Topics The 2022 Life Science Intellectual Property Forum was held -COVID-19 Pandemic: Challenges and Prospects for Innovation Ecosystems -COVID-19 Pandemic: Challenges and Prospects for Solutions

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On February 18, 2022, the "2022 Life Science IP Forum" titled "Challenges and Prospects for Solutions in the Innovation Ecosystem Found in the COVID-19 Pandemic" was held in online format, hosted by the Pharmaceutical Manufacturers Association of Japan and supported by the Japan Bioindustry Association. The event was held in an online format. More than 300 participants attended the forum. This report provides an overview of the speeches and panel discussions.

Introduction

At the Forum held in FY2020, it was pointed out that the research and development of domestically produced vaccines against novel coronavirus infection (COVID-19) had fallen behind that of Western companies, and that it was necessary from the perspective of national security to promote measures against infectious diseases from peacetime, The current status and potential of mRNA drug discovery, which is expected to be applied not only to vaccines but also to pharmaceuticals; efforts to improve the clinical trial environment for vaccine development in Japan; efforts by the Japan Agency for Medical Research and Development (AMED) to support vaccine research and development; and intellectual property in the pharmaceutical industry for COVID-19 infection countermeasures. The panelists, representing industry, academia, and government, gave presentations on efforts in the pharmaceutical industry from the viewpoint of intellectual property for COVID-19 infection control. In the panel discussion that followed, there was a lively discussion on issues related to patent protection for mRNA drug discovery, expectations for support for drug discovery ventures, issues and expectations for industry-academia-government collaboration to strengthen the vaccine production and development system, IP management in times of emergency such as pandemics, and economic security and international cooperation. Lively discussions were held on the following topics.

mRNA Drug Discovery: New Developments in Vaccines and Pharmaceuticals

Dr. Keishi Hitotaka, Professor, Department of Biomaterials and Functional Medicine, Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University

Today, I would like to talk about the overall picture of mRNA vaccine and drug discovery and also introduce my own research results. mRNA is an "information transfer molecule" and in principle, any protein can be made from it, and since it is not inserted into the genome, safety concerns are small. mRNA vaccines are in the pipeline, The pipeline of mRNA vaccines is dominated by the COVID-19 vaccine, but many others are in development, including vaccines for other infectious diseases.

Historically, the first report of a gene administered into an animal's body to produce a protein was made in 1990. However, research did not proceed because mRNA is unstable and induces a strong immune response through innate immune mechanisms.

One of the important breakthroughs was the discovery by Dr. Carico Catalin in 2005 that the use of RNA containing pseudouridine suppresses immune responses. Since then, improvements in nucleic acid modification have been made, but the target cells, expressed proteins, and method of administration (formulation) all have different nucleic acid modification conditions that must be optimized individually. On the other hand, since mRNA itself is a known natural product, it is not possible to obtain a substance patent. It is possible to patent a modified nucleic acid, but it is difficult to obtain a basic patent that everyone must use.

Another important aspect for mRNA drugs is the drug delivery system (DDS). Nucleic acid DDS with lipid nanoparticles (LNPs) has long been studied, and LNPs are used almost exclusively in coronavirus vaccines. The reason for this is that in addition to high expression efficiency, LNPs have the ability to induce immunity (adjuvant effect). On the other hand, LNPs are also the cause of adverse reactions in vaccines, but since the ingredients of each company are undisclosed, it is difficult to discuss the science behind them. There is also a polymer particle technology that uses synthetic polymers instead of lipids, which we are developing.

Another important point about mRNA vaccines against coronaviruses is that they can induce both liquid and cellular immunity simultaneously.

Starting with coronaviruses, more than 80 new viral infections have occurred since 1980. However, only three cases have led to vaccine development. The market for individual regional infectious diseases is small, making vaccine development unprofitable for pharmaceutical companies. However, mRNA vaccines can be developed quickly and at low cost by simply replacing the sequence, so even if each one is small, it could become a large market.

Another important area is cancer immunotherapy. An example is the creation of vaccines that target neoantigens caused by genetic mutations unique to cancer cells. With mRNA, it would be possible to collect cancer cells from each patient and design the antigen.

Current mRNA vaccines are injected into the muscle, in part because protein expression from mRNA is highly available in muscle. However, with future technological development, it may be possible to administer the mRNA outside of muscle, and this is currently being studied.

Although there have been many reports on therapeutic mRNA at the publication level, the field is still in its infancy. Here, I would like to introduce the research results of our research group.

The first is an attempt to administer mRNA for cartilage-inducible transcription factor (RUNX1) to joints. Using synthetic polymeric nanocarriers, we administered RUNX1 mRNA to osteoarthritis model mice and succeeded in inducing a thin and broad uptake of mRNA into cartilage tissue, thereby achieving a therapeutic effect of inhibiting cartilage degeneration. This project is now underway with venture companies, including Tokyo Medical and Dental University and the University of Tokyo, with the aim of starting clinical trials in FY2023 with AMED funding.

The second is the brain case, which is still in the research stage, but is aimed at neuroprotective therapy for ischemic brain disease. We have created a mouse model that blocks cerebral blood vessels and administered mRNA encoding brain-derived neurotrophic factor (BDNF). This is thought to be due to the transient formation of a microenvironment that acts to protect neurons by the specific uptake of mRNA into astrocytes and the secretion of BDNF into the peri-neuronal area. Treatment by such a mechanism is not possible with protein administration, and the use of mRNA may lead to treatment and drug discovery based on a different mechanism of action, even if the same protein is used. We have started collaboration with Accelrys on this project and plan to expand it to a joint research project with Arcturus, a company that develops mRNA.

I am very much in agreement with Dr. Moderna's words that "mRNA can be applied to almost all diseases" and "we are rewriting the textbooks. mRNA drug discovery involves three key technologies: (1) mRNA molecules, (2) DDS, and (3) mRNA "information" (what to administer and what to cure), all of which are equally important. (what to administer and what to cure)" are all equally important. In particular, how to patent the "information" part of mRNA, i.e., what kind of protein to administer to what kind of cells, will be an important point in mRNA drug discovery. mRNA production technology in large quantities has not yet been established, which is also important from an economic security perspective. mRNA research can only be conducted through the integration of various fields. Finally, I would like to thank all of my collaborators.

Efforts to Improve the Clinical Trial Environment for Vaccine Development in Japan

Dr. Yumiko Nomura, Director, Office of Clinical Trial Promotion, Research and Development Promotion Division, Medical Affairs Bureau, Ministry of Health, Labour and Welfare

We will explain the promotion of clinical trials in addition to the government's efforts to develop a vaccine.

As part of the MHLW's efforts in the early realization of vaccines, we have promoted the "Accelerated Parallel Plan" for vaccine development and have supported development activities by providing a prompt second supplementary budget in FY2020, especially for research and production systems that could be a burden on the corporate side. Regarding support for manufacturing facilities, we established a fund and worked toward the early commercialization of vaccines. In addition to the above, we also secured funds for syringes, needles, and other vaccination systems, as well as for vaccine supply systems, in order to improve the system for the early commercialization of vaccines.

Furthermore, in the U.S., clinical trials are led by national institutes such as the National Institutes of Health (NIH). In Japan, we also support clinical trials conducted by companies, and based on the awareness that it is important to produce and secure vaccines domestically, the third supplementary budget was allocated for large-scale clinical trials of vaccines.

The background to the emergence of the Strategy for Strengthening the Vaccine Development and Production System is that it has been a challenge to have vaccines developed in Japan produced domestically, and the government has discussed shortcomings and areas for improvement, which were compiled together with measures.

In particular, with regard to clinical trials, we recognize that we did not take sufficient measures to promptly launch large-scale clinical trials in the rapidly changing environment of the coronary expansion.

In the short term, we are considering supporting companies and academia that are rapidly advancing vaccine development by, for example, participating in clinical trials at core clinical research hospitals*1 and related hospitals as medical institutions and using contract research organizations (CROs), based on their needs, In the mid- to long-term, we are considering the use of post-contract research organizations (CROs).

As a medium- to long-term response, we believe it is necessary to train human resources at the aforementioned core clinical research hospitals and other development bases in order to build a system in Japan in normal times as a post-Corona company. In addition, in preparation for large-scale clinical trials, we have been cooperating with overseas partners, particularly in the area of clinical research and clinical trial network bases in Asia, not limited to COVID-19.

We have been working on various measures related to coronaviruses, such as the development of a prompt and flexible Investigational Review Board (IRB) review, Q&A on conducting clinical trials in coronaviruses, not limited to COVID-19 therapeutic agents, and rules for COVID-19 patients' participation in clinical trials. Finally, we will continue to work on the development of clinical research at the core hospital.

Last but not least, we will continue to promote clinical trials utilizing core clinical research hospitals and support further network building.

AMED's R&D Support - AMED's Efforts to Support Vaccine R&D

Dr. Atsushi Shiomi, Director, Department of Practical Application, Japan Agency for Biomedical Research and Development

I would like to explain the status of support for research and development related to countermeasures against novel coronavirus infection, etc. From FY2019 to FY2021, 15.07 billion yen has been allocated to the AMED through supplementary budgets and other means. The main projects are the Research and Development of Innovative Drugs for Emerging and Re-emerging Infectious Diseases and the Vaccine Development Promotion Project for the development of therapeutic drugs and vaccines, and the Development of Technology for Countermeasures against Viral Infections for the development of diagnostic methods, devices, and systems. The total number of projects we have supported is 400, of which about 50% are still ongoing, and we are grateful for your efforts to achieve results as quickly as possible, despite the restrictions on activities due to the coronary disaster.

In the early stage of the epidemic, we worked on issues such as drug repositioning and rapid testing using existing testing equipment, etc. In addition, it was necessary to focus on issues that required immediate results, such as vaccine development, etc. Therefore, we worked on exit-oriented research and development such as clinical trials and clinical studies. Therefore, the company was involved in exit-oriented research and development such as clinical trials and clinical studies.

Since then, the ratio of basic research and applied research has been increasing, but we felt it necessary to steadily prepare for new infectious disease outbreaks from normal times.

Next, I would like to talk about the development status of therapeutic drugs. In the early stages of the new coronavirus epidemic, from the viewpoint of creating a therapeutic drug quickly, we supported research and development mainly through drug repositioning, and clinical trials are underway for several issues.

We provide consistent support for vaccine development, from basic research to non-clinical and clinical trials, and we support vaccines of various modalities, including recombinant protein vaccines, mRNA and DNA vaccines, and others.

We will continue to work on measures against new coronaviruses with the aim of maximizing results, and we believe it is necessary to prepare for new mutant strains and new infectious disease outbreaks in the future. The Strategy outlines the background and factors, as well as policies necessary to establish a system that will enable the rapid development and supply of vaccines. As one of these policies, in relation to the strengthening of the funding function of research expenses with strategic nature, it was decided to establish the Center for Advanced Research and Development Strategy (SCARDA) in AMED, and to examine measures to promote research and development from normal times to emergency times, and to firmly promote research and development from basic to practical applications. We are currently discussing the detailed functions of SCARDA with the relevant ministries and agencies.

Finally, regarding support for ventures, drug discovery R&D is a field with a long development period, a low success rate, high risk and high return, and a high degree of difficulty in commercialization. In particular, large funds are required for Phase 1 and Phase 2 clinical trials. This project aims to solve this shortage of large-scale development funds by referring to the New Energy and Industrial Technology Development Organization (NEDO) STS project (commercialization support for R&D-type tartups in the seed stage) and other programs, We are considering launching a business utilizing the discerning and hands-on capabilities of an accredited venture capital (VC) firm.

Efforts of the pharmaceutical industry in terms of intellectual property in COVID-19 infection

Yohei Ishida, Chairman, Intellectual Property Committee, Pharmaceutical Manufacturers Association of Japan

Today, I would like to talk about the efforts of the pharmaceutical industry in the area of COVID-19 infection, focusing on the intellectual property aspect. Intellectual property in the pharmaceutical industry is characterized by the importance of a small number of patents, including substance patents covering the active ingredients and usage patents covering the indications, which is different from the situation in other fields such as automobiles and home appliances, where a large number of patents exist for a single product. In addition, drug development requires a long development period and a large upfront investment, which is recovered after the product is launched, making the patent system and the pharmaceutical protection system, including the extension system, extremely important.

Vaccines were developed and supplied within a short period of time after the COVID-19 infection explosion, and this was due to the continuation of research and development based on intellectual property over many years. With the expansion of vaccine manufacturing capacity, it is projected that approximately 12 billion doses of vaccine will be supplied by the end of 2021, and approximately 24 billion doses by June 2022. And in developing, manufacturing, and supplying this vaccine, a number of alliances are progressing in an unprecedentedly short period of time. The fact that vaccines were developed and provided quickly in such a short period of time is due to the progress of IP-based alliances. IP is not an obstacle in vaccine development and supply, and other factors such as fair distribution, supply systems, and vaccine evasion are thought to be influencing the challenges in vaccine supply.

As for IP trends surrounding COVID-19, in the discussion on the Agreement on Aspects of Intellectual Property Rights (TRIPS) Agreement, there was a South Africa-India proposal, a US statement, and a European Union (EU) proposal regarding the handling of IP after 2020, but the impact of COVID-19 on the World Trade However, discussions have not progressed due to the postponement of the World Trade Organization (WTO) Ministerial Conference due to the impact of COVID-19. In addition, the TRIPS Agreement allows for compulsory licensing under certain conditions, but Brazil has proposed a bill to amend compulsory licensing, and there are other developments that require close monitoring of the future operation of the agreement. Other developments in the international community include the June 2021 G7 Joint Statement and the G7 Carbis Bay Health Declaration.

As for the pharmaceutical industry's commitment to COVID-19, in coordination with international movements, the International Federation of Pharmaceutical Manufacturers and Associations (IFPMA) and others released the "Five Steps for Promptly Improving Equity in COVID-19 Vaccine Supply" in May 2021, which calls for the pharmaceutical industry's commitment to the production and equitable distribution of the vaccine It outlines the commitment of the pharmaceutical industry to the production and equitable distribution of vaccines, as well as the demands of stakeholders in each country. Many pharmaceutical companies are now actively pursuing alliances and sharing necessary knowledge, intellectual property, and data with collaborative R&D partners in order to comply with COVID-19. Various vaccine developments continue in Japan, and new initiatives are underway around the world to expand the manufacturing and supply of small molecule therapeutics to low- and middle-income countries through the framework of existing Medicines Patent Pools (MPPs).

One of the key missions of pharmaceutical companies is to contribute to people's healthy lives by providing medicines, vaccines, and other products based on new innovations. Intellectual property is one of the sources of such innovation and an important incentive for research and development. We believe that by conducting R&D in collaboration with many stakeholders based on their respective intellectual properties, we will be able to create various innovations and provide new drugs, vaccines, etc. with a greater sense of speed.

In order to enable a rapid response to future pandemics, it is considered important to promote countermeasures against infectious diseases from normal times. On top of that, it is considered necessary to create an environment in which vaccines, therapeutics, etc. can be fairly supplied by promoting voluntary and prompt alliances based on the intellectual property system and utilizing existing frameworks such as COVAX*2 and MPP for production expansion in the event of a pandemic. In the future, the pharmaceutical industry will continue to work for the development of vaccines and therapeutics under the intellectual property system and contribute to people's healthy lives by further promoting efforts to create innovation through collaboration among industry, government, and academia, which is called the "drug discovery ecosystem".

Panel Discussion

How to handle IP rights in pandemic response measures including COVID-19

Moderator: Mr. Shigeo Takakura, Professor, Meiji University School of Law
Panelists: Mr. Keishi Ridaka, Ms. Yumiko Nomura, Mr. Atsushi Shiomi, Mr. Yohei Ishida

A panel discussion was held on the role of IP in a pandemic. The main theme of the discussion was whether "the importance of IP will also change" during a pandemic, when government support will be greater and the business model will be different from that of pharmaceuticals under normal circumstances. Discussions also focused on the possibility of new developments in mRNA technology and IP strategies for such developments, as well as the relationship between venture creation and IP.

IP management, patent enforcement and vaccine supply in emergency situations

Moderator: Mr. Shigeo Takakura

Relationship between mRNA and patents

mRNA itself is naturally occurring and cannot be protected by patent rights. On the other hand, various technologies for delivery and modified nucleic acids exist, and there are many patents related to them.

In the case of the COVID-19 vaccine, the fact that the utility of targeting the spike protein was already known from the experience of developing vaccines for SARS and other diseases was said to be a factor in its early development success. In light of this, "information" on the proteins used in vaccines is an important point, and it is thought that this is the element that will be patented. Companies that possess such information will have a strong competitive edge.

The basic mRNA technology will become common. This will make it difficult to secure business potential with the basic technology itself. However, delivery and other technologies need to be optimized on an individual basis, and such technologies can be patented. Also, the key point is what kind of protein to express, and there are infinite possibilities there.

Looking at mRNA technologies to date, it is thought that companies license the basic mRNA technology from academia, while optimizing it in terms of delivery technology, etc., patenting the technology, and combining these technologies to protect the whole.

Since mRNA drug discovery is a collection of many technologies, it is usually difficult for a single bio-venture to cover all the information related to mRNA production, DDS, and its application by a single company. In particular, the last information is available in medical research and medical practice, so collaboration between bio-ventures and medicine is considered particularly important in drug discovery.

When applying mRNA technology, issues of novelty and inventive step may arise, and patenting may be difficult. This is troubling because patent rights are important in commercialization. In order to develop technologies originating from academia, a more flexible patenting system may be important.

Support for venture creation

At COVID-19, the activities of European and U.S. ventures were conspicuous. On the other hand, drug discovery ventures are not active in Japan. In the U.S. and other countries, there is a large amount of investment and an environment that is conducive to venture development. I have high expectations for the government-led measures to support venture businesses. I would like to see Japan also create an environment conducive to the development of venture businesses.

The AMED's support program is a support program that takes advantage of the hands-on support capabilities of accredited VCs specializing in drug discovery and aims to expand investment in drug discovery ventures by VCs, which is what makes it different from existing support programs.

Recently, we have been hearing about comprehensive collaborations between companies and universities, rather than individual relationships between companies and ventures. I imagine that the corporate side sees the benefit of having access to a variety of technologies through comprehensive collaboration.

I would like to see a further development of the technology development ecosystem, where technologies are fostered in the venture and then applied in the pharmaceutical industry.

Industry-government-academia collaboration to strengthen the vaccine production and development system

In vaccine prevention trials, rather than utilizing core clinical research hospitals, it may be necessary for the national and local governments to take the initiative in gathering healthy people.

As an advanced clinical trial, the use of core clinical research hospitals is beneficial because of the high safety risk when administered to humans for the first time. In vaccine development, existing frameworks such as CROs and clinical pharmacology institutes may be utilized, but how to collect a large number of healthy people in a short period of time is a major challenge.

SCARDA needs an R&D strategy to utilize research in peacetime in emergency situations. For this purpose, we need experts to collect and analyze information on advanced technologies, and we would like to establish a network to collect information in cooperation with other institutions.

Handling of research results with government support

AMED's basic policy is that intellectual property rights related to research results in commissioned projects belong to the contractor. Although the consignment agreement includes a provision for granting licenses without charge when specifically necessary for the public interest upon request of the government, this has never been requested.

The Emergency Fund for Vaccine Production System is intended to support not only domestic production of foreign vaccines that have already been successfully developed, but also production facilities for vaccines that are currently under development. However, a detailed development plan must be submitted within a certain period of time, indicating that the development is on track to a certain degree. The committee examines the feasibility of the project and decides whether or not to support it.

Economic security and international cooperation

In the field of vaccines, more Western companies are taking up the challenge of development than Japanese companies, but there is an opinion that Japan should promote vaccine development from the viewpoint of economic security and establish a system that can at least produce vaccines domestically.

While the idea of joint development under international cooperation is necessary, the Ministry of Health, Labour and Welfare's "Vision 2021 for the Pharmaceutical Industry" indicates that from the perspective of economic security, vaccines, treatments for infectious diseases, and essential drugs should be made available for domestic production to ensure the safety of the public. We will be following both sides of the issue.

In order to supply new vaccines in a short period of time, it may be necessary to utilize mRNA. When considering economic security from the viewpoint of domestic production, since the development of technology that can produce mRNA in large quantities with high quality is still in progress domestically, rather than the design of mRNA, we can make an international contribution by successfully promoting research and development on the wonderful technological seeds that lead to this, and at the same time, we can establish a domestic production and By successfully promoting research and development on these excellent technological seeds, we can contribute to the international community and at the same time, establish a domestic production and supply system.

(Intellectual Property Forum Preparatory Committee)

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