[Federal Register Volume 87, Number 83 (Friday, April 29, 2022)]
[Notices]
[Pages 25495-25499]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2022-09210]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES


Screening Framework Guidance for Providers and Users of Synthetic 
Oligonucleotides

AGENCY: Office of the Secretary, Assistant Secretary for Preparedness 
and Response (ASPR), Department of Health and Human Services (HHS).

ACTION: Notice.

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SUMMARY: The Assistant Secretary for Preparedness and Response is 
issuing this revised guidance on a screening framework guidance for 
providers and users of synthetic oligonucleotides. The Revised Guidance 
sets forth recommended baseline standards for the gene and genome 
synthesis industry, as well as best practices for Institutions, 
Principal Users, End Users, and Third-Party Vendors of 
oligonucleotides, regarding screening orders and maintaining records 
consistent with current U.S. regulations. In addition, this Revised 
Guidance seeks to encourage best practices to address biosecurity 
concerns associated with the potential misuse of synthetic 
oligonucleotides to bypass existing regulatory controls and commit 
unlawful acts.

FOR FURTHER INFORMATION CONTACT: Dr. Mariam Lekveishvili; Division of 
Policy; Office of Strategy, Policy, Planning, and Requirements; Office 
of the Assistant Secretary for Preparedness and Response; U.S. 
Department of Health and Human Services; phone: (202) 260-3586; email: 
<a href="/cdn-cgi/l/email-protection#531e32213a323e7d1f363825363a203b253a3f3a133b3b207d343c25"><span class="__cf_email__" data-cfemail="0845697a61696526446d637e6d617b607e6164614860607b266f677e">[email protected]</span></a>.

SUPPLEMENTARY INFORMATION: Questions regarding aspects of the Guidance 
that may be appropriate to update based on changes in technologies 
since the Guidance was originally issued in 2010 were published as a 
Notice in the Federal Register on August 26, 2020, for a period of more 
than 120 days for public comment. Fourteen individual responses were 
received. The responses to that Notice are available at the following 
website: https://aspr.hhs.gov/legal/syndna/Pages/comment.aspx.

Screening Framework Guidance for Providers and Users of Synthetic 
Oligonucleotides

    Introduction: Continuing advances in oligonucleotide synthesis 
technology and the open availability of genetic sequence data pose 
potential concerns among the scientific community, the oligonucleotide 
synthesis industry, the U.S. Government, and the public that 
individuals with ill intent could exploit biotechnology for harmful 
purposes. The U.S. Government has acted to reduce dangers to human, 
animal, and plant health due to biological pathogens and toxins. For 
instance, it has issued the federal Select Agent Regulations, which 
regulate a subset of microbial organisms and toxins determined to have 
the potential to pose a severe threat to public health and safety, 
animal health, plant health, or animal or plant products. These 
regulations are administered by the Federal Select Agent Program 
(FSAP), which sets forth requirements for the possession, use, and 
transfer of biological select agents and toxins.\1\ A second layer of 
regulation is provided by the Export Administration Regulations' 
Commerce Control List (CCL) \2\ which identifies agents and genetic 
sequences that require licenses before export from the United States. 
However, these regulated pathogens and toxins do not represent the 
entirety of the potential risks to public health, agriculture, plants, 
animals, or the environment that could arise from the misuse of 
synthetic oligonucleotides. Non-regulated pathogens and toxins as well 
as other novel types of sequences or specific types of batch orders, 
may also pose significant risks if they are misused.
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    \1\ https://www.selectagents.gov/sat/list.htm.
    \2\ https://www.bis.doc.gov/index.php/regulations/commerce-control-list-ccl.
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    Individuals with no legitimate, bona fide, and peaceful need should 
be prevented from accessing genetic materials that could contribute to 
pathogenicity or harm, even when they are not from FSAP- or CCL-listed 
pathogens or toxins. Purchasing or synthesizing oligonucleotides could 
enable individuals without a legitimate and peaceful purpose to possess 
genetic sequences that would pose risks if misused. Such synthesis, 
through directly ordering either long genomic sequences or short 
genomic sequences--that can be used to create longer genomic-length 
oligonucleotides, using molecular techniques that have become 
increasingly available--to modify non-

[[Page 25496]]

pathogenic strains or create pathogens or toxins de novo, has obviated 
the need for access to the naturally occurring agents or naturally 
occurring genetic material from these agents. The potential 
availability of dangerous agents has thereby been greatly expanded. The 
Revised Guidance reaffirms the need to screen for genetic sequences 
from regulated organisms and toxins, but also recognizes that screening 
should evolve to encompass sequences that are recognized to contribute 
to pathogenicity or toxicity, as information regarding these sequences 
and their verified function, as well as improved methods to screen 
become available (or as feasible).
    This Revised Guidance is intended to guide all entities involved in 
the provision and use of synthetic oligonucleotides in establishing and 
operating a screening framework for oligonucleotide orders, including 
mechanisms to identify sequences obfuscated to circumvent lists of 
regulated organisms or toxins or sequences that are not Best Matches to 
any sequences in GenBank. To minimize the risk that unauthorized 
individuals or individuals with ill intent will obtain oligonucleotides 
containing SOCs, the Revised Guidance now provides recommendations to 
not only Providers, but also Third-Party Vendors, Institutions, 
Principal Users, and End Users of synthetic oligonucleotides, to use 
responsible business practices to maintain records of all orders and 
transfers of SOCs. This Revised Guidance includes recommendations for 
verifying the legitimacy of Customers when filling orders for synthetic 
oligonucleotides that encode SOCs. The Revised Guidance further 
provides recommendations for Manufacturers, as oligonucleotide 
synthesis equipment may allow individuals with malintent to circumvent 
regulations that restrict access to regulated pathogens and toxins or 
to obtain oligonucleotides containing other SOCs without a legitimate 
and peaceful purpose. As in the original Guidance, this Revised 
Guidance aims to minimize any negative impacts on the conduct of 
research and business operations, by leveraging ongoing best practices.
    Institutional policies and procedures already in place for safe 
possession, use, and transfer of these materials, as well as federal 
and international guidance, such as the Department of Health and Human 
Services, Centers for Disease Control and Prevention, and National 
Institutes of Health Biosafety in Microbiological & Biomedical 
Laboratories (BMBL) \3\ and the World Health Organization Laboratory 
Biosafety Manual,\4\ should be used wherever possible to complement the 
measures suggested in this Revised Guidance to maximize safe and secure 
practices while seeking to minimize the burden on legitimate life 
science research.
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    \3\ https://www.cdc.gov/labs/BMBL.html.
    \4\ https://www.who.int/publications/i/item/9789240011311.
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    Request for Comments: A request for public comments on the issues 
covered in this Notice was published in the Federal Register (85 FR 
52611, August 26, 2020, Review and Revision of the Screening Framework 
Guidance for Providers of Synthetic Double-Stranded DNA) for public 
consideration and comment for a period of more than 120 days. This 
Revised Guidance was drafted through a deliberative interagency process 
to address the topics raised in public comments as well as other 
concerns from the interagency.
    The Office of the Assistant Secretary for Preparedness and Response 
(ASPR) within the Department of Health and Human Services (HHS) is 
submitting this Revised Guidance for public consideration and comment 
for a period of 60 days. ASPR is the lead agency in a broad interagency 
process considering possible changes to the Guidance and whether to 
issue the proposed Revised Guidance as final guidance. The public is 
encouraged to submit written comments on the proposed changes to the 
Guidance, whether additional measures would be needed to best ensure 
safety and security in life sciences research and innovation, whether 
the suggested scope of screening and intended audience is feasible, and 
whether impacts are expected from implementing this Revised Guidance. 
Comments may be submitted at the following website: https://aspr.hhs.gov/legal/syndna/Pages/comment.aspx.
    Definitions: The following definitions are applicable:
    Customer: For the purposes of this Revised Guidance, the individual 
or organization, such as an Institution, that orders or requests 
synthetic oligonucleotide from a Provider, or that purchases benchtop 
synthesis equipment from a Manufacturer.
    End User: The laboratorian that possesses and uses synthetic 
oligonucleotides that they have received from a Customer, Principal 
User, or another End User.
    Manufacturer: An entity that produces and sells equipment for 
synthesizing oligonucleotides. Manufacturers may provide equipment to 
Institutions, Principal Users, or Third-Party Vendors.
    Principal User: The individual that originates the order or 
synthesizes oligonucleotides themselves and oversees the use of ordered 
or synthesized sequences in the laboratory. The Principal User may also 
be the End User.
    Provider: The entity that synthesizes and distributes 
oligonucleotides. A Provider is understood to be an entity synthesizing 
oligonucleotides for and distributing oligonucleotides to a Customer, 
rather than a research scientist collaborating with a colleague.
    Sequence of Concern (SOC): Sequences derived from or encoding 
select agents and toxins or items on the CCL, except when also found in 
unregulated organisms; or sequences that contribute to toxicity or 
pathogenicity, whether derived from or encoding regulated or 
unregulated biological agents.\5\
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    \5\ Pathogenicity or toxicity that threatens public health, 
agriculture, plants, animals, or the environment. SOCs include 
sequences for which a direct and harmful impact on a host has been 
verified based on published experimental data; and, where 
experimental data do not exist, based on homology to a sequence 
encoding a verified function.
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    Synthetic oligonucleotides subject to screening: DNA or RNA, 
single- or double-stranded, of lengths 50 base pairs (bp) or longer if 
ordered in quantities of less than one micromole, or lengths 20 bp or 
longer if ordered in quantities of one micromole or greater.
    Third-Party Vendor: An entity that orders oligonucleotides from 
Providers and sells the oligonucleotides in turn, with or without 
reformulation, or resells equipment for synthesizing oligonucleotides.
    Verifying Legitimacy: Information that would allow Providers, 
Manufacturers, Principal Users, or End Users to authenticate the 
recipient of materials or equipment as a legitimate member of the 
scientific community. Information such as proposed end-use of the 
order, institutional or corporate affiliation (if applicable), the name 
of a biosafety officer (if available), proof of registration or 
licensing with FSAP or DOC (if applicable), or other proof of a 
legitimate research program (such as a publication history or business 
licenses) may be helpful for such verification.

Goals and Scope of the Guidance

    Goals: This Revised Guidance has two parallel goals. As in the 
original Guidance, a primary goal is to minimize the risk that 
unauthorized individuals

[[Page 25497]]

or individuals with malicious intent will use nucleic acid synthesis 
technologies to obtain organisms for which possession, use, and 
transfer is regulated by FSAP and CCL. The Revised Guidance also aims 
to limit the potential for individuals with malicious intent to use 
synthetic oligonucleotides to create novel high-risk pathogens using 
sequences from unregulated organisms.
    Scope: The Revised Guidance pertains to the sale or transfer of 
synthetic oligonucleotides, i.e., DNA and RNA, whether single- or 
double-stranded. The Revised Guidance recommends that a database of 
known SOCs for pathogens, toxins, or otherwise illicit or dangerous 
substances is developed and used to determine if the purchase or 
transfer includes SOCs. It also recommends methods to ensure the 
legitimacy of Customers, Principal Users, and End Users of synthetic 
oligonucleotides. The Revised Guidance also aims to ensure that 
entities maintain records of transfers for oligonucleotides containing 
SOCs.
    The Revised Guidance was developed to align with Providers' and 
Customers' existing protocols and business practices; to be implemented 
without unnecessary cost; and to minimize any negative impacts on the 
conduct of research and business operations. Where practical to do so, 
entities can use existing business practices to verify the legitimacy 
of Principal Users and End-Users and to track the transfer of materials 
containing SOCs. Many Providers have already instituted measures to 
address these concerns. The ongoing development of best practices in 
this area is commendable and encouraged, particularly in light of the 
continued advances in oligonucleotide sequencing and synthesis 
technologies.
    Recommendations for Providers, Users, and Manufacturers: The 
Revised Guidance aims to ensure that Customers, Principal Users, and 
End Users ordering SOCs are legitimate. It also recommends that 
Manufacturers install certain safeguards in oligonucleotide synthesis 
equipment that ensure only legitimate customers can synthesize SOCs. It 
also recommends that transfers of SOCs, from Principal Users to End 
Users, and from Third-Party Vendors to Principal Users and End Users, 
are reported to the original Customer, such as the Institution that 
originated the order. This Revised Guidance encourages entities 
transferring synthetic oligonucleotides containing SOCs (i.e., the 
Third-Party Vendor, Principal User, or Institution) to know to whom 
they are transferring and to conduct screening to verify that the 
recipients have a legitimate, bona fide, and peaceful purpose to use 
the oligonucleotides. The Revised Guidance recommends that the 
Customers who place these orders use responsible business practices to 
maintain records of transfers.
    Principal Users and End Users are best positioned to understand the 
nature of the oligonucleotides and oversee and shepherd their 
responsible use. Users may also transfer oligonucleotides to other End 
Users, such as colleagues, and certain recommendations are made for 
this case in the Revised Guidance. To this end, Customers are 
encouraged to streamline the screening of their synthetic 
oligonucleotide orders by providing verification of their legitimacy to 
Providers and Third-Party Vendors, if they know that their order 
contains SOCs. Information such as proposed end-use of the order, 
institutional or corporate affiliation (if applicable), the name of a 
biosafety officer (if available), proof of registration or licensing 
with FSAP or DOC (if applicable), or other proof of a legitimate 
research program (such as a publication history or business licenses) 
will be helpful to the Provider or Third-Party Vendor of the synthetic 
oligonucleotides in verifying legitimacy. Preemptively providing this 
information is likely to limit the time and expense for Providers in 
fulfilling these orders in a manner that ensures safety and security.
    Providers and Third-Party Vendors of synthetic oligonucleotides are 
encouraged to do the following in this context:
    <bullet> Know to whom they are distributing a product.
    <bullet> Know if the product that they are synthesizing and/or 
distributing contains, in part or in whole, SOCs.
    <bullet> Notify Customers and Principal Users when their order 
contains SOCs.
    <bullet> Implement adequate cybersecurity measures to protect the 
intellectual property and identity of Customers.\6\
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    \6\ Providers and Third Party Vendors are encouraged to follow 
the ISA/IEC 27032:2012 & ISO/IEC 62443 standards for cybersecurity 
and information security.
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    <bullet> Where follow-up screening does not resolve concerns about 
an order, report the order to the FBI.
    <bullet> This Revised Guidance recommends archiving for at least 8 
years the following information for orders containing SOCs: Customer 
information (point-of-contact name, organization, address, email, and 
phone number), order sequence information (nucleotide sequences 
ordered, vector used), and order information (date placed and shipped, 
shipping address, receiver name).
    Customers, Principal Users, and End Users of synthetic 
oligonucleotides are encouraged to develop best practices in four main 
areas in this context:
    <bullet> Customers, Principal Users, and End Users who know that 
their synthetic oligonucleotide order contains SOCs are encouraged to 
preemptively provide information that will assist the Provider or 
Third-Party Vendor in verifying their legitimacy.
    <bullet> Customers, Principal Users, End Users, and Third-Party 
Vendors are encouraged to only transfer synthetic oligonucleotides 
containing SOCs to suitable and trustworthy individuals with a 
scientifically sound reason to use these oligonucleotides.
    <bullet> Customers, Principal Users, End Users, and Third-Party 
Vendors are also encouraged to maintain records of these transfers and 
to communicate them to their biosafety officer, or equivalent, using 
the responsible business practices in place in their organizations.
    <bullet> The Revised Guidance recommends recording transfers of 
oligonucleotides containing SOCs from Principal Users and End Users to 
any other individuals not listed in the original order, such as through 
a Material Transfer Agreement (MTA) or another sample tracking process. 
The Revised Guidance also recommends that records of SOCs and their 
transfers are retained for at least 8 years. Business practices already 
in place at Institutions may be used to fulfill this recommendation.
    <bullet> Institutions with in-house oligonucleotide synthesis 
capabilities are also encouraged to apply these recommendations for use 
or transfers of oligonucleotides synthesized in-house.
    Manufacturers of benchtop synthesis equipment are encouraged to 
consider three areas for developing best practices in this context:
    <bullet> Manufacturers should screen Customers seeking 
oligonucleotide synthesizers to ensure customer legitimacy, and that 
the equipment is appropriate for their needs. If the Customer indicates 
plans to produce SOCs, Manufacturers should develop prescreening 
mechanisms to determine legitimate use.
    <bullet> Manufacturers and their Customers should implement 
mechanisms to track continuously the legitimacy of users of their 
equipment, including when it is potentially transferred to new 
Principal and End Users during the lifecycle of these equipment (see 
CUSTOMER SCREENING for criteria to verify legitimacy of User).
    <bullet> Manufacturers should provide the capability into their 
oligonucleotide

[[Page 25498]]

synthesizers to enable secure internet connectivity to screen sequences 
for SOCs and to authenticate legitimate users.\7\ Manufacturers are 
also encouraged to include a data logging function to maintain a record 
of the oligos synthesized on the equipment. Furthermore, Manufacturers 
should develop a mechanism to authenticate the user of these equipment 
before synthesizing oligonucleotides containing SOCs.
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    \7\ Manufacturers are encouraged to follow the ISO/IEC 
27032:2012 & ISO ISA/IEC 62443 standards for cybersecurity and 
information security.
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    Sequence Screening Methodology: Providers should screen orders to 
determine whether they contain SOCs. Appropriate sequence screening 
software must be selected by providers of synthetic oligonucleotides. 
This Revised Guidance recommends that providers use a local sequence 
alignment technique, such as the BLAST family of tools. BLAST is 
available for download for free at the National Center for 
Biotechnology Information (NCBI) website.\8\ Similar tools are also 
freely or commercially available or could be designed by the provider 
to meet their sequence screening needs. Specific criteria for the 
statistical significance of the hit (BLAST's e-values) or percent 
identity values are not included in this Revised Guidance because these 
details depend on the specific screening protocol. Providers are 
encouraged to determine whether synthetic oligonucleotide orders 
contain sequences that are Best Matches over 50 bp windows to any SOC. 
By using the Best Match approach, the sequence with the greatest 
percent identity over each 16 amino acid or 50 bp fragment, in all six 
reading frames, should be considered the Best Match, regardless of the 
statistical significance or percent identity. The Best Match approach 
is intended to minimize the number of sequence hits due to sequences 
that are shared among both SOCs and non-SOCs.
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    \8\ http://blast.ncbi.nlm.nih.gov/Blast.cgi.
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    These sequence screening recommendations do not preclude the use of 
a curated database of sequences that may contribute to pathogenicity or 
toxicity to identify SOCs. This Revised Guidance recognizes that a 
database of known sequences that contribute to pathogenicity and 
toxicity in humans, animals, and plants, and that have a direct and 
harmful impact on a host, may not yet exist, and encourages the 
development of such a database for screening SOCs, provided that 
measures are taken to prevent such a database from being misused. These 
measures should include establishing a security office, protocols, and 
personnel reliability program, based on an assessment of risk, to guide 
selection, implementation, and monitoring of cybersecurity and 
information security capabilities and protection. Measures should 
ensure database confidentiality and integrity (including user access 
controls and sequence encryption in transit and at rest) and compliance 
with applicable laws such that sequences of concern data are protected 
against unauthorized access, exfiltration, or other use. Providers may 
also choose to use other screening approaches that they assess to be 
equivalent or superior to the Best Match approach or supplement it, 
including a customized database or approaches that evaluate the 
biological risk associated with non-select agents and toxins sequences 
or, for international orders, sequences not associated with items on 
the CCL. This Revised Guidance encourages the continued development of 
best practices to address risks associated with oligonucleotide 
synthesis technologies.
    Although no curated database of sequences from regulated and 
unregulated pathogens that pose no biosecurity concerns (i.e., white 
list of genes that pose no pathogenic risk) is presently available, 
Providers may wish to consider developing solutions for determining 
which sequences from pathogens, regulated or unregulated, should not 
cause concern (such as housekeeping genes).
    Providers, Third-Party Vendors, and professional consortia are 
encouraged to develop secure mechanisms designed to respect privacy, 
security, commercial, Intellectual Property, and other concerns to 
detect SOCs that may be broken up among multiple Providers or Vendors, 
or among multiple orders at a single Provider or Vendor over a period 
of time, to evade screening.
    Batch Orders: Some synthetic oligonucleotide orders may be 
appropriate for screening even if all components of the order are 
oligonucleotides shorter than 50 bp in length. In some cases, orders of 
oligonucleotides in quantities of one micromole or more may indicate 
that the Customer, Principal User, or End User may intend to use 
molecular biological techniques to ligate oligonucleotides into larger 
oligonucleotide complexes. Such an approach could be used to construct 
50 bp or longer oligonucleotides that themselves may constitute SOCs. 
To minimize the risk in this scenario, this Revised Guidance encourages 
screening all constituents of batch orders of oligonucleotides 20 bp or 
longer if ordered in quantities of one micromole or greater, using a 
short oligonucleotide alignment software package. If the resulting 
ungapped alignment of any constituents of the batch order is a Best 
Match to any 50 bp window of any SOC, Providers should consider that 
order as containing SOCs and perform standard follow-up Customer 
screening.
    Customer Screening: In addition to verifying the Customer identity 
for all orders, verifying legitimacy of Customers and Users is 
recommended when orders contain SOCs and for orders of benchtop 
synthesis equipment. Customers and Users are encouraged to streamline 
the Customer screening process by providing verification of their 
legitimacy when submitting an order containing SOCs. Information about 
the proposed end-use of the order, institutional or corporate 
affiliation (if applicable), the name of a biosafety officer (if 
available), proof of registration or licensing with FSAP or DOC (if 
applicable), or other proof of a legitimate research program (such as a 
publication history or business licenses) will be helpful to the 
Provider or Third-Party Vendor.
    This Revised Guidance encourages Customers and Principal Users to 
also verify the legitimacy of End Users receiving SOCs. Records of such 
verification and transfer can be created and maintained by using 
business practices that document such transfers (e.g., MTAs). The 
Principal User is best positioned to determine the legitimacy of any 
End User to whom SOCs are transferred. Keeping a record of such 
transfers should not cause undue burden on the essential research 
carried out across the biotechnology enterprise, and may therefore 
entail only a minor adaptation of responsible business practices 
already in place.
    Providers should be aware of regulatory and statutory prohibitions 
for U.S. persons from dealing with certain foreign persons, entities, 
and companies. Providers are encouraged to check the Customer against 
the International Trade Administration consolidated list of individuals 
and entities for which the United States Government maintains 
restrictions on certain exports, reexports, or transfers of items.\9\ 
In the event that a company, entity, or person on the list appears to 
match that of a Customer or User, additional due diligence should be 
conducted before proceeding. There may be a strict export prohibition, 
requirement for seeking a license application, evaluation of Customers

[[Page 25499]]

and Users to ensure it does not result in an activity prohibited by any 
U.S. export regulations, or other restriction. Before taking further 
action, to ensure full compliance with all the terms and conditions of 
the restrictions placed on the parties on this list, the Provider must 
check the official publication of restricted parties in the Federal 
Register. They should also check the official lists of restricted 
parties maintained on the websites of the Departments of Commerce, 
State, and the Treasury.
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    \9\ https://www.trade.gov/consolidated-screening-list.
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    Following up with the U.S. Government in Cases Where Malintent is 
Suspected by Providers or Third-Party Vendors: If sequence or Customer 
screening raises concerns that are not alleviated through follow-up 
screening, Providers and Third-Party Vendors are encouraged to contact 
the nearest FBI Field Office Weapons of Mass Destruction (WMD) 
Coordinator. Institutions are encouraged to work with their Principal 
Users and End Users to help them understand that only individuals with 
legitimate, bona fide, and peaceful need should obtain oligonucleotides 
containing SOCs.
    Records Retention: The Revised Guidance recommends that Providers, 
Third-Party Vendors, and Manufacturers:
    <bullet> Using responsible business practices, retain records of 
Customer orders for at least 8 years.
    <bullet> Archive the following information: Customer information 
(point-of contact name, organization, address, email, and phone 
number), order sequence information (nucleotide sequences ordered, 
vector used), and order information (date placed and shipped, shipping 
address, receiver name).
    <bullet> Develop and document protocols for sequence screening and 
for determining whether a sequence hit qualifies as a SOC and maintain 
records of these protocols--even if no longer current--for at least 8 
years.
    <bullet> Retain screening documentation of all hits for at least 8 
years, even if the order was deemed acceptable.
    <bullet> Retain records of any follow-up screening, even if the 
order was ultimately filled, for at least 8 years.
    Periodic Review, Evaluation, and Improvement of This Guidance: This 
Revised Guidance is addressing biosecurity risks that have emerged in a 
dynamic and rapidly developing technological landscape. It is likely 
that new risks will emerge and that new technological approaches will 
also appear to address biosecurity risks. As such, this Revised 
Guidance encourages the further development of mechanisms to detect 
SOCs and screening strategies for sequences that contribute to 
pathogenicity and toxicity. For instance, strategies may be used by 
malicious Customers to obfuscate SOCs, including engineering pathogenic 
or toxic proteins with completely novel sequences. In such cases, 
synthetic oligonucleotide orders may contain 50 bp windows that are not 
a match to any known sequence. Although there are likely several 
legitimate explanations for orders of sequences with no matches in 
nature (e.g., oligonucleotides to populate microarrays or to store 
digital information), in such cases, it may be possible to use 
predictive bioinformatic algorithms to screen sequences that are not a 
match to any known sequences to determine if they could produce 
proteins that are structurally and functionally identical to SOCs. This 
Revised Guidance encourages Providers to continue to develop these 
methods to best ensure the safety of the synthetic oligonucleotide 
research enterprise. Likewise, while there is not a comprehensive and 
curated database available presently for sequences that may contribute 
to pathogenicity or toxicity by enabling the circumvention of medical 
countermeasures (MCM), such as therapeutics or vaccines, such 
information may become increasingly available in coming years. This 
Revised Guidance encourages the identification of such MCM-evasive 
sequences and may revisit the definition of SOCs in the future, given 
advances in this field.

Dawn O'Connell,
Assistant Secretary for Preparedness and Response.
[FR Doc. 2022-09210 Filed 4-28-22; 8:45 am]
BILLING CODE 4150-37-P


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