Federal Register / Vol. 69, No. 232 / Friday, December 3, 2004 / Notices 70267

Licensing Contact: Norbert Pontzer; 

(301) 435–5502; 

pontzern@mail.nih.gov

The simple diatomic molecule nitric 

oxide (NO) is known to play a diverse 

and complex role in cellular physiology. 

NCI scientists have previously produced 

a number of nucleophile/nitric oxide 

adducts (diazeniumdiolates) that 

spontaneously dissociate at 

physiological pH to release nitric oxide 

by stable first order kinetics. These 

compounds are finding diverse 

therapeutic uses as pharmacological 

agents. Growing evidence suggests that 

redox related forms of NO such as 

nitroxyl (HNO) also have a rich 

pharmacological potential and may 

complement that of NO. The present 

invention provides compounds that 

release both NO and HNO under 

physiological conditions, compositions 

comprising those compounds and 

methods of using the compounds alone 

and in conjunction with medical 

devices such as stents to treat disease. 

Included among the compositions 

claimed is a glycosylated prodrug 

derivative that can be cleaved to active 

form by b–D-glucosidase (J. Am. Chem. 

Soc. 2004, 126, 12880–12887). 

A Method With Increased Yield for 

Production of Polysaccharide-Protein 

Conjugate Vaccines Using Hydrazide 

Chemistry 

Che-Hung Robert Lee and Carl Frasch 

(FDA), U.S. Provisional Application 

No. 60/493,389 filed 06 Aug 2003 

(DHHS Reference No. E–301–2003/0–

US–01)

Licensing Contact: Peter Soukas; (301) 

435–4646; soukasp@mail.nih.gov.

Current methods for synthesis and 

manufacturing of polysaccharideprotein conjugate vaccines employ 

conjugation reactions with low 

efficiency (about twenty percent). This 

means that up to eighty percent of the 

added activated polysaccharide (PS) is 

lost. In addition, inclusion of a 

chromatographic process for 

purification of the conjugates from 

unconjugated PS is required. 

The present invention utilizes the 

characteristic chemical property of 

hydrazide groups on one reactant to 

react with aldehyde groups or cyanate 

esters on the other reactant with an 

improved conjugate yield of at least 

sixty percent. With this conjugation 

efficiency the leftover unconjugated 

protein and polysaccharide would not 

need to be removed and thus the 

purification process of the conjugate 

product can be limited to diafiltration to 

remove the by-products of small 

molecules. The new conjugation 

reaction can be carried out within one 

or two days with reactant 

concentrations between 1 and 25 mg/mL 

at PS/protein ratios from 1:2 to 3:1, at 

temperatures between 4 and 40 degrees 

Centigrade, and in a pH range of 5.5 to 

7.4, optimal conditions varying from PS 

to PS. 

Therefore, this invention can reduce 

the cost of conjugate vaccine 

manufacture.

Dated: November 24, 2004. 

Steven M. Ferguson, 

Director, Division of Technology Development 

and Transfer, Office of Technology Transfer, 

National Institutes of Health.

[FR Doc. 04–26596 Filed 12–2–04; 8:45 am] 

BILLING CODE 4140–01–P

DEPARTMENT OF HEALTH AND 

HUMAN SERVICES 

National Institutes of Health 

Prospective Grant of Exclusive 

License: Dendrimer Based MRI 

Contrast Agents

AGENCY: National Institutes of Health, 

Public Health Service, DHHS

ACTION: Notice.

SUMMARY: This is notice, in accordance 

with 35 U.S.C. 209(c)(1) and 37 CFR 

404.7(a)(1)(i), that the National 

Institutes of Health (NIH), Department 

of Health and Human Services, is 

contemplating the grant of an exclusive 

worldwide license to practice the 

invention embodied in:

E–151–2002 ‘‘Methods for Functional 

Kidney Imaging Using Dendrimer Conjugate 

Agents,’’ U.S. Patent App. Serial No. 10/

229,316 and International Patent Application 

No. PCT/US02/27297; 

E–240–2001 ‘‘Macromolecular Imaging 

Agents for Liver Imaging,’’ U.S. Patent App. 

Serial No. 10/481,706, International Patent 

Application No. PCT/US02/20118, European 

Patent Application 02752092.3; 

E–338–2003 ‘‘Method for Imaging the 

Lymphatic Systems Using Dendrimer-Based 

Contrast Agents,’’ U.S. Patent App. Serial No. 

10/756,948; 

E–317–2004 ‘‘Synthetic Metal Ion 

Chelating Amino Acid Suitable for Use in 

Solid Phase Peptide Synthesis.’’ Filed 

October 4, 2004 (Serial Number to be 

determined);

to Dendritic NanoTechnologies, Inc., a 

Delaware corporation having its 

principle place of business in Mount 

Pleasant, Michigan. The United States of 

America is the assignee to the patent 

rights of the above inventions. 

The contemplated exclusive license 

may be granted in the field of use of 

MRI imaging contrast agents.

DATES: Only written comments and/or 

applications for a license received by 

the NIH Office of Technology Transfer 

on or before February 1, 2005 will be 

considered.

ADDRESSES: Requests for a copy of the 

patent application, inquiries, comments 

and other materials relating to the 

contemplated license should be directed 

to: Michael A. Shmilovich, Esq., Office 

of Technology Transfer, National 

Institutes of Health, 6011 Executive 

Boulevard, Suite 325, Rockville, MD 

20852–3804; Telephone: (301) 435–

5019; Facsimile: (301) 402–0220; E-mail: 

shmilovm@mail.nih.gov. A signed 

confidentiality nondisclosure agreement 

will be required to receive copies of the 

patent applications.

SUPPLEMENTARY INFORMATION: The patent 

applications intended for licensure 

disclose and/or cover the following: 

E–151–2002—Methods for Functional 

Kidney Imaging Using Dendrimer 

Conjugate Agents 

The invention is a method for 

functional kidney imaging using small 

dendrimer-based MRI contrast agents 

that transiently accumulate in renal 

tubules. The accumulation enables 

visualization of renal structure and 

function, permitting assessment of 

structural and functional damage to the 

kidneys. Six small dendrimer-based 

MRI contrast agents have been 

synthesized, and their 

pharmacokinetics, whole body retention 

and renal MRI images were evaluated in 

mice. Surprisingly, despite having 

unequal renal clearance properties, all 

of the dendrimer agents clearly 

visualized the renal anatomy and 

proximal straight tubules of the mice 

better than Gd-[DTPA]-dimeglumine. 

Dendrimer conjugate contrast agents 

prepared from PAMAM–G2D, DAB–

G3D and DAB–G2D dendrimers were 

excreted rapidly and may be acceptable 

for use in clinical applications. 

E–240–2001—Macromolecular Imaging 

Agents for Liver Imaging

The invention is a macromolecular 

imaging agent comprising a 

polyalkylenimine dendrimer conjugated 

to a metal chelate that has been shown 

to be an excellent agent for imaging liver 

micrometastases as small as about 0.3 

mm in a magnetic resonance image of 

the human liver. In a particular 

embodiment, the imaging agent is a 

diaminobutane-core polypropylenimine 

dendrimer having surface amino groups 

conjugated to gadolinium metal 

chelates. The invention makes possible 

the earlier detection of metastatic 

disease, leading to earlier application of 

a therapeutic regime and an improved 

prognosis. Accordingly, the method of 

70268 Federal Register / Vol. 69, No. 232 / Friday, December 3, 2004 / Notices 

using the imaging agent in the detection 

of metastatic disease in the liver is also 

within the scope of the invention. 

E–338–2003—Method for Imaging the 

Lymphatic Systems Using DendrimerBased Contrast Agents 

The invention is a 4D method of 

Magnetic Resonance lymphography 

using a 240kD contract agent based on 

generation-6 polyamidoamine 

dendrimer (G6). The use of the G6 

contrast agent greatly enhances 

visualization of lymphatics and node 

drainage associated with mammary 

tumors and further aids in the diagnosis 

of metastatic breast cancer. After direct 

injection of the G6 contrast agent into 

mice, lymphatics and nodes were 

visualized in both spontaneous (HER2 

transgenic mouse) and xenografted (PT–

18) breast tumors to metastatic lymph 

nodes. The conventional clinically 

approved MRI contract agent, Gd-

[DTPA]-dimeglumine (<1kD) was 

unable (in murine models) to depict 

lymphatics when used in conjunction 

with the same imaging system. The 

invention provides a novel method of 

using a known contrast agent to 

visualize lymphatic drainage that has 

not been previously reported. 

E–317–2004—Synthetic Metal Ion 

Chelating Amino Acid Suitable for Use 

in Solid Phase Peptide Synthesis 

The invention is metal chelators, 

metal chelator-targeting moiety 

complexes, metal chelator-targeting 

moiety-metal conjugates, kits, and 

methods of preparing them. These 

chelators are useful in diagnosing and/

or treatment of cancer and thrombosis. 

The metal chelators may be used in 

conventional synthetic methods to form 

targeting moieties (e.g., peptides, 

proteins, and Starburst polyamidoamine 

dendrimers (PAMAM), capable of 

conjugating diagnostic and/or 

therapeutic metals. The formulae for 

two such chelators is shown below:

The prospective exclusive license will 

be royalty bearing and will comply with 

the terms and conditions of 35 U.S.C. 

209 and 37 CFR 404.7. The prospective 

exclusive license may be granted unless, 

within sixty (60) days from the date of 

this published notice, NIH receives 

written evidence and argument that 

establishes that the grant of the license 

would not be consistent with the 

requirements of 35 U.S.C. 209 and 37 

CFR 404.7. 

Properly filed competing applications 

for a license filed in response to this 

notice will be treated as objections to 

the contemplated license. Comments 

and objections submitted in response to 

this notice will not be made available 

for public inspection, and, to the extent 

permitted by law, will not be released 

under the Freedom of Information Act, 

5 U.S.C. 552.

Dated: November 24, 2004. 

Steven M. Ferguson, 

Director, Division of Technology Development 

and Transfer, Office of Technology Transfer, 

National Institutes of Health.

[FR Doc. 04–26595 Filed 12–2–04; 8:45 am] 

BILLING CODE 4140–01–U

DEPARTMENT OF HEALTH AND 

HUMAN SERVICES 

Public Health Service 

National Toxicology Program; National 

Institute of Environmental Health 

Sciences (NIEHS); National Institutes 

of Health (NIH) Notice of Additional 

Data and Analyses for the Assessment 

of the Current Validation Status of In 

Vitro Testing Methods for Identifying 

Potential Ocular Irritants 

Summary 

The National Toxicology Program 

(NTP) Interagency Center for the 


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