CRISPR Technology in the Agricultural Industry: Patent and Regulatory Updates

Introduction

The ability to edit eukaryotic DNA entails an almost limitless ability to alter the genetic makeup of the plants that become our food. Recently, scientific attention has been directed to applying a class of new gene-editing techniques that utilize CRISPR to food crops for the introduction of commercially desirable traits. Gene-edited crops can have a positive impact on food productivity, quality, and environmental sustainability, and CRISPR is unique in its relative simplicity, robust flexibility, cost-effectiveness, and wide scope of use. The increased use of CRISPR in agriculture has endless applications, the consequences of which are only recently being analyzed. 

CRISPR & the Power of Gene Editing

The term CRISPR refers generally to a class of gene-editing mechanisms derived from prokaryotic immune systems. These mechanisms feature two main components: guiding RNA molecules that direct the second component, CRISPR-associated ("Cas") proteins, to the target region of cellular DNA. These Cas proteins induce a double-stranded break in the DNA and allow for targeted manipulation of the desired genetic code. There is incredible diversity in the CRISPR-Cas system and a multitude of different Cas proteins that can be fine-tuned to induce desired changes with high specificity—including the activation or deactivation of individual genes, or the insertion of genes from other organisms into the target genome.

CRISPR's flexibility stands in sharp contrast to the previous generation of gene-editing technologies, such as Zinc Finger Nucleases and Transcription Activator-Like Effector Nucleases ("TALENs"), which require massive amounts of preemptive research and development and have a far more limited scope of use. This simultaneous precision and flexibility therefore provides ample opportunity for gene-edited optimization of food crops and has already been used in some instances to create, for example, browning-resistant mushrooms. In late 2021, in Japan, the first CRISPR-edited food product was introduced to the global market: tomatoes with high levels of GABA, a naturally occurring neurotransmitter, due to a CRISPR-inactivated gene.

The power of CRISPR has incredible potential for innovation, but the rights and regulations associated with CRISPR have been elusive and, at times, contentious. CRISPR's game-changing technology was the subject of a series of patent priority, inventorship, and, hence, ownership disputes between high-profile research institutions—the recent results of which have significant implications for global food supplies.

Patent Landscape

Like most cutting-edge technologies, the invention of CRISPR was accompanied by a flurry of patent application filings in the United States and elsewhere, as researchers who brought CRISPR to light sought to protect and monetize their rights as inventors. Numerous academic institutions—including Harvard's and MIT's Broad Institute, the University of California, University of Vienna, Vilnius University, The Rockefeller University, and companies such as ToolGen, Inc., Sigma-Aldrich (Millipore Sigma), Caribou Biosciences, Inc., Editas Medicine, Inc., Keygene N.V., Depixus, Blueallele Corp., and CRISPR Therapeutics AG, among numerous other institutions and companies—have secured U.S. and foreign patent rights related to the applications of CRISPR technology. As CRISPR continues to expand in use, especially in the case of CRISPR-edited agriculture that evade many regulations other GMO foods cannot, the complexity of the patent landscape will almost certainly continue to grow. 

EU Regulatory Landscape

In general, the EU subjects agricultural products edited with CRISPR technology to the full suite of genetically modified organism ("GMO") premarket approval, safety, and labeling requirements. The primary EU regulation on point, Directive 2001/18/EC (the "GMO Directive"), was promulgated in 2001 by the European Parliament and Council of the European Union. The GMO Directive requires all EU Member States to create appropriate precautionary measures regarding the release of GMOs in the market. However, the definition of GMO in the GMO Directive apparently excludes CRISPR modification, stating that a GMO is as "an organism, with the exception of human beings, in which the genetic material has been altered in a way that does not occur naturally by mating and/or natural recombination." 

It was not until 2018 that the EU addressed this gap in the GMO Directive. In July 2018, the Court of Justice of the European Union explained in Case C-528/16 that organisms obtained by mutagenesis are GMOs within the meaning of the GMO Directive. "Only organisms obtained by means of techniques/methods of mutagenesis which have conventionally been used in a number of applications and have a long safety record are excluded from the scope of that directive." 

The following year, in November 2019, the Council of the EU formally requested that the European Commission "submit a study in light of the Court of Justice's judgment in Case C-528/16 regarding the status of novel genomic techniques under Union law, and a proposal, if appropriate in view of the outcomes of the study." The 117-page study was issued in April 2021, and ultimately affirms the holding in Case C-528/16, stating that the "study makes it clear that organisms obtained through new genomic techniques [including CRISPR] are subject to the GMO legislation." Based on the study's findings, the European Commission requested public input on proposed legislation for "plants obtained by targeted mutagenesis and cisgenesis and for their food and feed products." The public consultation period expired on July 22, 2022. The European Commission plans to finalize the proposed framework in 2023.

United States Regulatory Landscape

In contrast to the EU approach, the United States does not currently regulate CRISPR-edited agricultural products as GMOs. The United States regulates biotechnology and genetic modification in food through a "Coordinated Framework" between the U.S. Department of Agriculture ("USDA"), Food and Drug Administration ("FDA"), and Environmental Protection Agency ("EPA"). 

At a high level, the USDA regulates the use of biotechnology in plant products through the Plant Protection Act. The USDA explains that the Plant Protection Act provides the USDA's Animal and Plant Health Inspection Service ("APHIS") with authority to regulate "organisms and products that are known or suspected to be plant pests or to pose a plant pest risk, including those that have been altered or produced through genetic engineering." Further, in 2018, the USDA's Agricultural Marketing Service promulgated the National Bioengineered Food Disclosure Standard, 7 CFR Part 66 (the "BE Disclosure Standard"), which created a "new national mandatory bioengineered [] food disclosure standard" and associated recordkeeping requirements, effective January 1, 2022. The BE Disclosure Standard defines bioengineered food as food products that contain "genetic material that has been modified through in vitro [DNA]" and "for which the modification could not otherwise be obtained through conventional breeding or found in nature." Notably, the USDA has not explicitly clarified whether CRISPR-edited agricultural products are considered "bioengineered foods" and subject to the BE Disclosure Standard. Rather, in a presentation from 2020, the USDA stated that it "intends to make determinations about whether a specific modifications would be considered 'found in nature' or obtained through 'conventional breeding' on a case-by-case basis." (For more information on the BE Disclosure Standard, refer to Jones Day's May 2022 publication, Are Your Labels Up to Date? Assuring Compliance with the USDA's National Bioengineered Food Disclosure Standard.)

Additionally, the FDA regulates the use of biotechnology in plants with a focus on ensuring that foods are safe for human consumption. In 1992, the FDA issued a Statement of Policy regarding Foods Derived from New Plant Varieties, in which the FDA stated that "[t]he regulatory status of a food, irrespective of the method by which it is developed, is dependent upon objective characteristics of the food and the intended use of the food (or its components)." Since then, the FDA has reviewed genetic modifications to food in the context of food additives, such that FDA approval is required to use food additives unless it is generally recognized as safe ("GRAS"). In the opinion of the FDA, a GMO is not GRAS if the altered substance "differs significantly in structure, function or composition from substances found currently in food." In contrast, a GMO is GRAS if it is "naturally occurring" in the food product, even if is bioengineered to be present at a "greater level" than found in nature or if there are "minor variations in molecular structure that do not affect safety." As explained in the introduction, CRISPR technology differs from conventional gene editing because it does not introduce new substances into a product that are not naturally present. Accordingly, CRISPR-edited agricultural products are not generally regulated by the FDA as food additives. 

The EPA also reviews the use of biotechnology in plants, as it regulates the distribution, sale, and use of pesticides to ensure that they will "not pose unreasonable risks to human health or the environment when used according to label directions." Further, when the EPA evaluates plant-incorporated protectants ("PIPs"), which are genetically engineered pesticides, the EPA "requires extensive studies containing numerous factors, such as risks to human health, nontarget organisms, and the environment; potential for gene flow; and the need for insect resistance management plans." As such, CRISPR-edited pesticides may be regulated by the EPA as PIPs.

Conclusion

The patent and regulatory landscapes of the use of CRISPR technology in food are continuing to unfold across the world. Accordingly, agriculture companies and the broader agricultural industry should pay close attention to all developments.