There is still a lack of effective therapies for treating SARS-CoV-2-infected patients, as doubts remain whether antibodies provide sufficient immunity for COVID-19, and the safety of vaccines under development needs further study. The treatment of coronavirus from the perspective of RNA interference-based gene therapy offers a more direct approach to combating viral genes in addition to traditional drugs and vaccines and is likely to have a promising future. In this paper, an analysis of the emerging patent landscape was given on gene therapies for coronavirus under development, highlighting patent applications' basic status, geographical distribution, time-series analysis of new inventors, and ranking of patent applicants. Relevant patents were also reviewed and summarized to provide ideas for the control of the current COVID-19 pandemic.
Efforts to develop drugs and vaccines for COVID-19 have mostly targeted important targets early in the viral life cycle and have been hampered by limited knowledge of the molecular details of SARS-CoV-2 [
So, antibodies and therapies would be valuable for the suffering patients, especially the elderly. However, there is still a lack of effective therapies for treating SARS-CoV-2-infected patients [
RNAi-based treatments for COVID-19 in clinical and preclinical trials.
Developer/researcher | Product description | Phase | Anticipated next steps |
---|---|---|---|
Mateon Therapeutics | Ot-101, a TGF-beta antisense drug candidate | Clinical | Phase II study IND submitted to FDA on April 27, 2020; phase II trials approved in Peru, Nov 2020 |
AIM Immunotech/National Institute of Infectious Diseases in Japan/Roswell Park Comprehensive Cancer Center | Ampligen (rintatolimod) | Preclinical | Phase I/II trial in combination with interferon alfa-2b, in cancer patients with COVID-19 not yet recruiting July 2020; |
Neurimmune/Ethris | Inhaled mRNA | Preclinical | Phase I to start Q4 2020 |
Sarepta Therapeutics/US Army Medical Research Institute of Infectious Diseases (USAMRIID) | Antisense oligonucleotides, peptide conjugated | Preclinical | Clinical trials for COVID-19 |
Sirnaomics | RNAi, TESTING 150 RNAiS | Preclinical | Clinical trials for COVID-19 |
VIR Biotech/Alnylam Pharmaceuticals | VIR-2703 (ALN-COV) siRNA candidate | Preclinical | Clinical trials for COVID-19; phase I to start by the end of 2020 |
Section
To provide a patent landscape and to identify technologies that use gene therapy to coronavirus diseases, we performed a search in the Derwent Innovation (DI) database. The search strategy is based on the combination of International Patent Classification (IPC), DWPI Manual Codes (MC), and keywords. The topics of “gene therapy” and “coronavirus” were searched in “classification number, title, abstract, and claims.” The classification numbers for gene therapy were IPC (A61K 48/00), MC (B14-S03A or B14-S03B or B14-S03C or B14-S03D or C14-S03 or C14-S03 or C14-S03A or C14-S03B or C14-S03C), and keywords (“gene therapy” or “gene therapeu
After the SARS outbreak in 2003, researchers applied for a large number of RNAi vaccine-related patents, in which the design of siRNAs mainly targeted PI4KB, N protein gene, M protein gene, RdRp, ORF3a gene, and M, N, and E genes. Gene delivery vectors were also the focus of research, including plasmid, adenovirus vector, AAV vectors, recombinant RV vector, polymeric nanoparticle, lipid nanoparticle (LNP), eukaryotic expression vector pCMV-Myc, cationic polymers, peptides, hyaluronic acid conjugates, and multiblock copolymers (Table
Gene therapy-related patents for SARS and MERS.
Publication number | Application date | Organization | Virus/mechanism | Gene targets/vectors |
---|---|---|---|---|
WO2017044507A2 | 2016/9/7 | Sirnaomics Inc. | MERS-CoV; siRNA | PLpro, RdRp, S protein; polymeric nanoparticle, liposomal nanoparticle |
CN102453712A | 2010/10/19 | Chinese Academy of Medical Sciences | SARS-CoV; siRNA | PI4KB; adenovirus; VeroE6 cell |
CN101597607A | 2005/3/25 | Chinese Academy of Medical Sciences | SARS-CoV; siRNA | N protein; pCMV-Myc |
CN101173275A | 2006/10/31 | Chinese Academy of Medical Sciences | SARS-CoV; siRNA | M protein |
CN101113158A | 2006/12/18 | Sichuan University | SARS-CoV; siRNA | RdRp; plasmid |
CN101085986A | 2006/6/8 | Shanghai Institutes for Biological Sciences, CAS | SARS-CoV; siRNA | ORF3a |
WO2006130855A2 | 2006/6/1 | California Institute of Technology | SARS-CoV | Recombinant retrovirus |
CN1704123A | 2004/6/1 | Guangzhou Tuopu Genetech Ltd. | SARS-CoV; siRNA | Cationic polymers, peptides |
CN1648249A | 2004/1/19 | Shanghai Institutes for Biological Sciences, CAS | SARS-CoV; siRNA | 19–25 consecutive nucleic acids on the M, N, and E genes |
US20050095618A1 | 2004/7/28 | Chinese University of Hong Kong | SARS-CoV; siRNA | S protein |
WO2005019410A2 | 2004/4/26 | Intradigm Corporation | SARS-CoV; dsRNA | nsp1, nsp9, S; aqueous glucose solution |
WO2004092383A2 | 2004/4/13 | Sirna Therapeutics, Inc. | siRNA, dsRNA, miRNA, shRNA | Chemically synthesized, modulate the expression of SARS virus RNA |
US20140294752A1 | 2014/4/1 | Research & Business FDN Sungkyunkwan Univ. | Hyaluronic acid conjugate | To deliver RNA, DNA, siRNA, aptamer, antisense oligodeoxynucleotide, antisense RNA, ribozyme, DNAzyme |
WO2014144486A2 | 2014/3/14 | Children’s Hospital of Philadelphia | Recombinant vector plasmid | Cell, viral particle, and AAV particle comprising the recombinant vector plasmid |
WO2013123503A1 | 2013/2/19 | Children’s Hospital of Philadelphia | AAV-Rh74 vector for gene transfer | AAV vector comprising a heterologous polynucleotide |
WO2010111522A2 | 2010/3/25 | University of California | Mesenchymal stem cell | For delivery of siRNA, miRNA, or dsRNA polynucleotide into a target cell |
WO2010054266A2 | 2009/11/6 | University of Washington | Multiblock copolymers | For delivery of siRNA, antisense oligonucleotide, dicer substrate, miRNA, aiRNA, shRNA, or siRNA |
Researchers are also developing gene therapy drugs based on the RNAi mechanism in the wake of the MERS outbreak. Four miRNA and five siRNA molecules targeting the ORF1ab gene of MERS-CoV were confirmed to cause a decrease in viral activity [
Although there have been many articles and patents reporting on RNAi-based gene therapy for SARS, only a few studies have explored its application to SARS-CoV-2. N protein and nucleocapsid protein of SARS-CoV-2 may play an important role in suppressing RNAi to overcome the host defense in cells [
As of August 12, 2020, a total of 192 INPADOC patent families were retrieved. Derwent Data Analyzer (DDA) was used to analyze patent data from 1993 to 2019 to provide comparative information on coronavirus gene therapy patents, focusing on annual trends in the field, geographical distribution, and major applicants. As there is a time lag of 18 months between the priority date and the date of publication, the 2019–2020 figures are for references only, which include a total of 20 SARS-Cov-2-related gene therapy patents as of November 11, 2020.
Research and patenting activities on coronaviruses have been closely linked to related outbreaks. The annual distribution of global patent applications shows that there were very few patent applications before 2002. In 2003, the outbreak of SARS triggered a rapid increase in global patent applications. However, the number gradually declined after 2005 due to the eradication of SARS epidemic by conventional medicine. From 2013 to 2015, the MERS epidemic stimulated global research with a small increase in patent applications (Figure
Trends in patent applications and old and new inventors.
The time-series analysis of new inventors gives an idea of the activity and market importance of the field of technology. The grey and blue bars in Figure
In terms of geographical distribution, the patents are mainly from the US, China, Japan, and Korea, accounting for 84% of the world’s total patents. The US ranks first in the world in terms of the number of patents, far ahead of other countries, accounting for 50% of the world’s total patents, which matches the position of the US as a major gene therapy country. As epidemic-stricken countries, China and the Republic of Korea have relatively muscular scientific research strength, so they follow the US in terms of patent application volume. Japan, as a neighboring country of China and the Republic of Korea, also has a larger patent application volume (Figure
Ranking of patent filings in the earliest priority countries.
An analysis of the global patent layout shows that patents were basically filed in their own countries. The reason is simple: under PCT Article 21, the international publication of the international application by the International Bureau shall be effected promptly after the expiration of 18 months from the priority date of that application. After the outbreaks were quickly brought under control, most PCT applications did not see a market.
Further, a legal status analysis revealed that among the 192 INPADOC families retrieved, only 33 were live, 5 indeterminate, while 154 dead, implicating that innovation in the field is rapid, with new technologies rapidly phasing out old ones that have lost their value.
To understand who was in the coronavirus gene therapy industry, we analyzed main organizations in patent applications (Figure
Global ranking of patent applicants.
Global ranking of inventors.
Gene therapy works by introducing a new or modified gene into the body to help treat a disease. Several gene delivery vectors were used in gene therapy, including plasmid transfection, electroporation, liposomes, cationic polymer nanoparticles, and viral vectors, which can be divided into adenovirus (AV), adeno-associated virus (AAV), lentivirus (LV), herpes simplex virus (HSV), and retrovirus (RV) [
On the other hand, recombinant AAVs (rAAVs) are the leading platform for in vivo delivery of gene therapies [
Top ten cited patents related to gene therapy for coronavirus.
Due to the time lag between patent filing and publication, many developed medical technologies have not been published and, therefore, could not be included in the scope of this study. However, at present, the global distribution of patents presented in this study shows that the US and China have the leading number of patents and are technologically more advanced and were able to develop novel therapies to curb the pandemic. Research centers and pharmaceutical companies in the US, France, and China should join forces and draw inspiration from past research experiences to accelerate the development of effective therapies.
In summary, with patterns of past patent activities providing lessons for current research, we outline a scenario of the current trends in coronavirus gene therapy through analysis of the patent landscape of the field, demonstrating the potential for gene therapy to be used against COVID-19. We expect that the six existing RNAi therapies will be successful in clinical trials and will soon be available for the effective treatment of SARS-CoV-2, and this patent landscape will help defeat the COVID-19 pandemic. It may also be a great opportunity to promote the development of gene therapy.
The authors have declared no conflicts of interest.
This work was supported by the National Natural Science Foundation of China (grant no. 61976192) and the Zhejiang Soft Science Research Program (2019C35070).