PATENT PROTECTION OF mRNA VACCINES AND REGULATORY AUTHORIZATION

Researchers have been studying and working with mRNA vaccines for decades. Interest in these vaccines has grown since they can be developed in a laboratory using readily available materials for low-cost manufacture and safe administration. This means that the process can be standardized and scaled up, which make vaccine development faster than traditional methods of making vaccines.

As soon as the necessary information about the virus that causes COVID-19 was available, scientists began designing the mRNA instructions for cells to build the unique spike protein into an mRNA vaccine.

For most emerging virus vaccines, the main obstacle is not the effectiveness of conventional approaches but the need for more rapid development and large-scale deployment.

How mRNA vaccines work

Messenger ribonucleic acid (mRNA) vaccines are a novel technology that stimulates the body’s own immune response. These vaccines contain information from mRNA, including the “blueprint” or code of a specific virus trait (virus antigen). The information enables the body to produce this antigen on its own: mRNA transfers the information for the production of the antigen to our cell machinery that makes proteins. Cells in our body then present the antigen on their surface and thus trigger the desired specific immune response. When the body comes into contact with the virus, the immune system recognizes the specific antigen and can fight the virus and thus the infection quickly and in a targeted manner.

mRNA vaccines are safe because they are not made with pathogen particles or inactivated pathogens; therefore, they are non-infectious. RNA does not integrate itself into the host genome and the RNA strand in the vaccine is degraded once the protein is made.

Due to the high yields of in vitro transcription reactions, mRNA vaccines have the potential for rapid, inexpensive and scalable manufacturing.

mRNA vaccines can be used for infectious diseases, particularly for viruses, that cause both acute (Influenza, Ebola, Zika, etc.) and chronic (HIV-1, herpes simplex virus, etc.) infections.

Cancer vaccines can be designed to target tumor-associated antigens that are preferentially expressed in cancerous cells, for example, blood cancers, melanoma, glioblastoma (brain cancer), renal cell carcinoma, prostate cancer, etc. Most cancer vaccines are therapeutic, rather than prophylactic, and seek to stimulate cell-mediated responses, such as those from CTLs, that are capable of clearing or reducing tumor burden.

Four of the vaccine candidates currently in clinical trials to prevent COVID-19 are mRNA vaccines: mRNA-1273 (Moderna), BNT-162 (BioNTech), CVnCoV (CureVac), and LNP-nCoVsaRNA (Imperial College London).

Types of RNA vaccine

  1. Non-replicating mRNA.
  1. In vivo self-replicating mRNA.
  1. In vitro dendritic cell non-replicating mRNA vaccine.

Protection by Patent

Patent Rights play an important role in encouraging investment on research of new technologies. The patent system is designed to support innovation and, at the same time, offer a mechanism to ensure that such innovations are accessible to society. Published patents and patent applications are an important source of technical and legal information.

Scientists have studied the use of mRNA as a novel therapeutic since the early 1990s. The first patent family identified was published in 1990. However, it was not until 2005 that a group of researchers from the University of Pennsylvania published findings on mRNA technology that have since been deemed critical to the development of mRNA-based therapies. US Securities and Exchange Commission filings, highlighted by Knowledge Ecology International, reveal a series of sublicenses for mRNA-related patents that stem from the University of Pennsylvania to both Moderna and BioNTech. The 2017 filings indicate that the University of Pennsylvania exclusively licensed their patents to mRNA RiboTherapeutics, which then sublicensed them to its affiliate CellScript. CellScript proceeded to sublicense the patents to Moderna and BioNTech; however, the patent numbers are redacted in all the filings, making it difficult to determine which are relevant to the production of COVID-19 vaccines.

Another key aspect of an mRNA vaccine platform is the ability to deliver the mRNA to a cell using a lipid nanoparticle. Some early work on lipid nanoparticles was done jointly by the University of British Columbia and Arbutus Biopharmaceuticals in 1998. US Securities and Exchange Commission filings show that patents relating to this early technology were solely assigned to the University of British Columbia and then licensed back to Arbutus.

Patent-filing activity grew dramatically over the past 5 years for both infectious disease and cancer indications. The number of applications for infectious disease indications surpassed those for cancer over the past 3 years, which could reflect increased interest in vaccines following epidemic outbreaks of MERS-CoV, Ebola virus and Zika virus. In August 2019, Moderna received FDA Fast Track Designation for an investigational Zika virus vaccine (mRNA-1893) currently being evaluated in a phase I study.

According to PATENTSCOPE – WIPO, from 2012 to 2021, 1,834 patent applications related with mRNA have been published. The main filing countries are the following:

Country
United States of America366
European Patent Office268
PCT253
China245
Australia149
Canada122
Japan89
Republic of Korea62
India56
Mexico33

The applicants who have filed the most patent application are listed below:

Applicant
CUREVAC AG102
CUREVAC GMBH68
MODERNATX INC60
BIONTECH RNA PHARMACEUTICALS GMBH44
MEDIMMUNE VACCINES INC36
VIRONOVATIVE BV35
INSTITUT PASTEUR28
HUMAN GENOME SCIENCES INC27
PASTEUR INSTITUT24
BIONTECH AG22

The present IP landscape includes foundational patents in modified mRNA technologies and delivery technologies that are essential for mRNA therapeutics and vaccines, including their application in specific unmet needs in infectious diseases, cancer (immuno-oncology), and rare and cardiometabolic diseases, among others.

Compulsory licenses

Compulsory licensing is when a government allows someone else to produce a patented product or process without the consent of the patent owner or plans to use the patent-protected invention itself. It is one of the flexibilities in the field of patent protection included in the WTO’s agreement on Intellectual Property —Trade-Related Aspects of Intellectual Property Rights (TRIPS) Agreement.

To explain the public policy objectives for a compulsory licensing mechanism, countries refer to striking a balance between the interest of patentees and that of third parties, public interest, and/or society; preventing abuses that may result from the exercise of exclusive rights; and promoting the public interest at large, such as in situations of public interest and emergency motivated by considerations of public health, nutrition, and national security. Some possible grounds for compulsory licensing are suggested in Article 5A of the Paris Convention (e.g., abuse of patent rights, including failure of the patent holder to work the invention) and in Article 31 of the TRIPS Agreement (e.g., national emergency and public noncommercial use).

Compulsory licenses are thus not limited to public health emergencies or other urgent situations, as is sometimes mistakenly believed. A range of grounds have been set out in national laws, such as:

  • Non-working or insufficient working
  • Anti-competitive practices
  • Public interest
  • National emergency or circumstances of extreme urgency.
  • Dependent and blocking patents.

In Mexico, compulsory licenses can be granted based on articles 146-153 of the Federal Law for the Protection of Industrial Property, which states they can be granted for non-working the patent and national emergency or circumstances of extreme urgency:

“…In cases of serious diseases, the General Health Council will declare priority attention, ex officio or at the request of national institutions specialized in said disease that are accredited before it, in which the causes of emergency or national security are justified. Once the declaration issued by the Council has been published in the Official Gazette, pharmaceutical companies may request the granting of a license of public utility to the Institute, which will grant it, after hearing the parties and the opinion of the Council, within a period not exceeding ninety days from the date of submission of the respective application…”

Emergency Use Authorization for Vaccines

The Emergency Use Authorization (EUA) authority allows FDA to help strengthen the nation’s public health protections against chemical, biological, radiological, and nuclear (CBRN) threats including infectious diseases, by facilitating the availability and use of medical countermeasures (MCMs) needed during public health emergencies, such as the current COVID‑19 pandemic.

Under an Emergency Use Authorization, FDA may allow the use of unapproved medical products -or unapproved uses of approved medical products- in an emergency to diagnose, treat, or prevent serious or life-threatening diseases or conditions when certain statutory criteria have been met, including that there are no adequate, approved, and available alternatives. Taking into consideration input from the FDA, manufacturers decide whether and when to submit an Emergency Use Authorization request to FDA. Once submitted, FDA will evaluate the Emergency Use Authorization request and determine whether the relevant statutory criteria are met, taking into account the totality of the scientific evidence about the vaccine that is available to FDA.

There are no specific guidelines from the FDA or European Medicines Agency (EMA) for mRNA vaccine products. However, the increasing number of clinical trials conducted under EMA and FDA oversight indicate that regulators have accepted the approaches proposed by various organizations to demonstrate that products are safe and acceptable for testing in humans. Because mRNA falls into the broad vaccine category of genetic immunogens, many of the guiding principles that have been defined for DNA vaccines and gene therapy vectors can likely be applied to mRNA with some adaptations to reflect the unique features of mRNA.

Emergency use of vaccines in Mexico

The Federal Commission for the Protection against Sanitary Risks (COFEPRIS) is the health authority responsible for protecting the Mexican population from the risks that may arise from the consumption or use of medicines and medical devices, as well as from those derived from the consumption of food and of other products that we use on a daily basis, while also issuing import and export permits for these products.

The Mexican Government published on March 30, 2020 the agreement declaring a health emergency due to force majeure, the disease epidemic generated by the SARS-CoV2 virus (COVID-19). Furthermore, on November 11, 2020, it published an Agreement instructing the Ministry of Health and the Federal Commission for the Protection against Sanitary Risks to carry out the following actions:

  • to resolve the appropriateness of granting applicants the sanitary registration of health supplies in a period shorter than that mentioned in the equivalence Agreements that have been issued by the former to date, as well as for shorter terms to be established for those that are issued later; and
  • to analyze, in accordance with the applicable legal framework, the relevance of reducing the documents required in the equivalence Agreements, without implying affecting the quality, safety and efficacy of the drugs and health supplies already indicated.

CONCLUSIONS

Unwarranted restrictions on competition, whether resulting from the abuse of a dominant position resulting from intellectual property rights or other factors, or from anti-competitive agreements, can be addressed through competition law enforcement. Regarding innovation, a key concern is merger control, where competition authorities must ensure that mergers do not threaten R&D pipelines.

Incremental innovation can improve the safety, therapeutic effect or method of delivery of an existing medicine or vaccine. Whether such inventions merit the granting of a patent is judged on a case-by-case basis.

Regulation should promote access to medical technologies of proven quality, safety and efficacy and should not unnecessarily delay the market entry of products.

Challenges for regulatory systems that impact access include lack of political support and adequate resources, a focus on regulating products without effective oversight of the whole supply chain, poorly developed systems for post-marketing surveillance, and different standards for locally produced versus imported products.

In this area, both regulatory and IP tools can be used in a complementary way to combat substandard and falsified products.

REFERENCES

https://www.nature.com/articles/nrd.2017.243

Wolff, J. A. et al. Direct gene transfer into mouse muscle in vivo. Science 247, 1465–1468 (1990).

https://www.nature.com/articles/d41573-020-00119-8
https://biontech.de/covid-19-portal/mrna-vaccines
https://www.modernatx.com/mrna-technology/modernas-intellectual-property
https://biontech.de/how-we-translate/intellectual-property
https://www.phgfoundation.org/briefing/rna-vaccines
https://www.nature.com/articles/s41587-021-00912-9
https://www.prnewswire.com/news-releases/rna-vaccine-patent-landscape-2021-mrna-as-vaccines-won-the-race-for-the-covid-19-vaccine-301244449.html
https://www.fda.gov/vaccines-blood-biologics/vaccines/emergency-use-authorization-vaccines-explained
https://www.fda.gov/emergency-preparedness-and-response/coronavirus-disease-2019-covid-19/covid-19-vaccines
https://www.ema.europa.eu/en/documents/presentation/presentation-eus-regulatory-process-evaluation-approval-vaccines-fergus-sweeney_en.pdf
https://www.fda.gov/vaccines-blood-biologics/vaccines/emergency-use-authorization-vaccines-explained