41440 Federal Register / Vol. 74, No. 157 / Monday, August 17, 2009 / Notices 

TABLE 1.—ESTIMATED ANNUAL REPORTING BURDEN1—Continued 

Citation No. of 

Respondents 

Annual Frequency 

per Response 

Total Annual 

Responses 

Hours per 

Response Total Hours 

Total 186 

1There are no capital costs or operating and maintenance costs associated with this collection of information. 

FDA’s estimate of the number of 

respondents in table 1 is based on the 

number of regulatory submissions 

submitted to TTB for beers that do not 

meet the definition of a ‘‘malt beverage’’ 

under the FAA Act. Based on its records 

of submissions received from 

manufacturers of such products, TTB 

estimates the number of respondents to 

be 12 and the number of submissions 

annually to be 25. Thus, FDA adopts 

TTB’s estimate of 12 respondents, and 

an annual frequency per response of 2, 

in table 1 of this document. 

FDA’s estimate of the hours per 

response for each regulation is based on 

FDA’s experience with food labeling 

under the agency’s jurisdiction. The 

estimated hours per response for 

§§ 101.3, 101.4, 101.5, 101.9, 101.22, 

and 101.105 in table 1 of this document 

are equal to, and based upon, the 

estimated hours per response approved 

by OMB in OMB Control No. 0910– 

0381. FDA further estimates that the 

labeling burden of section 403(w)(1) of 

the FD&C Act, which specifies 

requirements for the declaration of food 

allergens, will be 1 hour based upon the 

similarity of the requirements to that of 

§ 101.4. Finally, FDA estimates that a 

respondent will spend 1 hour reading 

the guidance document, once finalized. 

Thus, FDA estimates that 12 

respondents will each label two 

products annually, for a total of 24 

labels. FDA estimates that the 

manufacturers will spend 7.25 hours 

(0.5 hours + 1 hour + 0.25 hour + 4 

hours + 0.5 hour + 1 hour = 7.25 hours) 

on each label to comply with FDA’s 

labeling regulations and the 

requirements of section 403(w)(1), for a 

total of 174 hours (24 labels x 7.25 hours 

= 174 hours). In addition, 12 

respondents will each spend 1 hour 

reading the guidance document, for a 

total of 12 hours. Thus, FDA estimates 

the total hour burden of the proposed 

collection of information to be 186 

hours (174 hours + 12 hours = 186 

hours). 

Before the proposed information 

collection provisions contained in this 

draft guidance become effective, FDA 

will publish a notice in the Federal 

Register announcing OMB’s decision to 

approve, modify, or disapprove the 

information collection provisions. An 

agency may not conduct or sponsor, and 

a person is not required to respond to, 

a collection of information unless it 

displays a currently valid OMB control 

number. 

This draft guidance also refers to 

previously approved collections of 

information found in FDA regulations. 

The collections of information in 

§§ 101.3, 101.4, 101.5, 101.9, 101.22, 

and 101.105 have been approved under 

OMB Control No. 0910–0381. 

III. Comments 

Interested persons may submit written 

or electronic comments regarding this 

draft guidance document, including 

comments regarding the proposed 

collection of information. Written 

comments should be submitted to the 

Division of Dockets Management (see 

ADDRESSES). Electronic comments 

should be submitted to http:// 

www.regulations.gov. Submit a single 

copy of electronic comments or two 

paper copies of any mailed comments, 

except that individuals may submit one 

paper copy. Comments are to be 

identified with the docket number 

found in brackets in the heading of this 

document. Received comments may be 

seen in the Division of Dockets 

Management between 9 a.m. and 4 p.m., 

Monday through Friday. 

IV. Electronic Access 

Persons with access to the Internet 

may obtain the draft guidance at http:// 

www.fda.gov/FoodGuidances. 

V. References 

We have placed the following 

references on display in the Division of 

Dockets Management (see ADDRESSES). 

The references may be seen between 9 

a.m. and 4 p.m., Monday through 

Friday. FDA has verified the Web site 

addresses, but it is not responsible for 

any subsequent changes to the Web site 

addresses after this document publishes 

in the Federal Register. 

1. FDA Compliance Policy Guide (CPG) 

7101.04 (Dealcoholized Wine and Malt 

Beverages- Labeling), available at http:// 

www.fda.gov/ICECI/ComplianceManuals/ 

CompliancePolicyGuidanceManual/ 

ucm074430.htm and CPG 7101.05 (Labeling 

—Diluted Wines and Cider with Less Than 

7% Alcohol), available at http:// 

www.fda.gov/ICECI/ComplianceManuals/ 

CompliancePolicyGuidanceManual/ 

ucm074431.htm. 

2. Memorandum of Understanding 225– 

88–2000 between FDA and Bureau of 

Alcohol, Tobacco and Firearms, available at 

http://www.fda.gov/AboutFDA/Partnerships

Collaborations/MemorandaofUnderstanding

MOUs/DomesticMOUs/ucm116370.htm. 

3. TTB Ruling 2008–3 dated July 7, 2008, 

available at http://www.fda.gov/AboutFDA/ 

PartnershipsCollaborations/Memorandaof

UnderstandingMOUs/DomesticMOUs/ 

ucm116370.htm. 

Dated: August 11, 2009. 

Jeffrey Shuren, 

Associate Commissioner for Policy and 

Planning. 

[FR Doc. E9–19640 Filed 8–14–09; 8:45 am] 

BILLING CODE 4160–01–S 

DEPARTMENT OF HEALTH AND 

HUMAN SERVICES 

National Institutes of Health 

Government-Owned Inventions; 

Availability for Licensing 

AGENCY: National Institutes of Health, 

Public Health Service, HHS. 

ACTION: Notice. 

SUMMARY: The inventions listed below 

are owned by an agency of the U.S. 

Government and are available for 

licensing in the U.S. in accordance with 

35 U.S.C. 207 to achieve expeditious 

commercialization of results of 

Federally-funded research and 

development. Foreign patent 

applications are filed on selected 

inventions to extend market coverage 

for companies and may also be available 

for licensing. 

ADDRESSES: Licensing information and 

copies of the U.S. patent applications 

listed below may be obtained by writing 

to the indicated licensing contact at the 

Office of Technology Transfer, National 

Institutes of Health, 6011 Executive 

Boulevard, Suite 325, Rockville, 

Maryland 20852–3804; telephone: 301/ 

496–7057; fax: 301/402–0220. A signed 

Confidential Disclosure Agreement will 

be required to receive copies of the 

patent applications. 

Development of a New Carbohydrate 

Antibody to GalNac1–3Gal 

Description of Technology: The 

present invention provides a 

monoclonal antibody that binds 

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Federal Register / Vol. 74, No. 157 / Monday, August 17, 2009 / Notices 41441 

specifically to the antigen GalNAc1– 

3Gal present in human cancers, 

including squamous cell cancer, human 

cervical cancer, human esophageal 

cancer, human laryngeal cancer, and 

human skin cancer. The antibody can be 

used to monitor expression of this 

carbohydrate for a variety of purposes. 

In immunohistochemical staining of 

tissues, the antibody stains a variety of 

carcinomas, with good staining of 

cervical, larynx, and skin squamous cell 

carcinomas. Positive antibody staining 

of cervical cancer tissue correlates with 

a good prognosis (increased 5 year 

survival rate) and as such may be useful 

as a prognostic marker. NCI also has the 

parent cell line for production of the 

antibody and several other variant 

antibodies with similar reactivity. 

Applications 

• Cervical cancer diagnostics and 

prognosis. 

• A research tool. 

Market 

• Cancer is the second leading cause 

of death in the U.S.A. There is an acute 

need for cancer biomarkers that can be 

detected from clinically relevant 

samples and used for early diagnosis, 

therapeutic follow-up and prognosis of 

malignant diseases. 

• Estimated new cases and deaths 

from cervical (uterine cervix) cancer in 

the United States in 2009: 11,270 new 

cases; 4,070 deaths according to the 

National Cancer Institute. 

Inventors: Jeffrey C. Gildersleeve et al. 

(NCI). 

Patent Status: U.S. Provisional 

Application No. 61/165, 675 filed 01 

Apr 2009 (HHS Reference No. E–058– 

2009/0–US–01). 

Licensing Status: Available for 

licensing. 

Licensing Contact: Betty B. Tong, 

Ph.D.; 301–594–6565; 

tongb@mail.nih.gov. 

Deletion of the Beta 20–21 Loop in HIV 

GP120 Exposes the CD4 Binding Site for 

Improved Antibody Binding and 

Antibody 

Description of Technology: With the 

number of individuals infected with 

HIV approaching nearly one percent 

(1%) of the world’s population, an 

effective vaccine is urgently needed. As 

an enveloped virus, HIV hides most of 

its proteins and genes from humoral 

recognition behind a protective lipid 

bilayer. An available exposed viral 

target for neutralizing antibodies is the 

envelope spike. Genetic, immunologic 

and structural studies of the HIV 

envelope glycoproteins have revealed 

extraordinary diversity as well as 

multiple overlapping mechanisms of 

humoral evasion, including selfmasquerading glycan, immunodominant 

variable loops, and conformational 

masking. These evolutionarily-honed 

barriers of antigenic diversity and 

immune evasion have confounded 

traditional means of vaccine 

development. It is believed that 

immunization with effectively 

immunogenic HIV gp120 envelope 

glycoprotein can elicit a neutralizing 

response directed against gp120, and 

thus HIV. The need exists for 

immunogens that are capable of eliciting 

a protective immune response. 

This application claims isolated 

immunogens, including variant gp120 

polypeptides and the use of these 

polypeptides to induce an immune 

response to HIV. This application also 

claims virus-like particles including the 

variant gp120 polypeptides. More 

specifically, this application claims 

virus-like particles including variant 

gp120–HBsAg hybrid constructs, which 

may also include at least one TLR 

ligand. 

Application: Development of Human 

Immunodeficiency Virus (HIV) 

vaccines, therapeutics and diagnostics. 

Advantages: VLP gp120 vaccine, use 

of HBsAg vector for delivery. 

Development Status: Vaccine 

candidates have been synthesized and 

preclinical studies have been 

performed. 

Inventor: Ira Berkower (FDA). 

Publication: I Berkower et al. Targeted 

deletion in the beta20-beta21 loop of 

HIV envelope glycoprotein gp120 

exposes the CD4 binding site for 

antibody binding. Virology. 2008 Aug 

1;377(2):330–338. 

Patent Status: U.S. Provisional 

Application 61/155,782 filed 26 Feb 

2009 (HHS Reference No. E–299–2008/ 

0–US–01). 

Licensing Status: Available for 

licensing. 

Licensing Contact: Peter A. Soukas, 

J.D.; 301–435–4646; 

soukasp@mail.nih.gov. 

Multilayered RF Coil System for 

Improving Transmit B1 Field 

Homogeneity in High-Field MRI 

Description of Technology: Available 

for licensing and commercial 

development is a multilayered radiofrequency (RF) coil system for 

improving the transmit B1 field 

homogeneity for magnetic resonance 

imaging (MRI) at high field strengths. 

The current invention aims at 

manipulating the inhomogeneous 

profile of the transmit B1 field, which 

causes MR images to become less 

uniform as the magnetic field strength is 

increased, by utilizing an inner array of 

RF elements (e.g. surface coils) within 

and coupled to an outer transmit unit 

(e.g. a birdcage coil or other volume 

coil). Improvement in B1 field 

homogeneity is achieved by tuning the 

surface coils of the inner layer to an 

appropriate resonant frequency and 

then passively coupling them to the 

outer-layer volume coil. Furthermore, 

the amount of coupling is determined 

by the intrinsic properties of the 

transmit unit and can be adjusted 

accordingly. The current design 

provides an effective approach for 

reducing B1 field homogeneity at high 

fields and can be implemented without 

the need for independent RF channels, 

thereby reducing MRI system 

complexity. Furthermore it can be 

readily implemented on existing MRI 

coil systems by detuning surface coils 

rather than decoupling them during the 

transmit phase. 

Applications 

• High-Field MRI. 

• Improvement of MR Image 

Uniformity. 

Market: Manufacturers of MRI 

hardware and accessories. 

Development Status: The technology 

is ready to be used and requires only 

testing in humans for development. 

Inventors: Alan Koretsky, Jeff Duyn, 

Shumin Wang, Hellmut Merkle 

(NINDS). 

Publications 

1. S Wang and JH Duyn, ‘‘ThreeDimensional Automatic Mesh Generation for 

Hybrid Electromagnetic Simulations’’, IEEE 

Antennas and Propagation Magazine, Vol. 51, 

pp. 71–85, April 2009. 

2. H Merkle, J Murphy-Boesch, S Wang, P 

van Gelderen, AP Koretsky, and JH Duyn, 

‘‘Graded Transmit B1 Field Correction at 7T 

Using Tunable Inner Elements’’, ISMRM 

High-field Workshop, Rome, Italy, October 

2008. 

3. H Merkle, S Wang, P van Gelderen, TQ 

Li, J Murphy-Boesch, AP Koretsky, and JH 

Duyn, ‘‘B1 Transmit Field Correction at 7T 

Using Coupled Inner Elements’’, ISMRM 

2008, Toronto, Canada, May, 2008. 

4. S Wang, H Merkle, AP Koretsky, and JH 

Duyn, ‘‘Improving High-Field Transmit B1 

Field Homogeneity Using Coupled Inner 

Elements’’, 15th Scientific Meeting and 

Exhibition, International Society for 

Magnetic Resonance in Medicine, Berlin, 

Germany, May 2007. 

Patent Status 

• U.S. Provisional Application No. 

60/900,972 filed 13 Feb 2007 (HHS 

Reference No. E–020–2007/0–US–01). 

• PCT Application No. PCT/US2008/ 

001911 filed 13 Feb 2008 (HHS 

Reference No. E–020–2007/0–PCT–02). 

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41442 Federal Register / Vol. 74, No. 157 / Monday, August 17, 2009 / Notices 

Licensing Status: Available for 

licensing. 

Licensing Contact: John Stansberry, 

Ph.D.; 301/435–5236; 

stansbej@mail.nih.gov. 

Collaborative Research Opportunity: 

The Laboratory of Functional and 

Molecular Imaging (LFMI) at the 

National Institute of Neurological 

Disorders and Stroke (NINDS) is seeking 

statements of capability or interest from 

parties interested in collaborative 

research to further develop, evaluate, or 

commercialize MRI applications that 

aim to provide novel functional and 

molecular imaging techniques to study 

brain structure and function. Please 

contact Melissa Maderia, Ph.D. at 

maderiam@mail.nih.gov or 301–451– 

3943 for more information. 

Quantifying Gene Relatedness via 

Nonlinear Prediction of Gene 

Expression Levels 

Description of Technology: This 

invention relates to a new way to 

analyze the function of a newly 

identified gene. Working together, the 

genes within a genomic system 

constitute a control system for 

modulating gene expression activity and 

protein production. Regulation within 

this control system depends on 

multivariate relations among genes. 

Therefore, a key window into 

understanding genomic activity is to 

quantify the manner in which the 

expression profile among a set of genes 

can be used to predict the expression 

levels of other genes. This invention 

provides the experimental, statistical, 

and computational basis for nonlinear 

and linear multivariate prediction and 

co-determination among gene 

expression levels, and it is applied in 

the context of cDNA microarrays. Using 

these measures of multi-gene 

interactivity, it is possible to infer 

genomic regulatory mechanisms and 

thereby identify the manner in which 

genetic malfunction contributes to 

cancer and developmental anomalies. 

Inventors: Michael Bittner (NHGRI), 

Yidong Chen (NHGRI), et al. 

Patent Status: U.S. Patent No. 

7,003,403 issued 21 Feb 2006 (HHS 

Reference No. E–059–2000/0–US–01). 

Licensing Status: Available for 

licensing. 

Licensing Contact: Jeffrey A. James, 

Ph.D.; 301–435–5474; 

jeffreyja@mail.nih.gov. 

Isolated Helicobacter hepaticus 

Description of Technology: An 

isolated bacterium of the genus 

Helicobacter, characterized by the 16S 

ribosomal RNA encoding nucleotide 

sequence defined in the Sequence 

Listing as SEQ ID NO:1 is provided. An 

isolated nucleic acid having the 

nucleotide sequence defined in the 

Sequence Listing as SEQ ID NO:1 is 

provided. Such a nucleic acid can be 

used for diagnosis of infection with H. 

hepaticus. A nucleic acid of the present 

invention in a vector suitable for 

expression of the nucleic acid is also 

provided. The vector can be in a host 

suitable for expressing the nucleic acid. 

A purified antigen specific for H. 

hepaticus is provided. A method of 

making an animal model for chronic 

Helicobacter infection is also provided. 

Inventors: Jerrold M. Ward et al. 

(NCI). 

Patent Status: U.S. Patent 5,610,060 

issued 11 Mar 1997 (HHS Reference No. 

E–010–1994/0–US–01). 

Licensing Status: Available for 

licensing. 

Licensing Contact: Jeffrey A. James, 

Ph.D.; 301–435–5474; 

jeffreyja@mail.nih.gov. 

Recombinant Vaccines Based on 

Poxvirus Vectors 

Description of Technology: The 

technology offered for licensing is 

foundational in the area of recombinant 

DNA vaccines. In the last several years, 

facilitated through a licensing program 

of the NIH, the technology has been 

broadly applied in the development and 

commercialization of several novel 

human and veterinary vaccines in the 

areas of infectious disease as well as 

cancer therapeutics. The NIH wishes to 

expand its licensing program of the 

subject technology in a variety of 

applications that will benefit public 

health. 

Briefly, the technology describes and 

claims methods of constructing 

recombinant vaccines utilizing any 

recombinant poxvirus, and in particular 

vaccinia virus (i.e. Modified Vaccinia 

Ankara or other strains) as a backbone 

that carries a foreign DNA. The foreign 

DNA can be related to a viral pathogen 

for example, or to a tumor-associated 

antigen. Upon administration of the 

recombinant virus to a human or animal 

subject, the foreign gene is expressed in 

vivo to elicit an immune response 

against the respective pathogen or the 

respective tumor. 

The technology takes advantage of the 

unique properties of poxviruses as a 

delivering vehicle and of the ease of 

preparation of such constructs. 

The applications of this technology 

have been extensively covered by many 

publications, including more than 100 

publications from the inventor (see 

sampling below). The publications 

cover a wide variety of vaccines such as 

HIV, papilloma virus, influenza and 

others. 

Note: Samples of plasmids and vaccinia 

virus used in the invention are deposited in 

the American Type Culture Collection and in 

the NIH and may be available for licensees 

upon request. 

Applications 

• Prophylactic and/or therapeutic 

vaccines. 

• Infectious disease and cancer 

Human and animal vaccines. 

• Immunotherapy. 

• Protein expression system. 

Advantages: Recombinant Poxviruses 

vectors in DNA vaccines have exhibited 

some advantages as compared to other 

viral vectors such as adenovirus, 

retrovirus or papillomavirus: 

• High safety profile. 

• Wide host range. 

• Ability to accommodate large 

amounts of foreign DNA including 

multiple genes. 

• No loss of infectivity upon insertion 

of foreign DNA. 

• Unique transcriptional regulatory 

signals of the virus facilitates flexibility 

in genome strategy. 

In addition, the following properties 

have been demonstrated: 

• Immunization with vacciniavectored vaccines provides long-lasting 

protection. 

• Vaccinia virus is very stable and no 

cold-chain is required in distribution 

network. 

• Induce mucosal immune response. 

• Induce humeral and cellular 

immunity. 

Development Status: Fully developed. 

The technology has been already 

successfully implemented in 

commercial veterinary vaccines (i.e. 

rabies) and is in advance clinical trials 

in several companies in the area of 

cancer immunotherapy. 

Market 

• The market for vaccines against 

infectious diseases is in the multibillion 

dollars and keeps growing at an annual 

rate of approximately 40%. This is 

compared to approximately 8% growth 

for the overall pharmaceutical 

companies. Live recombinant vaccines 

as offered in the subject technology offer 

an attractive alternative to existing 

vaccines as well as for future vaccines 

and therefore may be commercially 

attractive for vaccine and 

pharmaceutical companies. 

• The market for therapeutic cancer 

vaccines, which is the subject of this 

technology, is expected to mirror the 

growth seen in the monoclonal antibody 

market and reach sales in excess of $5 

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Federal Register / Vol. 74, No. 157 / Monday, August 17, 2009 / Notices 41443 

billion by 2012 according to some 

reports. 

Overall, the potential commercial 

opportunity based on the subject 

technology is immense. 

Inventors: Bernard Moss et al. 

(NIAID). 

Publications: The inventor, Dr. 

Bernard Moss, is an author of more than 

100 publications in the area covered by 

the subject patents. The following is just 

a sampling of his publications in the 

area: 

1. B Moss and PL Earl. Overview of the 

vaccinia virus expression system. Curr Protoc 

Mol Biol. 2002 Nov; Chapter 16: Unit16.15. 

2. HL Robinson, S Sharma, J Zhao, S 

Kannanganat, L Lai, L Chennareddi, T Yu, 

DC Montefiori, RR Amara, LS Wyatt, B Moss. 

Immunogenicity in macaques of the clinical 

product for a clade B DNA/MVA HIV 

vaccine: elicitation of IFN-gamma, IL–2, and 

TNF-alpha coproducing CD4 and CD8 T 

cells. AIDS Res Hum Retroviruses. 2007 

Dec;23(12):1555–1562. 

3. LS Wyatt, PL Earl, J Vogt, LA Eller, D 

Chandran, J Liu, HL Robinson, B Moss. 

Correlation of immunogenicities and in vitro 

expression levels of recombinant modified 

vaccinia virus Ankara HIV vaccines. Vaccine 

2008 Jan 24;26(4):486–493. 

4. M Hebben, J Brants, C Birck, JP Samama, 

B Wasylyk, D Spehner, K Pradeau, A Domi, 

B Moss, P Schultz, R Drillien. High level 

protein expression in mammalian cells using 

a safe viral vector: modified vaccinia virus 

Ankara. Protein Expr Purif. 2007 

Dec;56(2):269–278. 

Patent Status: The technology is 

described and claimed in the following 

four (4) patents that were issued in the 

U.S. in 2006 (HHS Reference E–552– 

1982/2): 

1. USPN 6,998,252 issued February 

14, 2006, ‘‘Recombinant Poxviruses 

Having Foreign DNA Expressed under 

the Control of Poxvirus Regulatory 

Sequences’’. 

2. USPN 7,015,024 issued March 21, 

2006, ‘‘Compositions Containing 

Recombinant Poxviruses Having Foreign 

DNA Expressed Under the Control of 

Poxvirus Regulatory Sequences’’. 

3. USPN 7,045,313 issued May 16, 

2006, ‘‘Recombinant Vaccinia Virus 

Containing Chimeric Gene Having 

Foreign DNA Flanked by Vaccinia 

Regulatory DNA’’. 

4. USPN 7,045,136 issued May 16, 

2006, ‘‘Methods of Immunization Using 

Recombinant Poxviruses Having Foreign 

DNA Expressed Under the Control of 

Poxvirus Regulatory Sequences’’. 

Licensing Status: Available for 

licensing. 

Licensing Contacts: Uri Reichman, 

Ph.D., MBA; 301–435–4616; 

ur7a@nih.gov; RC Tang, JD, LLM; 301– 

435–5031; tangrc@mail.nih.gov. 

Dated: August 10, 2009. 

Richard U. Rodriguez, 

Director, Division of Technology Development 

and Transfer, Office of Technology Transfer, 

National Institutes of Health. 

[FR Doc. E9–19693 Filed 8–14–09; 8:45 am] 

BILLING CODE 4140–01–P 

DEPARTMENT OF HEALTH AND 

HUMAN SERVICES 

National Institutes of Health 

Government-Owned Inventions; 

Availability for Licensing 

AGENCY: National Institutes of Health, 

Public Health Service, HHS. 

ACTION: Notice. 

SUMMARY: The inventions listed below 

are owned by an agency of the U.S. 

Government and are available for 

licensing in the U.S. in accordance with 

35 U.S.C. 207 to achieve expeditious 

commercialization of results of 

Federally-funded research and 

development. Foreign patent 

applications are filed on selected 

inventions to extend market coverage 

for companies and may also be available 

for licensing. 

ADDRESSES: Licensing information and 

copies of the U.S. patent applications 

listed below may be obtained by writing 

to the indicated licensing contact at the 

Office of Technology Transfer, National 

Institutes of Health, 6011 Executive 

Boulevard, Suite 325, Rockville, 

Maryland 20852–3804; telephone: 301/ 

496–7057; fax: 301/402–0220. A signed 

Confidential Disclosure Agreement will 

be required to receive copies of the 

patent applications. 

Superior Method of Preparing 

Dendrimers for Use as Magnetic 

Resonance Imaging (MRI) Contrast 

Agents 

Description of Technology: There is a 

need to develop more efficient 

gadolinium-containing (Gd) contrast 

agents for magnetic resonance imaging 

(MRI) as the small molecules presently 

used clinically have the disadvantage of 

being rapidly cleared from circulation 

and excreted by the kidneys. 

Dendrimer-based macromolecular 

MRI contrast agents in which numerous 

chelated Gd ions are covalently attached 

to a multivalent dendritic architecture 

are a promising class of diagnostic 

agents for medical imaging applications. 

Clinical development of the dendrimerbased agents has been limited as the 

current methods for synthesizing them 

result in a complex mixture that 

produces inconsistent imaging results. 

The present technology describes the 

development of a new method of preforming the metal-ligand chelate in 

alcohol prior to conjugation to the 

dendrimer. Specifically, for example, a 

1B4M–DTPA–Gd chelate is preformed 

in methanol and purified prior to 

conjugation to a PAMAM dendrimer 

molecule. This results in a dendrimerbased MRI contrast agent with greatly 

improved homogeneity and stability, 

and possessing an unexpectedly greater 

molar relaxivity that allows the use of 

much less of the agent than previously 

required to obtain comparable images. 

The use of a DOTA–Gd chelate is 

equally possible. 

Application: An improved method for 

synthesis of dendrimer-based MRI 

contrast agents that is greatly suited for 

clinical development. 

Advantages 

• Efficient preparation of stable 

dendrimer-based contrast agents 

suitable for medical imaging. 

• Higher molar relaxivity translates 

into a lower dosage needed for imaging. 

• Ability to control dendrimer size 

conducive for development of 

compartment-specific imaging agents. 

Market: Dendrimers show particular 

promise for the development of cancer 

imaging agents. The ability to 

exquisitely control dendrimer size 

enables delivering them to specific 

compartments such as small tumors 

allowing for early cancer detection. 

Gadolinium (Gd) chelates are 

extensively used as MRI contrast agents 

and have proven to be safe. The 

combination of gadolinium chelates 

with dendrimer chemistry could greatly 

enhance the versatility of MRI imaging. 

Inventors: Kido Nwe and Martin W. 

Brechbiel (NCI). 

Publications 

1. K Nwe, H Xu, CA Regino, M Bernardo, L 

Ileva, L Riffle, KJ Wong, MW Brechbiel. 

A new approach in the preparation of 

dendrimer-based bifunctional 

diethylenetriaminepentaacetic acid MR 

contrast agent derivatives. Bioconjugate 

Chem. 2009 Jul;20(7):1412–1418. 

2. OA Gansow, MW Brechbiel, MA 

Magerstadt. Complexes of functionalized 

tetraazacyclododecane chelates with 

bismuth, lead, yttrium, actinium, or 

lanthanide metal ions. U.S. Patent 

5,428,154 issued 27 Jun 1995. 

Patent Status: U.S. Provisional 

Application No. 61/180,327 filed 21 

May 2009 (HHS Reference No. E–207– 

2009/0–US–01). 

Related Technology: OA Gansow, MW 

Brechbiel, MA Magerstadt, ‘‘Complexes 

of Functionalized 

Tetraazacyclododecane Chelates with 

Bismuth, Lead, Yttrium, Actinium, or 

mstockstill on DSKH9S0YB1PROD with NOTICES