violations of the fundamental right to life. This scenario could lead to the emergence of a class of genetically enhanced individuals, which could be viewed as infringing upon the right to life of those who are not naturally selected or edited.

Moreover, there are concerns regarding Biopiracy associated with CRISPR, as this genome editing technology could be utilized to gather, store, and share genetic data from indigenous communities without their consent. This raises potential issues of privacy breaches and confidentiality violations. The term “biopiracy,” coined by scholar-activist Pat Mooney, signifies both unequal gene flows and a claim of global injustice, highlighting disparities in (genetic) resource access and control between the Global North and the Global South.

The development of novel gene editing techniques like CRISPR is progressing swiftly, enabling plant breeders to utilize genetic markers to guide trait-level alterations in individual genomes. To employ CRISPR effectively, Digital Sequence Information (DSI) is essential so that inventors can identify which genes are desirable for further editing. Ensuring the availability of this information in the public domain becomes crucial to mitigate biopiracy concerns.

Concerns also arise regarding the potential exploitation of genetic resources from indigenous communities through genome editing, potentially leading to biopiracy and violation of their human rights. Additionally, the human rights of individuals with disabilities are pertinent to the emerging medical technologies in gene editing. There are worries that genome editing might be employed to eliminate or “cure” certain genetic conditions, resulting in a devaluation of the lives of individuals with these conditions and a violation of their human rights.

Transitioning from performing gene editing in “somatic” cells (such as healthy liver cells or cancers with damaging mutations) to “germ” cells may seem straightforward, as it employs the same CRISPR-Cas9 laboratory techniques. However, the process of snipping out detrimental mutations, inserting a “normal” DNA sequence, and then reassembling the DNA presents physiological benefits alongside challenges in translating the technology from the laboratory to the patient’s bedside. Distinguishing between the hype surrounding the technology and its practical, immediate applications remains a challenge.

The therapeutic potential of “genome surgery” for humanity still lies distant on the horizon, highlighting the complexity and uncertainties surrounding the technology’s practical implementation.[14]

CONCLUSION AND SUGGESTIONS

“Intellectual Property has the shelf life of a banana,” a statement attributed to Bill Gates, holds particular significance, especially within the realm of genome editing technologies. There is a pressing need to strike a delicate balance between incentivizing advancements in biotechnology and safeguarding public interests, calling for improvements in the existing patent systems. Achieving a level of refinement and consistency in laws worldwide, particularly concerning genome editing technologies such as CRISPR-Cas9 is crucial.

While genome editing technologies offer substantial medical benefits, they also present numerous complexities, concerns, and significant ethical, legal, and social questions that must be addressed. Ensuring responsible use of the technology and upholding human rights are paramount. However, similar to the evolution of past technologies, the introduction of regulations through legal reforms, especially in Intellectual Property Rights (IPR) Laws, is expected to eventually mitigate ethical dilemmas and protect the interests of humanity.

Establishing regulations and oversight mechanisms is essential to prevent the potential misuse of genome editing technology and to guarantee the protection of human rights.[15]Top of Form

DNA sequences are not considered suitable subjects for copyright protection. Additionally, some gene innovations incorporated in marketed products cannot be safeguarded by trade secrets, as trade secret protection does not apply to information that is not kept confidential. Patent protection is often deemed inappropriate due to the perception that patent rights may be overly robust compared to the actual contribution made by the inventor. To address these challenges, it becomes imperative to establish a framework that provides the initial innovator with incentives to invest resources, while also ensuring that subsequent innovators have unfettered access to the original innovation.

Efforts are needed to encourage public institutions to contribute towards placing genes and gene fragments in the public domain. Collaborative endeavors by public institutions have resulted in the creation of databases containing raw DNA sequences from humans and other organisms, which are now accessible to the public. The more gene fragments are made publicly available, the more challenging it becomes to establish the novelty and non-obviousness of a particular sequence.

The absence of proprietary rights in open-source software allows for diverse uses and enhancements of products without the fear of facing accusations from proprietary software companies. This highlights the importance of exploring foundational principles of a new legal framework rooted in liability regimes rather than exclusive proprietary ones.

A new legal regime should aim to address the crucial issue of the relationship between initial innovators and subsequent innovators in a sequence of innovations. This entails fostering innovation without hindering follow-on innovations, striking a balance that encourages progress and accessibility within the field of genome editing technologies.

There are several potential adjustments to Intellectual Property Rights (IPR) laws that could enhance the protection of genome editing technologies. A crucial initial step involves expanding the definition of genetically modified microorganisms (GMM). The Agreement on Trade-Related Aspects of Intellectual Property Rights (TRIPS) delineates the scope of patentable subject matter. The current practice of not adopting a definition utilized by IPR laws in developed countries appears to stem from the absence of a standardized scientific definition. Presently, IPR laws define GMMs as living organisms that have undergone genetic modification. However, this definition could be broadened to encompass non-living GMMs, such as enzymes, viruses, and other bioproducts.

Concurrently, adjustments could be made to Patent laws outside India to promote open access to gene editing technologies. This could be achieved through the establishment of a “compulsory licensing” system akin to Section 84 of the Indian Patent Act 1970. Such a system would enable other researchers and companies to access the technology under specific conditions, such as during a global pandemic.

International collaboration is indispensable for amending IPR laws, including the creation of a mechanism to harmonize patent laws across different countries. This harmonization would facilitate the protection of inventions by companies and researchers across multiple jurisdictions.

In an effort to promote innovation and advance genome-wide analysis and engineering technologies, the Department of Biotechnology established a dedicated Task Force on “Genome Engineering Technologies and Their Utilizations” in 2014. Furthermore, there is a need to enhance infrastructure for initiatives that support research and upcoming technologies like gene editing. The establishment of such a task force would pave the way for the development of regulations concerning disruptive technologies in the field of biotechnology, such as CRISPR.

In conclusion, IPR laws concerning the protection of genome editing technologies should strike a balance between fostering innovation and economic growth while addressing safety, ethical, and human rights concerns. These laws should be formulated and implemented to encourage responsible development and use of genome editing technologies, ensuring that the benefits of the technology are widely accessible and equitably shared. [16]

REFERENCES

Dae Hwan Koo, Effective Protection of DNA Sequences and Gene Innovations, IIP Bulletin 1 (2007), https://www.iip.or.jp/e/summary/pdf/detail2006/e18_17.pdf
Helga Schinkel& Stefan Schillberg, Genome Editing: Intellectual Property And Product Development In Plant Biotechnology, PUBMED, ( March 31, 2024, 2:30 PM),https://pubmed.ncbi.nlm.nih.gov/27146974/
Integrated Intellectual Property Management For Genetic Material And Genetic Sequence Data, Intellectual Property Guide for Genetic Resources and Genetic Sequence Data, https://www.wipo.int/export/sites/www/tk/en/docs/ip_gr_grdataguidefin.pdf
Nicole Lynn, CRISPR-Cas9, Talens And Zfns – The Battle In Gene Editing, PROTEINTECH (March 30, 2024, 9:20 PM), https://www.ptglab.com/news/blog/crispr-cas9-talens-and-zfns-the-battle-in-gene-editing/#:~:text=Cas9%20creates%20a%20site%2Dspecific,by%20host%20DNA%20repair%20machiner
Pancham Rathod & Sheetal Tiwari, PATENT AND GENOME EDITING TECHNOLOGIES: ISSUES AND CHALLENGES, Vol I IPR Journal , 93 (2023), https://www.nlunagpur.ac.in/PDF/Publications/5-Current-Issue/8.PATENT%20AND%20GENOME%20EDITING%20TECHNOLOGIES.pdf
Rajendra K. Bera, Synthetic Biology and Intellectual Property Rights, INTECHOPEN, (4 April,2024, 2:59 AM), https://www.intechopen.com/chapters/48297
Yuan-Chuan Chen, Introductory Chapter: Gene Editing Technologies and Applications, INTECHOPEN, (March 27,2024, 6: 20 PM), https://www.intechopen.com/chapters/66368

[1]Integrated Intellectual Property Management For Genetic Material And Genetic Sequence Data, Intellectual Property Guide for Genetic Resources and Genetic Sequence Data, https://www.wipo.int/export/sites/www/tk/en/docs/ip_gr_grdataguidefin.pdf

[2] Yuan-Chuan Chen, Introductory Chapter: Gene Editing Technologies and Applications, INTECHOPEN, (March 27,2024, 6: 20 PM), https://www.intechopen.com/chapters/66368

[3] Integrated Intellectual Property Management For Genetic Material And Genetic Sequence Data, supra note 2, at 12

[4] Helga Schinkel& Stefan Schillberg, Genome Editing: Intellectual Property And Product Development In Plant Biotechnology, PUBMED, ( March 31, 2024, 2:30 PM),https://pubmed.ncbi.nlm.nih.gov/27146974/

[5] Yuan-Chuan Chen, supra note 2

[6] Nicole Lynn, CRISPR-Cas9, Talens And Zfns – The Battle In Gene Editing, PROTEINTECH (March 30, 2024, 9:20 PM), https://www.ptglab.com/news/blog/crispr-cas9-talens-and-zfns-the-battle-in-gene-editing/#:~:text=Cas9%20creates%20a%20site%2Dspecific,by%20host%20DNA%20repair%20machinery.

[7] Dae Hwan Koo, Effective Protection of DNA Sequences and Gene Innovations, IIP Bulletin 1 (2007), https://www.iip.or.jp/e/summary/pdf/detail2006/e18_17.pdf

[8] Pancham Rathod & Sheetal Tiwari, PATENT AND GENOME EDITING TECHNOLOGIES: ISSUES AND CHALLENGES, Vol I IPR Journal , 93 (2023), https://www.nlunagpur.ac.in/PDF/Publications/5-Current-Issue/8.PATENT%20AND%20GENOME%20EDITING%20TECHNOLOGIES.pdf

[9] Rajendra K. Bera, Synthetic Biology and Intellectual Property Rights, INTECHOPEN, (4 April,2024, 2:59 AM), https://www.intechopen.com/chapters/48297

[10] 566 U. S., 2012

[11] 2013 WL 2631062 (June 13, 2013)

[12] [2014] FCAFC 115

[13] Dae Hwan Koo, supra note 2, at 5.

[14] Pancham Rathod & Sheetal Tiwari, supra note 2, at 100.

[15] Id. at 101.

[16] Dae Hwan Koo, supra note 3, at 6.

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