Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on January 23, 2026 has been entered.
Claims 1, 21-29, 31-33, 35-38, 40 and 41 are pending.
Claim 1 is withdrawn from further consideration by the examiner, 37 C.F.R. 1.142(b) as being drawn to non-elected inventions.
Claims 21-29, 31-32, 35-38, 40 and 41, drawn to a method of making an antibody, are being acted upon in this Office Action.
Priority
Applicant’ claim priority to provisional application 61/657,556, filed June 8, 2012, and 61/725,433, filed November 12, 2012 is acknowledged.
Rejection Withdrawn
The written description and enablement rejections of claims 21-32 and 35-41 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph are withdrawn in view of the claim amendment.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the claims at issue are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); and In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on a nonstatutory double patenting ground provided the reference application or patent either is shown to be commonly owned with this application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO internet Web site contains terminal disclaimer forms which may be used. Please visit http://www.uspto.gov/forms/. The filing date of the application will determine what form should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to http://www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
Claims 21-29, 31-32, 35-38, 40 and 41 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-10, 14 and 18 of U.S. Patent No. 11,958,909. Although the claims at issue are not identical, they are not patentably distinct from each other because while the ‘909 patent issued from the application which served as the parent for the present case, the examined application was filed as a CON, not a DIV, and therefore no shield against double patenting that might be provided by 35 U.S.C 121 would be applicable here.
Issued claim 1 recites a method of detecting an antigen, comprising: contacting a sample comprising the antigen with an antibody conjugate or a pharmaceutical composition comprising the antibody conjugate, wherein the antibody conjugate comprises an isolated antibody of the IgG1 class comprising a heavy chain and a light chain, wherein the antibody conjugate binds to the antigen, and wherein: the heavy chain comprises at least one non-natural amino acid residue at a specific site selected from the group consisting of heavy chain residues 19, 25, 40, 52, and 70 according to the Kabat numbering scheme and heavy chain residues 119, 121, 180, 190, 222, 241, and 404 according to the EU index of Kabat; or the light chain comprises a non-natural amino acid residue at a specific site selected from the group consisting of the light chain residues 7, 22, and 152 according to the Kabat numbering scheme; or a combination thereof; or an aglycosylated variant thereof; wherein each non-natural amino acid residue is independently selected from the group consisting of ortho-substituted tyrosine, meta-substituted tyrosine, para-substituted phenylalanine, ortho-substituted phenylalanine, and meta-substituted phenylalanine; wherein at least one of the non-natural amino acids is linked to a payload capable of being detected; and detecting a complex formed between the antibody and the antigen, which corresponds to instant claim 21.
A person of skill in the art, reading the claims of the ‘909 patent, would look to the patent and follow the ‘909 patent’s express instruction on how to make the product within the patent, e.g., Examples 1, 2, 6, 13, thereby arriving at the method of the examined claims.
Issued claim 2 recites the method of claim 1, wherein the antibody is aglycosylated, which corresponds to instant claim 22.
Issued claim 3 recites the method of claim 1, wherein the light chain is selected from λ, and κ, which corresponds to instant claim 23.
Issued claim 4 recites the method of claim 1, wherein said non-natural amino acid residue comprises a moiety selected from the group consisting of amino, carboxy, acetyl, hydrazino, hydrazido, semicarbazido, sulfanyl, azido, and alkynyl, which corresponds to instant claim 24.
Issued claim 5 recites the method of claim 1, wherein each non-natural amino acid residue is according to the formula
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wherein each L is independently a phenylene; and each R is independently a functional group selected from the group consisting of a labeling moiety, amino, carboxy, acetyl, hydrazino, hydrazido, semicarbazido, sulfanyl, azido, and alkynyl, which corresponds to instant claim 25.
Issued claim 6 recites the method of claim 1, wherein the non-natural amino acid residue is selected from a group consisting of p-acetyl-L-phenylalanine, O-methyl-L-tyrosine, 3-methyl-phenylalanine, O-4-allyl-L-tyrosine, 4-propyl-L-tyrosine, fluorinated phenylalanine, isopropyl-L-phenylalanine, p-azido-L-phenylalanine, p-acyl-L-phenylalanine, p-benzoyl-L-phenylalanine, p-iodo-phenylalanine, p-bromophenylalanine, p-amino-L-phenylalanine, isopropyl-L-phenylalanine, p-propargyloxy-phenylalanine, and p-azidomethyl-L-phenylalanine, which corresponds to instant claim 26.
Issued claim 7 recites the method of claim 6, wherein the non-natural amino acid residue is a p-azido-L-phenylalanine residue, which corresponds to instant claim 27.
Issued claim 8 recites the method of claim 6, wherein the non-natural amino acid residue is a p-azidomethyl-L-phenylalanine residue, which corresponds to instant claim 28.
Issued claim 9 recites the method of claim 1, wherein said payload is linked to the non-natural amino acid, or a residue thereof, via one or more linkers, which corresponds to instant claim 21.
Issued claim 10 recites the method of claim 1, wherein the pharmaceutical composition comprises the antibody that is at least 95% by mass of the total antibody mass of said composition, which corresponds to instant claim 34.
Issued claim 14 recites the method of claim 1, wherein the payload is selected from a label, dye, radioactive moiety, nanoparticle, and fluorophore, which corresponds to instant claim 30.
Issued claim 18 recites the method of claim 1, wherein payload is selected from a nanoparticle, a spin label, a fluorophore, a metal-containing moiety, a radioactive moiety, or a photocaged moiety, which corresponds to instant claim 30.
Applicants’ arguments filed January 23, 2026 have been fully considered but are not found persuasive.
Applicant’s indication of willingness to consider filing a terminal disclaimer as appropriate once all pending claims are otherwise allowable is acknowledged. As such, the rejection is maintained.
Claims 21-29, 31-32, 35-38, 40 and 41 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9, 15-16 of U.S. Patent No. 10,669,347. Although the claims at issue are not identical, they are not patentably distinct from each other because while the ‘347 patent issued from the application which served as the grandparent for the present case, the examined application was filed as a CON, not a DIV, and therefore no shield against double patenting that might be provided by 35 U.S.C 121 would be applicable here.
Issued claim 1 recites an isolated antibody of the IgG class comprising a heavy chain and a light chain, wherein: the heavy chain comprises at least one non-natural amino acid residue at a specific site selected from the group consisting of heavy chain residue 52 according to the Kabat numbering scheme and heavy chain residues 119, 222, and 241 according to the EU index of Kabat; or the light chain comprises a non-natural amino acid residue at the light chain residue 152; or a combination thereof; or an aglycosylated variant thereof, wherein each non-natural amino acid residue is independently selected from the group consisting of ortho-substituted tyrosine, meta substituted tyrosine, para-substituted phenylalanine, ortho-substituted phenylalanine, and meta-substituted phenylalanine, which corresponds to instant claim 21.
A person of skill in the art, reading the claims of the ‘347 patent, would look to the patent and follow the ‘347 patent’s express instruction on how to make the product within the patent, e.g., Examples 1 for Synthesis of Exemplary Antibodies Containing Non-Natural Amino Acids, Examples 3, 6, 13 for Transfer of Sites of Non-Natural Amino Acid Incorporation to Another Antibody, thereby arriving at the method of the examined claims.
Issued claim 2 recites the antibody of claim 1, wherein the antibody is a glycosylated, which corresponds to instant claim 22.
Issued claim 3 recites antibody of claim 2, wherein the light chain is selected from λ, and κ.
Issued claim 4 recites antibody of claim 2, that is of a class or subclass selected from the group consisting of IgG1, IgG2, IgG3, and IgG4, which corresponds to instant claim 23.
Issued claim 5 recites the antibody of claim 2,. wherein said non-natural amino acid residue comprises a moiety selected from the group consisting of amino, carboxy, acetyl, hydrazino, hydrazido, semicarbazido, sulfanyl, azido and alkynyl, which corresponds to instant claim 24.
Issued claim 6 recites the antibody of claim 2, wherein each non-natural amino acid residue is according to the formula
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wherein each L is independently a phenylene; and each R is independently a functional group selected from the group consisting of a therapeutic moiety, a labeling moiety, amino, carboxy, acetyl, hydrazino, hydrazido, semicarbazido, sulfanyl, azido, and alkynyl, which corresponds to instant claim 25.
Issued claim 7 recites antibody of claim 2, wherein the non-natural amino acid residue is selected from the group consisting of p-acetyl-L-phenylalanine, O-methyl-L-tyrosine, 3-methyl-phenylalanine, O-4-allyl-L-tyrosine, 4-propyl-L-tyrosine, fluorinated phenylalanine, isopropyl-L-phenylalanine, p-azido-L-phenylalanine, p-acyl-L-phenylalanine, p-benzoyl-L-phenylalanine, p-iodo-phenylalanine, p-bromophenylalanine, p-amino-L-phenylalanine, isopropyl-L-phenylalanine, p-propargyloxy-phenylalanine, and p-azidomethyl-L-phenylalanine, which corresponds to instant claim 26.
Issued claim 8 recites antibody of claim 2, wherein the non-natural amino acid residue is p-azido-L-phenylalanine, which corresponds to instant claim 27.
Issued claim 9 recites antibody of claim 2, wherein the non-natural amino acid residue is p-azidomethyl-L-phenylalanine, which corresponds to instant claim 28.
Applicants’ arguments filed January 23, 2026 have been fully considered but are not found persuasive.
Applicant’s indication of willingness to consider filing a terminal disclaimer as appropriate once all pending claims are otherwise allowable is acknowledged. As such, the rejection is maintained.
Claims 21-29, 31-32, 35-38, 40 and 41 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12, 18-28, 34 and 35 of U.S. Patent No. 9,738,724. Although the claims at issue are not identical, they are not patentably distinct from each other because while the ‘724 patent issued from the application which served as the great grandparent for the present case, the examined application was filed as a CON, not a DIV, and therefore no shield against double patenting that might be provided by 35 U.S.C 121 would be applicable here.
Issued claim 1 recites an isolated antibody of the IgG class comprising a heavy chain and a light chain wherein:
a. the light chain has one or more non-natural amino acid residue residues at specific sites selected from the group consisting of light chain residues 7 and 22 according to the Kabat numbering scheme; and/or
b. the heavy chain has one or more non-natural amino acid residue residues at specific sites selected form the group consisting of heavy chain residues 19, 25, 40, and 70 according to the Kabat numbering scheme and heavy chain residues 121, 180, and 190 according to the EU index of Kabat; or an aglycosylated variant thereof, wherein each non-natural amino acid residue is independently selected from the group consisting of ortho-substituted tyrosine, meta substituted tyrosine, para-substituted phenylalanine, ortho-substituted phenylalanine, and meta-substituted phenylalanine, which corresponds to instant claim 21.
A person of skill in the art, reading the claims of the ‘724 patent, would look to the patent and follow the ‘724 patent’s express instruction on how to make the product within the patent, e.g., Examples 1, 2, 13, thereby arriving at the method of the examined claims.
Issued claim 2 recites the antibody of claim 1 wherein the antibody is aglycosylated, which corresponds to instant claim 22.
Issued claim 3 recites an isolated antibody of the IgG class comprising a heavy chain and a light chain wherein the heavy chain has a non-natural amino acid residue at site 404 according to the EU index of Kabat, or an aglycosylated variant thereof, wherein the non-natural amino acid residue is independently selected from the group consisting of ortho-substituted tyrosine, meta substituted tyrosine, para-substituted phenylalanine, ortho-substituted phenylalanine, and meta-substituted phenylalanine, which corresponds to instant claim 21.
Issued claim 4 recites the antibody of claim 3, wherein the antibody is aglycosylated, which corresponds to instant claim 22.
Issued claim 5 recites the antibody of claim 4, wherein the antibody has a higher thermal stability (T.sub.m1) compared to the corresponding wild-type antibody following conjugation of a linker-drug to the non-natural amino acid, which corresponds to instant claim 31.
Issued claim 6 recites the antibody of claim 4, wherein the light chain is selected from λ and κ, which corresponds to instant claim 23.
Issued claim 7 recites the antibody of claim 4, wherein the heavy chain is selected from the group consisting of IgG1, IgG2, IgG3, and IgG4, which corresponds to instant claim 32.
Issued claim 8 recites the antibody of claim 4, wherein the non-natural amino acid residue is substituted with a moiety selected from the group consisting of amino, carboxy, acetyl, hydrazino, hydrazido, semicarbazido, sulfanyl, azido, and alkynyl, which corresponds to instant claim 24.
Issued claim 9 recites the antibody of claim 4, wherein the non-natural amino acid residue is according to the formula
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wherein each L is independently a phenylene; and each R is independently a functional group selected from the group consisting of a therapeutic moiety, a labeling moiety, amino, carboxy, acetyl, hydrazino, hydrazido, semicarbazido, sulfanyl, azido, and alkynyl, which corresponds to instant claim 25.
Issued claim 10 recites the antibody of claim 4, wherein the non-natural amino acid residue is selected from the group consisting of p-acetyl-L-phenylalanine, O-methyl-L-tyrosine, 3-methyl-phenylalanine, O-4-allyl-L-tyrosine, 4-propyl-L-tyrosine, fluorinated phenylalanine, isopropyl-L-phenylalanine, p-azido-L-phenylalanine, p-acyl-L-phenylalanine, p-A benzoyl-L-phenylalanine, p-iodo-phenylalanine, p-bromophenylalanine, p-amino-L-phenylalanine, isopropyl-L-phenylalanine, p-propargyloxy-phenylalanine, and p-azidomethyl-L-phenyl alanine, which corresponds to instant claim 26.
Issued claim 11 recites the antibody of claim 4, wherein the non-natural amino acid residue is p-azido-L-phenylalanine, which corresponds to instant claim 27.
Issued claim 12 recites the antibody of claim 4, wherein the non-natural amino acid residue is p-azidomethyl-L-phenyl alanine, which corresponds to instant claim 28.
Issued claim 19 recites a composition comprising the antibody of claim 4, wherein said antibody is at least 95% by mass of the total antibody mass of said composition, which corresponds to instant claim 34.
Issued claim 20 recites the antibody of claim 2 wherein the one or more non-natural amino acid residues are at specific sites selected from the group consisting of heavy chain residues 25 and 40 according to the Kabat numbering scheme, heavy chain residues 121, 180, and 190 according to the EU index of Kabat, and light chain residues 7 and 22, according to the Kabat numbering scheme, which corresponds to instant claim 21.
Issued claim 21 recites the antibody of claim 2 wherein the one or more non-natural amino acid residues are at specific sites selected from the group consisting of light chain residues 7 and 22 according to the Kabat numbering scheme and heavy chain residues 121 and 180, according to the EU index of Kabat, which corresponds to instant claim 21.
Issued claim 22 recites the antibody of claim 2, wherein the light chain is selected from λ and κ, which corresponds to instant claim 23.
Issued claim 23 recites the antibody of claim 2, wherein the heavy chain is selected from the group consisting of IgG1, IgG2, IgG3, and IgG4, which corresponds to instant claim 32.
Issued claim 24 recites the antibody of claim 2, wherein said one or more non-natural amino acid residue is substituted with a moiety selected from the group consisting of amino, carboxy, acetyl, hydrazino, hydrazido, semicarbazido, sulfanyl, azido, and alkynyl, which corresponds to instant claim 24.
Issued claim 25 recites the antibody of claim 2, wherein each of the one or more non-natural amino acid residues is according to the formula
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wherein each L is independently a phenylene; and each R is independently a functional group selected from the group consisting of a therapeutic moiety, a labeling moiety, amino, carboxy, acetyl, hydrazino, hydrazido, semicarbazido, sulfanyl, azido, and alkynyl, which corresponds to instant claim 23.
Issued claim 26 recites the antibody of claim 2, wherein the one or more non-natural amino acid residues are selected from the group consisting of p-acetyl-L-phenylalanine, O-methyl-L-tyrosine, 3-methyl-phenylalanine, O-4-allyl-L-tyrosine, 4-propyl-L-tyrosine, fluorinated phenylalanine, isopropyl-L-phenylalanine, p-azido-L-phenylalanine, p-acyl-L-A phenylalanine, p-benzoyl-L-phenylalanine, p-iodo-phenylalanine, p-bromophenylalanine, p-amino-L-phenylalanine, isopropyl-L-phenylalanine, p-propargyloxy-phenylalanine, and p-azidomethyl-L-phenylalanine, which corresponds to instant claim 26.
Issued claim 27 recites the antibody of claim 2, wherein at least one non-natural amino acid residue is p-azido-L-phenylalanine, which corresponds to instant claim 27.
Issued claim 28 recites the antibody of claim 2, wherein at least one non-natural amino acid residue is p-azidomethyl-L-phenylalanine, which corresponds to instant claim 29.
Issued claim 34 recites a composition comprising the antibody of claim 2, wherein said composition is substantially pure.
Issued claim 35 recites a composition comprising the antibody of claim 2 wherein said antibody is at least 95% by mass of the total antibody mass of said composition.
Applicants’ arguments filed January 23, 2026 have been fully considered but are not found persuasive.
Applicant’s indication of willingness to consider filing a terminal disclaimer as appropriate once all pending claims are otherwise allowable is acknowledged. As such, the rejection is maintained.
Claims 21-29, 31-32, 35-38, 40 and 41 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 of U.S. Patent No. 9,764,039. Although the claims at issue are not identical, they are not patentably distinct from each other because the claims and the disclosure of the ‘039 patent teaches the claim method; the examined application was voluntary filed by the applicant and not in response to an Office requirement for restriction and therefore no shield against double patenting that might be provided by 35 U.S.C 121 would be applicable here, see MPEP 804.1.
Issued claim 1. An antibody of the IgG class comprising six or fewer site-specific non-natural amino acid residues, wherein at least one of said site-specific non-natural amino acid residues comprises an azide moiety and at least one of said site-specific non-natural amino acid residues comprises a tetrazine moiety, wherein at least one of the said site-specific non-natural amino acid residues comprising the azide moiety or the tetrazine moiety is at heavy chain site 404 according to the EU index of Kabat which corresponds to instant claim 21.
2. The antibody of claim 1, wherein the six or fewer site-specific non-natural amino acid residues are in a single heavy chain or heavy chain variable domain, which corresponds to instant claim 21.
3. The antibody of claim 1, wherein at least one site-specific non-natural amino acid is in a light chain or light chain variable domain, which corresponds to instant claim 21.
4. The antibody of claim 1, wherein at least one site-specific non-natural amino acid is in a light chain or light chain variable domain and a site-specific non-natural amino acid at site 404 is in each of two heavy chains, which corresponds to instant claim 21.
5. The antibody of claim 1, wherein at least one site-specific non-natural amino acid is in each of two light chains or light chain variable domains and a site-specific non-natural amino acid at site 404 is in a heavy chain, which corresponds to instant claim 21.
6. The antibody of claim 1, wherein at least one site-specific non-natural amino acid is in each of two light chain or light chain variable domains, which corresponds to instant claim 21.
7. The antibody of claim 1, wherein said site-specific non-natural amino acid residues are not one of the 20 common amino acids or pyrrolysine or selenocysteine, or post-translationally modified variants thereof, which corresponds to instant claims 21, 26-29.
8. The antibody of claim 1 comprising two to six site-specific non-natural amino acid residues, wherein said site-specific non-natural amino acid residues are not one of the 20 common amino acids or pyrrolysine or selenocysteine, or post-translationally modified variants thereof which corresponds to instant claims 21, 26-29.
9. The antibody of claim 1, wherein at least one of said site-specific non-natural amino acid residue is at one or more sequence positions selected from the group consisting of light chain residues 7 and 22 according to the Kabat numbering scheme, light chain residue 152 according to the EU index of Kabat, heavy chain residues 19, 25, 40, 52, 70, and 110 according to the Kabat numbering scheme, and heavy chain residues 119, 121, 136, 180, 190, 221, and 222 according to the EU index of Kabat, which corresponds to instant claim 21.
.
10. The antibody of claim 1, wherein the antibody comprises a heavy chain according to SEQ ID NO:1.
11. The antibody of claim 1, wherein the antibody comprises a light chain according to SEQ ID NO:2.
12. The antibody of claim 1, comprising a light chain of a type selected from λ, and κ, which corresponds to instant claim 23.
13. The antibody of claim 1, that is of a class or subclass selected from the group consisting of IgG1, IgG2, IgG3 and IgG4, which corresponds to instant claim 32.
14. The antibody of claim 9, wherein each further site-specific non-natural amino acid residue comprises a moiety selected from the group consisting of amino, carboxy, acetyl, hydrazino, hydrazido, semicarbazido, sulfanyl, and alkynyl, wherein said site-specific non-natural amino acid residue is not one of the 20 amino acids or pyrrolysine or selenocysteine, or post-translationally modified variant thereof, which corresponds to instant claims 24, 25.
15. The antibody of claim 1, wherein said antibody is a full-length antibody, which corresponds to instant claims 21, 32.
16. The antibody of claim 1, wherein each site-specific non-natural amino acid residue is according to the formula
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wherein each L is independently a divalent linker; and each R is independently a reactive group, a therapeutic moiety, or a labeling moiety, wherein R of the site-specific non-natural amino acid residue at site 404 and R of a second site-specific non-natural amino acid residue are independently selected from azido and tetrazine, and wherein R of the second site-specific non-natural amino acid residue is different from R of the site-specific non-natural amino acid residue at site 404, which corresponds to instant claims 21, 25.
17. The antibody of claim 16 wherein each further non-natural amino acid residue comprises an R that comprises a reactive group selected from the group consisting of amino, carboxy, acetyl, hydrazino, hydrazido, semicarbazido, sulfanyl, azido, alkynyl, and tetrazine, which corresponds to instant claim 24.
18. The antibody claim 16 wherein each L is a divalent linker selected from the group consisting of a bond, alkylene, substituted alkylene, heteroalkylene, substituted heteroalkylene, arylene, substituted arylene, heteroarlyene and substituted heteroarylene.
A person of skill in the art, reading the claims of the ‘039 patent, would look to the patent and follow the ‘039 patent’s express instruction on how to perform the method to make the product within the patent, e.g., Examples 1, 2, 3, 6, 9, 11, 17, thereby arriving at the method of the examined claims.
Claims 21-29, 31-32, 35-38, 40 and 41 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-17 of U.S. Patent No. 11,344,626. Although the claims at issue are not identical, they are not patentably distinct from each other because the claims and the disclosure of the ‘626 patent teaches the claim method; ; the examined application was voluntary filed by the applicant and not in response to an Office requirement for restriction and therefore no shield against double patenting that might be provided by 35 U.S.C 121 would be applicable here, see MPEP 804.1.
Issued claim 1. An antibody of the IgG class comprising: a first site-specific non-natural amino acid residue and a second site-specific non-natural amino acid residue, wherein at least one non-natural amino acid is at a residue position selected from the list consisting of: a. heavy chain residues 136, 404, 190, 180, and 121, according to the EU index of Kabat; b. heavy chain residue 70, according to the Kabat numbering scheme; and c. light chain residues 7 and 22 according to the Kabat numbering scheme; wherein the first and the second site specific non-natural amino acid residues comprise a moiety selected from the group consisting of amino, carboxyl, acetyl, hydrazino, hydrazido, semicarbazido, sulfanyl, azido, alkynyl, tetrazine, and strained alkene, wherein the first site-specific non-natural amino acid residue is different from the second-specific non-natural amino acid residue, and wherein the first and second site specific non-natural amino acid residues have different reactive groups that are capable of mutually non-overlapping site-specific conjugations in the same reaction, which corresponds to instant claims 21, 24.
2. The antibody of claim 1 comprising one or more site-specific non-natural amino acid residues in a single light chain polypeptide.
3. The antibody of claim 1 comprising two or more site-specific non-natural amino acid residues in a single heavy chain polypeptide.
4. The antibody of claim 1 comprising at least one site-specific non-natural amino acid in a light chain polypeptide and at least one site-specific non-natural amino acid in each of two heavy chain polypeptides, which corresponds to instant claim 21.
5. The antibody of claim 1 comprising at least one site-specific non-natural amino acid in each of two light chain polypeptides and at least one site-specific non-natural amino acid in a heavy chain polypeptide, which corresponds to instant claim 21.
6. The antibody of claim 1 comprising at least one site-specific non-natural amino acid in each of two light chain polypeptides and at least one site-specific non-natural amino acid in each of two heavy chain polypeptides, which corresponds to instant claim 21.
7. The antibody of claim 1 comprising three, four, five, six, seven, eight, nine, or ten site-specific non-natural amino acid residues, which corresponds to instant claim 21.
8. The antibody of claim 1 comprising two to six non-natural amino acid residues.
9. The antibody of claim 1 comprising the light chain is selected from the group consisting of from λ, and κ, which corresponds to instant claim 23.
10. The antibody of claim 1 wherein the IgG is selected from the group consisting of IgG1, IgG2, and IgG3, which corresponds to instant claim 32.
11. The antibody of claim 1 wherein the antibody is selected from the group consisting of Fv, Fab, (Fab′).sub.2, single chain Fv (scFv), single chain Fv-Fc (scFv-Fc) and full-length antibody, which corresponds to instant claim 33.
12. The antibody of claim 1 wherein at least one of said non-natural amino acid residues comprises an azide moiety, which corresponds to instant claims 21, 26, 27, 28.
13. The antibody of claim 1 wherein at least one of said non-natural amino acid residues comprises an acetyl moiety, which corresponds to instant claims 21, 26, 29.
14. The antibody of claim 1 wherein at least one of said non-natural amino acid residues comprises an azide moiety and at least one of said non-natural amino acid residues comprises an acetyl moiety.
15. The antibody of claim 1 wherein each non-natural amino acid residue is according to the formula
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wherein each L is independently a divalent linker; and each R independently comprises a moiety selected from the group consisting of amino, carboxyl, acetyl, hydrazino, hydrazido, semicarbazido, sulfanyl, azido, alkynyl, tetrazine, and strained alkene, which corresponds to instant claim 25.
16. The antibody of claim 15 wherein each R is a reactive group selected from the group consisting of amino, carboxy, acetyl, hydrazino, hydrazido, semicarbazido, sulfanyl, azido, alkynyl, tetrazine, and a strained alkene, which corresponds to instant claims 24, 25.
17. The antibody of claim 15 wherein each L is a divalent linker selected from the group consisting of a bond, alkylene, substituted alkylene, heteroalkylene, substituted heteroalkylene, arylene, substituted arylene, heteroarlyene and substituted heteroarylene.
A person of skill in the art, reading the claims of the ‘626 patent, would look to the patent and follow the ‘626 patent’s express instruction on how to perform the claimed method to make the product within the patent, e.g., Examples 1, 2, 3, 6, 9, 11, 17, thereby arriving at the method of the examined claims.
Claim rejections under - 35 U.S.C. 112
The following is a quotation of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), first paragraph:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 21, 22, 23, 24, 26, 29, 32, 35, 36 and 40 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention. This is new matter.
21. (Currently Amended) A method of making an antibody conjugate, comprising:
contacting a nucleic acid template encoding one or more polypeptide chains of an antibody of the IgG class to a reaction mixture, wherein the reaction mixture translates the nucleic acid template, and wherein the reaction mixture comprises one or more orthogonal tRNAs aminoacylated with one or more non-natural amino acids, wherein each orthogonal tRNA base pairs with a codon in the nucleic acid template encoding a site-specific position in the antibody, and wherein the antibody has one or more non-natural amino acids at site-specific positions in the one or more polypeptide chains, and wherein the antibody comprises:
a heavy chain comprising at least one non-natural amino acid residue at a specific site selected from the group consisting of heavy chain residues 19, 25, 40, 52, and 70 according to the Kabat numbering scheme and heavy chain residues 119, 121, 180, 190, 222, 241, and 404 according to the EU index of Kabat; or
a light chain comprising a non-natural amino acid residue at a specific site selected from the group consisting of the light chain residues 7, 22, and 152 according to the Kabat numbering scheme; or
a combination thereof,
wherein each non-natural amino acid residue is independently selected from the group consisting of ortho-substituted tyrosine, meta-substituted tyrosine, para-substituted phenylalanine, ortho-substituted phenylalanine, and meta-substituted phenylalanine.
The recitation of “a reaction mixture … one or more non-natural amino acids” in claim 21 has no written support in the specification and the claims as originally filed.
The specification discloses:
[0374] In certain embodiments, an antibody can be prepared in a cell-free reaction mixture comprising at least one orthogonal tRNA aminoacylated with an unnatural amino acid, where the orthogonal tRNA base pairs with a codon that is not normally associated with an amino acid, e.g. a stop codon; a 4 bp codon, etc. The reaction mixture also comprises a tRNA synthetase capable of aminoacylating the orthogonal tRNA with an unnatural amino acid. Usually the orthogonal tRNA synthetase, which is susceptible to degradation by proteases present in bacterial cell extracts, is exogenously synthesized and added to the reaction mix prior to initiation of polypeptide synthesis. The orthogonal tRNA may be synthesized in the bacterial cells from which the cell extract is obtained, may be synthesized de novo during the polypeptide synthesis reaction, or may be exogenously added to the reaction mix.
Note that the reaction mixture is a cell-free mixture.
The specification exemplifies:
[0399] The variants were then expressed in a cell-free protein synthesis reaction as follows as described in Zawada et al., 2011, Biotechnol. Bioeng. 108(7).sub.1570-1578 with the modifications described below. Unsubstituted trastuzumab was also made as a control. Cell-free extracts were treated with 50 μM iodoacetamide for 30 min at RT (20° C.) and added to a premix containing all other components except for heavy chain DNA from variants of interest. Cell free reactions were initiated by addition of plasmid DNA of heavy chain DNA variants and incubated at 30° C. for 12 h on a shaker at 450 rpm in 96 deep well plates. The reaction was incubated further at 4° C. for 5 h. The final concentration in the protein synthesis reaction was 30% cell extract, 1 mM para-azido phenylalanine (pAzF) (RSP Amino Acids), 0.125 mg/mL M jannaschii amber suppressor tRNA, 0.37 mg/mL M jannaschii pAzF-specific amino-acyl tRNA synthetase (FRS), 2 mM GSSG, 0.29 mg/mL PDI (Mclab), 100 μg/mL E. coli DsbC, 8 mM magnesium glutamate, 10 mM ammonium glutamate, 130 mM potassium glutamate, 35 mM sodium pyruvate, 1.2 mM AMP, 0.86 mM each of GMP, UMP, and CMP, 2 mM amino acids (except 0.5 mM for Tyrosine and Phenylalanine), 4 mM sodium oxalate, 1 mM putrescine, 1.5 mM spermidine, 15 mM potassium phosphate, 100 nM T7 RNAP, 2 μg/mL trastuzumab light chain DNA, 8 μg/mL trastuzumab-(His)6 heavy chain DNA. Each trastuzumab variant was produced in 1 mL scale in 96 deep well plates in duplicates. A total of three plates were used to express the variants, each compared to expression of an unsubstituted trastuzumab to normalize for expression across the plates. It should be noted that all trastuzumab variants thus produced were aglycosylated.
However, the specification does not disclose multiple non-natural amino acids in the IgG class of antibody. This is new matter.
Closest Prior art
Hutchins et al (J. Mol Biol 406: 595-603, 2011; PTO 1449) teaches a method of site-specific incorporate unnatural amino acid to a light chain residue 152, e.g., N152 of the kappa constant region in the Fab of trastuzumab (IgG1 class) in vivo.
However, Hutchins does not teach that the position is numbering according to the Kabat numbering scheme and the method comprises contacting a nucleic acid template encoding one or more polypeptide chains of an antibody of the IgG class to a cell-free reaction mixture, wherein the reaction mixture translates the nucleic acid template, and wherein the reaction mixture comprises one or more orthogonal tRNAs aminoacylated with one or more non-natural amino acids, wherein each orthogonal tRNA base pairs with a codon in the nucleic acid template encoding a site-specific position in the antibody, and wherein the antibody has one or more non-natural amino acids at site-specific positions in the one or more polypeptide chains, and
wherein the antibody comprises: a heavy chain comprising at least one non-natural amino acid residue at a specific site selected from the group consisting of heavy chain residues 19, 25, 40, 52, and 70 according to the Kabat numbering scheme and heavy chain residues 119, 121, 180, 190, 222, 241, and 404 according to the EU index of Kabat; or
a light chain comprising a non-natural amino acid residue at a specific site selected from the group consisting of the light chain residues 7, 22, and 152 according to the Kabat numbering scheme; or
a combination thereof
WO2008066583 (Goerke hereafter, published June 5, 2008; PTO 1449) teaches a cell-free synthesis of proteins containing unnatural amino acids, see entire document, in particular. The protein is synthesized in a cell-free reaction mixture comprising at least one orthogonal tRNA aminoacylated with an unnatural amino acid, where the orthogonal tRNA base pairs with a codon that is not normally associated with an amino acid, e.g. a stop codon as per claim 40; a 4 bp codon as per claim 41, etc., see para. [06], Summary of the Invention. Example of unnatural amino acids include o-methyl-L-tyrosine, p-acetyl-L-phenylalanine, or p-azido-L-phenylalanine were site-specifically introduced at an amber stop codon using an orthogonal tRNATy7Tyrosine- synthetase pair from Methanococcus jannaschii, see para. [76].
However, Goerke does not teach IgG class of antibody, much less contacting a nucleic acid template encoding one or more polypeptide chains of an antibody of the IgG class to a reaction mixture, wherein the reaction mixture translates the nucleic acid template, and wherein the reaction mixture comprises one or more orthogonal tRNAs aminoacylated with one or more non-natural amino acids, wherein each orthogonal tRNA base pairs with a codon in the nucleic acid template encoding a site-specific position in the antibody, and wherein the antibody has one or more non-natural amino acids at site-specific positions in the one or more polypeptide chains, and
wherein the antibody comprises: a heavy chain comprising at least one non-natural amino acid residue at a specific site selected from the group consisting of heavy chain residues 19, 25, 40, 52, and 70 according to the Kabat numbering scheme and heavy chain residues 119, 121, 180, 190, 222, 241, and 404 according to the EU index of Kabat; or
a light chain comprising a non-natural amino acid residue at a specific site selected from the group consisting of the light chain residues 7, 22, and 152 according to the Kabat numbering scheme; or
a combination thereof.
Tian (WO2008030612, published March 13, 2008; PTO 1449) teaches site-specific incorporation of unnatural amino acids, e.g., pAF in antibody (see para. [193] to [199], [202]), e.g., Recombinant humanized anti-HER2 antibody (Herceptin), see para. [203] or human IgG1 Fc at position 121 using Orthogonal tRNA (O-tRNA), aminoacyl-tRNA synthetase in vivo, see Examples 2 and 3, in particular.
However, Tian does not teach the method step of contacting a nucleic acid template encoding one or more polypeptide chains of an antibody of the IgG class to a reaction mixture, wherein the reaction mixture translates the nucleic acid template, and wherein the reaction mixture comprises one or more orthogonal tRNAs aminoacylated with one or more non-natural amino acids, wherein each orthogonal tRNA base pairs with a codon in the nucleic acid template encoding a site-specific position in the antibody, and wherein the antibody has one or more non-natural amino acids at site-specific positions in the one or more polypeptide chains, and
wherein the antibody comprises: a heavy chain comprising at least one non-natural amino acid residue at a specific site selected from the group consisting of heavy chain residues 19, 25, 40, 52, and 70 according to the Kabat numbering scheme and heavy chain residues 119, 121, 180, 190, 222, 241, and 404 according to the EU index of Kabat; or
a light chain comprising a non-natural amino acid residue at a specific site selected from the group consisting of the light chain residues 7, 22, and 152 according to the Kabat numbering scheme; or
a combination thereof.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to PHUONG HUYNH whose telephone number is (571)272-0846. The examiner can normally be reached on 9:00 a.m. to 6:30 p.m. The examiner can also be reached on alternate alternative Friday from 9:00 a.m. to 5:30 p.m.
If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Misook Yu, can be reached at 571-272-0839. The fax phone number for the organization where this application or proceeding is assigned is 571-272-0839.
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/PHUONG HUYNH/ Primary Examiner, Art Unit 1641
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