DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims 1-132 have been cancelled. Claims 133-184 have been newly introduced.
Specification
The substitute specification filed 7/12/2023 has been entered. The amendments to Table 1 on pages 262-265 of the substitute specification on 8/10/2023 are acknowledged.
The replacement sequence listing submitted 7/12/2023 has been entered.
The request for corrected ADS and official filing receipt on 7/31/2023 is acknowledged. A corrected filing receipt was issued 8/10/2023.
The replacement drawings (sheets 1/107) submitted on 8/10/2023 were improper as they were not properly marked. See 8/28/2023 communication. Replacement drawings (sheets 1/107) were resubmitted on 8/30/2023. These drawings are acceptable.
Election/Restrictions
Applicant’s election without traverse of Group I in the reply filed on 1/8/2026 is acknowledged.
Upon further consideration of the claims, the antibody of Group II, claim 141, has been rejoined with the claims of Group I.
Upon further consideration of the claims, the species requirement has been withdrawn.
Claims 182-184 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 1/8/2026.
Claims 133-181 are under consideration.
Table A discloses the sequences (CDRs, VH, VL, HC, LC) for various anti-GLP1R antibodies. Each of these specific antibodies is free of the art. The prior art does not disclose or suggest antibodies having these sequences.
Antibodies REGN9268 (mAb 17) (see claim 140, part (a)) and REGN9267 (mAb 5) (see claim 140, part (f)) have the same HCDRs and LCDRs.
Antibodies REGN7990 (mAb 3) (see claim 140, part (b)), REGN15869 (see claim 140, part (c)), REGN18121- (see claim 140, part (v)), REGN18123- (see claim 140, part (w)), and REGN7989 (mAb 11) (see claim 140, part (i)) have the same HCDRs and LCDRs.
Antibodies REGN8070 (mAb 16) (see claim 140, part (d)) and REGN8069 (mAb 12) (see claim 140, part (j)) have the same HCDRs and LCDRs.
Antibodies REGN8072 (mAb 4) (see claim 140, part (e)) and REGN8071 (mAb 13) (see claim 140, part (k)) have the same HCDRs and LCDRs.
Antibodies REGN7988 (mAb 15) (see claim 140, part (g)) and REGN7987 (mAb 14) (see claim 140, part (q)) have the same HCDRs and LCDRs.
Antibodies REGN5619 (mAb 2) (see claim 140, parts (h) and (p)) (listed twice in Table A with different SEQ ID NOS., see lines with HCVR SEQ ID NOS: 166 and 295) and REGN9426 (mAb 6) (see claim 140, part (l)) have the same HCDRs and LCDRs.
Antibodies REGN9270 (mAb 18) (see claim 140, part (r)) and REGN9278 (mAb 19) (see claim 140, part (s)) have the same HCDRs and LCDRs.
Antibodies REGN9279 (mAb 20) (see claim 140, part (t)) and REGN9280 (mAb 21) (see claim 140, part (u)) have the same HCDRs and LCDRs.
Antibody REGN5617 (mAb9; mAb10) (see claim 140, part (o)) has a unique set of HCDRs and LCDRs.
Antibodies REGN5203 (COMP mAb 1) (see claim 140, part (m)) and REGN4204 (mAb 7) (see claim 140, part (n)) have the same HCDRs and LCDRs.
The light chains of SEQ ID NO: 44, 64, 84, 104, 124, 164, 184, 269; 273; 293; 313; 373; and 413 have the Q-tag of SEQ ID NO: 18 (LLQGSG) as amino acids 1-6.
The heavy chains of SEQ ID NO: 142, 203, 223, 243, 263, 267, 331, 351, and 391 have the Q-tag of SEQ ID NO: 18 (LLQGSG) as amino acids 1-6.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph 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 the first paragraph of pre-AIA 35 U.S.C. 112:
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 133-139, 141-171, and 175-181 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 applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Independent claim 133 recites that the anti-GLP1R antibody:
(i) comprises a heavy chain immunoglobulin or variable region thereof that comprises CDR-H1, CDR-H2 and CDR-H3 of a heavy chain immunoglobulin or variable region thereof that comprises the amino acid sequence set forth in SEQ ID NO: 26; 46; 66; 86; 106; 126; 146; 166; 187; 207; 227; 247; 275; 295; 315; 335; 355; 375; 395; 42; 62; 82; 414; 416; 102; 122; 142; 162; 182; 203; 223; 243; 263; 267; 271; 291; 311; 331; 351; 371; 391 or 411; or a variant thereof;
and/or
a light chain immunoglobulin or variable region thereof that comprises CDR-L1, CDR-L2 and CDR-L3 of a light chain immunoglobulin or variable region thereof that comprises the amino acid sequence set forth in SEQ ID NO: 34; 54; 74; 94; 114; 134; 154; 174; 195; 215; 235; 255; 283; 303; 323; 343; 363; 383; 403; 44; 64; 84; 104; 124; 144; 164; 184; 205; 225; 245; 265; 269; 273; 293; 313; 333; 353; 373; 393; or 413; or a variant thereof;
(ii) is an antibody or antigen-binding fragment thereof that competes for binding to GLP1R with said antibody or antigen-binding fragment of (i);
and/or
(iii) is an antibody or antigen-binding fragment thereof that binds to the same epitope of GLP1R as said antibody or antigen-binding fragment of (i).
In part (i), SEQ ID NOS: 26, 46, 66, 86, 106, 126, 146, 166, 187, 207, 227, 247, 275, 295, 315, 335, 355, 375, and 395 correspond to HCVR sequences where these HCVR sequences are found in the HC of SEQ ID NOS: 42, 62, 82, 102, 122, 142, 162, 182, 203, 223, 243, 263, 291, 311, 331, 351, 371, 391, and 411, respectively. The HCVR of SEQ ID NO: 66 is also found in the HC of SEQ ID NOS: 414 and 416. The HC of SEQ ID NOS: 267 and 271 correspond to REGN5203 (COMP mAb1) and REGN5204 (mAb 7), respectively. See Table A.
In part (i), SEQ ID NOS: 34, 54, 74, 94, 114, 134, 154, 174, 195, 215, 235, 255, 283, 303, 323, 343, 363, 383, and 403 correspond to LCVR sequences where these LCVR sequences are found in the LC of SEQ ID NOS:44, 64, 84, 104, 124, 144, 164, 184, 205, 225, 245, 265, 293, 313, 333, 353, 373, 393, and 413, respectively. The LC of SEQ ID NOS: 269 and 273 correspond to REGN5203 (COMP mAb1) and REGN5204 (mAb 7), respectively. See Table A.
Claim 133, part (i), includes variants of each of the sequences recited. As written, the claim encompasses antibodies where only the CDRs for the HCVR or the LCVR, but not both, are specified (see the “and/or” limitation in part (i)). As written, the variation can be within the CDRs.
Claims 133, part (i), includes mixing HCVR CDR sequences from one antibody such as REGN9268 (HCVR of SEQ ID NO: 26) with LCVR CDR sequences from an unrelated antibody such as REGN7990 (LCVR of SEQ ID NO: 54). (See the “and/or” limitation in part (i)).
Claim 133, part (ii), includes antibodies that compete for binding to GLP1R with the structurally variable antibodies of claim 133, part (i). The structure of these antibodies is not known. These antibodies are not adequately described.
Claim 133, part (iii), includes antibodies that bind to the same epitope of GLP1R as the structurally variable antibodies of claim 133, part (i). The specification does not disclose or identify the epitopes bound by the structurally variable antibodies of claim 133, part (i). These antibodies are not adequately described.
Claim 141 is an independent claim. Claim 141, part (i), includes variants of each of the sequences recited. As written, the claim encompasses antibodies where only the CDRs for the HCVR or the LCVR, but not both, are specified (see the “and/or” limitation in part (i)). As written, the variation can be within the CDRs. The claim includes mixing HCVR CDR sequences from one antibody such as REGN9268 (HCVR of SEQ ID NO: 26) with LCVR CDR sequences from an unrelated antibody such as REGN7990 (LCVR of SEQ ID NO: 54). (See the “and/or” limitation in part (i)). Claims 141, part (ii), is an antibody or antigen-binding fragment thereof that competes for binding to GLP1R with said antibody or antigen-binding fragment of (i); and/or part (iii) is an antibody or antigen-binding fragment thereof that binds to the same epitope of GLP1R as said antibody or antigen-binding fragment of (i). The structure of the antibodies of part (ii) is not known. These antibodies are not adequately described. With respect to part (iii), the specification does not disclose or identify the epitopes bound by the structurally variable antibodies of claim 133, part (i). These antibodies are not adequately described.
Claim 165 is directed to the antibody-tethered drug conjugate of claim 133, wherein the antibody-tethered drug conjugate has a half life of longer than 7 days in plasma, and/or wherein the antibody-tethered drug conjugate does not bind to G protein-coupled receptors (GPCRs) other than GLP1R. The specification does not describe those features that provide this antibody specificity.
Claim 169 includes mixing VH or HC sequences from one antibody such as REGN9268 (HCVR of SEQ ID NO: 42) with the LCVR sequences from an unrelated antibody such as REGN7990 (LCVR of SEQ ID NO: 54). See the “and/or” limitation. See also claim 171.
Claim 170 includes mixing HCVR CDRs from one antibody with the LCVR CDRs from an unrelated antibody. In addition, each CDR can be a variant of the recited CDR. As written, the claim also encompasses antibodies where only the CDRs for the HCVR or the LCVR, but not both, are specified (see the “and/or” limitation).
Claim 176 only specifies the HC, including unspecified variants, and not the LC.
Claim 178 only specifies the HC, including unspecified variants, and not the LC
The genus of GLP1R antibodies encompassed by the claims is not adequately described.
The antibodies set forth in Table A are adequately described. However, the genus of GLP1R antibodies encompassed by the claims are highly variant as discussed above. The antibodies of Table A are insufficient to support all of the combinations and variants encompassed by the claims. Table A discloses 23 antibodies; however, most of the antibodies in the table have an essentially duplicate antibody also in the table. At least for example, the antibodies differ by the presence or absence of the six amino acid Q-tag of SEQ ID NO: 18 on the HCVR, LCVR, HC or LC. At least for example, antibodies REGN9268 (mAb 17) and REGN9267 (mAb 5) have the same HCDRs and LCDRs. The HCVR of SEQ ID NO: 26 and 126 are the same. The LCVR of 34 and 134 differ by the presence of SEQ ID NO: 18 at the N-terminus of SEQ ID NO: 34. The HC of SEQ ID NO: 42 and 142 differ by the presence of SEQ ID NO: 18 at the N-terminus of SEQ ID NO: 142. The LC of SEQ ID NO: 44 and 144 differ by the presence of SEQ ID NO: 18 at the N-terminus of SEQ ID NO: 44.
The specification does not disclose a reasonable number of embodiments within the claimed genus of antibodies that are representative of the various combinations of six CDRs, including variants, required for antigen binding to GLP1R. It is not considered to be so predictable what antigens would be bound.
Those of ordinary skill in the art would have known that the full six CDR sequences are required to form the part of an antibody, i.e. the paratope, that specifically binds the target antigen. See at least the abstract and introduction of Al Qaraghuli et al. who states the six CDRs form a continuous surface to form the paratope that binds the epitope of the cognate antigen. Many of the instant claims define only the heavy chain CDRs or the light chain CDRs and do not define both.
Those of ordinary skill in the art at the time of the effective filing date would have known that variations in one or more CDRs of a known antigen-binding antibody could change or eliminate binding to a particular antigen. At least for example, Iwahashi et al. discloses that the effect of CDR replacement or a single amino acid change on the antigen binding site structure can only be known by actual structural analysis. See at least abstract and first full paragraph on page 1089. The specification does not disclose variations that can be made to the CDRs that would result in antigen binding.
Kranz et al. (Proc. Natl Acad. Sci, USA, 78(9):5807-5811, 1981) showed that in mixing heavy and light chains from six monoclonal anti-fluorescyl antibodies, heterologous heavy and light chain mixtures did not form anti-fluorescyl active sites (p. 5809, col. 1, first part of second paragraph). In another experiment (supra, p. 5809, col. 1, third paragraph), “Of the 30 possible heterologous H and L chain combinations, 13 did not reassociate within detectable limits..., 13 reassociated but with less affinity than the homologous association,.. and 4 associated with greater affinity than the homologous reassociation....” In the instant claims, the VH from one antibody can be mixed with any VL from another antibody and CDRs with significant structural diversity (in view of the variations permitted) are combined in the claims. Herold et al. (Scientific Reports, 7:12276, DOI:10.1038/s41598-01 7-12519-9, Sept. 2017, p. 2, end of second paragraph), looked at VH/VL interfaces and how changes affected antigen binding and found, “Our results on the effects of mutations on domain structure, stability, association and antigen binding together with CDR exchange experiments reveal complex relationships between structural and functional properties within the VL and VH domains.” It was discussed that (p. 11, start of 3rd paragraph), “The relationship between structure, stability and binding affinity of VH and VL is still unclear. This is an important aspect for understanding antibody architecture both as the basis of our immune system and also in the context of the engineering of antibodies for therapeutic purposes. In this context, it was found that in mutants an increase in affinity is often accompanied by a decrease in stability and vice versa - and these consequences are difficult to predict.” The reference concludes (p. 14, end of 2nd paragraph and 3rd paragraph), “[B]inding to the antigen is affected by each CDR loop differently and changes in loop mobility can in principle affect antigen binding affinity in an unpredictable way…Taken together our data indicate that multiple determinants regulate the VH/VL association and the affinity for the antigen. The interplay between interface interactions and CDRs turned out to be complex with mutual influences on VH/VL association and antigen binding.” Herold et al. and Kranz et al. illustrate the unpredictability of mixing antibody VH/VL chains from different antibodies (and implicitly their CDRs) with respect to binding properties.
The specification does not adequately describe the genus of antibodies embraced by the claims.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 137, 139-140, 172-174, and 180 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 137 is confusing in its dependency on claim 136. Both claims reference the payload (P) structure of SEQ ID NO: 519. It appears that the structure present in claim 137 may be implying a particular stereochemistry for the recited payload but this is unclear.
Claim 139 is confusing in its dependency on claim 138. Both claims reference the linker-payload structure of SEQ ID NO: 507. It appears that the structure present in claim 139 may be implying a particular stereochemistry for the recited linker-payload but this is unclear.
Claim 140 recites in part “wherein the structure of a linker-payload that is conjugated to amino acids 1-6 (LLQGSG (SEQ ID NO: 18)) of SEQ ID NO: 44, 64, 84, 104, 124, 144, 164, 184, 205; 225; 245; 265; 269; 273; 293; 313; 333; 353; 373; 393; or 413 via amino acid 3 (Gln) is represented by...” This is confusing as SEQ ID NOS: 144, 205, 225, 265, 269, 333, 353, and 393 do not have the six amino acids of SEQ ID NO: 18 at their N-terminus. Clarification is requested. SEQ ID NO: 18 is identified as a Q-tag. See for example, claim 168. It is noted that claim 140 appears to contain a word-processing error in reciting “represented by[[:]] (SEQ ID NOS 506-507.” In addition, the claim does not appear to show both SEQ ID NOS: 506 and 507. Only one structure is shown. See for example claim 138. Clarification is requested. Claim 140 also recites “optionally, wherein the heavy chain immunoglobulin does not comprise a C-terminal lysine or lysine and glycine.” This is confusing. It is unclear if this intends that the heavy chains recited in parts (a)-(e) and (g)-(u) can have the C-terminal amino acid (K) deleted or the two C-terminal amino acids (GK) deleted. Clarification is requested.
Claim 172 is confusing in reciting “and/or” between parts (r) and (s). The antibody-tethered drug conjugate of claim 133 is directed to a single antibody being conjugated and not multiple antibodies.
Claim 172, part (a), recites SEQ ID NOS: 26 and 134 SEQ ID NO: 26 for REGN9268 (mAb17) is the same as SEQ ID NO: 126 of REGN9267 (mAb5). See Table A. The antibody of claim 172, part (a), corresponds to REGN9268. As written, claim 172, part (a), is claiming the same antibody as in claim 172, part (f). This is confusing.
Claims 172, part (j), recites SEQ ID NOS: 86 and 215. SEQ ID NO: 94 for REGN8070 (mAb16) is the same as SEQ ID NO: 215 of REGN8069 (mAb12). See Table A. The antibody of claim 172, part (j), corresponds to REGN8070. As written, claim 172, part (j), is claiming the same antibody as in claim 172, part (d). This is confusing.
Claim 173 is confusing in reciting parts (a)-(v) followed by a second part (c).
Claim 174 is confusing as the structure for SEQ ID NO: 507 is not the same as the structure for SEQ ID NO: 507 in claim 183. See rejection of claim 139 above. In addition, “attachement” is spelled incorrectly.
Claim 180 is indefinite in reciting a “pharmaceutical dosage form.” As no treatment or therapeutic effect is recited, it is unknown what amount of the antibody-tethered drug conjugate of claim 133 must be present to meet the limitations of the claims. The metes and bounds of the claim cannot be determined.
Conclusion
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/Marianne P Allen/Primary Examiner, Art Unit 1647
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