Huidagene Secures U.S. Patent for China's First Homegrown CRISPR-Cas13 Gene Editing Platform, Files IPO Prospectus

On February 28, 2022, the United States Patent and Trademark Office (USPTO) issued a decision on priority in the long-standing patent dispute over CRISPR-Cas9 inventions through interference proceedings (Patent Interference No. 106,115), ruling that the team led by Chinese-American scientist Feng Zhang from the Broad Institute holds the patent for using the CRISPR-Cas9 system in eukaryotic cells.

Although this does not signify the end of the patent dispute between Feng Zhang’s team and the team of Nobel laureates Emmanuelle Charpentier and Jennifer Doudna (hereinafter referred to as the “CVC team”), this protracted tug-of-war has highlighted the immense commercial value embedded in the foundational patents for gene-editing tools.

Currently, patents related to CRISPR-Cas technology are predominantly held by European and American countries. Breakthroughs in basic scientific research, along with the licensing and implementation of foundational patents, have become critical to the development of China’s gene editing and gene therapy industries.

In January 2022, the foundational patents for Cas13X (also known as Cas13e) and Cas13Y (also known as Cas13f), CRISPR-Cas13 systems independently developed by Huida Gene, were officially granted by the United States Patent and Trademark Office. This achievement made them the first self-developed CRISPR-Cas13 gene-editing tools from China to receive patent authorization in the United States, thereby breaking the patent monopoly held by European and American entities in the field of gene-editing tools. According to Freedom-to-Operate (FTO) analysis results, the CRISPR-Cas13X/Y systems owned by Huida Gene show no risk of patent infringement in either China or the United States.

Independent intellectual property rights in gene-editing technology will provide more options and safeguards for the future implementation and commercialization of gene-editing products in China.

Through the patent interference proceedings (Patent Interference No. 106,115), the USPTO determined that the team of Chinese-American scientist Feng Zhang from the Broad Institute had achieved reduction to practice earlier than the CVC team for CRISPR-Cas9 systems functioning in eukaryotic cells. Consequently, under the first-to-invent patent examination system then still in effect in the United States, the Broad Institute was granted priority, thereby upholding its patents on the use of CRISPR-Cas9 systems in eukaryotic cells. In contrast, the same technical solution proposed by the CVC team was deemed unpatentable due to lack of novelty, and a separate decision issued on the same day rejected the claims related to the use of CRISPR-Cas9 systems in eukaryotic cells in a series of U.S. patent applications filed by the CVC team.

However, this does not mean that the patent battle between the two parties has come to an end, as the CVC team still has the possibility of continuing to appeal.

Prior to this, the CVC team had also challenged the Zhang Feng team’s claims regarding the use of the CRISPR-Cas9 system in eukaryotic cells before the USPTO, based on its own claims for a CRISPR-Cas9 system with no limitation on the environment of use. In the interference proceeding (Patent Interference No. 106,048), the USPTO did not examine the patentability of either party’s claims, as it determined that there was no interference between them and that both could stand. This means that using the CRISPR-Cas9 system in eukaryotic cells requires licenses from both parties, as such use falls within the scope of both parties’ claims.

Perhaps the CVC team was unwilling to accept this outcome, so it once again requested the USPTO to initiate another round of interference proceedings based on its claims limited to CRISPR-Cas9 systems for use in eukaryotic cells. The USPTO determined that the CVC team and the Zhang Feng team constituted an interference with respect to these same claims. Consequently, in Interference No. 105,115, the USPTO further examined which party first invented a CRISPR-Cas9 system with a single guide RNA capable of cleaving or editing DNA in eukaryotic cells to affect gene expression. The result was as stated in the opening paragraph of this article.

CRISPR-Cas9 is currently the most widely used gene-editing tool worldwide, making the protracted patent battle over it a matter of global attention. Who holds the invention patent for the application of CRISPR-Cas9 in eukaryotic cells? This is no longer a simple “lawsuit.” Over the past decade, the two parties have engaged in a tug-of-war over this intellectual property, driven by the immense commercial value at stake.

The foundational patent for the application of CRISPR-Cas9 in eukaryotic cells, which was contested by the Zhang Feng team and the CVC team, covers the use of this technology in all eukaryotes, including various plants and animals, particularly humans. This means that any commercial company wishing to apply this technology to DNA editing in animals, plants, or humans must obtain permission from the patent holders and pay patent licensing fees.

Based on CRISPR-Cas9 technology, CRISPR Therapeutics, the gene therapy company founded by Emmanuelle Charpentier, and Intellia Therapeutics, founded by Jennifer Doudna, both went public on the NASDAQ in 2016. As of March 20, 2022, the market capitalizations of CRISPR Therapeutics and Intellia Therapeutics reached $5.232 billion and $5.401 billion, respectively. Both companies are developing gene-editing drugs based on CRISPR-Cas9.

In China, since West China Hospital of Sichuan University pioneered the world’s first human clinical trial involving the CRISPR–Cas9 system in July 2016—applying the CRISPR-Cas9 system to ex vivo knockout of the PD-1 gene in T cells for reinfusion therapy in metastatic non-small cell lung cancer—the CRISPR-Cas9 system has been widely applied by numerous domestic companies across various fields.

In recent years, although scientists in China have continuously optimized guide RNA and Cas9 proteins to improve efficiency and reduce off-target effects, they have been unable to circumvent the foundational patents of the CRISPR-Cas9 system. Consequently, the commercialization of related products faces the latent risk of being constrained by these core patents. As a result, some scientists have begun to explore the development of superior gene-editing tools that can secure independent foundational patent rights.

On May 2, 2021, a team of scientists from Huida Genomics published a research paper online in Nature Methods titled “Programmable RNA editing with compact CRISPR–Cas13 systems from uncultivated microbes.” Through computational analysis of large-scale metagenomic data from microorganisms, the study identified two novel CRISPR-Cas13 systems: Cas13X (also known as Cas13e) and Cas13Y (also known as Cas13f).

It is reported that Huida Gene, the only company in China with independent intellectual property rights for CRISPR-Cas gene-editing tools, has implemented a comprehensive patent strategy domestically and internationally for the CRISPR-Cas13X/Y system and its related derivative technologies. In January 2022, the company was granted a U.S. patent by the United States Patent and Trademark Office for the underlying CRISPR-Cas13X/Y system.

Unlike the CRISPR-Cas9 system, the CRISPR-Cas13 system is an RNA editing tool widely used in RNA knockdown, single-base RNA editing, site-specific RNA modification, live-cell RNA tracking, and nucleic acid detection. Compared with traditional RNA interference technology, the CRISPR-Cas13 system offers higher efficiency and specificity, as well as improved safety and stability. Furthermore, unlike CRISPR-Cas9-mediated DNA editing, the CRISPR-Cas13 system does not cause permanent changes to genomic DNA, thereby providing unique advantages in disease treatment, particularly in terms of safety.

In 2015, the laboratory of evolutionary biologist Eugene Koonin at the National Center for Biotechnology Information (NCBI), in collaboration with Feng Zhang’s team, pioneered the discovery of CRISPR-Cas13 systems suitable for RNA editing within microbial metagenomic databases using computational biology methods. These systems include Cas13a (C2c2), Cas13b (C2c6), and Cas13c (C2c7) proteins, and subsequent studies demonstrated their ability to efficiently knock down target RNA in mammalian cells. In 2018, the smaller Cas13d protein was further discovered. However, when attempting to develop RNA-editing therapeutics, Cas13a/b/c/d proteins all present challenges due to their large size, which makes them difficult to package into a single adeno-associated virus (AAV) vector for in vivo delivery.

Huida Gene discovered that Cas13X.1 (Cas13e.1) has a size of only 775 amino acids, making it one of the smallest Cas13 proteins currently known; the currently prioritized Cas13Y.1 (Cas13f.1) is also compact at only 790 amino acids. This ultra-small size effectively addresses the bottleneck associated with in vivo AAV delivery of Cas13.

Furthermore, the CRISPR-Cas13X/Y system demonstrates high efficiency, with in vitro RNA editing efficiencies exceeding 95% and in vivo editing efficiencies surpassing 90%; high specificity, offering greater targeting precision compared to existing systems; and high safety, characterized by low off-target rates and minimal collateral activity. The application of the CRISPR-Cas13X/Y system holds promise for the development of various highly efficient and safe RNA therapeutics, thereby expanding the possibilities for gene therapy in a broader range of diseases.

As a novel gene-editing tool, CRISPR-Cas13 has also attracted significant interest from the capital market due to its demonstrated application potential. Feng Zhang’s team has exclusively licensed its CRISPR-Cas13-related patents to Beam Therapeutics, a base editing company he co-founded. The company went public on the NASDAQ in 2020 and currently has a market capitalization of $4.338 billion.

As a technology platform company in the field of gene editing, Huida Genetics possesses independently owned intellectual property rights for its gene editing tools, as well as the capability to continuously iterate and optimize these tools. With the advancement of its self-developed in vivo gene editing pipeline and extensive external collaborations, the company will further promote the implementation and commercialization of gene editing technology products in China.