ADVANCED NMR SPECTROSCOPY INSTRUMENTATION

Release Date:  December 23, 1998

RFA: RR-99-004

P.T.

National Center for Research Resources

Letter of Intent Receipt Date:  February 17, 1999
Application Receipt Date:  March 17, 1999

PURPOSE

It is the purpose of this Request for Applications (RFA) to stimulate advanced
NMR instrumentation development, particularly for liquid phase protein and solid
state membrane protein applications, and their effective integration into high-
field NMR spectrometer systems.  The Small Business Innovation Research (SBIR)
program has supported such development efforts; however, the extent of such
support has been limited.  Recently, the NIH has announced that applicants may
request a larger budget and period of support if necessary for completion of the
project (See NIH Guide for Grants and Contracts, February 13, 1998
(http://grants.nih.gov/grants/guide/notice-files/not98-014.html).  This RFA provides
a means within the SBIR program to more fully accommodate the high expenses
involved in such technology development, particularly multidisciplinary staffing,
custom-fabrication, and long-term project support through the prototype
development stage.

The contribution of NMR to structural studies of macromolecules in the tens of
kDalton molecular weight range is well-recognized, and new pulse sequences
promise to substantially raise existing upper molecular weight limits on NMR
solution structure determination.  Nevertheless, the contribution of NMR to
structural biology is presently limited by both sensitivity and spectral
resolution.  NMR structure studies are time-intensive, but essential,
particularly for biological structures which cannot be crystallized and for
studies of the dynamical behavior of biomolecules.  A recent report (High Field
NMR: A New Millennium Resource; (http://www.magnet.fsu.edu/NMRcoll) points out
the virtual revolution in biological NMR which would occur if an order of
magnitude gain in sensitivity could be achieved, bringing many experiments within
the feasible envelope and increasing the throughput of current studies.  To
accomplish this, it is essential to stimulate innovative new research and
development efforts in the following areas: design of 1GHz+ superconducting
magnets for NMR spectroscopy, development of flexible probes for such high-field
spectrometers, and related preamplifier design.

HEALTHY PEOPLE 2000

The Public Health Service (PHS) is committed to achieving the health promotion
and disease prevention objectives of "Healthy People 2000", a PHS-led national
activity for setting priority areas.  This RFA, Advanced NMR Spectroscopy
Instrumentation, is related to several of the priority areas.  Potential
applicants may obtain a copy of "Healthy People 2000" (Full Report: Stock No.
017-001-00474-0 or Summary Report: Stock No. 017-001-00473-1) through the
Superintendent of Documents, Government Printing Office, Washington, DC
20402-9325 (telephone 202-512-1800).

ELIGIBILITY REQUIREMENTS

Eligibility requirements are described in the SBIR OMNIBUS SOLICITATIONS.  Any
small business, independently owned and operated by United States citizens or
permanent resident aliens may apply.  The business must be organized for-profit,
cannot be dominant in its field of expertise, and must have its principal place
of business in the United States.  Including any affiliates, the company can be
the employer of no more than 500 people.

MECHANISM OF SUPPORT

Support for this RFA is through the SBIR mechanism, which is a set-aside program.

Applications can be submitted for support as Phase I SBIR (R43) or Phase II SBIR
(R44) grants; or under the SBIR FAST-TRACK option as described in the OMNIBUS
SOLICITATIONS.  Phase II applications in response to this RFA will only be
accepted as competing continuations of previously funded NIH Phase I SBIR awards. 
The Phase II proposal must be a logical extension of the Phase I research.

Information on the FAST-TRACK process and the SBIR OMNIBUS SOLICITATIONS are
available at: http://grants.nih.gov/grants/funding/sbir.htm.

Awards will be administered under NIH grants policy as stated in the National
Institutes of Health Grants Policy Statement issued October 1, 1998
(http://grants.nih.gov/grants/policy/nihgps/).

FUNDS AVAILABLE

It is expected that two to six awards will be made in FY99, and approximately $2
million from the SBIR set-aside will be designated for this purpose.  However,
the number of awards will be dependent upon receipt of a sufficient number and
diversity of applications with high scientific merit.

RESEARCH OBJECTIVES

Along with X-ray crystallography, multi-dimensional NMR spectrometry provides the
structural foundation of biomedical science.  Our understanding of the catalytic,
structural, and control roles of proteins and nucleic acids is based on our
ability to relate, at atomic levels of detail, macromolecular structure and
dynamics to function.  NMR provides essential dynamical insights, which are
rarely available utilizing X-ray-based approaches.  NMR spectroscopy is now
making an important transition to magnetic field strengths of greater than 1GHz
in order to capture both sensitivity and resolution advantages, which translate
into higher molecular weight limits on three dimensional structure determinations
and lower macromolecule concentration requirements.  Higher magnetic fields,
combined with improved probe designs and new pulse sequences, promise to open a
wide range of biological systems to study using NMR spectrometry.

While much progress has recently been made in the development of NMR probes,
particularly superconducting and new MAS designs, there continues to be much
untapped potential, including, for instance: high temperature superconducting
probe designs with triple resonance and pulsed field gradient capabilities,
microcoil probe design, and technological developments associated with
application of dynamic nuclear polarization.  New magnet technology is itself an
active area of development, involving materials as well as engineering aspects. 
It is also recognized that preamplifier development is a critical component of
any high-sensitivity NMR system.

The objective of this RFA is to support the development of advanced high-field
NMR components or systems, such as magnets, probes, and low-noise preamplifiers;
their implementation in functioning prototypes; their evaluation, and ultimate
commercialization.  These components will ultimately be integrated into high-
sensitivity and potentially high-throughput NMR systems.  This RFA recognizes
that such technology development efforts require the sustained focus of
multidisciplinary groups, potentially involve utilization of expensive
fabrication processes, and as a consequence require a wide range of financial
resources.

INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS

It is the policy of the NIH that women and members of minority groups and their
sub-populations must be included in all NIH-supported biomedical and behavioral
research projects involving human subjects, unless a clear and compelling
rationale and justification is provided that inclusion is inappropriate with
respect to the health of the subjects or the purpose of the research.  This
policy results from the NIH Revitalization Act of 1993 (Section 492B of Public
Law 103-43).

All investigators proposing research involving human subjects should read the
"NIH Guidelines For Inclusion of Women and Minorities as Subjects in Clinical
Research", which has been published in the Federal Register of March 20, 1994 (FR
59 14508-14513) and in the NIH Guide for Grants and Contracts, Volume 23, Number
11, March 18, 1994.

Investigators may also obtain copies of the policy from the program staff listed
under INQUIRIES.  Program staff may also provide additional relevant information
concerning the policy.

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS

It is the policy of NIH that children (i.e., individuals under the age of 21)
must be included in all human subjects research conducted or supported by the
NIH, unless there are clear and compelling scientific and ethical reasons not to
include them.  This policy applies to all initial (Type 1) applications submitted
for receipt dates after October 1, 1998.

All investigators proposing research involving human subjects should read the
"NIH Policy and Guidelines on the Inclusion of Children as Participants in
Research Involving Human Subjects": that was published in the NIH Guide for
Grants and Contracts, March 6, 1998, and is available at the following URL
address: http://grants.nih.gov/grants/guide/notice-files/not98-024.html.

LETTER OF INTENT

Prospective applicants are asked to submit a letter of intent that includes a
descriptive title of the proposed research, the name, address, and telephone
number of the Principal Investigator, the identities of other key personnel and
participating institutions, and the number and title of the RFA in response to
which the application may be submitted. Although a letter of intent is not
required, is not binding, and does not enter into the review of a subsequent
application, the information that it contains allows NCRR staff to estimate the
potential review workload and avoid conflict of interest in the review.

The letter of intent is to be sent to Ms. Joellen Harper at the address listed
under INQUIRIES by the letter of intent receipt date listed in the heading of
this RFA.

APPLICATION PROCEDURES

This RFA must be read in conjunction with the OMNIBUS SOLICITATION OF THE PUBLIC
HEALTH SERVICE FOR SMALL BUSINESS INNOVATION RESEARCH GRANT (SBIR) APPLICATIONS. 
All of the instructions within the omnibus solicitation apply with the following
exceptions:

o  Special Receipt Date
o  Additional review considerations
o  More flexible time and budget specifications
o  Different page limits

Applications received in response to this RFA are to be prepared as described in
the OMNIBUS SOLICITATIONS for the SBIR program.  OMNIBUS SOLICITATIONS are
available electronically through the NIH, Office of Extramural Research "Small
Business Funding Opportunities" website:
http://grants.nih.gov/grants/funding/sbir.htm.  Hard copies, subject to
availability, may be obtained from the PHS SBIR/STTR Solicitation Office, phone
(301) 206-9385; FAX (301) 206-9722; email a2y@cu.nih.gov.  Helpful information
in preparation of the application can be obtained at:
http://grants.nih.gov/grants/funding/sbirsttradvice.htm.

Applications in response to this RFA are to be submitted on the applicable grant
application forms as follows:

SBIR Phase I  PHS 6246-1 (1/98) http://grants.nih.gov/grants/funding/sbir1/SBIR.htm

SBIR Phase II  PHS 6246-2 (1/98)
http://grants.nih.gov/grants/funding/sbir2/index.htm

The application forms are also located in the back pages of the OMNIBUS
SOLICITATIONS.  Applications will be accepted on March 17, 1999.  The RFA title
and number must be typed in line 2 on the face page of the application form.

If an application is received after the application receipt date, it will be
returned to the applicant without review.  The Center for Scientific Review (CSR)
will not accept any application in response to this RFA that is essentially the
same as one currently pending review, unless the applicant withdraws the pending
application.  This does not preclude the submission of substantial revisions of
applications already reviewed, but such applications must include an introduction
addressing the previous critique.

SBIR projects submitted for Phase II support in response to this RFA must
demonstrate successful Phase I feasibility prior to a Phase II award. 
Applications can be submitted for Phase I or Phase II support, or as a combined
Phase I and II (Fast Track).  Phase II applications will only be accepted as
continuations of previously funded Phase I grants.  The Phase II proposal must
be a logical extension of the Phase I research, but not necessarily a Phase I
supported in response to this RFA.

PHASE I: Demonstration of feasibility for the next step in the NMR technology
development process.  It would be expected, but not required, that Phase I would
support relatively early discovery and evaluation projects.  Phase I projects
should focus on research required to advance to the next stage in the development
process and present a plan and time line outlining accomplishments and milestones
to be achieved at each stage.  Applicants should emphasize innovative aspects of
the proposed technology development and the nature of the new capabilities which
will follow from a successful development effort.  Applicants should include a
general plan for the complete development project and clearly state how the
proposed Phase I fits into this plan.  The complete application (including all
form pages and "continuation" pages suggested by the OMNIBUS SOLICITATIONS
instructions or application form pages) may not exceed 50 pages, excluding: cover
letters; the one-page "Introduction" required when submitting a revised (amended)
application; letters of commitment from collaborators and consultants; the
"Checklist" (form page 6); and the "Personal Data on Principal Investigator" form
page.

For this RFA, projects normally will be supported in Phase I for up to two years
with a budget of up to $700,000, total costs, per year.  Budgets proposed must
be commensurate with the research, design, and construction efforts described in
the application.  Larger budgets could be considered if required for conduct of
the research and appropriately justified in the application.  The second year of
support will be contingent upon NCRR programmatic evaluation to ensure that
investigators are accomplishing milestones and time lines presented in the
original application.

PHASE II: Full prototype development leading to Phase III commercialization. 
Support can be requested for development work leading to full-scale prototypes,
their testing, development of software for data transfer, and evaluation of user
interfaces.

It is not possible for the SBIR program to provide full funding for the
commercialization of advanced detectors.  Thus, a co-funding partner or other
sources of support should be identified prior to a Phase II award.  The funds
and/or resources to be dedicated to activities directly related to the
commercialization of detectors by the partner/company, including details of the
commitment contingencies, must be clearly specified in the application. 
Appropriate documentation of the commitment must be provided.

Phase II awards can be for up to four years and $750,000 total costs, per year. 
As with Phase I, requests for larger budgets may be considered, and support for
years two to four is dependent upon NCRR programmatic review of progress
including achievement of proposed milestones and evaluation of additional
information not required in the original application.  As for Phase I, the Phase
II application page limit is 50 pages.

FAST TRACK: Applications may be submitted for combined Phase I and Phase II FAST
TRACK consideration as described in the OMNIBUS SOLICITATIONS.  However, due to
the complex nature of NMR technology development, it is recommended that only
well defined and more advanced projects be proposed for support through this
mechanism.

Phase I, FAST TRACK applications must specify clear, measurable goals that should
be achieved prior to Phase II funding.  Failure to provide measurable goals in
the Phase I application and/or sufficient detail in the Phase II application may
be sufficient reason for the peer review committee to exclude the Phase II from
consideration.  Special provisions described in this RFA pertaining to Phase I
and Phase II also apply to FAST TRACK applications.

An additional requirement of the FAST TRACK mechanism is the commitment of funds
and/or resources for commercialization of the product to ensure a rapid
transition to the market.  These funds are in addition to the funds required for
research support in Phase II described above.  A Commitment Appendix to the Phase
II application must be included which specifies the amount of funds and/or nature
of resources that will be dedicated to the SBIR project and must describe those
activities.  If such commitment is from an investor or partner organization, a
copy of the agreement or a letter describing the details of the agreement must
be provided.  The small business concern must also submit a concise Product
Development Plan (limited to five pages) as an Appendix to the Phase II
application addressing the four areas described in the instructions for FAST
TRACK applications in the OMNIBUS SOLICITATIONS.  The Fast Track application page
limit is 60 pages (excluding the required pages described above).

Potential applicants are encouraged to contact program staff for guidance and to
read the advice and information on the web sites.  However, responsibility for
planning, direction, and execution of the proposed research will be solely that
of the applicant.

The completed original application and two legible copies must be sent or
delivered to:

CENTER FOR SCIENTIFIC REVIEW
NATIONAL INSTITUTES OF HEALTH
6701 ROCKLEDGE DRIVE, ROOM 1040, MSC 7710
BETHESDA, MD 20892-7710
BETHESDA, MD 20817 (for express/courier service)

The submission, review, and award schedule for this Request for Applications is:

Application receipt date: March 17, 1999
CSR Committee Review: June/July 1999
Council Review: September 1999
Earliest Funding: September 1999

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed by the CSR for completeness and by
NCRR for responsiveness.  Applications not adhering to application instructions
described above and those applications that are incomplete or non-responsive will
be returned to the applicant without review.

Applications will be reviewed for scientific and technical merit and the
documented ability of the investigators to meet the RESEARCH OBJECTIVES of this
RFA by an initial review group convened by the Center for Scientific Review, in
accordance with the standard NIH peer review procedures.  As part of the initial
merit review, all applications will receive a written critique and undergo a
process in which only those applications deemed to have the highest scientific
merit, generally the top half of the applications under review, will be
discussed, assigned a priority score, and receive a second level review by the
National Advisory Research Resources Council.

REVIEW CRITERIA

Review criteria are essentially as described in the OMNIBUS SOLICITATIONS with
the additional considerations specified for this RFA.

o  The soundness and technical merit of the proposed approach.

o  The qualifications of the proposed principal investigator, supporting staff,
and consultants.

o  The scientific, technical, or technological innovation of the overall
magnet/probe technology development plan.

o  The potential of the proposed research for commercial application.

o  The appropriateness of the budget requested.

o  The adequacy and suitability of the facilities and research environment.

o  Where appropriate, the adequacy of assurances detailing the proposed means for
(a) safeguarding human or animal subjects and/or (b) protecting against or
minimizing any adverse effect on the environment.

o  Potential impact of the developed technology on structural biology research.

Phase I applications should specify clear, measurable goals (milestones) that
should be achieved prior to initiating Phase II.  Failure to provide clear,
measurable goals may be sufficient reason for the initial review group to judge
the application non-competitive.

The initial review group will also examine the adequacy of plans to include both
genders and minorities, and their subgroups, as appropriate for the scientific
goals of the research, plans for the recruitment and retention of subjects; the
adequacy of plans for including children as appropriate for the scientific goals
of the research, or justification for exclusion; the provisions for the
protection of human and animal subjects and the safety of the research
environment.

AWARD CRITERIA

Funding decisions for Phase I or Phase II applications will be based on the
quality of the proposed project as determined by peer review, program priorities,
potential impact on structural biology research, and availability of funds.

FAST TRACK, Phase II applications may be funded following submission of the Phase
I progress report and other documents necessary for continuation.  Phase II
applications will be selected for funding based on the initial priority score,
NCRR's assessment of the Phase I progress and determination that Phase I goals
were achieved, the project's potential for commercial success, and the
availability of funds.

INQUIRIES

Inquiries concerning this RFA are encouraged.  The opportunity to clarify any
issues or questions from potential applicants is welcome.

Direct inquiries regarding programmatic issues to:

Dr. Abraham Levy
Biomedical Technology
National Center for Research Resources
6705 Rockledge Drive, Room 6160, MSC 7965
Bethesda, MD 20892-7965
Telephone: (301) 435-0755
FAX: (301) 480-3659

Or send an email inquiry to:
BTAdir@ep.ncrr.nih.gov

Direct inquiries regarding fiscal matters to:

Ms. Joellen Harper
Office of Grants and Contracts Management
National Center for Research Resources
6705 Rockledge Drive, Room 6086, MSC 7965
Bethesda, MD 20892-7965
Telephone (301) 435-0844
Harperj@ncrr.nih.gov

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance No.
93.371.  Awards are made under authorization of the Public Health Service Act,
Title III, Part A (Public Law 78-410), as amended by Public Law 99-158, 42 USC
241 and 285) and administered under PHS grants policies and Federal Regulations
42 CFR 52 and 45 CFR 74.  This program is not subject to the intergovernmental
review requirements of Executive Order 12372 or Health Systems Agency review.

The PHS strongly encourages all grant and contract recipients to provide a smoke-
free workplace and promote the non-use of all tobacco products.  In addition,
Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain
facilities (or in some cases, any portion of a facility) in which regular or
routine education, library, day care, health care or early childhood development
services are provided to children.  This is consistent with the PHS mission to
protect and advance the physical and mental health of the American people.


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