On September 7, 2022, the United States Department ofAgriculture's Animal and Plant Health Inspection Service(USDA-APHIS) announced the completion of the firstRegulatory Status Review (RSR) of a genetically engineered plantunder the SECURE rule. APHIS concluded that a new geneticallyengineered tomato produced by Norfolk Plant Sciences is unlikely topose an increased plant pest risk compared to a conventionaltomato, and is therefore not subject to regulation under the SECURErule. This means that these tomato plants, which have beenengineered to produce deep purple tomatoes with enhancednutritional quality, may be legally imported, moved interstate, or"released" into the environment (including, for example,in a field trial) in the United States without a permit fromAPHIS.

Notably, this finding also means that subsequent genetictransformation events involving the same combination of plantspecies, trait, and mechanism of action ("PTMOA") asNorfolk Plant Sciences' purple tomatoes are also no longerregulated under the SECURE rule. Thus, other subspecies andvarieties of Solanum lycopersicum that have been modifiedto produce the same trait by the same mechanism ofactioneven if by different transgenic eventsare nowexempt under 340.1(c) of the SECURE rule. More informationon this so-called PTMOA exemption is available in APHIS's"Guide for Requesting a Confirmation of Exemptionfrom Regulations under 7 CFR part 340" (published August31, 2022; document ID BRS-GD-2020-0001). This approach is differentfrom the "event-by-event" regulation that was previouslyrequired, and represents the first time that APHIS has made an RSRdetermination under its new rules.

Additional information about the contours of the SECURE rule andthe genetic engineering that Norfolk Plant Sciences used to producetheir purple tomato is provided below.

The SECURE rule (7 CFR part 340) governs how APHISregulates certain organisms developed using genetic engineering,with the goal of protecting U.S. agriculture from plant pest risksunder the Plant Protection Act of 2000 (7 U.S.C. 7701et seq.). It replaced the previous version of 7 CFR part 340, whichhad been in place largely unchanged since APHIS's biotechnologyregulations were established in 1987, in phases between May 18, 2020 and October 1,2021.

The new regulations completely overhauled and streamlined theregulatory process for assessing the plant pest risk oforganisms developed using genetic engineering, taking into accountadvances in scientific understanding, and focusing more on theproperties of the engineered organism and less on the method(s)used to produce it.

The revised regulations exempt certain types of modificationsfrom regulation; such exemptions are self-determined, though developers may voluntarily requestconfirmation from APHIS that a given exemption applies. Thisexemption/confirmation process replaced the previous "Am I Regulated?"process on June 17, 2020, and APHIS has since issued 15 confirmation lettersas of this writing, with the earliest in April 2021.

However, no plant had made it through the new RSR process untilnow. The RSR process is an option for instances in which no SECURErule exemptions apply to a given engineered plant, but thedeveloper feels that the plant nonetheless does not pose anincreased plant pest risk and should therefore not be regulated bythe SECURE rule. The RSR process replaced the previous"petition" process for requesting deregulation from 7 CFRpart 340 due to low likelihood of posing a plant pest risk.

The RSR process became available for corn, soybean, cotton,potato, tomato, and alfalfa on April 5, 2021, and for all otherplant species on October 1, 2021. APHIS received Norfolk PlantSciences' RSR request on August 4, 2021 and responded onSeptember 6, 2022 (both the request and the response documents areavailable here, under RSR number 21-166-01rsr). As ofthis writing, Norfolk Plant Sciences' tomato is the only RSRrequest publicly available on APHIS's website.

Under the RSR process, APHIS reviews "the biologicalproperties of the plant; and the trait (or new characteristic); andthe mechanism of action (or how the genetic modification causes thenew trait to occur)" in order to evaluate plant pest risk. There are twopotential steps to this process, depending on what APHIS determinesduring the first step. In Step 1, APHIS identifies whether theengineered plant poses a plausible pathway to increased plant pestrisk compared to a "comparator" plant. If APHIS finds nosuch pathway, the RSR process concludes, and APHIS notifies therequestor that the plant in question is not subject to regulationunder the SECURE rule. This was the outcome for Norfolk PlantSciences' tomato.

On the other hand, if APHIS does determine that the engineeredplant may plausibly pose an increased plant pest risk, there areseveral potential next steps. First, the developer may accept thatthe plant is regulated under the SECURE rule, and then eitherrequest a permit before moving or releasing the plant, or take nofurther action and not move or release the plant. Alternatively oradditionally, the developer may request that APHIS proceed to Step 2 of the RSR process, which entails amore involved review, subsequent publication in the FederalRegister, and solicitation and review of public comments before afinal determination. As of this writing, no plant has gone throughthis second step of the RSR process.

As described in its RSR request, Norfolk Plant Sciences createdits purple tomato plant by Agrobacterium-mediatedinsertional mutagenesis of the "MicroTom" tomato variety,and subsequent crossing into other tomato varieties. The plants areengineered to increase expression of their natural anthocyaninpigments, which is what causes the fruits to have a deep purplecolor and also enhances their nutritional value.

Specifically, the inserted DNA contains two transcriptionfactors from the snapdragon plant (Antirrhinum majus),which serve to activate production of the tomato's nativeanthocyanin biosynthesis pathway, causing increased anthocyaninproduction. Each of these two transcription factor genes, calledDel and Ros1, is expressed from the T-DNA under anative tomato promotor that causes fruit-specific expression. TheT-DNA also includes the nptII selectable marker with apromotor and terminator from Agrobacterium tumefaciens,which have a decades-long history of safe use and consumption.

Complete genome sequencing revealed that the T-DNA was insertedat a single site in chromosome 4, accompanied by several smalldeletions. Phenotypic evaluation of the transformed plants revealedthat they grew effectively the same as non-transgenic tomatoes,except that they produce deep purple fruit with significantlyhigher anthocyanin content. Photos of the plants and fruit areavailable in the published RSR request.

APHIS considered the information disclosed in Norfolk PlantSciences' RSR request, alongside "publicly availableresources, and APHIS' familiarity with tomato and knowledge ofthe trait, phenotype, and mechanism of action" and "didnot identify any plausible pathway by which [the] modified tomato,or any of its sexually compatible relatives, would pose anincreased plant pest risk relative to a comparator tomato"(21-116-01 RSR Response, page 1). As such, APHIS concluded thatthese purple tomatoes are not subject to regulation under theSECURE rule.

It is important to note that deregulation from APHIS'sSECURE rule does not mean that the plant is wholly removed fromU.S. federal regulatory oversight. For example, regulationsimplemented by the Food and Drug Administration (FDA),Environmental Protection Agency (EPA), and/or other arms of USDA(such as Plant Protection and Quarantine (PPQ) import and exportregulations, and/or Agricultural Marketing Service (AMS) labelingrequirements) may still apply. Along those lines, Norfolk PlantSciences' RSR request states that Norfolk Plant Sciencessubmitted a food and feed safety and nutritional assessment of thePurple Tomato to FDA under the voluntary Biotechnology Notification Consultationprogram, which was received as BNF number 178. As of thiswriting, FDA has not yet published a completed consultation forNorfolk Plant Sciences' purple tomato.

This regulatory review is an important milestone for regulationof genetically engineered plants in the United States. It is thefirst public test of the SECURE rule's RSR process since itsimplementation more than a year ago, when it became one of the mostscientifically progressive such review processes in the world, atleast on paper. The deregulation of Norfolk Plant Sciences'purple tomatoes shows that USDA-APHIS is embracing its newproduct-focused regulations. Although the review took more than ayearsignificantly longer than the 180 days promised by APHIS for Step1the process will likely become more efficient as the agencyand developers become more familiar and comfortable with the newsystem. It will be interesting to see how the exemption and reviewprocesses grow and possibly become more streamlined with additionaluse.

Because of the generality of this update, the informationprovided herein may not be applicable in all situations and shouldnot be acted upon without specific legal advice based on particularsituations.

Morrison & Foerster LLP. All rights reserved

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Purple Tomato Is First Genetically Engineered Plant To Be Deregulated Through USDA's New Regulatory Status Review Process - Life Sciences,...