Patent wars for COVID-19 mRNA vaccines

Intern journalist Zhu Xinxin Edited by Xie Xin

The COVID-19 mRNA vaccine is entering a patent war.

Recently, Moderna, known for developing the new crown MRA vaccine, lost a key patent case for the development of the mRNA vaccine, and the U.S. Federal Circuit confirmed the earlier ruling of the Patent Approval and Appeal Board (PTAB), rejecting Moderna's request to withdraw the two patents of the Canadian pharmaceutical company Arbutus "435" and "069".

The patent at stake in the lawsuit is "lipid nanoparticle" (LNP), the vector delivery technology used in mRNA vaccines.

mRNA, or messenger RNA, is able to pass genetic information from genes to protein synthesis factories and guide protein synthesis. Therefore, by designing mRNA drugs or vaccines, human cells can make corresponding proteins to play a therapeutic or preventive effect.

Vaccines are based on the idea of inducing the immune system to produce an immune response to block the virus. Unlike traditional vaccines, which inject protein antigens directly into the body, mRNA vaccines use unique genetic fragments of the virus to transpose into mRNA, thereby making specific proteins in the body. Therefore, traditional vaccines usually have to grow viruses in vitro environments, relying on the process of cell expansion, which requires longer preparation time, while mRNA vaccines only need to use the gene sequence of the virus to synthesize the relevant sequence of mRNA, so that the early synthesis is faster.

But mRNA therapies face the conundrum of how to get into cells. Exogenous mRNAs are fragile, easily degraded by enzymes, difficult to enter the cell to function, and require "protective devices" to deliver them into the cell, while LNPs have been shown to be effective in carrying mRNA drugs, vaccines, etc. LNPs can encapsulate mRNA and mimic human low-density lipoproteins (LDLs), which are ingested into the body through endogenous pathways to target specific cells.

Therefore, without LNP delivery technology, related drugs cannot safely enter the human body, and the technical route of mRNA and human gene editing will not be opened.

Prior to the application of the mRNA COVID-19 vaccine, the U.S. Food and Drug Administration (FDA) had approved RNAi therapies delivered using LNP technology. In 2018, onpattro (patisiran), an RNAi therapy developed by Alnylam, used LNP technology to deliver RNAi therapy for the treatment of patients with hereditary transthyrin protein amyloidosis (hATTR).

In December 2020, the FDA granted Moderna's COVID-19 vaccine candidate mRNA-1273 Emergency Use Authorization (EUA), making Moderna the second pharmaceutical company after Pfizer to be authorized to market a COVID-19 vaccine in the United States. The success of the Pfizer/BioNTech and Moderna mRNA covid-19 vaccines has sparked enthusiasm for further optimization of LNP technology. Effective LNP delivery technology is not only critical for the development of new mRNA vaccines, but also has the potential to deliver mRNA therapies, gene therapies, and CRISPR gene editing therapies.

Currently, internationally recognized mRNA giants are Moderna, BioNTech and CureVac. But LNP technology patents do not belong to these three companies.

According to Forbes, the biggest contributor to LNP delivery technology was Canadian biochemist Ian MacLachlan. After MacLachlan left his company, the CEO changed the name to Arbutus and decided to focus on collaborating on the development of hepatitis B drugs, but retained patent ownership of the tetralipid drug delivery system.

In 2012, a company called Achitoas licensed LNP technology from Arbutus, which in turn subsisted to Moderna. Arbutus argued that the secondary sublicense was illegal and filed a lawsuit in 2016, in which Arbutus won, and the court issued an interim injunction prohibiting Acauitas' sublicensment.

In 2018, Arbutus reached a settlement with Acauitas, whereby Arbutus terminated its license to Acauitas and limited The use of Moderna's lipid nanoparticles using Arbutus to four vaccine candidates that have identified viruses (respiratory viruses RSV, influenza A, Zika and Chikungya virus), but not mRNA vaccines, and Moderna can no longer use the technology to develop other products.

The move put Moderna's vaccine development in a difficult position. Moderna challenged Arbutus' three LNP key patents "127", "435" and "069" and sought to revoke the relevant patent protections from the PATENT Trial and Appeal Board of the United States Patent and Trademark Office, PTAB. Moderna says it has developed its own LNP delivery system and no longer needs Arbutus' technology. But Arbutus insists that any of Modelna's lipid nanoparticle (LNP) delivery system patents are infringers.

In July 2020, PTAB finally ruled that "127" was invalid, "069" remained valid, part of "435" claims were invalid, and the remaining claims continued to be valid. Later, Moderna appealed challenging the outcome of the PTAB's review. In December 2021, the Federal Circuit dismissed Moderna's appeal.

For years, Moderna claimed that the company was using its own delivery technology, but when it tested the COVID-19 vaccine on mice, it used the same four lipids as MacLachlan's technology, and in the same proportions.

Moderna insists that the preclinical formulation of the vaccine is not the same as the vaccine itself. Its subsequent regulatory filings show that the company's vaccine does use the same four lipids as MacLachlan delivery technology, but one of the lipids is patented by the company and has a "slightly changed" proportion of its use.

The situation is similar for Pfizer and BioNTech. The FDA documents show that their vaccine delivery technology uses the same four lipids, a ratio that is nearly identical to the one the MacLachlan team had when it filed the patent, even though one of the lipids is the new "patented version."

According to public information, Moderna currently has a total of 23 mRNA drug product pipelines, including the only commercial product new crown vaccine.

Driven by its COVID-19 vaccine, Moderna generates $10-20 billion in annual revenue. According to Modernna's third quarter 2021 report, Moderna's revenue for the quarter was $4.969 billion, and product sales are expected to be between $15 billion and $18 billion in 2021 and between $17 billion and $22 billion in 2022. In this case, Arbutus, if it chooses to sue Moderna, will be expected to receive a lot of compensation.