Title of Invention	"A PEPTIDE IMMUNOGEN-PROTEIN/POLYPEPTIDE CARRIER CONJUGATE AND A METHOD FOR PREPARING THE SAME"
Abstract	The present invention relates to a peptide immunogen-protein/polypeptide carrier conjugate having the formula: wherein, C is a protein/polypeptide carrier selected from the group consisting of CRM197, Streptococcus pyogenes ORF1224, Streptococcus pyogenes ORF1664, Streptococcus pyogenes ORF2452, and Chlamydia pneumoniae ORF T858, Xd is a derivatized functional group of an amino acid residue of the protein/polypeptide carrier P is a peptide immunogen molecule covalently attached to the derivatized functional group of the amino acid residue of the protein/polypeptide carrier, R is a capping molecule covalently attached to the derivatized functional group of an amino acid residue of the protein/polypeptide carrier, wherein the functionality of the carrier is preserved such that it retains its ability to elicit the desired immune responses against the peptide immunogen that would otherwise not occur without a carrier, n is an integer greater than 0, but less than or equal to 38, and p is an integer greater than 0, but less than or equal to 38. The present invention also relates to a method for preparing the said compound.

Title of Invention

"A PEPTIDE IMMUNOGEN-PROTEIN/POLYPEPTIDE CARRIER CONJUGATE AND A METHOD FOR PREPARING THE SAME"

Abstract

The present invention relates to a peptide immunogen-protein/polypeptide carrier conjugate having the formula: wherein, C is a protein/polypeptide carrier selected from the group consisting of CRM197, Streptococcus pyogenes ORF1224, Streptococcus pyogenes ORF1664, Streptococcus pyogenes ORF2452, and Chlamydia pneumoniae ORF T858, Xd is a derivatized functional group of an amino acid residue of the protein/polypeptide carrier P is a peptide immunogen molecule covalently attached to the derivatized functional group of the amino acid residue of the protein/polypeptide carrier, R is a capping molecule covalently attached to the derivatized functional group of an amino acid residue of the protein/polypeptide carrier, wherein the functionality of the carrier is preserved such that it retains its ability to elicit the desired immune responses against the peptide immunogen that would otherwise not occur without a carrier, n is an integer greater than 0, but less than or equal to 38, and p is an integer greater than 0, but less than or equal to 38. The present invention also relates to a method for preparing the said compound.

Full Text	The present invention relates to a peptide immunogen-protein/polypeptide carrier conjugate and a method for preparing the same. CROSS-REFERENCES TO RELATED APPLICATIONS [0001] This application claims the benefit under 35 U.S.C. § 119(e) of U.S. Provisional Patent Application Serial No. 60/530,480, filed December 17,2003, which is incorporated herein by reference in its entirety for all purposes BACKGROUND OF THE INVENTION [0002] The essence of adaptive immunity is the ability of an organism to react to the presence of foreign substances and produce components (antibodies and cells) capable of specifically interacting with and protecting the host from their invasion. An "antigen" or "immunogen" is a substance that is able to elicit this type of immune response and. also is capable of interacting with the sensitized cells and antibodies that are manufactured against it. [0003] Antigens or immunogens are usually macromolecules that contain distinct antigenic sites or "epitopes" that are recognized and interact with the various components of the immune system. They can exist as individual molecules composed of synthetic organic chemicals, proteins, lipoproteins, glycoproteins, RNA, DNA, or polysaccharides, or they may be parts of cellular structures (bacteria or fungi) or viruses (Harlow and Lane 1988a,b, c; Male et al., 1987). [0004] Small molecules like short peptides, although normally able to interact with the products of an immune response, often cannot cause a response on their own. These peptide immunogens or "haptens" as they are also called, are actually incomplete antigens, and, although not able by themselves to cause immunogenicity or to elicit antibody production, can be made immunogenic by coupling them to a suitable carrier. Carriers typically are protein antigens of higher molecular weight that are able to cause an immunological response when adrninistered in vivo. [0005] In an immune response, antibodies are produced and secreted by the B-lymphocytes in conjunction with the T-helper (Th) cells. In me majority of hapten-carrier systems, the B cells produce antibodies that are specific for both the hapten and the carrier. In these cases, the T lymphocytes will have specific binding domains on the carrier, but will not recognize [0090] Preferably, the fragment of Aß administered lacks an epitope that would generate a T-cell response to the fragment Generally, T-cell epitopes are greater than 10 contiguous amino acids. Therefore, preferred fragments of Aß are of size 5-10 or preferably 7-10 contiguous amino acids or most preferably 7 contiguous amino acids; i.e., sufficient length to generate an antibody response without generating a T-cell response. Absence of T-cell epitopes is preferred because these epitopes are not needed for immunogenic activity of fragments, and may cause an undesired inflammatory response in a subset of patients (Anderson et al, (2002) J. Immunol. 168,3697-3701; Senior (2002) Lancet Neurol. 1,3). [0091] Fragment Aß1 5-25 and subfragments of 7-8 contiguous amino acids thereof are preferred because these peptides consistently generate a high immunogenic response to Aß peptide. These fragments include Apl6-22, Apl6-23, Aß16-24, Aß17-23, Aß17-24, Aßl8-24, and Aß18-25. Particularly preferred Aß15-25 subfragments are 7 contiguous amino acids in length. The designation AJ315-21 for example, indicates a fragment including residues 15-21 of Aß and lacking other residues of Aß. and preferably 7-10 contiguous amino acids. These fragments can generate an antibody response that includes end-specific antibodies. [0092] Peptide immunogens of Aßs require screening for activity in clearing or preventing amyloid deposits (see WO 00/72880 (IN 206050), which is incorporated herein in its entirely for all purposes). Administration of N-terminal fragments of Aß induces the production of antibodies that Tecognize AJ3 deposits in vivo and in vitro. Fragments lacking at least one, and sometimes at least 5 or 10 C-terminal amino acids present in naturally occurring forms of Aß are used in some methods. For example, a fragment lacking 5 amino acids from the C-terminal end of Aß43 includes the first 38 amino acids from the N-terminal end of Aß. [0093] Unless otherwise indicated, reference to Ap includes the natural human amino acid sequences indicated above as well as analogs including allelic, species and induced variants. Analogs typically differ from naturally occurring peptides at one, two or a few positions, often by virtue of conservative substitutions. Analogs typically exhibit at least 80 or 90% sequence identity with natural peptides. Some analogs also include unnatural amino acids or modifications of N- or C-tcrminal amino acids at one, two, or a few positions. For example, the natural aspartic acid residue at position 1 and/or 7 of Aß can be replaced with iso-aspartic acid. [0094} Examples of unnatural amino acids are D, alpha, alpha-disubstituted amino acids, N-alkyl amino acids, lactic acid, 4-hydroxyproline, gamma-carboxyglutamate, epsilon- 1,N,N-trimethyllysihe, epsilon-N-acetyllysine, O-phosphoserine, N-acetylserine, N-formylmethiomne, 3-methylhistidine, 5-hydroxylysine, omega-N-methylarginine, ß-alanine, ornithine, norleucine, norvaline, hydroxproline, thyroxine, gamma-arnino butyric acid, homoserine, citrulline, and isoaspartic acid. Immunogenic peptides also include analogs of Aß and fragments thereof. Some therapeutic agents of the invention are all-D peptides, e.g., all-D Aß all-D Aß fragment, or analogs of all-D Aß or all-D Aß fragment Fragments and analogs can be screened for prophylactic or therapeutic efficacy in transgenic animal models in comparison with untreated or placebo controls as described in WO 00/72880 (IN 206050). [0095] Peptide immunogens also include longer polypeptides that include, for example, an immunogenic of Aß peptide, together with other amino acids. For example, preferred immunogenic peptides include fusion proteins comprising a segment of Ap linked to a heterologous amino acid sequence that induces a helper T-cell response against the heterologous amino acid sequence and thereby a B-cell response against the Ap segment. Such nolypeptides can be screened for prophylactic or therapeutic efficacy in animal models in comparison with untreated or placebo controls as described in WO 00/72880 (IN 206050). [0096] The Aß peptide, analog, immunogenic fragment or other polypeptide can be administered in disaggregated or aggregated form. Disaggregated Aß or fragments thereof means monomelic peptide units. Disaggregated Aß or fragments thereof are generally soluble, and are capable of self-aggregating to form soluble oligomers, protofibrils and ADDLs. Oligomers of Aß and fragments thereof are usually soluble and exist prefominantly as alpha-helices or random coils. Aggregated Aß or fragments thereof means oligomers of Aß or fragments thereof that have associate into insoluble beta-sheet assemblies. Aggregated Aß or fragments thereof also means fibrillar polymers. Fibrils are usually insoluble. Some antibodies bind either soluble Aß or fragments thereof or aggregated Aß or fragments thereof. Some antibodies bind both soluble Aß or fragments thereof and aggregated Aß or fragments thereof. [0097] Immunogenic peptides also include multimers of monomeric immunogenic peptides. Immunogenic peptides other than Aß peptides should induce an immunogenic response against one or more of the preferred fragments of Aß listed above (e.g., Aß1-3,1-7, 1-10, and 3-7). [0098] Immunogenic peptides of the present invention are linked to a carrier using a method of the present invention to form a conjugate. The immunogenic peptide can be linked WE CLAIM: 1. A peptide immunogen-protein/polypeptide carrier conjugate having the formula: (Formula Removed) wherein, C is a protein/polypeptide carrier selected from the group consisting of CRM197, Streptococcus pyogenes ORF1224, Streptococcus pyogenes ORF1664, Streptococcus pyogenes ORF2452, and Chlamydia pneumoniae ORF T858, X is a derivatized functional group of an amino acid residue of the protein/polypeptide carrier P is a peptide immunogen molecule covalently attached to the derivatized functional group of the amino acid residue of the protein/polypeptide carrier, R is a capping molecule covalently attached to the derivatized functional group of an amino acid residue of the protein/polypeptide carrier, wherein the functionality of the carrier is preserved such that it retains its ability to elicit the desired immune responses against the peptide immunogen that would otherwise not occur without a carrier, n is an integer greater than 0, but less than or equal to 38, and p is an integer greater than 0, but less than or equal to 38. 2. The conjugate as claimed in claim 1, wherein the protein/polypeptide carrier is CRM197. 3. The conjugate as claimed in claim 1, wherein the peptide immunogen is selected from the group consisting of a bacterial protein, a viral protein, a fungal protein, a parasite protein and a eukaryotic protein. 4. The peptide immunogen-protein/polypeptide carrier conjugate as claimed in claim 1, wherein the peptide immunogen comprises a terminal cysteine residue. 5. The peptide immunogen-protein/polypeptide carrier conjugate as claimed in claim 4, wherein the cysteine residue is located at the C-terminus of the peptide immunogen. 6. The peptide immunogen-protein/polypeptide carrier conjugate as claimed in claim 4, wherein the cysteine residue is located at the N-terminus of the peptide immunogen. 7. The peptide immunogen-protein/polypeptide carrier conjugate as claimed in claim 4, wherein the capping reagent is selected from the reagent group consisting of cysteamine, N-acetylcysteamine, ethanolamine, sodium hydroxide, sodium carbonate, ammonium bicarbonate and ammonia. 8. The peptide immunogen-protein/polypeptide carrier conjugate as claimed in claim 7, wherein the capping reagent is N-acetylcysteamine. 9. A method for preparing a peptide immunogen-protein/polypeptide carrier conjugate as claimed in claim 1, the method comprising the steps of: (a) derivatizing one or more functional groups of the protein/polypeptide carrier to generate a derivatized carrier with reactive sites; (b) reacting the derivatized protein/polypeptide carrier of step (a) with a reactive group of an amino acid of the peptide immunogen such that the peptide immunogen is conjugated to the derivatized protein/polypeptide carrier via the functional groups; and (c) further reacting the conjugate with a capping reagent to inactive free, reactive unreacted functional groups on the derivatized protein/polypeptide carrier, whereby the functionality of the carrier is preserved, such that it retains its ability to elicit the desired immune responses against the peptide immunogen that would otherwise not occur without a carrier. 10. The method as claimed in claim 9, wherein the protein/polypeptide carrier is CRM197. 11. The method as claimed in claim 9, wherein the peptide immunogen is selected from the group consisting of a bacterial protein, a viral protein, a fungal protein, a parasite protein, and a eukaryotic protein. 12. The method as claimed in claim 9, wherein the functional group of one or more amino acid molecules of the protein/polypeptide carrier is derivatized using a cross-linking reagent. 13. The method as claimed in claim 12, wherein the protein/polypeptide carrier is derivatized with a haloacetylating agent. 14. The method as claimed in claim 9, wherein the capping reagent that is used to inactivate free, reactive, functional groups on the activated protein/polypeptide carrier is selected from the reagent group consisting of cysteamine, N-acetylcysteamine, ethanolamine, sodium hydroxide, sodium carbonate, ammonium bicarbonate and ammonia. 15. The method as claimed in claim 9, further comprising adding a terminal cysteine residue to the peptide immunogen prior to step (b). 16. The method as claimed in claim 15, wherein the terminal cysteine residue is added to the C-terminus of the peptide immunogen. 17. The method as claimed in claim 15, wherein the terminal cysteine residue is added to the N-terminus of the peptide immunogen.

Full Text

The present invention relates to a peptide immunogen-protein/polypeptide carrier conjugate and a method for preparing the same.
CROSS-REFERENCES TO RELATED APPLICATIONS
[0001] This application claims the benefit under 35 U.S.C. § 119(e) of U.S. Provisional Patent Application Serial No. 60/530,480, filed December 17,2003, which is incorporated herein by reference in its entirety for all purposes
BACKGROUND OF THE INVENTION
[0002] The essence of adaptive immunity is the ability of an organism to react to the presence of foreign substances and produce components (antibodies and cells) capable of specifically interacting with and protecting the host from their invasion. An "antigen" or "immunogen" is a substance that is able to elicit this type of immune response and. also is capable of interacting with the sensitized cells and antibodies that are manufactured against it.
[0003] Antigens or immunogens are usually macromolecules that contain distinct antigenic sites or "epitopes" that are recognized and interact with the various components of the immune system. They can exist as individual molecules composed of synthetic organic chemicals, proteins, lipoproteins, glycoproteins, RNA, DNA, or polysaccharides, or they may be parts of cellular structures (bacteria or fungi) or viruses (Harlow and Lane 1988a,b, c; Male et al., 1987).
[0004] Small molecules like short peptides, although normally able to interact with the products of an immune response, often cannot cause a response on their own. These peptide immunogens or "haptens" as they are also called, are actually incomplete antigens, and, although not able by themselves to cause immunogenicity or to elicit antibody production, can be made immunogenic by coupling them to a suitable carrier. Carriers typically are protein antigens of higher molecular weight that are able to cause an immunological response when adrninistered in vivo.
[0005] In an immune response, antibodies are produced and secreted by the B-lymphocytes in conjunction with the T-helper (Th) cells. In me majority of hapten-carrier systems, the B cells produce antibodies that are specific for both the hapten and the carrier. In these cases, the T lymphocytes will have specific binding domains on the carrier, but will not recognize

[0090] Preferably, the fragment of Aß administered lacks an epitope that would generate a T-cell response to the fragment Generally, T-cell epitopes are greater than 10 contiguous amino acids. Therefore, preferred fragments of Aß are of size 5-10 or preferably 7-10 contiguous amino acids or most preferably 7 contiguous amino acids; i.e., sufficient length to generate an antibody response without generating a T-cell response. Absence of T-cell epitopes is preferred because these epitopes are not needed for immunogenic activity of fragments, and may cause an undesired inflammatory response in a subset of patients (Anderson et al, (2002) J. Immunol. 168,3697-3701; Senior (2002) Lancet Neurol. 1,3).
[0091] Fragment Aß1 5-25 and subfragments of 7-8 contiguous amino acids thereof are preferred because these peptides consistently generate a high immunogenic response to Aß peptide. These fragments include Apl6-22, Apl6-23, Aß16-24, Aß17-23, Aß17-24, Aßl8-24, and Aß18-25. Particularly preferred Aß15-25 subfragments are 7 contiguous amino acids in length. The designation AJ315-21 for example, indicates a fragment including residues 15-21 of Aß and lacking other residues of Aß. and preferably 7-10 contiguous amino acids. These fragments can generate an antibody response that includes end-specific antibodies.
[0092] Peptide immunogens of Aßs require screening for activity in clearing or preventing amyloid deposits (see WO 00/72880 (IN 206050), which is incorporated herein in its entirely for all purposes). Administration of N-terminal fragments of Aß induces the production of antibodies that Tecognize AJ3 deposits in vivo and in vitro. Fragments lacking at least one, and sometimes at least 5 or 10 C-terminal amino acids present in naturally occurring forms of Aß are used in some methods. For example, a fragment lacking 5 amino acids from the C-terminal end of Aß43 includes the first 38 amino acids from the N-terminal end of Aß.
[0093] Unless otherwise indicated, reference to Ap includes the natural human amino acid sequences indicated above as well as analogs including allelic, species and induced variants. Analogs typically differ from naturally occurring peptides at one, two or a few positions, often by virtue of conservative substitutions. Analogs typically exhibit at least 80 or 90% sequence identity with natural peptides. Some analogs also include unnatural amino acids or modifications of N- or C-tcrminal amino acids at one, two, or a few positions. For example, the natural aspartic acid residue at position 1 and/or 7 of Aß can be replaced with iso-aspartic acid.
[0094} Examples of unnatural amino acids are D, alpha, alpha-disubstituted amino acids, N-alkyl amino acids, lactic acid, 4-hydroxyproline, gamma-carboxyglutamate, epsilon-

1,N,N-trimethyllysihe, epsilon-N-acetyllysine, O-phosphoserine, N-acetylserine, N-formylmethiomne, 3-methylhistidine, 5-hydroxylysine, omega-N-methylarginine, ß-alanine, ornithine, norleucine, norvaline, hydroxproline, thyroxine, gamma-arnino butyric acid, homoserine, citrulline, and isoaspartic acid. Immunogenic peptides also include analogs of Aß and fragments thereof. Some therapeutic agents of the invention are all-D peptides, e.g., all-D Aß all-D Aß fragment, or analogs of all-D Aß or all-D Aß fragment Fragments and analogs can be screened for prophylactic or therapeutic efficacy in transgenic animal models in comparison with untreated or placebo controls as described in WO 00/72880 (IN 206050).
[0095] Peptide immunogens also include longer polypeptides that include, for example, an immunogenic of Aß peptide, together with other amino acids. For example, preferred immunogenic peptides include fusion proteins comprising a segment of Ap linked to a heterologous amino acid sequence that induces a helper T-cell response against the heterologous amino acid sequence and thereby a B-cell response against the Ap segment. Such nolypeptides can be screened for prophylactic or therapeutic efficacy in animal models in comparison with untreated or placebo controls as described in WO 00/72880 (IN 206050).
[0096] The Aß peptide, analog, immunogenic fragment or other polypeptide can be administered in disaggregated or aggregated form. Disaggregated Aß or fragments thereof means monomelic peptide units. Disaggregated Aß or fragments thereof are generally soluble, and are capable of self-aggregating to form soluble oligomers, protofibrils and ADDLs. Oligomers of Aß and fragments thereof are usually soluble and exist prefominantly as alpha-helices or random coils. Aggregated Aß or fragments thereof means oligomers of Aß or fragments thereof that have associate into insoluble beta-sheet assemblies. Aggregated Aß or fragments thereof also means fibrillar polymers. Fibrils are usually insoluble. Some antibodies bind either soluble Aß or fragments thereof or aggregated Aß or fragments thereof. Some antibodies bind both soluble Aß or fragments thereof and aggregated Aß or fragments thereof.
[0097] Immunogenic peptides also include multimers of monomeric immunogenic peptides. Immunogenic peptides other than Aß peptides should induce an immunogenic response against one or more of the preferred fragments of Aß listed above (e.g., Aß1-3,1-7, 1-10, and 3-7).
[0098] Immunogenic peptides of the present invention are linked to a carrier using a method of the present invention to form a conjugate. The immunogenic peptide can be linked

WE CLAIM:
1. A peptide immunogen-protein/polypeptide carrier conjugate having the formula:
(Formula Removed)
wherein,
C is a protein/polypeptide carrier selected from the group consisting of CRM197,
Streptococcus pyogenes ORF1224, Streptococcus pyogenes ORF1664, Streptococcus
pyogenes ORF2452, and Chlamydia pneumoniae ORF T858,
X is a derivatized functional group of an amino acid residue of the protein/polypeptide
carrier
P is a peptide immunogen molecule covalently attached to the derivatized functional group of
the amino acid residue of the protein/polypeptide carrier,
R is a capping molecule covalently attached to the derivatized functional group of an amino
acid residue of the protein/polypeptide carrier, wherein the functionality of the carrier is
preserved such that it retains its ability to elicit the desired immune responses against the
peptide immunogen that would otherwise not occur without a carrier,
n is an integer greater than 0, but less than or equal to 38, and
p is an integer greater than 0, but less than or equal to 38.
2. The conjugate as claimed in claim 1, wherein the protein/polypeptide carrier is CRM197.
3. The conjugate as claimed in claim 1, wherein the peptide immunogen is selected from the group consisting of a bacterial protein, a viral protein, a fungal protein, a parasite protein and a eukaryotic protein.
4. The peptide immunogen-protein/polypeptide carrier conjugate as claimed in claim 1, wherein the peptide immunogen comprises a terminal cysteine residue.
5. The peptide immunogen-protein/polypeptide carrier conjugate as claimed in claim 4, wherein the cysteine residue is located at the C-terminus of the peptide immunogen.
6. The peptide immunogen-protein/polypeptide carrier conjugate as claimed in claim 4, wherein the cysteine residue is located at the N-terminus of the peptide immunogen.
7. The peptide immunogen-protein/polypeptide carrier conjugate as claimed in claim 4, wherein the capping reagent is selected from the reagent group consisting of cysteamine, N-acetylcysteamine, ethanolamine, sodium hydroxide, sodium carbonate, ammonium bicarbonate and ammonia.
8. The peptide immunogen-protein/polypeptide carrier conjugate as claimed in claim 7, wherein the capping reagent is N-acetylcysteamine.
9. A method for preparing a peptide immunogen-protein/polypeptide carrier conjugate as claimed in claim 1, the method comprising the steps of:

(a) derivatizing one or more functional groups of the protein/polypeptide carrier to generate a derivatized carrier with reactive sites;
(b) reacting the derivatized protein/polypeptide carrier of step (a) with a reactive group of an amino acid of the peptide immunogen such that the peptide immunogen is conjugated to the derivatized protein/polypeptide carrier via the functional groups; and
(c) further reacting the conjugate with a capping reagent to inactive free, reactive unreacted functional groups on the derivatized protein/polypeptide carrier, whereby the functionality of the carrier is preserved, such that it retains its ability to elicit the desired immune responses against the peptide immunogen that would otherwise not occur without a carrier.

10. The method as claimed in claim 9, wherein the protein/polypeptide carrier is CRM197.
11. The method as claimed in claim 9, wherein the peptide immunogen is selected from the group consisting of a bacterial protein, a viral protein, a fungal protein, a parasite protein, and a eukaryotic protein.
12. The method as claimed in claim 9, wherein the functional group of one or more amino
acid molecules of the protein/polypeptide carrier is derivatized using a cross-linking reagent.
13. The method as claimed in claim 12, wherein the protein/polypeptide carrier is
derivatized with a haloacetylating agent.
14. The method as claimed in claim 9, wherein the capping reagent that is used to
inactivate free, reactive, functional groups on the activated protein/polypeptide carrier is
selected from the reagent group consisting of cysteamine, N-acetylcysteamine, ethanolamine,
sodium hydroxide, sodium carbonate, ammonium bicarbonate and ammonia.
15. The method as claimed in claim 9, further comprising adding a terminal cysteine
residue to the peptide immunogen prior to step (b).
16. The method as claimed in claim 15, wherein the terminal cysteine residue is added to
the C-terminus of the peptide immunogen.
17. The method as claimed in claim 15, wherein the terminal cysteine residue is added to the N-terminus of the peptide immunogen.

Documents:

3139-DELNP-2006-Abstract-(03-03-2011).pdf

3139-DELNP-2006-Abstract-(18-03-2011).pdf

3139-delnp-2006-abstract.pdf

3139-DELNP-2006-Claims-(03-03-2011).pdf

3139-DELNP-2006-Claims-(18-03-2011).pdf

3139-DELNP-2006-Correspondence Others-(19-10-2011).pdf

3139-delnp-2006-correspondence-others 1.pdf

3139-DELNP-2006-Correspondence-Others-(03-03-2011).pdf

3139-DELNP-2006-Correspondence-Others-(18-03-2011).pdf

3139-delnp-2006-correspondence-others.pdf

3139-DELNP-2006-Description (Complete)-(03-03-2011).pdf

3139-delnp-2006-description (complete).pdf

3139-DELNP-2006-Drawings-(03-03-2011).pdf

3139-delnp-2006-drawings.pdf

3139-DELNP-2006-Form-1-(03-03-2011).pdf

3139-delnp-2006-form-1.pdf

3139-delnp-2006-form-18.pdf

3139-DELNP-2006-Form-2-(03-03-2011).pdf

3139-delnp-2006-form-2.pdf

3139-DELNP-2006-Form-3-(03-03-2011).pdf

3139-DELNP-2006-Form-3-(19-10-2011).pdf

3139-delnp-2006-form-3.pdf

3139-delnp-2006-form-5.pdf

3139-DELNP-2006-GPA-(03-03-2011).pdf

3139-delnp-2006-pct-304.pdf

3139-DELNP-2006-Petition 137-(03-03-2011).pdf

3149-DELNP-2006-Correspondence Others-(25-11-2011).pdf

3149-DELNP-2006-Form-3-(25-11-2011).pdf

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Patent Number

250723

Indian Patent Application Number

3139/DELNP/2006

PG Journal Number

04/2012

Publication Date

27-Jan-2012

Grant Date

23-Jan-2012

Date of Filing

01-Jun-2006

Name of Patentee

WYETH

Applicant Address

FIVE GIRALDA FARMS, MADISON, NJ 07940, USA

Inventors:

#	Inventor's Name	Inventor's Address
1	RASAPPA G. ARUMUGHAM	102 BARTON LANE CHAPEL HILL, NC 27516, USA
2	A. KRISHNA PRASAD	105, WORSHAM DRIVE, CHAPEL HILL, NC 27516, USA

PCT International Classification Number

C07K

PCT International Application Number

PCT/US2004/042701

PCT International Filing date

2004-12-17

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	60/530,480	2003-12-17	U.S.A.