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 .
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
DETAILED ACTION
The amendments filed on 11/11/2025 which claims 1, 7, 13, 16, 20, and 25 were amended is acknowledged. Claims 3 and 5 were canceled.
Claims 1-2, 4, and 6-30 are pending in the instant application.
Priority
This application claims priority to the provisional application 63659954 filed on 6/14/2024 and 63552519 filed on 2/12/2024.
Election/Restriction
Applicant’s election without traverse of Group I, claims 1-20 and 25 and the structure of claim 13 in the reply filed on 7/4/2025 remains in effect.
Claims 9-10, 11-12, 14-15, 17, 21-24, and 26-30 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected group/species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 7/4/2025.
Claims 1-2, 4, 6-8, 13, 16, 18-20, 25
Claims 1-2, 4, 6-8, 13, 16, 18-20, and 25 are examined herein.
Withdrawn Objections
The objection to the specification has been partially withdrawn; applicant (i) removed the hyperlinks, (ii) restored bullet point c in the claim 25; and (iii) added the sequence GGFG as SEQ ID NO: 36. However, applicant did not add SEQ ID NO: 36 to the drawings or to the “brief description of the drawings”.
Withdrawn Rejections
The rejection of claims 1-2, 4, 6-8, 11, 13, 16, 18-20, and 25 under § 112(b) is withdrawn in light of the amendments; the claim now includes the language of “or the antigen-binding fragment thereof”.
The rejection of claims 13, 16, and 20 under § 112(b) is withdrawn in light of the amendments; applicant deleted “about” in these claims.
Claim Interpretation
Claim 1 was interpreted as “(i) and (ii) and (iii) and [(iii) and/or (iv)]”. See the rejection under 112(b) of this claim for further details.
Objections to the Drawings/Specification
The specifications and figures are objected to because the amino acid sequence GGFG listed
in the “Brief Description of the Figures” section and their corresponding Drawings lack SEQ ID
numbers in Fig. 5-6, 8-9, and 12-17. The sequence GGFG corresponds to SEQ ID NO: 36.
Claim Rejections – 35 USC § 112(b)
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 1-2, 6-8, 16, 18-19, and 25 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 1
Claim 1 contains two conjunctions in a bulleted list, wherein it is unclear if it is to be interpreted as “(i) and (ii) and (iii) and [(iii) and/or (iv)]” or if it is to be interpreted as “(i) and/or [(ii) and(iii)] and/or (iv)”. Because of these multiple interpretations, this claim is rendered indefinite. If applicant is claiming the former, then it should be delineated as “(i), (ii), and (iii)” wherein bullet points (iii) and (iv) are combined with the “and/or”. More specifically, applicant should delineate the options between semi-colons as such:
“wherein the antibody or the antigen-binding fragment thereof comprises:
i. a heavy chain variable region (VH) comprising complementarity-determining regions (CDRs) 1, 2 and 3 as set forth in SEQ ID NOS: 5, 6, and 7, or as set forth in SEQ ID NOS: 11, 12, and 13;
ii. a light chain variable region (VL) comprising complementarity-determining regions 1, 2 and 3 as set forth in SEQ ID NOS: 8, 9, and 10, or as set forth in SEQ ID NOS: 14, 15, and 16; and
iii. a heavy chain constant region as set forth in SEO ID NO: 17, or a light chain constant region as set forth in SEO ID NO: 18.”
Dependent claims 2, 6-8, 16, 18-19, and 25 fail to cure these deficiencies, thus are also rendered indefinite.
Claim Rejections – 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1-2, 4, 6-8, 13, 16, 18-20, and 25 are rejected under 35 U.S.C. 103 as being unpatentable over Pasqualini (US20230139913) in view of Chen (US20220289833), Arap (US20230293710), Nara (US20230365662), Hettman (WO2015155998), and Bird (doi: 10.1007/978-1-4939-9929-3_8). This rejection has been modified to solely address the amendments.
claim 1,2
Regarding claims 1-2, Pasqualini teaches a VH with 100% sequence identity with instant SEQ ID NO: 1 (SEQ ID NO: 61), which comprises the CDRs of instant SEQ ID NOs: 5-7, underlined below.
instant_1 ---------QVRLQESGPGLVKPSQTLSLTCTVSGGSISSGGYYWSWIRQHPGKGLEWIG 51
Pasqualini_61 YTKLSSSGTQVRLQESGPGLVKPSQTLSLTCTVSGGSISSGGYYWSWIRQHPGKGLEWIG 180
***************************************************
instant_1 YIYYSGSTYYNPSLESRVTISVDTSKNQFSLKLSSVTAADTAVYYCARYSSIDAFEIWGQ 111
Pasqualini_61 YIYYSGSTYYNPSLESRVTISVDTSKNQFSLKLSSVTAADTAVYYCARYSSIDAFEIWGQ 240
************************************************************
instant_1 GTMVTVSS 119
Pasqualini_61 GTMVTVSS 248
***********
Pasqualini teaches a VL with 100% sequence identity with instant SEQ ID NO: 3 (SEQ ID NO: 38), which comprises the CDRs of instant SEQ ID NOs: 8-10, underlined below.
instant_3 SYVLTQPPSVSVAPGKTATITCGGDDIGSKSVHWYQQKPGQAPVLVVYDDGDRPSGIPER 60
Pasqualini_38 SYVLTQPPSVSVAPGKTATITCGGDDIGSKSVHWYQQKPGQAPVLVVYDDGDRPSGIPER 60
************************************************************
instant_3 FSGSNSGNTATLAISRVEAGDEADYYCQVWDSSSDQYVFGSGTKLTVL 108
Pasqualini_38 FSGSNSGNTATLAISRVEAGDEADYYCQVWDSSSDQYVFGSGTKLTVL 108
************************************************
Pasqualini teaches the antibody may be conjugated to a toxin (para 0018), for the purpose of generating an antibody drug conjugate (ADC) as a suitable anti-cancer therapeutic (para 0033) for individuals comprising neoplasms expressing GRP78 (pg 0170). Pasqualini teaches the ADC comprises an intervening linker connecting the toxin to the antibody (para 0170), wherein the linker is cleavable or non-cleavable (para 0239), thus satisfying the limitation of formula A-(L-D)x, wherein x is 1.
Pasqualini does not teach the conjugate comprising the heavy chain constant region of instant SEQ ID NO: 17 nor the light chain constant region of instant SEQ ID NO: 18.
Chen teaches the light chain constant region of the antibody Tezepelumab which comprises the same light chain constant region as instant SEQ ID NO: 18 (SEQ ID NO: 35), shown below.
instant_18 ------------------------------------------------GQPKAAPSVTLF 12
Chen_36 FSGSNSGNTATLTISRGEAGDEADYYCQVWDSSSDHVVFGGGTKLTVLGQPKAAPSVTLF 120
************
instant_18 PPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYL 72
Chen_36 PPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYL 180
************************************************************
instant_18 SLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS 106
Chen_36 SLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS 214
**********************************
Chen also teaches the heavy chain constant region of Tezepelumab, which comprises 92% sequence identity to instant SEQ ID NO: 17 (SEQ ID NO: 36), shown below.
instant_17 --ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ 58
Chen_35 SSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ 180
*************.*:*** .*************************************
instant_17 SSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELL 118
Chen_35 SSGLYSLSSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCV---ECPPCPAPPV- 236
****************.:***** ***:********** ** *.* ******* :
instant_17 GGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQ 178
Chen_35 AGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQ 296
.*************************************:*********************
instant_17 YNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR 238
Chen_35 FNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKTISKTKGQPREPQVYTLPPSR 356
:***:********:*****************.***********:****************
instant_17 EEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKS 298
Chen_35 EEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKS 416
*****************************************:******************
instant_17 RWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 330
Chen_35 RWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 448
********************************
Chen teaches Tezepelumab is compatible with conjugation to a drug (para 0021-0022). Chen teaches Tezepelumab targets the cytokine, Thymic stromal lymphopoietin (TSLP) (abstract; para 0003).
Arap teaches an ADC targeting EphA5 (pg 25, para 0392), comprising a constant region that is amenable to conjugation using the “thiobridge” technology, using the bis-tosyl containing precursor shown below (pg 9, para 0167; pg 11, para 0173). The “thiobridge” moiety has been boxed-in below.
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Arap teaches the HC constant region of instant SEQ ID NO: 17 (SEQ ID NO: 14), shown below.
instant_17 ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS 60
Arap_14 ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS 60
************************************************************
instant_17 GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGG 120
Arap_14 GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGG 120
************************************************************
instant_17 PSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYN 180
Arap_14 PSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYN 180
************************************************************
instant_17 STYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREE 240
Arap_14 STYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREE 240
************************************************************
instant_17 MTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRW 300
Arap_14 MTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRW 300
************************************************************
instant_17 QQGNVFSCSVMHEALHNHYTQKSLSLSPGK 330
Arap_14 QQGNVFSCSVMHEALHNHYTQKSLSLSPGK 330
******************************
It would have been obvious to combine the teachings of Pasqualini, Chen, and Arap because (1) Pasqualini provides the complete set of six CDRs for binding GRP78 which can be used as part of an anti-cancer ADC therapeutic; (2) Chen provides the same light chain constant region and a similar heavy chain constant region of an antibody that is amenable to conjugation with a cytotoxic drug; and (3) Arap provides the same heavy chain constant region that is amenable to conjugation using bridging disulfide linkers. One of skill in the art need only to exchange light chain constant region of Pasqualini with that of Chen and or exchange the heavy chain constant region of Pasqualini with that of Arap, to arrive at the instantly claimed invention. One of skill in the art would have had a reasonable expectation of success of performing this exchange as all the references teach that their antibodies are amenable to conjugation to a drug.
claim 4
Regarding base claim 4, the heavy chain of instant SEQ ID NO: 21 consists of the sequence MGWSCIILFLVATATGVHS, instant SEQ ID NO: 1 (VH), and instant SEQ ID NO: 17, in that order. The light chain of instant SEQ ID NO: 23 consists of the sequence MGWSCIILFLVATATGVHS, instant SEQ ID NO: 3 (VL), and instant SEQ ID NO: 18. As mentioned above in the rejection of claims 1-2, Pasqualini teaches both the VH and VL regions of this antibody.
Pasqualini does not teach HC constant region of instant SEQ ID NO: 21, nor the LC constant region of instant SEQ ID NO: 23, as mentioned previously in the rejection of claim 3. Pasqualini also does not teach the sequence MGWSCIILFLVATATGVHS being appended to the VH and VL regions.
Nara teaches appending the sequence MGWSCIILFLVATATGVHS (Nara SEQ ID NO: 277) to the HC of an antibody comprising the same framework regions as instant SEQ ID NO: 21 (SEQ ID NO: 221), shown below.
instant_21 MGWSCIILFLVATATGVHSQVRLQESGPGLVKPSQTLSLTCTVSGGSISSGGYYWSWIRQ 60
Nara_221 MGWSCIILFLVATATGVHSQVQLQESGPGLVKPSETLSLTCTVSGFSLS--IYSVHWIRQ 58
*********************:************:********** *:* * ****
instant_21 HPGKGLEWIGYIYYSGSTYYNPSLESRVTISVDTSKNQFSLKLSSVTAADTAVYYCARYS 120
Nara_221 PPGKGLEWIGMIWGGGSSDYNSALKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARNG 118
********* *: .**: ** :*:********************************* .
instant_21 SIDAFEIWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN 180
Nara_221 NFYAMDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN 178
.: *:: *****:***********************************************
instant_21 SGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKS 240
Nara_221 SGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKS 238
******************************************************:*****
instant_21 CDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYV 300
Nara_221 CDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYV 298
************************************************************
instant_21 DGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKA 360
Nara_221 DGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKA 358
************************************************************
instant_21 KGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLD 420
Nara_221 KGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLD 418
****************:*:*****************************************
instant_21 SDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 468
Nara_221 SDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 466
************************************************
Nara teaches a sequence with 100% sequence identity to the LC constant region of instant SEQ ID NO: 18 (SEQ ID NO: 219), shown below.
instant_18 GQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSK 60
Nara_219 GQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSK 60
************************************************************
instant_18 QSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS 106
Nara_219 QSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS 106
**********************************************
Nara also teaches appending the sequence MGWSCIILFLVATATGVHS to the LC of antibody (e.g. SEQ ID NO: 278). Nara teaches the leader sequence is advantageous for the production of antibody products by yeast cells, which are capable of recognizing the leader sequences and capable of secreting peptides comprising said leader sequences (para 0344). Nara teaches that yeast are capable of post-translational modifications of secreted peptides, (e.g. glycosylation) thus can be more advantageous over bacterial production strategies for immunoglobulins (para 0344).
It would have been obvious to combine the teachings of Pasqualini, Arap, and Nara because (1) Pasqualini provides the complete set of six CDRs for binding GRP78 which can be used as part of an anti-cancer ADC therapeutic; (2) Arap provides a functional antibody framework region that is amenable to conjugation; and (3) Nara provides the leader sequence necessary for yeast expression of the antibody. One of skill in the art would have had a reasonable expectation of success because Nara teaches yeast are capable of excreting antibodies when the leader sequence is present; Pasqualini teaches the set of six CDRs are capable of binding GRP78 as a useful means of targeting an anti-cancer ADC therapeutic; and Arap teaches that their antibody framework region is amenable to conjugation to a linker/drug as part of an ADC.
claim 6
Regarding claim 6, Pasqualini teaches the linker is optionally cleavable (para 0239).
claim 7-8
Regarding claims 7-8, Pasqualini does not teach a GGFG linker.
Hettman teaches an anti-Her3 conjugate of the structure below, comprising an MC moiety, GGFG-D linker, and the 2-hydroxyacetylamide of Exatecan (a.k.a. Dxd) (pg 140, described regions have been boxed in below). Hettman teaches the ADCs of their invention target cancer cells using the anti-HER3 antibody in order to deliver a cytotoxic exatecan drug (pg 4-5, para 0012-0013).
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It would have been obvious to combine the teachings of Pasqualini and Hettman because (1) Pasqualini provides the complete set of six CDRs for binding GRP78 which can be used as part of an anti-cancer ADC therapeutic; and (2) Hettman provides an exemplary linker and drug known to be amenable to antibody conjugation as an anti-cancer ADC. One of skill in the art would have had a reasonable expectation of success because Pasqualini teaches their ADC is effective in targeting cancer cells and Hettman teaches the linker and drug combination is also effective in treating cancer cells when conjugated to a cancer-targeting antibody.
claim 13,16,18-20
Regarding claims 13, 16, and 18-20, Pasqualini teaches a VH with 100% sequence identity with instant SEQ ID NO: 1 (SEQ ID NO: 61), which comprises the CDRs of instant SEQ ID NOs: 5-7, underlined below.
instant_1 ---------QVRLQESGPGLVKPSQTLSLTCTVSGGSISSGGYYWSWIRQHPGKGLEWIG 51
Pasqualini_61 YTKLSSSGTQVRLQESGPGLVKPSQTLSLTCTVSGGSISSGGYYWSWIRQHPGKGLEWIG 180
***************************************************
instant_1 YIYYSGSTYYNPSLESRVTISVDTSKNQFSLKLSSVTAADTAVYYCARYSSIDAFEIWGQ 111
Pasqualini_61 YIYYSGSTYYNPSLESRVTISVDTSKNQFSLKLSSVTAADTAVYYCARYSSIDAFEIWGQ 240
************************************************************
instant_1 GTMVTVSS 119
Pasqualini_61 GTMVTVSS 248
***********
Pasqualini teaches a VL with 100% sequence identity with instant SEQ ID NO: 3 (SEQ ID NO: 38), which comprises the CDRs of instant SEQ ID NOs: 8-10, underlined below.
instant_3 SYVLTQPPSVSVAPGKTATITCGGDDIGSKSVHWYQQKPGQAPVLVVYDDGDRPSGIPER 60
Pasqualini_38 SYVLTQPPSVSVAPGKTATITCGGDDIGSKSVHWYQQKPGQAPVLVVYDDGDRPSGIPER 60
************************************************************
instant_3 FSGSNSGNTATLAISRVEAGDEADYYCQVWDSSSDQYVFGSGTKLTVL 108
Pasqualini_38 FSGSNSGNTATLAISRVEAGDEADYYCQVWDSSSDQYVFGSGTKLTVL 108
************************************************
Pasqualini teaches the antibody may be conjugated to a toxin (para 0018), for the purpose of generating an antibody drug conjugate (ADC) as a suitable anti-cancer therapeutic (para 0033) for individuals comprising neoplasms expressing GRP78 (pg 0170). Pasqualini teaches the ADC comprises an intervening linker connecting the toxin to the antibody (para 0170), wherein the linker is cleavable or non-cleavable (para 0239), thus satisfying the limitation of formula A-(L-D)x, wherein x is 1.
Pasqualini is silent on the particular linker structure to the antibody.
Hettman teaches an anti-Her3 conjugate comprising an MC moiety, GGFG-D linker, and the 2-hydroxyacetylamide of Exatecan (a.k.a. Dxd) (pg 140), shown above.
Arap teaches an ADC targeting EphA5 (pg 25, para 0392), comprising a constant region that is amenable to conjugation using the “thiobridge” technology (pg 9, para 0167; pg 11, para 0173).
Bird teaches the ThioBridge technology in Fig 1 (reproduced below).
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Bird teaches:
“Disulfide rebridging strategies can address the issues of site selectivity and homogeneity and offer several key advantages over the more stochastic conjugation methods, including homogeneous drug loading and controlling the site of conjugation at the interchain disulfides… Disulfide rebridging methods for ADC production includes Abzena’s ThioBridge® technology and typically involves a two-step sequence (Fig. 1)… for a typical human IgG1, four reduced disulfide bonds yield eight free sulfhydryl residues. The second step involves conjugation of a bis-functional electrophilic reagent capable of reacting with a pair of sulfhydryl residues to covalently rebridge the disulfide bonds” (pg 114, para 2-3).
In sum, Bird teaches the same method of linking the antibody to the linker as instantly claimed (boxed below on instant structure of claim 13) via bis-tosyl precursor, and the ThioBridge technology generates a DAR of 4 for typical human IgG1’s, thus satisfying the limitation of x being 4.
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It would have been obvious to combine the teachings of Pasqualini, Arap, Hettman, and Bird because (1) (1) Pasqualini provides the complete set of six CDRs for binding GRP78 which can be used as part of an anti-cancer ADC therapeutic; (2) Hettman provides an exemplary linker and drug known to be amenable to antibody conjugation as an anti-cancer ADC; (3) Arap provides an antibody framework region that is compatible for conjugation using the ThioBridge technology; and (4) Bird describes the ThioBridge technology reliably provides a more homogenous population of ADCs. One of skill in the art would have had a reasonable expectation of success because Arap teaches their framework region is amenable to conjugation using the ThioBridge technology; Bird explains the generalizable utility and advantages of the ThioBridge technology; Pasqualini provides the complete set of six CDRs for binding GRP78 which can be used as part of an anti-cancer ADC therapeutic; and Hettman provides an exemplary linker and drug known to be amenable to antibody conjugation as an anti-cancer ADC.
claim 25
Regarding claim 25, Pasqualini teaches a nucleic acid encoding the antibody (pg 3, para 0020). While Pasqualini is silent on the particular nucleic acid sequence encoding instant SEQ ID NO: 1 (Pasqualini’s SEQ ID NO: 61) that corresponds to the nucleic acid of instant SEQ ID NO: 27, because of the redundancy of the nucleic acid code, given a particular amino acid sequence, one of skill in the art would have found it obvious to generate a corresponding nucleic acid capable of encoding instant SEQ ID NO: 1.
Response to Arguments
Applicant’s arguments filed on 11/11/2025 have been fully considered but they are not persuasive.
Objection; pg 14, para 3-pg 15, para 1
“Applicant contends that the instances where "GGFG" is used as part of a reagent name do not qualify as an "unbranched sequence or linear region of a branched sequence containing 4 or more specifically defined amino acids”. Thus the drawings do not require a SEQ ID NO for these instances.
Applicant has described GGFG as a shorthand for “glycine-glycine-phenylalanineglycine tetrapeptide” which by applicant’s admission is a “tetrapeptide linker moiety”. While it is understood that the description “’TBLR-GGFG-Dxd’ is the name of an L-D reagent that includes a reactive moiety with a cleavable linker bonded to a cytotoxin” and not an intended explicit reference to the sequence, it does unfortunately still call out an amino acid sequence. If applicant described it as “TBLR-L-Dxd” instead, this would clearly refer to a name, but in the instant case “GGFG” is a literal sequence. Absent this strict requirement for SEQ ID NOs wherever a sequence occurs, it would add an extra layer of interpretation by examiners for when a sequence is a sequence and when a sequence is a name—of which there is no criteria supplied in the MPEP for making said delineation. Thus, this objection over the drawings/specification is maintained.
103; pg 16, para 6-pg 17, para 5
Applicant argues the combination of references fail to teach the newly added limitation of SEQ ID NOs: 17-18. Applicant argues Arap is not prior art under 102(b)(2)(c). Applicant argues the references of Pasqualini, Nara, Hettman, and Bird fail to remedy these deficiencies in light of Arap failing to establish a case of prima facie obviousness.
The newly added limitation of the ADC comprising either SEQ ID NO: 17 and/or 18 has been supplanted by the inclusion of the reference of Chen and reiterated in the reference of Arap. Regarding the 102(b)(2)(c) exception, Applicant did not file a declaration explaining the role of the other inventors, so the art of “Pasqualini” (US20230139913) is still valid under 102(a)(1) and therefore still valid for a 103 rejection. Absent a declaration explaining the role of Renata Pasqualini, Wadih Arap, Fortunato Ferrara, Sara D’Angelo, and Andrew R.M. Bradbury, the office cannot determine which parts of this application were obtained from Staquincini. The same is true for the art of “Arap” (US20230293710), wherein there is no declaration explaining the role of Wadih Arap and Renata Pasqualini. If these other inventors provided the teachings of the instant invention, then they weren’t obtained from the instant inventor and thus remain valid as prior art. Applicant is reminded that a common assignee (e.g. MBrace Therapeutics) is irrelevant to the exceptions, as the claims were previously rejected under 102(a)(1) using the reference of Pasqualini. More pertinently, there exists no 1-year grace period for rejections under 35 U.S.C. § 103. Because a prima facie case of obviousness still exists, the other references were still found to remedy the deficiencies of Arap.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to LAURA ANN ESSEX whose telephone number is 571-272-1103. The examiner can normally be reached Mon - Fri 8:30-5:00.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey Stucker can be reached on 571-272-0911. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/L.A.E./
Examiner, Art Unit 1675
/JEFFREY STUCKER/Supervisory Patent Examiner, Art Unit 1675