HR001121S0038.pdf

Broad Agency Announcement Reimagining Protein Manufacturing (RPM)

BIOLOGICAL TECHNOLOGIES OFFICE

HR001121S0038

August 23, 2021

HR001121S0038, RPM

TABLE OF CONTENTS

PART I: OVERVIEW INFORMATION

PART II: FULL TEXT OF ANNOUNCEMENT

1. Funding Opportunity Description

1.1. Program Overview

1.2. Technical Approach And Structure

1.3. Program Metrics

1.4. General Requirements

2. Award Information

2.1. General Award Information

2.2. Fundamental Research

3. Eligibility Information

3.1. Eligible Applicants

3.2. Organizational Conflicts of Interest

3.3. Cost Sharing/Matching

4. Application and Submission Information

4.1. Address to Request Application Package

4.2. Contact and Form of Application Submission

Disclosure of Information and Compliance with Safeguarding Covered Defense Information Controls

4.3. Funding Restrictions

4.4. Other Submission Information

5. Application Review Information

5.1. Evaluation Criteria

5.2. Review of Proposals

6. Award Administration Information

6.1. Submission Status Notifications

6.2. Administrative and National Policy Requirements

6.3. Reporting

6.4. Electronic Systems

7. Agency Contacts

8. Other Information

9. APPENDIX 1 – Volume II checklist

PART I: OVERVIEW INFORMATION

Federal Agency Name – Defense Advanced Research Projects Agency (DARPA), Biological Technologies Office (BTO)

Funding Opportunity Title – Reimagining Protein Manufacturing (RPM) Announcement Type – Initial Announcement Funding Opportunity Number – HR001121S0038 North American Industry Classification System (NAICS) – 541714 Catalog of Federal Domestic Assistance Numbers (CFDA) – 12.910 Research and

Technology Development Dates o Posting Date: August 23, 2021 o Proposal Abstract Due Date and Time: September 23, 2021, 4:00 PM ET o Full Proposal Due Date and Time: November 16, 2021, 4:00 PM ET o BAA Closing Date: November 16, 2021 o Proposers’ Day: August 26, 2021 https://sam.gov/opp/e552cf52e2654fe6bf9d9c17e965bb3b/view

Concise description of the funding opportunity – The Reimagining Protein Manufacturing (RPM) program aims to ensure timely Department of Defense (DoD) access to critical medical countermeasures (MCMs) by establishing the foundational technologies needed for fully distributed, on-demand manufacturing of protein-based MCMs and associated raw materials. To achieve this goal, RPM will develop technologies to enable immediate synthesis (lead time approximately 24 hours) of bioactive protein MCMs and raw material production enzymes at a yield corresponding to ≥ 500 doses per week. This technology will allow the DoD to rapidly secure access to both therapeutic proteins and enzymes needed for nucleic acid-based MCM synthesis, and reduce reliance on complex supply chains.

Anticipated individual awards – Multiple awards are anticipated.

Types of instruments that may be awarded – Procurement contract, grant, cooperative agreement, or other transaction.

Agency contact

The BAA Coordinator for this effort may be reached at:

RPM@darpa.mil

DARPA/BTO

ATTN: HR001121S0038

675 North Randolph Street Arlington, VA 22203-2114 https://sam.gov/opp/e552cf52e2654fe6bf9d9c17e965bb3b/view mailto:RPM@darpa.mil

PART II: FULL TEXT OF ANNOUNCEMENT

1. Funding Opportunity Description

This publication constitutes a Broad Agency Announcement (BAA) as contemplated in Federal Acquisition Regulation (FAR) 6.102(d)(2) and 35.016 and 2 C.F.R. § 200.203. Any resultant award negotiations will follow all pertinent law and regulation, and any negotiations and/or awards for procurement contracts will use procedures under FAR 15.4, Contract Pricing, as specified in the BAA.

1.1. PROGRAM OVERVIEW

DoD access to critical proteins is currently limited by the slow response times of protein production methods. State-of-the-art (SOA) protein-based MCM production relies on massive centralized infrastructure and complex pipelines that require lengthy cellular engineering, sufficient growth of cells for production, and intensive purification and quality control. Current response times are several months for production alone, with additional time needed for dispersing MCMs to vulnerable populations. Distributed manufacturing paradigms may transform these timelines into those relevant to DoD response, especially in denied, degraded, or disrupted operational environments.

Other DARPA programs have invested in distributed manufacturing of pharmaceuticals and nucleic acids. Here, RPM focuses on protein production (which is generally complex) and bioactivity (which relies on correct folding and post-translational modifications [PTMs]).

Establishing a distributed protein production platform involves two broad types of challenges:

engineering and biochemistry. RPM seeks to overcome difficult upstream biochemistry challenges associated with protein production (i.e., RPM will not develop a fully automated system or device for production).

To significantly advance the DoD’s ability to rapidly manufacture proteins in a fully distributed setting, RPM will address the following biochemistry challenges: (1) achieving relevant quantities of MCM (≥ 500 doses per week); (2) ensuring protein production lead time within ~24 hours of receiving DNA/RNA template (including reagent generation and reaction set-up); and

(3) producing fully bioactive proteins with complex folding and controlled PTMs.

1.2. TECHNICAL APPROACH AND STRUCTURE

1.2.1. Technical Areas

The RPM program will develop technologies to enable high-yield synthesis of protein MCMs with short lead times and correct PTMs. To this end, the RPM program is focused on two technical areas:

Technical Area 1 (TA1): Production Yield and Time. Protein synthesis technologies for near-immediate synthesis of proteins at high yields.

Technical Area 2 (TA2): Post-Translational Modifications. Protein production approaches to add PTMs in a controlled manner to ensure the final product is bioactive and of high quality.

Protein quality characteristics will be evaluated throughout the program to ensure the developed technologies produce a high-quality product. Both technical areas must be developed and integrated concurrently over the duration of the effort. Proposals that fail to address both technical areas will be deemed non-conforming and may be rejected without further review.

TA1: Production Yield and Time.

On-demand synthesis modalities must rapidly achieve relatively high yields to be broadly adapted for distributed protein manufacturing devices. Today’s commercial protein production platforms require months to years for stable cell line creation, followed by weeks to months for protein production. This paradigm is not conducive to on-demand distributed protein production.

TA1 seeks to create new protein production paradigms that can operate with immediately (~24 hours) available reaction components and supplies. Performers may pursue cell-based, cell-free, or other approaches for protein synthesis. However, by the end of the program, the established method must be capable of initiating protein synthesis within approximately 24 hours of obtaining DNA or RNA template (i.e., the time needed to procure template sequence does not count toward the 24-hour lead timeline).

TA1 also seeks to synthesize at least 500 doses per week of critical protein-based MCMs, drugs, or reagents. RPM will produce at least five classes of proteins, including (but not limited to) subunit or conjugate vaccines, monoclonal antibodies, clotting factors, raw material enzymes for nucleic acid production, and other therapeutic proteins. Yield metrics vary depending on the protein – see details under TA1 metrics (Section 1.3).

The novel protein production approach must meet the following specifications:

Production Run Initiation: Protein synthesis methods must be able to begin operation within 24 hours of receiving DNA or RNA sequence template.

Production Run Length: Increased yields can be achieved by operating a single production run for a week or by a series of shorter or continuous runs. Methods that produce initial doses within days are preferred.

Reactor Volume: The chosen synthesis approach must achieve the yield metrics with a reactor volume < 10 L.

Starting Materials:

o Footprint: Given the anticipated downstream, distributed applications of this technology, it is important that the starting material quantity and footprint do not create logistical burden (i.e., should not exceed an approximately 4-ft3 pallet in size).

o Product Specificity: Technologies where the same starting materials can produce all classes of protein are preferred. However, approaches in which varied starting materials are used for different classes of protein are acceptable (e.g., reagent/cell line A is used for monoclonal antibodies while reagent/cell line B is used for subunit vaccines) as long as the rapid lead time is maintained.

o Reproducibility: Starting materials should be defined and well-characterized to ensure a reproducible protein production process.

Throughout the program, performers will utilize a variety of approaches to increase protein synthesis yield while decreasing the time for production. Some of these approaches may include, but are not limited to:

1) Optimizing reaction conditions or reaction vessels.

2) Engineering the source of cell lysate (if cell-free).

3) Modifying the host organism (if cell-based).

4) Engineering the RNA or DNA encoding the protein of interest.

5) Utilizing a stable integration site (landing pad) for cell-line stabilization (if cell-based).

6) Using non-model/non-traditional organisms for protein synthesis.

Proposers must provide the following information in the proposal:

Approaches to increase yield;

Initial lead time to production and a plan to reduce lead time to approximately 24 hours;

Initial production run time and a plan for reduced run time not to exceed 1 week;

Reagents required for protein production (include reagent source information);

Anticipated footprint of protein production starting materials (e.g., cell lysates and excipients; final footprint should not exceed volume of a 4-ft3 pallet);

Details of the reaction vessel (e.g., volume, batch vs. continuous, monitoring capabilities, etc.);

Host used for protein production (if cell-based);

Source of cell lysate (if cell-free; e.g., CHO, E. coli, wheat germ, etc.);

Methods to characterize starting materials to ensure reproducibility;

Approximate reactor volume needed to create appropriate cell lysates (if cell-free; reactor volumes must not exceed 300 L);

Methods for protein purification; and Methods for maintaining and assuring sterility during production.

TA1 metrics (Section 1.3) will increase in difficulty and complexity over the course of the RPM program. To prove technical progress, performers will complete capability demonstrations at roughly 12-month intervals. Performers will send purified material from the production reaction to a government-provided Independent Verification & Validation (IV&V) team for downstream analysis. To ensure reproducibility of the performer approach, the IV&V team will also produce the target protein from performer-supplied starting material. The IV&V team will compare and contrast IV&V- and performer-produced protein to assess transferability of the protein production process.

TA2: Post-Translational Modifications.

Correct protein function typically relies on the presence of PTMs decorating the structure. PTMs pose a challenge to protein production because there are multiple types and variations of modifications, and their addition involves non-template driven cellular processes. Even though PTM importance is known, SOA protein production methods have not been able to add PTMs in a controlled, consistent manner. Therefore, current manufacturing approaches result in MCMs with a distribution of modifications that must be extensively characterized post-production before subsequent product use. The SOA method for protein modification hinders rapid manufacturing – every material production lot must use tightly controlled reaction conditions to ensure similar distribution of modifications lot-to-lot. Often, lot-to-lot similarity is not achieved, resulting in failed production runs, lost time, and increased cost. For RPM, on-demand synthesis modalities must achieve controlled addition of PTMs to ensure simplified downstream purification and analysis, and bioactivity of the resulting protein product.

TA2 seeks to produce proteins with controlled addition of PTMs that improve protein quality characteristics. PTMs of interest include, but are not limited to, N- and O-linked glycosylation, γ-carboxylation, β-hydroxylation, sulfation, and phosphorylation. For N-linked glycosylation specifically, approaches must be capable of adding both simple glycans (e.g., terminal mannose or galactose) and complex glycans (e.g., terminal sialic acid or branched glycans). The PTMs can occur either during (preferred) or after protein synthesis reactions. Technologies developed under this TA should represent an advancement of the SOA with respect to the addition of PTMs to protein MCMs. Given this, it is anticipated that approaches will be capable of reproducibly adding the desired PTMs, with downstream analysis showing low batch-to-batch variance.

Performers must be able to simultaneously achieve the time and yield metrics laid out in TA1 and PTM metrics laid out in TA2.

Throughout the program, performers will utilize a series of approaches to facilitate the addition of PTMs. Some of these approaches may include, but are not limited to:

1) Utilizing endogenous or exogenous biosynthetic machinery to facilitate addition of PTMs.

2) Genome mining to identify new biosynthetic pathways for addition of new/complex modifications.

3) Engineering of host cell lines.

4) Chemical modification.

5) Using engineered non-model/non-traditional organisms.

Proposers must describe the following in the proposal:

Types of PTMs planned;

Approach for adding each type of PTM, including whether endogenous or exogenous machinery will be used;

Rational design approach for enhancing protein characteristics; and

Analytics capabilities for measuring PTMs and assessing characteristics of the modified protein.

TA2 metrics (Section 1.3) will increase in difficulty and complexity over the course of the RPM program. To prove technical progress, performers will complete capability demonstrations at roughly 12-month intervals. Performers will send purified content from the production reaction to an IV&V team for downstream analysis. To ensure the reproducibility of the performer approaches, the IV&V team will also produce the target protein using performer-supplied starting material. The IV&V team will compare and contrast the IV&V and performer-produced protein to assess transferability of the post-translational protein modification process.

Protein Quality Characteristics.

RPM aims to develop technologies to produce therapeutic proteins and enzymes needed for nucleic acid-based MCM synthesis on a rapid timescale and at high yields. If successful, RPM will result in novel protein production technologies not previously deployed. It should be noted that the ultimate use case for the novel protein product technologies is the production of MCMs intended for use in human patients. As such, it is critical that quality proteins are produced throughout the program; RPM will assess protein quality characteristics as part of each capability demonstration. The quality characteristics will be selected in accordance with current release criteria (based on current manufacturing practices) and will include (but are not limited to) potency, purity, target binding/activity, glycosylation profile, composition, bioburden, and endotoxin concentrations (see Section 1.3 for details).

1.2.2. Program Target Proteins

Selected protein targets must include DoD-relevant proteins from each of the five listed classes, including (but not limited to) vaccine subunits, monoclonal antibodies, clotting factors, raw material nucleic acid production enzymes (e.g., T7 RNA polymerase or MutS), and other therapeutic proteins (e.g., G-CSF).

During Phase 1, performers will choose DoD-relevant proteins to produce during the annual capability demonstrations. Performers must select one protein > 5 kDa for year 1 and 2 proteins > 30 kDa for year 2. Each protein must represent a different class (i.e., three classes of proteins will be produced during Phase 1). Demonstrated PTMs must include O-linked glycosylation during year 1 and both N-linked and O-linked glycosylation during year 2 – if different modifications are proposed, a rationale must be provided. The proposal must list the selected proteins.

During Phase 2, performers will produce DARPA-selected proteins. DARPA will select complex proteins that contain N- and O-linked glycosylation and two additional types of PTMs. At least one protein selected for the capability demonstrations during years 3 and 4 will be > 150 kDa. It should be noted that not all therapeutic proteins require glycosylation, but RPM performers will be required to demonstrate the ability to glycosylate proteins.

1.2.3. Program Structure

The RPM program will be accomplished over two sequential Phases of increasing technical complexity (see Figure 1). Phases 1 and 2 are 26 and 24 months long, respectively. Progression to Phase 2 depends on funding availability and performance towards Phase 1-specific goals in capability demonstrations 1 and 2 as described below and outlined in Tables 2, 3, 5, and 6.

Phase 1 (Base, 26 months): Proof of Concept

During the 26-month Phase 1, performers will demonstrate a proof-of-concept technology for immediate synthesis (lead time < 5 days) of proteins from different classes (vaccine subunits, monoclonal antibodies, clotting factors, raw material enzymes, and other therapeutic proteins).

During Phase 1 of the program, performers must choose proteins from at least three different classes to demonstrate the broad applicability of the proposed technology. Performers must select one protein > 5 kDa for year 1 and 2 proteins for year 2 of which 1 is >30kDa. The proteins must be produced at high yields (TA1) and with the appropriate PTMs (TA2).

Goals of Phase 1 (metrics defined in Section 1.3):

Demonstrate protein synthesis on a small scale (> 1 mL) Demonstrate fast protein synthesis Show that high yield of different classes of proteins can be achieved Demonstrate that PTMs of the protein compare to SOA Demonstrate protein quality characteristics are equivalent to SOA by multiple metrics

(e.g., potency, purity, target binding/activity, glycosylation profile, composition, bioburden, and endotoxin concentrations)

Phase 2 (Option, 24 months): Prototype

During the 24-month Phase 2, performers will demonstrate a prototype technology for immediate, high-yield protein synthesis (lead time under 24 hours) of complex proteins from all five classes with PTMs required for bioactivity. At least one protein selected for the capability demonstrations during years 3 and 4 will be > 150 kDa.

Goals of Phase 2 (metrics defined in Section 1.3):

Demonstrate protein synthesis at scale (< 10 L) Demonstrate that immediate protein synthesis can be achieved (lead time ~ 24 hours) Show that high yield production of complex proteins can be achieved Demonstrate correct PTM of the produced protein Demonstrate produced proteins are improved over SOA by measuring protein quality characteristics (e.g., potency, purity, target binding/activity, glycosylation profile, composition, bioburden, and endotoxins concentrations)

Figure 1. Program Structure and General Overview

1.2.4. Capability Demonstrations

During the 50-month program, RPM performers will complete a series of four capability demonstrations at months 11, 22, 38, and 48. During the capability demonstrations and throughout the RPM program, performers will synthesize a variety of DoD-relevant proteins from five classes (vaccine subunits, monoclonal antibodies, clotting factors, raw material enzymes, and other therapeutic proteins). For capability demonstrations 1 and 2 at months 11 and 22, respectively, performers will be challenged to synthesize proteins of their choice. Performers must select one protein > 5 kDa for capability demonstration 1 and two proteins > 30 kDa for capability demonstration 2. All proteins must be chosen from a different class. To demonstrate flexibility of the platform, DARPA will select DoD-relevant proteins for capability demonstrations 3 and 4 at months 38 and 48, respectively.

Specific metrics associated with each Technical Area in the capability demonstrations are discussed below in Section 1.3 and Tables 2, 3, 5, and 6. A government-provided IV&V team will conduct a series of field-recognized analytical techniques to evaluate the purity (e.g., assessment of aggregation, fragments, % dimers, etc.), functionality, efficacy, and composition of the purified proteins produced during each capability demonstration. The characteristics of the produced proteins will be demonstrated in both Phases through in vivo efficacy studies and quality control assays for metrics such as potency, purity, target binding/activity, glycosylation profile, composition, bioburden, and endotoxin concentrations. Chosen MCM targets should be not only DoD-relevant but should also have defined assays for assessing efficacy (in vivo and/or in vitro); it is outside the scope of RPM to develop new efficacy assays. If the product is a raw material production enzyme and not for direct therapeutic use, activity will be demonstrated through downstream production capability or by measuring enzymatic activity. To ensure the reproducibility of the performer approaches, the IV&V team will use the respective performer’s process to produce the proteins selected for the capability demonstrations. The IV&V team will compare and contrast the IV&V and performer-produced proteins to assess transferability of the production process.

1.3. PROGRAM METRICS

To evaluate how effectively a proposed solution will achieve the stated program objectives, the Government hereby promulgates the following program metrics that may serve as the basis for determination of satisfactory progress to warrant continued funding. Although the program metrics are specified below, proposers should note that the Government has identified these goals with the intention of bounding the scope of effort while affording maximum flexibility, creativity, and innovation of proposed solutions to the stated problem. Proposals should cite the quantitative and qualitative success criteria that the effort will achieve by each Phase’s program milestone and intermediary metric measurement.

TA1 Metrics and Objectives

The overall program goals for TA1 are listed in Table 1. Performers will conduct a series of capability demonstrations throughout the program to ensure program goals are being met. TA1 metrics for each capability demonstration are listed in Table 2. Yield metrics will vary by protein class as the protein needed per dose varies dramatically for each MCM (see Table 3). Given the varied quantity per dose of each MCM, some variation in quantity metrics is anticipated depending on the chosen protein. Proposals must include relevant yield metrics for each performer-proposed protein to be produced in Phase 1. Should a performer choose a protein for which the metrics laid out in Table 3 are either inappropriate or vary greatly from those listed, the performer should propose an appropriate metric and rationale.

Table 1. TA1 Overall Program Goals Protein classes Ability to synthesize five classes of protein-based molecules including vaccine subunits, monoclonal antibodies, clotting factors, raw material enzymes, and other therapeutic proteins

Protein size > 150 kDa

Reactor size < 10 L

Purity > 95%

Yield ≥ 500 doses on demand per week

Lead time to production Start producing protein within 24 hours after obtaining DNA or RNA template for production

Table 2. TA1 metrics for each capability demonstration Metric 11 months 22 months 38 months 48 months

Number of proteins

1 performer-selected proteins

2 performer-selected proteins

3 DARPA-

selected proteins

3 DARPA-

selected proteins

Protein size > 5 kDa > 30 kDa > 150 kDa* > 150kDa*

Reactor size > 1 mL > 1 mL < 10 L < 10 L

Purity > 80% > 85% > 90% > 95%

Lead time < 14 days < 5 days 3-5 days ~24 hours

*During capability demonstrations 3 & 4, performers will be required to produce at least one protein > 150 kDa.

Table 3. TA1 yield metrics by program Phase*

Product Type 11 months 22 months 38 months 48 months Antibodies 3 grams (g)/week

(10 doses/week) 15 g/week (50 doses/week)

75 g/week (250 doses/week)

150 g/week (500 doses/week)

Subunit vaccine

2 mg/week (100 doses/week)

11 mg/week (500 doses/week)

55 mg/week (2500 doses/week)

110 mg/week (5000 doses/week)

Production enzymes

0.1 g/week 0.5 g/week 2.5 g/week 5 g/week

Clotting factors

50 mg/week (10 doses/week)

250 mg/week (50 doses/week)

1250 mg/week (250 doses/week)

2500 mg/week (500 doses/week)

Therapeutic proteins (e.g., scFv, nanobodies, GCSF)

Performer-determined metric that aligns with above prescribed metrics

Performer-determined metric that aligns with above prescribed metrics

Performer-determined metric that aligns with above prescribed metrics

Performer-determined metric that aligns with above prescribed metrics

*Proposed doses are approximate and are listed as broadly as possible – proposals should include appropriate quantity (grams of material) for the relevant proposed MCM dose. Some variation in quantity metrics is anticipated depending on the chosen protein.

TA2 Metrics and Objectives

The overall program goals for TA2 are described in Table 4. Performers will be evaluated and monitored over the duration of the program through a series of capability demonstrations to ensure program goals are being met. TA2 metrics for each capability demonstration are listed in Table 5. RPM performers will be required to modify proteins with N-linked and O-linked glycans. Proposals should list two additional types of PTMs that the proposed approach can achieve and the rationale for the selection. Approaches must be capable of reproducibly adding the desired PTMs, and downstream analysis must be performed (at performer site and/or IV&V site) to show low batch-to-batch variance.

It is anticipated that the controlled addition of PTMs will increase certain quality characteristics associated with the resulting protein product. For example, reproducible glycosylation with increased presence of certain glycans may have an effect not only on aggregation but also on the in vivo half-life of a protein MCM. Therefore, as part of Phase 2, RPM performers will need to demonstrate the ability to improve protein characteristics typically associated with PTMs. These characteristics may be drawn from the suggested quality characteristics in Table 6, or different characteristics may be proposed with their appropriate metrics.

Table 4. TA2 Overall Program Goals Post-translational modification

Ability to perform N- and O-linked glycosylation, and 2 other types of PTMs such as γ-carboxylation, β-hydroxylation, sulfation, and phosphorylation

Number of sites Perform PTMs at > 3 sites

Protein quality characteristics (Table 6)

Better than relevant SOA metric

Table 5. TA2 metrics for each capability demonstration Metric 11 months 22 months 38 months 48 months

Glycans O-linked glycans N- and O-linked glycans

N- and O-linked complex glycans

N- and O-linked complex glycans

Other types - - - 2 additional types

Number of sites - > 1 site - > 3 sites

Protein quality characteristics

(Table 6)

Equivalent to relevant SOA metric

Equivalent to relevant SOA metric

Better than relevant SOA metric

Better than relevant SOA metric

Protein Quality Control Metrics and Objectives

To ensure the quality of products, performers must show SOA equivalence to all characteristics listed in Table 6 during the capability demonstrations (or other relevant proposed characteristics if rationale is provided for why Table 6 metrics do not apply). Table 6 includes example metrics for a standard release assay – however, these metrics may deviate depending on the specific product. Therefore, for each proposed protein to be produced in Phase 1, proposals should include a discussion of the quality attributes that are most relevant. Proposals must specify the SOA protein characteristic metric that will be used for SOA comparison and the rationale for the metric selection. Final quality attributes can be discussed in consultation with the IV&V team (arranged by DARPA) and will be ultimately measured by the IV&V team.

Table 6. Protein Quality Characteristics Protein Quality Characteristic Example Quantitative Metric

Composition > 95% target product

Purity < 5% dimers, aggregates, fragments

Target binding/activity 50-150% relative potency

Glycosylation profile < 10% variance between batches

Potency/in vivo efficacy Proposer defined efficacy metric*

Bioburden 0 CFU/mL

Endotoxin < 0.5 EU/mL

*Given the variation in SOA efficacy for different MCMs, proposals should include appropriate efficacy metric

Performers must show SOA equivalence to appropriate metrics during capability demonstrations.

During capability demonstrations 3 and 4, performers must select at least one characteristic upon which to improve. While the goal of RPM is to improve the quality characteristics during Phase 2 through controlled PTMs, other metrics based on TA1 technologies could also show significant improvements. These include overall downstream process yield or percent yield per input of starting material; therefore, these relevant measures of success should be discussed in the proposal.

Phase 1 Metrics – Proof of Concept, Months 1-26 Phase 1 will include two capability demonstrations at months 11 and 22 of increasing complexity with required metrics as listed in Tables 2, 3, 5, and 6.

Phase 2 Metrics –Prototype, Months 27-50 Phase 2 will include two capability demonstrations at months 38 and 48 of increasing complexity with required metrics established above in Tables 2, 3, 5, and 6.

1.4. GENERAL REQUIREMENTS

1.4.1. Proposing Teams

It is expected that proposals will involve teams that have the expertise needed to achieve the goals of both TA1 and TA2. Specific content, communications, networking, and team formation are the sole responsibility of the proposer teams. Proposer teams must submit a single, integrated proposal led by a Principal Investigator (PI), under a single prime contractor that addresses all program Phases, as applicable.

DARPA will hold a Proposers Day (see Section 8, Other Information) to facilitate the formation of proposer teams and enable sharing of information among interested proposers through the DARPA Opportunities Page and the Proposers Day registration website.

1.4.2. IV&V

The Government is not soliciting IV&V proposals under HR001121S0038. To avoid potential conflicts of interest, performers for HR001121S0038 will not be allowed to compete for the IV&V contract. Throughout the program, the performers will work with a Government-furnished IV&V team. This partnership will be facilitated by the Government. The IV&V team will consist of subject matter experts from the Government, Federally Funded Research and Development Centers (FFRDCs), academia and/or other relevant domains capable of meeting the desired IV&V goals of the program as established by DARPA.

1.4.3. Transition Strategy

RPM aims to establish the foundational technologies needed for fully distributed, on-demand manufacturing of protein-based medical countermeasures (MCM), critical protein-based reagents, and associated raw materials. While no formal transition plan is required for the proposal, it should be noted that the technologies developed during RPM may lay the groundwork for follow-on development of a distributed platform for protein manufacturing.

1.4.4. Deliverables

All products – material and otherwise – to be provided to the Government as outcomes from conducted research should be defined in the proposal. Performers need to allot time and budget to fulfill obligations for travel to review meetings and the transmission of report documentation.

End of Phase reports: Three months prior to the end of Phase 1 (i.e., at Month 23) and one month prior to the end of Phase 2 (i.e., at Month 49), performers must draft and present to DARPA a written report of all research activities and metrics satisfied. This report will contain all relevant supporting data.

Monthly financial reports: Performers are required to provide financial status updates. The prime Performer shall include information for itself and all subawardees/subcontractors. These reports shall be in the form of an editable Microsoft (MS) ExcelTM file and shall provide financial data including, but not limited to:

Program spend plan by Phase and task Incurred program expenditures to date by Phase and task Invoiced program expenditures to date by Phase and task

Monthly technical progress reports: Performers are required to provide monthly research updates in the form of a standardized slide presentation given to DARPA and discussed with the program management team via teleconference. Length and level of detail is at the discretion of the Program Manager.

Quarterly technical progress reports: Performers are required to provide quarterly research updates in the form of a written report describing all research activities and metrics achieved during the quarter. Length and level of detail are at the discretion of the Program Manager.

Mid-Phase and End of Phase reviews: Leadership from each performer team (with additional key personnel at the discretion of the PI) will be required to present research progress in person at program review meetings. The purpose of these reviews is to ensure adequate engagement with the DARPA team to discuss details that might otherwise fall outside the scope of a routine technical brief; progress towards milestones and scientific goals; and any ongoing technical or programmatic challenges that must be overcome to achieve the overarching program goals.

Final Program Report: When the final funding Phase closes out, performer teams must provide a final report summarizing all research activities, outcomes, and molecular mechanisms discovered during the program; publications, research presentations, patent applications that result from the research pursued; and any additional deliverables requested by the contracting agent for this program.

2. Award Information

2.1. GENERAL AWARD INFORMATION

Multiple awards are possible. The amount of resources made available under this BAA will depend on the quality of the proposals received and the availability of funds.

The Government reserves the right to select for negotiation all, some, one, or none of the proposals received in response to this solicitation and to make awards without discussions with proposers. The Government also reserves the right to conduct discussions if it is later determined to be necessary. If warranted, portions of resulting awards may be segregated into pre-priced options. Additionally, DARPA reserves the right to accept proposals in their entirety or to select only portions of proposals for award. In the event that DARPA desires to award only portions of a proposal, negotiations may be opened with that proposer. The Government reserves the right to fund proposals in Phases with options for continued work, as applicable.

The Government reserves the right to request any additional, necessary documentation once it makes the award instrument determination. Such additional information may include but is not limited to Representations and Certifications (see Section VI.B.2., “Representations and Certifications”). The Government reserves the right to remove proposers from award consideration should the parties fail to reach an agreement on award terms, conditions, and/or cost/price within a reasonable time, and the proposer fails to timely provide requested additional information. Proposals identified for negotiation may result in a procurement contract, cooperative agreement, or other transaction, depending upon the nature of the work proposed, the required degree of interaction between parties, whether or not the research is classified as Fundamental Research, and other factors.

Proposers looking for innovative, commercial-like contractual arrangements are encouraged to consider requesting Other Transactions. To understand the flexibility and options associated with Other Transactions, consult http://www.darpa.mil/work-with-us/contract-management#OtherTransactions.

In accordance with 10 U.S.C. § 2371b(f), the Government may award a follow-on production contract or Other Transaction (OT) for any OT awarded under this solicitation if: (1) that participant in the OT, or a recognized successor in interest to the OT, successfully completed the entire prototype project provided for in the OT, as modified; and (2) the OT provides for the award of a follow-on production contract or OT to the participant, or a recognized successor in interest to the OT.

http://www.darpa.mil/work-with-us/contract-management#OtherTransactions http://www.darpa.mil/work-with-us/contract-management#OtherTransactions

In all cases, the Government contracting officer shall have sole discretion to select award instrument type, regardless of instrument type proposed, and to negotiate all instrument terms and conditions with selectees. DARPA will apply publication or other restrictions, as necessary, if it determines that the research resulting from the proposed effort will present a high likelihood of disclosing performance characteristics of military systems or manufacturing technologies that are unique and critical to defense. Any award resulting from such a determination will include a requirement for DARPA permission before publishing any information or results on the program. For more information on publication restrictions, see the section below on Fundamental Research.

2.2. FUNDAMENTAL RESEARCH

It is DoD policy that the publication of products of fundamental research will remain unrestricted to the maximum extent possible. National Security Decision Directive (NSDD) 189 defines fundamental research as follows:

‘Fundamental research’ means basic and applied research in science and engineering, the results of which ordinarily are published and shared broadly within the scientific community, as distinguished from proprietary research and from industrial development, design, production, and product utilization, the results of which ordinarily are restricted for proprietary or national security reasons.

As of the date of publication of this solicitation, the Government expects that program goals as described herein may be met by proposers intending to perform fundamental research and does not anticipate applying publication restrictions of any kind to individual awards for fundamental research that may result from this solicitation. Notwithstanding this statement of expectation, the Government is not prohibited from considering and selecting research proposals that, while perhaps not qualifying as fundamental research under the foregoing definition, still meet the solicitation criteria for submissions. If proposals are selected for award that offer other than a fundamental research solution, the Government will either work with the proposer to modify the proposed statement of work to bring the research back into line with fundamental research or else the proposer will agree to restrictions in order to receive an award.

Proposers should indicate in their proposal whether they believe the scope of the research included in their proposal is fundamental or not. While proposers should clearly explain the intended results of their research, the Government shall have sole discretion to determine whether the proposed research shall be considered fundamental and to select the award instrument type. Appropriate language will be included in resultant awards for non-fundamental research to prescribe publication requirements and other restrictions, as appropriate. This language can be found at http://www.darpa.mil/work-with-us/additional-baa.

For certain research projects, it may be possible that although the research to be performed by a potential awardee is non-fundamental research, its proposed subawardee’s effort may be fundamental research. It is also possible that the research performed by a potential awardee is fundamental research while its proposed subawardee’s effort may be non-fundamental research.

In all cases, it is the potential awardee’s responsibility to explain in its proposal which proposed http://www.darpa.mil/work-with-us/additional-baa efforts are fundamental research and why the proposed efforts should be considered fundamental research.

3. Eligibility Information

3.1. ELIGIBLE APPLICANTS

All responsible sources capable of satisfying the Government’s needs may submit a proposal that shall be considered by DARPA.

3.1.1. Federally Funded Research and Development Centers (FFRDCs) and Government Entities

FFRDCs FFRDCs are subject to applicable direct competition limitations and cannot propose to this solicitation in any capacity unless they meet the following conditions. (1) FFRDCs must clearly demonstrate that the proposed work is not otherwise available from the private sector. (2) FFRDCs must provide a letter, on official letterhead from their sponsoring organization, that (a) cites the specific authority establishing their eligibility to propose to Government solicitations and compete with industry, and (b) certifies the FFRDC’s compliance with the associated FFRDC sponsor agreement’s terms and conditions. These conditions are a requirement for FFRDCs proposing to be awardees or subawardees.

Government Entities Government Entities (e.g., Government/National laboratories, military educational institutions, etc.) are subject to applicable direct competition limitations. Government Entities must clearly demonstrate that the work is not otherwise available from the private sector and provide written documentation citing the specific statutory authority and contractual authority, if relevant, establishing their ability to propose to Government solicitations and compete with industry. This information is required for Government Entities proposing to be awardees or subawardees.

Authority and Eligibility At the present time, DARPA does not consider 15 U.S.C. § 3710a to be sufficient legal authority to show eligibility. While 10 U.S.C.§ 2539b may be the appropriate statutory starting point for some entities, specific supporting regulatory guidance, together with evidence of agency approval, will still be required to fully establish eligibility. DARPA will consider FFRDC and Government Entity eligibility submissions on a case-by-case basis; however, the burden to prove eligibility for all team members rests solely with the proposer.

3.1.2. Non-U.S. Organizations

Non-U.S. organizations and/or individuals may participate to the extent that such participants comply with any necessary non-disclosure agreements, security regulations, export control laws, and other governing statutes applicable under the circumstances.

3.2. ORGANIZATIONAL CONFLICTS OF INTEREST

FAR 9.5 Requirements In accordance with FAR 9.5, proposers are required to identify and disclose all facts relevant to potential OCIs involving the proposer’s organization and any proposed team member (subawardee, consultant). Under this Section, the proposer is responsible for providing this disclosure with each proposal submitted to the solicitation. The disclosure must include the proposer’s, and as applicable, proposed team member’s OCI mitigation plan. The OCI mitigation plan must include a description of the actions the proposer has taken, or intends to take, to prevent the existence of conflicting roles that might bias the proposer’s judgment and to prevent the proposer from having unfair competitive advantage. The OCI mitigation plan will specifically discuss the disclosed OCI in the context of each of the OCI limitations outlined in FAR 9.505-1 through FAR 9.505-4.

Agency Supplemental OCI Policy In addition, DARPA has a supplemental OCI policy that prohibits contractors/performers from concurrently providing Scientific Engineering Technical Assistance (SETA), Advisory and Assistance Services (A&AS) or similar support services and being a technical performer.

Therefore, as part of the FAR 9.5 disclosure requirement above, a proposer must affirm whether the proposer or any proposed team member (subawardee, consultant) is providing SETA, A&AS, or similar support to any DARPA office(s) under: (a) a current award or subaward; or (b) a past award or subaward that ended within one calendar year prior to the proposal’s submission date.

If SETA, A&AS, or similar support is being or was provided to any DARPA office(s), the proposal must include:

The name of the DARPA office receiving the support;

The prime contract number;

Identification of proposed team member (subawardee, consultant) providing the support; and An OCI mitigation plan in accordance with FAR 9.5.

Government Procedures In accordance with FAR 9.503, 9.504 and 9.506, the Government will evaluate OCI mitigation plans to avoid, neutralize or mitigate potential OCI issues before award and to determine whether it is in the Government’s interest to grant a waiver. The Government will only evaluate OCI mitigation plans for proposals that are determined selectable under the solicitation evaluation criteria and funding availability.

The Government may require proposers to provide additional information to assist the Government in evaluating the proposer’s OCI mitigation plan.

If the Government determines that a proposer failed to fully disclose an OCI; or failed to provide the affirmation of DARPA support as described above; or failed to reasonably provide additional information requested by the Government to assist in evaluating the proposer’s OCI mitigation plan, the Government may reject the proposal and withdraw it from consideration for award.

3.3. COST SHARING/MATCHING

Cost sharing is not required; however, it will be carefully considered where there is an applicable statutory condition relating to the selected funding instrument. Cost sharing is encouraged where there is a reasonable probability of a potential commercial application related to the proposed research and development effort.

4. Application and Submission Information

4.1. ADDRESS TO REQUEST APPLICATION PACKAGE

This announcement, any attachments, and any references to external websites herein constitute the total solicitation. If proposers cannot access the referenced material posted in the announcement found at http://www.darpa.mil, contact the administrative contact listed herein.

4.2. CONTACT AND FORM OF APPLICATION SUBMISSION

All submissions, including abstracts and proposals, must be written in English with type no smaller than 12-point font. Smaller font may be used for figures, tables, and charts. The page limitation includes all figures, tables, and charts. All pages shall be formatted for printing on 8- 1/2 by 11-inch paper. Margins must be 1-inch on all sides. Copies of all documents submitted must be clearly labeled with the DARPA BAA number, proposer organization, and proposal title/proposal short title.

4.2.1. Proposal Abstract Format

Proposers are strongly encouraged to submit an abstract in advance of a proposal to minimize effort and reduce the potential expense of preparing an out-of-scope proposal. DARPA will respond to abstracts providing feedback and indicating whether, after preliminary review, there is interest within BTO for the proposed work. DARPA will attempt to reply within 15 calendar days of receipt. Proposals may be submitted irrespective of comments or feedback received in response to the abstract. Proposals are reviewed without regard to feedback given as a result of abstract review. The time and date for submission of proposal abstracts are specified in Part I above.

The abstract is a concise version of the proposal comprising a maximum of eight (8) pages, including all figures, tables, and charts. All submissions must be written in English with type no smaller than 12-point font. Smaller font may be used for figures, tables, and charts. All pages shall be formatted for printing on 8-1/2 by 11-inch paper. Margins must be 1-inch on all sides. Copies of all documents submitted must be clearly labeled with the DARPA BAA number, proposer organization, and proposal abstract title.

The page limit does NOT include:

Official transmittal letter (optional);

Cover sheet;

Executive summary slide;

Resumes; and Bibliography (optional).

Abstracts must include the following components:

A. Cover Sheet (does not count towards page limit): Include the administrative and technical points of contact (name, address, phone, fax, e-mail, lead organization). Also http://www.darpa.mil/ include the BAA number, title of the proposed project, primary subcontractors, estimated cost, duration of the project, and the label “ABSTRACT.”

B. Goals and Impact: Clearly describe what is being proposed and what difference it will make (qualitatively and quantitatively), including brief answers to the following questions:

1. What is the proposed work attempting to accomplish or do?

2. How is it done today? And what are the limitations?

3. What is innovative in your approach, and how does it compare to the current

SOA?

4. What are the key technical challenges in your approach, and how do you plan to overcome these?

5. How much will it cost, and how long will it take?

C. Executive Summary Slides: The slide template is provided as Attachment 1 to the BAA posted at https://SAM.gov. Use of this template is required.

D. Technical Plan: Outline and address all technical areas and challenges inherent in the approach and possible solutions for overcoming potential problems. This section should provide specific objectives, metrics, and milestones at intermediate stages of the project to demonstrate a plan for accomplishment of the program goals.