"Novel Human Oral and Craniofacial Genes"

Request for Proposal No.: NIH-NHLBI-DR-98-20

Issue Date: March 19, 1998

Issued By: Patricia A. Smith
Contracting Officer
Contracts Operations Branch
II Rockledge Centre
6701 Rockledge Drive, MSC 7902
Bethesda, Maryland 20892-7902

Purchase Authority: Public Law 95-83, as amended

Small Business Set-Aside: No, SIC Code 8733

Proposal Due Date: June 26, 1998, 4:30 P.M. (Eastern Time)

Ladies and Gentlemen:

The National Heart, Lung, and Blood Institute (NHLBI) is soliciting proposals on behalf of the National Institute of Dental Research (NIDR) for services to characterize novel human genes expressed preferentially in embryonic rhombomeres and first branchial arch, oral cavity (including teeth, salivary glands and tongue), and maxilla. This Streamlined Technical Request For Proposal (RFP) consists of this combined solicitation form and cover letter (PART A), and three additional components, as follows:

  1. Work Statement;
  2. Reports/Deliverables;
  3. Evaluation Factors for Award, including Technical Evaluation Criteria;

These components contain the technical information required for the submission of a proposal for this acquisition. In addition, there are two other sections in this specific RFP. The section entitled "Specific RFP Instructions and Provisions" contains, for example, the proposal intent response form and the address for delivery of your proposal. The section entitled "Applicable RFP References" lists those items in the STREAMLINED RFP REFERENCES directory that apply to this RFP, including forms for submission of the proposal.

Although these documents contain sufficient information for you or your organization to submit a proposal, if you intend to submit a proposal in response to this RFP, IT IS ESSENTIAL THAT YOU IMMEDIATELY NOTIFY PATRICIA A. SMITH, CONTRACTING OFFICER, AT THE FOLLOWING INTERNET ADDRESS:



The original and twenty-five (25) copies of your technical proposal and the original and six (6) copies of your business proposal must be received by the Contracting Office no later than June 26, 1998, at 4:30 p.m. local time at the address listed in the item entitled "Packaging and Delivery of Proposals". Also, please complete the form entitled "Proposal Intent Response Sheet" and send it to the address indicated therein on or before May 4, 1998. This will allow us to expedite preparations for the peer review of proposals. Finally, your proposal must be organized and submitted in accordance with the "Technical Proposal Table of Contents." All three of these items are found under the "Specific RFP Instructions and Provisions" portion of this RFP, which follows the technical evaluation criteria section.

You are reminded that the "Technical Proposal Cover Sheet" must be completed in full detail and used as the cover sheet for each copy of your technical proposal. (This form is contained in this NIH WEB site under the FORMS, FORMATS, AND ATTACHMENTS file found in STREAMLINED RFP REFERENCES.) This information will be used to ensure that there will be no conflict of interest when selecting review committee members.

Offers will be valid for 120 days unless a different period is specified by the offeror on the form entitled, "Proposal Summary and Data Record, NIH 2043" also located at the site for FORMS, FORMATS, AND ATTACHMENTS.


If you have any additional questions regarding this RFP, please contact Mrs. Smith through the Internet using the electronic mail address listed above or phone (301) 435-0345, fax (301) 480-3430. COLLECT CALLS WILL NOT BE ACCEPTED.



After reviewing this Request For Proposal, click here (or simply select "BACK" twice to return to the original site for the NIH Request For Proposals Directory.) In this directory, entitled "NIH Request For Proposals Directory", following the list of NIH Institutes by name, is the section entitled "STREAMLINED RFP REFERENCES". Select (click on) each section you wish to review:

"STANDARD RFP INSTRUCTIONS AND PROVISIONS" for proposal preparation instructions and other standard provisions,
"OPTIONAL RFP INSTRUCTIONS AND PROVISIONS" for the special provisions identified in this specific RFP,
"FORM, FORMATS, AND ATTACHMENTS" to download the forms listed in this specific RFP that you will need to submit a proposal,
"REPRESENTATIONS AND CERTIFICATIONS" to download and complete the representations and certifications that must be submitted with your proposal, and
"SAMPLE CONTRACT FORMAT-GENERAL" to view some of the clauses that are typical for inclusion in a Research and Development type contract issued by NIH.

Patricia A. Smith
Contracting Officer


    1. Project Description

      Recent advances in DNA sequencing technology now enable researchers to discover previously unknown genes by automated sequencing of randomly selected clones from complementary DNA (cDNA) libraries prepared from specific tissues (1-4). Genes expressed specifically in a particular tissue can be enriched by subtraction of cDNA sequences expressed in other tissues (5-11), or they can be identified by comparative screening methods that include SAGE (serial analysis of gene expression), cDNA microarray chip screening (12-15), and other approaches.

      A unique opportunity exists for the National Institute of Dental Research to accelerate current research on the genetics and biology of human craniofacial development and disorders (e.g. see refs. 16-20) by generating and applying these powerful new tools in an NIDR genome project to discover novel human craniofacial genes. Several current needs addressed by such a project will include: a) the need for new DNA reagents by molecular and developmental biologists to determine which genes are essential in human craniofacial development; b) the need for sets of candidate genes for much more rapid gene mapping in linkage studies of human craniofacial defects; such genes can be identified by projects to discover novel genes that are active in craniofacial development; and c) a general need for a validated, centralized source of human craniofacial genes, sequence data, and probes.

      Potential fruitful approaches to reach these goals have been explored by Intramural researchers in the Craniofacial Developmental Biology and Regeneration Branch, who have successfully demonstrated the practicality of a broad search for previously unknown tooth and craniofacial genes in initial studies using rodent systems (21-24). The approaches involved generating tissue-specific cDNA libraries, random DNA sequencing, characterization of novel craniofacial genes, antibody production against selected clones to characterize protein expression and to probe function, candidate gene mapping, and linkage to a human genetic defect. This proposed contract will extend these approaches to human craniofacial genes, combined with the establishment of a national resource that would provide direct access to a sequence database, human craniofacial cDNA clones, and both published and unpublished data for free use by members of the craniofacial-oral-dental research community.

      The purpose of this contract is to discover and to begin to characterize novel human genes expressed preferentially in embryonic rhombomeres and first branchial arch, oral cavity (including teeth, salivary glands and tongue), and maxilla. It will provide a national resource of novel data and human DNA clones relevant to oral and craniofacial genetics and development.

      The characterization of genes involved in human craniofacial embryonic development should accelerate research into a variety of human syndromes and disorders affecting the craniofacial complex. Examples include inherited and acquired congenital disorders involving defects in critical genes and/or in genes-environmental interactions, tissue repair processes that use mechanisms which often overlap embryonic remodeling mechanisms, and inherited and acquired oral cancers expressing embryonic markers (e.g., Gorlin syndrome).

    2. Background and History

      Congenital defects involving the craniofacial complex afflict 5% of all infants born in the United States. The human and economic costs are enormous --- the lifetime costs for just one year's cohort of children born with cleft lip or palate in the U.S. is estimated to be nearly $1 billion. Determining the genetic basis for these inherited and acquired disorders should lead to improved diagnostics and genetic counseling, as well as novel approaches to potential therapy and prevention based on the discovery of new genes and their regulation (16-20). These advances are essential to reduce this formidable medical, social, and economic problem.

      Although approaches conceptually similar to those in this contract will eventually be applied to tens of thousands of other novel genes from other tissues identified in the Human Genome Project, craniofacial sites of gene action are unusually visible, and they represent by far the most common sites of congenital defects. Even so, disorders of craniofacial tissues are not primary therapeutic targets of pharmaceutical and biotechnology companies, and it is unlikely that any company would generate the proposed libraries or data. Nevertheless, identifying and characterizing individual craniofacial genes important in development should provide valuable insights into pathophysiology, as well as providing targets for diagnosis and therapy. Opportunities for potential therapeutic approaches include in utero preventive drug therapy, potential gene therapy in mothers identified as having a genetic predisposition to a particular craniofacial congenital defect, and novel biologically-based therapeutics that include biomimetics, biomaterials, and tissue engineering.

      Many craniofacial anomalies and increasing numbers of cancers are caused by a mutation or a defect in the function(s) of one or more genes (17-20). An increasing number of mutations have been identified for craniofacial syndromes, and a number of scientific opportunities have been identified to pursue studies designed to understand the molecular mechanisms required for sequential craniofacial, oral, and dental development at the molecular level. Innovative approaches appear warranted that involve the identification and cataloging of regulatory and structural genes involved in various stages of human craniofacial development as a logical first step to identify the causes of anomalies. The identification of the genes whose expression is highly tissue- and stage-specific during development of the craniofacial complex is important, since these gene products are likely to play key roles in the formation of its tissues.

      Discovery of many novel proteins and genes, as well as further antibody and functional characterization, is now possible using molecular cloning, random DNA sequencing of appropriately high-quality "libraries" of gene products, and creative screening approaches for genes expressed in a specific tissue and at particular developmental stages (1-15). In a preceding NIDR program to identify novel genes expressing in developing mouse and rat tooth and craniofacial tissues, database analyses indicated that roughly 35-50% of randomly sequenced clones have varying degrees of homology to known genes, but that the remaining 50-65% were never described previously and are therefore unique (e.g. see ref 21). Not surprisingly, a number of the previously identified genes in a tooth cDNA library were found to encode extracellular matrix proteins including such genes as amelogenin, collagen, and tenascin, but novel genes such as ameloblastin (22) and Krox 26 (24) have also been identified. This approach should lead to the discovery of many new genes.

      Defining key genes and their functions will be useful not only for the identification of susceptible developmental steps and causes of disease, but also potentially in the future for screening and generating animal models to test novel in utero therapeutic approaches (e.g., dietary alterations to bolster defective gene function). This project will benefit the public by providing the potential for new approaches to prevention and possible gene therapy, e.g. dietary and drug strategies for preventing craniofacial anomalies, and it may also eventually provide markers for oral cancers for diagnostic applications, as well as novel biomimetics and other biologicals.

    3. Statement of Work

      Independently, and not as an agent of the Government, the contractor shall furnish the necessary services, qualified personnel, equipment, facilities, and materials, not otherwise provided by the Government, to characterize novel human genes expressed preferentially in embryonic rhombomeres and first branchial arch, oral cavity (including teeth, salivary glands and tongue), and maxilla.

      Specifically, the Contractor shall:

      1. Produce a set of accurately staged tissue-specific and developmental stage-specific human craniofacial cDNA libraries, with documentation concerning the tissue (source and quality), embryonic stage, and quality of the library.

        The contractor shall strive to generate maximal numbers of full-length clones in representative libraries. Sources of these libraries shall include embryonic rhombomeres (i.e. 1-8) and first branchial arch, oral cavity (teeth, salivary glands and tongue), and maxilla. These libraries shall include standard, normalized, subtraction, and possibly SAGE libraries. The anticipated number of cDNA (and possibly SAGE) libraries shall be at least one dozen.

        Tentative tissues and stages shall be: Stage A: combined rhombomeres (i.e. 1-3, 3-5, 5-8) and forming first branchial arch at the time of the initiation of early neural crest cell migration [e.g. 3-5 weeks of gestation]; Stage B: early mandible, tongue, and maxilla [e.g. 6-7 weeks]; although technically difficult, obtaining libraries from early stages such as A and B shall be given particularly high priority; Stage C: maxilla and developing teeth at the time of palate fusion [e.g. 6-8 weeks]; and Stage D: later mandible, maxilla, teeth, and salivary glands [> 22 to < 3 months]. (Note To Offerors: It is anticipated that tissues dissected for Stages A, B, and C will not be combined within each stage, and that tissues dissected for Stage D will also generally be used for separate libraries.)

        Standard and normalized cDNA libraries rich in full-length clones shall be prepared from tissues at these stages, with at least one standard cDNA library prepared for each stage. Subtraction libraries shall also be constructed, e.g. stage A tissues versus stage C or D. The contractor shall provide evidence for the presence of cDNA that includes the 5' coding end of a large mRNA species, e.g. for fibronectin or laminin, as well as the for presence of less-abundant cDNA species, such as for growth factors and their cognate receptors. Quality control and characterization of libraries shall also include determining for each the average size of clones, titers of an amplified library, and partial 5' EST sequences of at least one hundred randomly selected clones from each. In addition, subtraction libraries should include an analysis of subtraction efficiency. Other libraries may include SAGE libraries, especially for early stages, as well as representational libraries (the latter may be more appropriate for the separate later-stage tissues).

      2. The libraries and RNA corresponding to the same stages or specific tissue used for these libraries shall be provided to the NIDR Project Officers. In addition, at least four developmental stage-specific or tissue-specific standard cDNA libraries shall be provided to the I.M.A.G.E. Consortium (ref. 3) for high-throughput sequencing, including at least one library from a very early stage.

      3. Apply screening approaches to compare the genes expressed in the different human craniofacial embryonic stages or tissues, in order to generate information that researchers in the field can use to obtain and characterize cDNA clones that are developmental stage-specific and tissue-specific.

        Gene expression screening methodologies such as high-density colony hybridization, SAGE, dot-blotting, or cDNA microarray chip approaches shall be used as appropriate to identify genes expressed preferentially in specific craniofacial tissues and in stage-specific patterns (5-13). Clones showing interesting patterns of regulation shall be sequenced. (Note To Offerors: Input is encouraged by the offeror for the most useful comparisons, e.g. an initial comparison of gene expression levels or subtracting between specific developmental stages between tissues such as maxilla versus liver, using approaches expected to be practical for small amounts of tissue, efficient, and cost-effective.)

      4. Identify and isolate stage-specific (particularly from early stages) or unusually highly expressed tissue-specific clones.

        The specific approaches used shall be chosen by the contractor with concurrence of the Project Officers. The individual clones shall be subjected to EST automated DNA sequencing and database searches for homologies and functional motifs. (Note To Offerors: A rough estimate of expected numbers of EST sequences is 1000, besides the number needed for preliminary characterization of libraries).

      5. Information generated by this contract, including DNA sequences and summaries of database searches, shall be provided to the Project Officers in a form ready for deposit in an NIDR World Wide Web page in order to make the data freely available.

        Data on expression levels of specific clones shall be presented in tabular and pictorial form (e.g., see the format used by the NCI Cancer Genome Anatomy Project site in reference 25). Materials shall be made available by the donation of pertinent cDNA clones and libraries to the American Type Culture Collection for distribution to all qualified investigators.

      (Note To Offerors: Offerors are encouraged to provide intellectual input and to propose any approaches that will result in efficient and optimal identification of novel differentially-expressed craniofacial genes, especially from early developmental stages.)

  1. Adams, M. D., J. M. Kelley, J. D. Gocayne, M. Dubnick, M. H. Polymeropoulos, H. Xiao, C. R. Merril, A. Wu, B. Olde, R. F. Moreno, and J. C. Venter. 1991. Complementary DNA sequencing: expressed sequence tags and human genome project. Science 252:1651-1656.
  2. Adams M. D., Kerlavage, A. R., Fleischmann, R. D., Fuldner, R. A., Bult, C. J., Lee, N. H. Kirkness, E. F., Weinstock, K. G., Gocayne, J. D., White, O., et al. (1995). Initial assessment of human gene diversity and expression patterns based upon 83 million nucleotides of cDNA sequence. Nature 377 (Suppl):3-174.
  3. Lennon, G., Auffray, C., Polymeropoulos, M., and Soares, M. B. (1996) The I.M.A.G.E. Consortium: an integrated molecular analysis of genomes and their expression. Genomics 33:151-152.
  4. Gerhold, D., and Caskey, C.T. (1996). It's the genes! EST access to human genome content. BioEssays 18: 973-981.
  5. Hoog, C. 1991. Isolation of a large number of novel mammalian genes by a differential cDNA library screening strategy. Nucleic Acids Res. 19:6123-6127.
  6. Brady, G. and N. N. Iscove. 1993. Construction of cDNA libraries from single cells. Methods Enzymol. 225:611-23.
  7. Rothstein, J. L., D. Johnson, J. Jessee, J. Skowronski, J. A. DeLoia, D. Solter, and B. B. Knowles. 1993. Construction of primary and subtracted cDNA libraries from early embryos. Methods Enzymol. 225:587-610.
  8. Soares, M. B., Bonaldo, M. F., Jelene, P., Su, L., Lawton, L., and Efstratiadis, A. (1994) Construction and characterization of a normalized cDNA library. Proc. Natl. Acad. Sci. U.S.A. 91:9228-9232.
  9. Sasaki, Y., Ayusawa, D., and Oishi, M. (1994) Construction of a normalized cDNA library by introduction of a semi-solid mRNA-cDNA hybridization system. Nucleic Acids Res. 22:987-992.
  10. Braun, B. S., Frieden, R., Lessnick, S. L., May, W. A., and Denny, C. T. (1995) Identification of target genes for the Ewing's sarcoma EWS/FLI fusion protein by representational difference analysis. Mol. Cell. Biol. 15:4623-4630.
  11. Bonaldo, M.F., Lennon, G., and Soares, M.B. (1996). Normalization and subtraction: two approaches to facilitate gene discovery. Genome Res. 6:791-806.
  12. Velculescu, V.E., Zhang, L., Vogelstein, B., and Kinzler, K.W. (1995). Serial analysis of gene expression. Science 270:484-487.
  13. Zhang, L., Zhou, W., Velculescu, V.E., Kern, S.E., Hruban, R.H., Hamilton, S.R., Vogelstein, B., and Kinzler, K.W. (1997). Gene expression profiles in normal and cancer cells. Science 276:1268-1272.
  14. Schena, M., Shalon, D., Heller, R., Chai, A., Brown, P.O., and Davis, R.W. (1996). Parallel human genome analysis: microarray-based expression monitoring of 1000 genes. Proc. Natl. Acad. Sci. U.S.A. 93:10614-10619.
  15. DeRisi, J., Penland, L., Brown, P.O., Bittner, M.L., Meltzer, P.S., Ray, M., Chen, Y., Su, Y.A., and Trent, J.M. (1996). Use of a cDNA microarray to analyse gene expression patterns in human cancer. Nat. Genet.14:457-460.
  16. Waitzman, N.J., Scheffler, R.M., and Romano, P.S. (1996). The Cost of Birth Defects. Estimates of the Value of Prevention. University Press of America, Inc., Lanham, MD.
  17. Slavkin, H.C. (1996). Meeting the challenges of craniofacial-oral-dental birth defects. J. Am. Dent. Assoc. 127:681-682.
  18. Winter, R.M. (1996). Analyzing human developmental abnormalities. BioEssays 18: 965-971.
  19. Slavkin, H.C. (1995). Molecular biology experimental strategies for craniofacial-oral-dental dysmorphology. Connect. Tissue Res. 32:233-239.
  20. Lewanda, A.F., and Jabs, E.W. (1994). Genetics of craniofacial disorders. Curr. Opin. Pediatr. 6:690-697.
  21. Matsuki, Y., Nakashima, M., Amizuka, N., Warshawsky, H., Goltzman, D., Yamada, K.M., and Yamada, Y. (1995). A compilation of partial sequences of randomly selected cDNA clones from the rat incisor. J. Dent. Res. 74:307-312.
  22. Krebsbach, P.H., Lee, S.K., Matsuki, Y., Kozak, C.A., Yamada, K.M., and Yamada, Y. (1996). Full-length sequence, localization, and chromosomal mapping of ameloblastin. A novel tooth-specific gene. J. Biol. Chem. 271:4431-4435.
  23. Lee, S.K., Krebsbach, P.H., Matsuki, Y., Nanci, A., Yamada, K.M., and Yamada, Y. (1996). Ameloblastin expression in rat incisors and human tooth germs. Int. J. Dev. Biol. 40: 1141-1150.
  24. Lee, S.K., Krebsbach, P., Ganss, B., Slavkin, H., and Yamada, Y. (1997). Krox 26, a new Kruppel-like zinc finger protein, plays a critical role in tooth development. J. Dent. Res. 76:365 (abstract).
  25. Pennisi, E. (1997). A catalog of cancer genes at the click of a mouse. Science 276:1023-1024.


    1. The contractor shall provide current data on the status of this project every two months. This submission shall include: 1) detailed information on the quality of RNA from tissues and on each library generated, including volume and estimated numbers of independent clones, as well as evidence for the presence of full-length clones; 2) primary and catalogued data comparing expression levels of genes at different stages and/or from different tissues, and 3) all sequence data and pertinent database search results. Whenever possible, data should be available for immediate analyses by the Project Officers using a computer relational database program. Two copies of the interim technical progress reports shall be submitted to the Project Officers and one copy to the Contracting Officer every two months.

    2. In addition to depositing clones in a public repository as decided in concurrence with the Project Officer, the contractor shall also provide the clones and at least 50% of the original phage or plasmid cDNA libraries to the Project Officers for stockpiling in the NIDR repository. All cDNA libraries and isolated clones shall be catalogued in a computer relational database program. Aliquots of each in the form of phage or bacteria frozen with DMSO at 70 degrees C and (if produced) plasmid DNA, shall be provided within 6 months of initial production or isolation to the Project Officers. Materials shall be arrayed and indexed in a format that permits rapid and accurate access for distribution.

    3. Two copies of a draft final report summarizing and tabulating the accomplishments of the contract shall be submitted to the Project Officer and one copy to the Contracting Officer no later than 2 months after the 3-year contract research completion date (by the end of the 38th month). This report shall document and summarize results of the entire period of performance and shall be in sufficient detail to describe comprehensively the results achieved. Twenty copies of the final version of the report shall be submitted to the Project Officer and one copy to the Contracting Officer on or before the end of the 39th month, which is the expiration date of the contract. (Note: actual calendar dates will be included in the contract at time of award.)

    4. Preparation of papers for publication that are derived from information gained through work associated with this contract, including collaboration with NIDR Project Officers, is encouraged. The contractor shall submit proposals for abstracts or papers to the Project Officers, NIDR, for review, potential collaborative involvement, and concurrence prior to making such papers publicly available. A copy of all published papers or abstracts relevant to this contract, whether published in collaboration or independently, shall be provided to the Project Officers.

    5. It is anticipated that the contractor shall be required to submit quarterly Financial Reports pertaining to this contract on NIH Form 2706 to the Contracting Officer.



    The technical proposal will receive paramount consideration in the selection of the Contractor for this acquisition. In the event that the technical evaluation reveals that two or more offerors are approximately equal in technical ability, then cost may become a significant factor in determining award. In any event, the Government reserves the right to make an award to the best advantage of the Government, cost and other factors considered.

    If a foreign R&D proposal is received, the peer review group will address the need or appropriateness of accomplishing the work overseas.

    The evaluation will be based on the demonstrated capabilities of the prospective Contractors in relation to the needs of the project as set forth in the RFP. The merits of each proposal will be evaluated carefully. Each proposal must document the feasibility of successful implementation of the requirements of the RFP. Offerors must submit information sufficient to evaluate their proposals based on the detailed criteria listed below.


    Listed below are mandatory qualification criteria. The qualification criteria establishes conditions that must be met at the time of receipt of initial proposals by the Contracting Officer in order for your proposal to be considered any further for award.

    1. The offeror must have documented experience in recombinant DNA technologies for the production of high-quality cDNA libraries from the small quantities of RNA expected for early embryonic tissues, as well as experience in analysis of data by molecular biology informatics.

    2. The offeror must have documented access to expertise in human craniofacial development.

    3. The offeror must have the ability to obtain adequate quantities of appropriate high-quality tissue samples from which they can reliably produce high-quality RNA for subsequent production of cDNA libraries rich in full-length sequences.


    The evaluation criteria are used by the technical evaluation committee when reviewing the technical proposals. The criteria below are listed in the order of relative importance with weights assigned for evaluation purposes.

    1. Scientific and technical merit of the proposed plans to generate and deliver tissue-specific and developmental stage-specific human craniofacial cDNA libraries, to identify and characterize craniofacial tissue-specific and developmental stage-specific clones, and to utilize informatics. (60 points).

    2. The qualifications, expertise, and experience of the Principal Investigator and staff in human craniofacial developmental biology. (20 points).

    3. Adequacy and availability of personnel with appropriate technical expertise (e.g., experience in generating high quality cDNA libraries, state of the art techniques for the identification of tissue- and developmental stage-specific clones, generating and arraying ESTs, etc.). (15 points).

    4. The adequacy and suitability of the facilities and research environment. (5 points).

    Total possible points: 100


  1. Specific RFP Instructions and Provisions, and

  2. Applicable RFP References


    NOTICE TO OFFERORS: This section contains proposal instructions and information which are specifically related to this acquisition. The information provided below is only a portion of the instructions and notices required for the submission of a proposal. References to additional, more general, information and forms regarding proposal preparation are contained under Section III. Applicable RFP References.

    The following specific RFP instructions and provisions apply to this Request For Proposal:

    1. Proposal Intent Response Sheet (submit prior to proposal submission- by May 4, 1998)
    2. Packaging and Delivery of Proposal
    3. SIC Code and Small Business Size Standard
    4. Number and Type of Award(s)
    5. Estimate of Effort
    6. Service of Protest
    7. Technical Proposal Table of Contents
    8. Other Provisions


    RFP No. NHLBI-DR-98-20
    TITLE OF RFP: Novel Human Oral and Craniofacial Genes










    Review Branch
    6701 Rockledge Drive, MSC 7924
    Bethesda, MD, 20892-7924
    Attention: Dr. James Scheirer

    or FAX TO: Dr. James Scheirer at (301) 480-3541


    Your proposal shall be organized as specified in the "Standard RFP Instructions and Provisions." Shipment and marking shall be as follows:

    In addition to the address cited below, mark each package as follows:

    "RFP NO. NHLBI-DR-98-20

    The number of copies required of each part of your proposal are:

    If hand delivered or delivery service:
    Review Branch
    Division of Extramural Affairs
    National Heart, Lung, and Blood Institute
    Rockledge Building, Room 7091
    6701 Rockledge Drive MSC 7924
    Bethesda, MD 20817-7924

    If using U.S. Postal Service:
    Review Branch, Division of Extramural Affairs
    National Institutes of Health
    National Heart, Lung, and Blood Institute
    6701 Rockledge Drive MSC 7924
    Bethesda, MD 20892-7924



    NOTE: The following information is to be used by the offeror in preparing its Representations and Certifications, specifically in completing the provisions entitled, SMALL BUSINESS PROGRAM REPRESENTATIONS, FAR 52.219-1:

    The standard industrial classification (SIC) code for this acquisition is 8733.

    The small business size standard is $5,000,000 average annual receipts over the three preceding fiscal years.

    THIS REQUIREMENT IS NOT SET-ASIDE FOR SMALL BUSINESS. However, the FAR requires in every solicitation (except for foreign acquisitions) the inclusion of the SIC code and corresponding size standard which best describes the nature of the requirement in the solicitation.


    It is anticipated that one award will be made from this solicitation and that award will be made in December 1998.

    It is anticipated that the award from this solicitation will be a multiple-year cost reimbursement, completion type contract with a period of performance of thirty-nine months, and that incremental funding will be used.


    To assist you in the preparation of your proposal, the Government considers the effort to perform this work to be approximately 3 FTE (full time equivalency) each year over the three year performance period. This estimate is furnished for the offeror's information only and is not to be considered restrictive for proposal purposes.
    Labor Category Level of Effort
    Each Year
    Study coordinator/Principal Investigator 10%
    research associate 100%
    senior technician 100%
    technician 100%
    Medical/surgical collaborator 5%
    Total 3.15 FTE

    All staffing levels proposed should be accompanied by specific justifications as to the type and hours of work expected to be performed by all personnel. Offerors will be required to propose levels of commitment whether compensated or donated effort, necessary to complete the work described in their proposals. It is expected that realistic levels of effort will be proposed such that an offeror's understanding of the work will be apparent.


    In accordance with FAR 52.233-2 SERVICE OF PROTEST (NOV 1988):

    (a) Protests, as defined in Section 33.101 of the Federal Acquisition Regulation, that are filed directly with an agency, and copies of any protests that are filed with the General accounting Office (GAO) shall be served on the Contracting Officer (addressed as follows) by obtaining written and dated acknowledgment of receipt from:

    Mr. Robert R. Carlsen
    Hand-Carried Address:
    National Institutes of Health
    National Heart, Lung, and Blood Institute
    Contracts Operations Branch
    II Rockledge Center, Room 6122
    6701 Rockledge Drive, MSC 7902
    Bethesda, MD 20817

    U.S. Postal Service:
    National Institutes of Health
    National Heart, Lung, and Blood Institute
    Contracts Operations Branch
    II Rockledge Center
    6701 Rockledge Drive, MSC 7902
    Bethesda, MD 20892-7902

    The copy of any protest shall be received in the office designated above within one day of filing a protest with GAO.


    Please number each page of text. Type density and size must be 10-12 points. If constant spacing is used, there should be no more than 15 cpi, whereas proportional spacing should provide an average of no more than 15 cpi. There must be no more than six lines of text within a vertical inch.

    The technical proposal should be organized as follows:

    1. TECHNICAL PROPOSAL COVER SHEET (Form is located in the Streamlined RFP References under "FORMS, FORMATS, ATTACHMENTS")--Page 1
    3. ABSTRACT--Page 3
      State the proposal's broad, long-term objectives and specific aims. Briefly and concisely describe the research design and methods for achieving these goals. DO NOT EXCEED one page in providing the abstract. Identify the RFP Number, Institution and Principal Investigator on the abstract.
    4. TECHNICAL PLAN (approximately 25 PAGES)
      Refer to Technical Proposal Instructions located in the Standard RFP Instructions and Provisions under Streamlined RFP References for more detail.
        1. Objectives--Page #
        2. Approach--Page #
        3. Methods--Page #
        4. Schedule--Page #

      2. PERSONNEL
        1. List of all Personnel in the project including Subcontractors, Consultants/Collaborators, by name, title, department and organization--Page #
        2. Principal Investigator/Project Director--Page #
        3. Other Investigators--Page #
        4. Additional Personnel--Page #
          [NOTE: For personnel, include a two-page biosketch under APPENDICES below.]

        List/describe all facilities, equipment and other resources available for this project.

        (Use specifically titled subparagraphs, as applicable.)

    5. OTHER SUPPORT--Page #
      Complete the Form "Summary of Current and Proposed Activities." All key personnel must be listed on this form. The form is located in the Streamlined RFP References under "FORMS, FORMATS, & ATTACHMENTS."

      (Form located in the Streamlined RFP References under "FORMS, FORMATS, & ATTACHMENTS.")


    8. APPENDICES--Page #
      List each Appendix and identify the number of pages for each one. Appendices must be clear and legible, and easily located. Include biosketches here.



      No Government furnished material, facilities, or equipment are envisioned for this acquisition.


      The Government reserves the right to award a contract without discussions if the Contracting Officer determines that the initial prices are fair and reasonable and that discussions are not necessary. If award will be made without conducting discussions, offerors may be given the opportunity to clarify certain aspects of their proposal (e.g., the relevance of an offeror's past performance information and adverse past performance information to which the offeror has not previously had an opportunity to respond) or to resolve minor or clerical errors.


      The offeror's business proposal shall include the basic cost/pricing information specified in the Standard RFP Instructions and Provisions, under the Streamlined RFP References Directory referenced in this RFP. In addition, the Government may require offerors included in the competitive range to submit additional information substantiating their proposed costs or prices. This additional cost/pricing information will be requested after establishment of the competitive range, and potentially includes payroll documentation, vendor quotes, invoice prices, and/or any other information deemed necessary by the Contracting Officer to evaluate the reasonableness of the price or to determine cost realism. The information may also include submission and certification of cost or pricing data.

    4. FAR 52.215-16, FACILITIES CAPITAL COST OF MONEY (October 1997)
      (This is applicable if you are a commercial organization.)

      1. Facilities capital cost of money (see FAR 15.408(h) will be an allowable cost under the contemplated contract, if the criteria for allowability in subparagraph 31.205-10(a)(2) of the Federal Acquisition Regulation are met. One of the allowability criteria requires the prospective Contractor to propose facilities capital cost of money in its offer.

      2. If the prospective Contractor does not propose this cost, the resulting contract will include the clause "Waiver of Facilities Capital Cost of Money."

    5. HUMAN MATERIALS (It is anticipated that this clause will appear in the contract.)

      It is understood that the acquisition and supply of all human specimen material (including fetal material) used under this contract will be obtained by the Contractor in full compliance with applicable State and Local laws and the provisions of the Uniform Anatomical Gift Act in the United States and that no undue inducements, monetary or otherwise, will be offered to any person to influence their donation of human material.

    6. PUBLICATION AND PUBLICITY (It is anticipated that this clause will appear in the contract.)

      The contractor shall acknowledge the support of the National Institutes of Health whenever publicizing the work under this contract in any media by including an acknowledgment substantially as follows:

      "This project has been funded in whole or in part with Federal funds from the National Institute of Dental Research, National Institutes of Health, under Contract No. ."

    7. HHSAR 352.270-6 PUBLICATION AND PUBLICITY (JULY 1991) (It is anticipated that this clause will appear in the contract.)

      Unless otherwise specified in this contract, the Contractor is encouraged to publish, and make available through accepted channels, the results of its work under this contract. A copy of each article submitted by the Contractor for publication shall be promptly sent to the Project Officer. The Contractor shall also inform the Project Officer when the article or other publication is published, and furnish a copy of it as finally published.


    This section identifies the items located in the Streamlined RFP References that are applicable to this Request For Proposal (RFP).

    The entire file entitled "STANDARD RFP INSTRUCTIONS AND PROVISIONS" is applicable to this RFP, except as modified by the inclusion of items from the "OPTIONAL RFP INSTRUCTIONS AND PROVISIONS" below and except for the new RFP provision, FAR 52.215-1 which is included in full text at the end of this section. This provision is important to review because it describes new rules for conducting negotiated competitive acquisitions. (This provision was not included in the Standard RFP Instructions and Provisions at the time this RFP was prepared, but may appear at a later date.)

    The following items are applicable from the file entitled "OPTIONAL RFP INSTRUCTIONS AND PROVISIONS". The full text of the provisions is available in the file.

    List of provisions which apply to this specific RFP:

    1. Notice: This requirement is Not Set-Aside for Small Business
    2. Late Proposals, Modifications of Proposal, and Withdrawal of Proposals, PHS 352.215-10
    3. Small, Small Disadvantaged and Women-Owned Small Business Subcontracting Plan
    4. "Just in Time"

    The following items are applicable to this specific RFP and are located in the file entitled "FORMS, FORMATS, AND ATTACHMENTS", under Streamlined RFP References:

    SUBMIT WITH TECHNICAL PROPOSAL (with original and every copy of technical proposal)

    1. Technical Proposal Cover Sheet
    2. Summary of Current and Proposed Activities
    3. Technical Proposal Cost Information


    1. Contract Pricing Proposal Cover Sheet, SF-1411, or equivalent, with every copy of business proposal.
    2. Proposal Summary and Data record, NIH-2043, with every copy of business proposal.
    3. Disclosure of Lobbying Activities, OMB SF-LLL, only one completed and signed original.
    4. Representations and Certifications, only one completed and signed original.


    1. Certificate of Current Cost or Pricing Data, NIH-1397, to be submitted with Final Proposal Revision, if required by the Contracting Officer.
    2. Small Business Subcontracting Plan, to be submitted as directed by the Contracting Officer.


    1. Invoice/Financing Requests Instructions for NIH Cost-Reimbursement Type Contracts, NIH(RC)-1
    2. NIH 2706, Financial Report of Individual Project/Contract, the form with instructions
    3. Procurement of Certain Equipment, NIH(RC)-7
    4. Protection of Human Subjects Assurance/ Identification/Certification/Declaration, OF 310

    The "SAMPLE CONTRACT FORMAT-GENERAL" under the Streamlined RFP References is applicable to this RFP. Selected clauses applicable to this acquisition will be included in the contract.

    NOTE: The following provision supersedes equivalent text and provisions contained in the Standard RFP Instructions and Provisions, current at the time this RFP was prepared. In the event of any conflicts, this provision shall take precedent.


    1. Definitions. As used in this provision--

      Discussions are negotiations that occur after establishment of the competitive range that may, at the Contracting Officer's discretion, result in the offeror being allowed to revise its proposal.

      In writing or written means any worded or numbered expression which can be read, reproduced, and later communicated, and includes electronically transmitted and stored information.

      Proposal modification is a change made to a proposal before the solicitation's closing date and time, or made in response to an amendment, or made to correct a mistake at any time before award.

      Proposal revision is a change to a proposal made after the solicitation closing date, at the request of or as allowed by a Contracting Officer as the result of negotiations.

      Time, if stated as a number of days, is calculated using calendar days, unless otherwise specified, and will include Saturdays, Sundays, and legal holidays. However, if the last day falls on a Saturday, Sunday, or legal holiday, then the period shall include the next working day.

    2. Amendments to solicitations. If this solicitation is amended, all terms and conditions that are not amended remain unchanged. Offerors shall acknowledge receipt of any amendment to this solicitation by the date and time specified in the amendment(s).

    3. Submission, modification, revision, and withdrawal of proposals. 1. Unless other methods (e.g., electronic commerce or facsimile) are permitted in the solicitation, proposals and modifications to proposals shall be submitted in paper media in sealedenvelopes or packages i. addressed to the office specified in the solicitation, and ii. showing the time and date specified for receipt, the solicitation number, and the name and address of the offeror. Offerors using commercial carriers should ensure that the proposal is marked on the outermost wrapper with the information in paragraphs c.1.i. and c.1.ii. of this provision.

      1. The first page of the proposal must show--
        1. The solicitation number;
        2. The name, address, and telephone and facsimile numbers of the offeror (and electronic address if available);
        3. A statement specifying the extent of agreement with all terms, conditions, and provisions included in the solicitation and agreement to furnish any or all items upon which prices are offered at the price set opposite each item;
        4. Names, titles, and telephone and facsimile numbers (and electronic addresses if available) of persons authorized to negotiate on the offeror's behalf with the Government in connection with this solicitation; and
        5. Name, title, and signature of person authorized to sign the proposal. Proposals signed by an agent shall be accompanied by evidence of that agent's authority, unless that evidence has been previously furnished to the issuing office.

      2. Late proposals and revisions. i. Any proposal received at the office designated in the solicitation after the exact time specified for receipt of offers will not be considered unless it is received before award is made and--

          1. It was sent by registered or certified mail not later than the fifth calendar day before the date specified for receipt of offers (e.g., an offer submitted in response to a solicitation requiring receipt of offers by the 20th of the month must have been mailed by the 15th);

          2. It was sent by mail (or telegram or facsimile, if authorized) or hand-carried (including delivery by a commercial carrier) if it is determined by the Government that the late receipt was due primarily to Government mishandling after receipt at the Government installation;

          3. It was sent by U.S. Postal Service Express Mail Next Day Service-Post Office to Addressee, not later than 5:00 p.m. at the place of mailing two working days prior to the date specified for receipt of proposals. The term "working days" excludes weekends and U.S. Federal holidays;

          4. It was transmitted through an electronic commerce method authorized by the solicitation and was received at the initial point of entry to the Government infrastructure not later than 5:00 p.m. one working day prior to the date specified for receipt of proposals; or

          5. There is acceptable evidence to establish that it was received at the activity designated for receipt of offers and was under the Government's control prior to the time set for receipt of offers, and the Contracting Officer determines that accepting the late offer would not unduly delay the procurement; or

          6. It is the only proposal received.

        1. Any modification or revision of a proposal or response to request for information, including any final proposal revision, is subject to the same conditions as in subparagraphs c.3.i.A. through c.3.i.E. of this provision.

        2. The only acceptable evidence to establish the date of mailing of a late proposal or modification or revision sent either by registered or certified mail is the U.S. or Canadian Postal Service postmark both on the envelope or wrapper and on the original receipt from the U.S. or Canadian Postal Service. Both postmarks must show a legible date or the proposal, response to a request for information, or modification or revision shall be processed as if mailed late. "Postmark" means a printed, stamped, or otherwise placed impression (exclusive of a postage meter machine impression) that is readily identifiable without further action as having been supplied and affixed by employees of the U.S. or Canadian Postal Service on the date of mailing. Therefore, offerors or respondents should request the postal clerk to place a legible hand cancellation bull's eye postmark on both the receipt and the envelope or wrapper.

        3. Acceptable evidence to establish the time of receipt at the Government installation includes the time/date stamp of that installation on the proposal wrapper, other documentary evidence of receipt maintained by the installation, or oral testimony or statements of Government personnel.

        4. The only acceptable evidence to establish the date of mailing of a late offer, modification or revision, or withdrawal sent by Express Mail Next Day Service-Post Office to Addressee is the date entered by the post office receiving clerk on the "Express Mail Next Day Service-Post Office to Addressee" label and the postmark on both the envelope or wrapper and on the original receipt from the U.S. Postal Service. "Postmark" has the same meaning as defined in paragraph c.3.iii. of this provision, excluding postmarks of the Canadian Postal Service. Therefore, offerors or respondents should request the postal clerk to place a legible hand cancellation bull's eye postmark on both the receipt and the envelope or wrapper.

        5. Notwithstanding paragraph c.3.i. of this provision, a late modification or revision of an otherwise successful proposal that makes its terms more favorable to the Government will be considered at any time it is received and may be accepted.

        6. Proposals may be withdrawn by written notice or telegram (including mailgram) received at any time before award. If the solicitation authorizes facsimile proposals, proposals may be withdrawn via facsimile received at any time before award, subject to the conditions specified in the provision entitled "Facsimile Proposals." Proposals may be withdrawn in person by an offeror or an authorized representative, if the representative's identity is made known and the representative signs a receipt for the proposal before award.

        7. If an emergency or unanticipated event interrupts normal Government processes so that proposals cannot be received at the office designated for receipt of proposals by the exact time specified in the solicitation, and urgent Government requirements preclude amendment of the solicitation or other notice of an extension of the closing date, the time specified for receipt of proposals will be deemed to be extended to the same time of day specified in the solicitation on the first work day on which normal Government processes resume. If no time is specified in the solicitation, the time for receipt is 4:30 p.m., local time, for the designated Government office.

      3. Unless otherwise specified in the solicitation, the offeror may propose to provide any item or combination of items.

      4. Proposals submitted in response to this solicitation shall be in English and in U.S. dollars, unless otherwise permitted by the solicitation.

      5. Offerors may submit modifications to their proposals at any time before the solicitation closing date and time, and may submit modifications in response to an amendment, or to correct a mistake at any time before award.

      6. Offerors may submit revised proposals only if requested or allowed by the Contracting Officer.

      7. Proposals may be withdrawn at any time before award. Withdrawals are effective upon receipt of notice by the Contracting Officer.

    4. Offer expiration date. Proposals in response to this solicitation will be valid for the number of days specified on the solicitation cover sheet (unless a different period is proposed by the offeror).

    5. Restriction on disclosure and use of data. Offerors that include in their proposals data that they do not want disclosed to the public for any purpose, or used by the Government except for evaluation purposes, shall--

      1. Mark the title page with the following legend: This proposal includes data that shall not be disclosed outside the Government and shall not be duplicated, used, or disclosed--in whole or in part--for any purpose other than to evaluate this proposal. If, however, a contract is awarded to this offeror as a result of--or in connection with-- the submission of this data, the Government shall have the right to duplicate, use, or disclose the data to the extent provided in the resulting contract. This restriction does not limit the Government's right to use information contained in this data if it is obtained from another source without restriction. The data subject to this restriction are contained in sheets [insert numbers or other identification of sheets]; and

      2. Mark each sheet of data it wishes to restrict with the following legend: Use or disclosure of data contained on this sheet is subject to the restriction on the title page of this proposal.

    6. Contract award. 1. The Government intends to award a contract or contracts resulting from this solicitation to the responsible offeror(s) whose proposal(s) represents the best value after evaluation in accordance with the factors and subfactors in the solicitation.

      1. The Government may reject any or all proposals if such action is in the Government's interest.

      2. The Government may waive informalities and minor irregularities in proposals received.

      3. The Government intends to evaluate proposals and award a contract without discussions with offerors (except clarifications as described in FAR 15.306(a)). Therefore, the offeror's initial proposal should contain the offeror's best terms from a cost or price and technical standpoint. The Government reserves the right to conduct discussions if the Contracting Officer later determines them to be necessary. If the Contracting Officer determines that the number of proposals that would otherwise be in the competitive range exceeds the number at which an efficient competition can be conducted, the Contracting Officer may limit the number of proposals in the competitive range to the greatest number that will permit an efficient competition among the most highly rated proposals.

      4. The Government reserves the right to make an award on any item for a quantity less than the quantity offered, at the unit cost or prices offered, unless the offeror specifies otherwise in the proposal.

      5. The Government reserves the right to make multiple awards if, after considering the additional administrative costs, it is in the Government's best interest to do so.

      6. Exchanges with offerors after receipt of a proposal do not constitute a rejection or counteroffer by the Government.

      7. The Government may determine that a proposal is unacceptable if the prices proposed are materially unbalanced between line items or subline items. Unbalanced pricing exists when, despite an acceptable total evaluated price, the price of one or more contract line items is significantly overstated or understated as indicated by the application of cost or price analysis techniques. A proposal may be rejected if the Contracting Officer determines that the lack of balance poses an unacceptable risk to the Government.

      8. If a cost realism analysis is performed, cost realism may be considered by the source selection authority in evaluating performance or schedule risk.

      9. A written award or acceptance of proposal mailed or otherwise furnished to the successful offeror within the time specified in the proposal shall result in a binding contract without further action by either party.

      10. The Government may disclose the following information in postaward debriefings to other offerors:

        1. The overall evaluated cost or price and technical rating of the successful offeror;

        2. The overall ranking of all offerors, when any ranking was developed by the agency during source selection;

        3. A summary of the rationale for award; and

        4. For acquisitions of commercial items, the make and model of the item to be delivered by the successful offeror.

(End of provision)

Alternate I (October 1997). As prescribed in 15.209(a)(1), substitute the following paragraph (f)(4) for paragraph (f)(4) of the basic provision:

(f)(4) The Government intends to evaluate proposals and award a contract after conducting discussions with offerors whose proposals have been determined to be within the competitive range. If the Contracting Officer determines that the number of proposals that would otherwise be in the competitive range exceeds the number at which an efficient competition can be conducted, the Contracting Officer may limit the number of proposals in the competitive range to the greatest number that will permit an efficient competition among the most highly rated proposals. Therefore, the offeror's initial proposal should contain the offeror's best terms from a price and technical standpoint.

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