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 1-2, 13-15, 23-24, 28, 31, 78-79, 85-86, 89-90 and 94-98 are currently pending
Claims 31 and 89-90 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 02/14/2024.
Claims 1-2, 13-15, 23-24, 28, 78-79, 85-86 and 94-98 Are under consideration.
Rejections/Objections Withdrawn
The 35 USC § 112(a) New Matter rejections of all claims subject to such rejections have been withdrawn in view of claim cancelation by claim amendments.
All 35 USC § 102(b) rejections of all claims have been withdrawn in view of claim amendments.
The 35 USC § 112(d) rejection of claim 95 has obviated by claim cancelation.
New Rejections/Objections Necessitated by Amendment
Claim Objections
Claims 1 and 95 are objected to because of the following informalities:
Claims 1 and 95 are directed to PDL1 binding polypeptides comprising variable groups Xaa and Xbb. Claim 1 permits Xaa to be an amino acid sequence having at least 90% homology to any one of SEQ ID NOs: 6-40 and Xbb to be an amino acid sequence having at least 90% homology to any one of SEQ ID NOs: 41-75. Claim 95 permits Xaa to be an amino acid sequence having at least 98% homology to any one of SEQ ID NOs: 6-40 and Xbb to be an amino acid sequence having at least 98% homology to any one of SEQ ID NOs: 41-75. However, all of the amino acid sequences SEQ ID NOs: 6-40 or SEQ ID NOs: 41-75 are 9 residues in length or fewer. As such, even a single amino acid change in any one of SEQ ID NOs: 6-75 would result in a % homology of 89%. Because of this, only sequences having 100% homology to the recited sequences are capable of satisfying the limitations of claims 1 and/or 95, thus causing the % homology language present in the claims to add nothing except for confusion.
Appropriate correction is required.
Claim Rejections - 35 USC § 103
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 (i.e., changing from AIA to pre-AIA ) 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.
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.
Claim(s) 1-2, 13-15, 23-24, 28, 78-79 and 85-86 is/are rejected under 35 U.S.C. 103 as being unpatentable over Jeffries (Jeffries, et al., J. Med. Chem. 2005 48:1344, of record) in view of Adams (Adams, et al.., Cancer Research 2004 64:5471, of record), Bertucci (Bertucci, et al., Oncoimmunology 2017 Vol. 6, No. 3; article ID e1278100, of record), Basran (Basran, et al., WO2019197583; Published 10/17/2019; Priority to 4/11/2018 via GB1805963.4) and as evidenced by Stallard (Stallard, “Researchers Gain Insight into How a Drug Fires up an Immune Response to Cancer” 12/19/2016; Memorial Sloan Kettering Cancer Center; URL = https://www.mskcc.org/news/researchers-gain-insight-how-drug-fires-immune-response-cancer Accessed 11/12/2024, of record))
Jeffries teaches on the subject of antibody drug conjugates (ADCs) comprising minor groove binding drugs, with a particular focus on the importance of hydrophilicity in drug-linker design. Jeffries teaches that drug effectiveness for cancer chemotherapies relies on differences between growth rates, biochemical pathways and physiological characteristics between normal and cancerous cells (Jeffries, 1344, ¶ 1). Jeffries teaches that effort has been put into ADCs for targeted drug delivery due to high selectivity for tumor associated antigens, favorable pharmacokinetics and relatively low intrinsic toxicities (Jeffries, p 1344, ¶ 1). Jeffries teaches that one of the design elements of the linker of Jeffries is a peptidic linker, which is specifically cleaved by lysosomal proteases and that such cleavage was followed by 1,6 fragmentation of a p-amino benzoic acid spacer between the peptide linker and the drug, resulting in the release of free drug (Jeffries, 1344, ¶ 2; p 1346, Fig. 1A). Jeffries teaches that several different types of linkers were tested and the linker designated cAC10-29 was used to make ADCs with a DAR (the maximum DAR based on available cysteines) with no detectable aggregation (Jeffries, p 1350, Table 1, Row 4). The linker of cAC10-29 of Jeffries satisfies. Regarding claims 1, 13, 14-15, the cAC10-29 conjugate of Jeffries possessed a maleimide crosslinker followed by a PEG4 linker (in the position corresponding to L1) followed by a substrate recognition sequence that is valine-citrulline followed by a self-immolative spacer that is p-amino benzoic acid.
Jeffries does not teach that the drug of the ADC is an immune activating agent that is Val-boroPro. Jeffries does not teach that the substrate recognition sequence is:
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… wherein R3 is methyl. Jeffries does not teach that the antibody component of the ADC is a PD-L1-binding affimer polypeptide having a sequence acceding to:
MIPRGLSEAKPATPEIQEIVDKVKPQLEEKTNETYGKLEAVQYKTQVLA-(Xaa)nSTNYYIKVRAGDNKYMHLKVFNGP-(Xaa)m-ADRVLTGYQVDKNKDDELTGF
….wherein (Xaa)n is selected from instant SEQ ID NOs 6-40 and (Xbb)m is an amino acid sequence having at least 90% homology to any one of instant SEQ ID NOs: 41-75
Adams teaches on the subject of the amino boronic dipeptide PT-100 (same as the Val-boroPro of the instant claims), a dipeptidyl peptidase inhibitor having antitumor properties (Adams, Abstract). Adams teaches that the growth of solid tumors is accompanied by tissue remodeling that comprises reactive stromal fibroblasts that are differentiated from normal fibroblasts by their production of certain proteases, including fibroblast activating protein (FAP) (Adams, p 5471, ¶ 1). Adams teaches that FAP is a serine protease that cleaves NH2 terminal peptides with the sequence NH2-Xaa-Pro, wherein Xaa is any natural amino acid (Adams, p 5471, ¶ 1). Adams teaches that the drug PT-100 is a drug that can stimulate the production of cytokines that are associated with T cell-mediated antitumor responses (Adams, p 5471, ¶ 2). Jeffries teaches that, in WHEI164 fibrosarcoma models, PT-100 was able to cause tumor rejection when administered early (Jeffries, p 5473, ¶2; Fig. 3), but will provide little to no benefit in immunocompromised mice (Jeffries, p 5474, ¶ 4). Jeffries also teaches that mice that had been treated with PT-100 to treat the WHEI164 tumors acquired complete resistance to a rechallenge with the same cell line (Jeffries, p 5474, ¶ 3).
Bertucci teaches on the subject of PD-L1 expression in soft tissue sarcomas (Bertucci, Abstract). Bertucci teaches that the PD-1/PD-L1 pathway is a key inhibitor of immune response to tumors, regulating the balance of tumor infiltrating lymphocytes and that blockade of this pathway with targeted antibodies has emerged as an effective therapeutic strategy for multiple cancers (Bertucci, p 2, ¶ 2). Bertucci teaches that in myxofibrosarcoma, 41% of patients had high expression of PD-L1 when PD-L1 mRNA was quantified (Bertucci, p 4, Table 2).
Basran teaches on the subject of PD-L1 binding affimer polypeptides (Basran, Abstract). Basran teaches that an affimer is a scaffold based on stefin A, and that the PD-L1-binding affimers of Basran comprise one or more solvent-accessible “loops” from stefin A have been replaced with amino acid sequences that confer the affimer to selectively bind PDL1 (Basran, p 39, ¶ 5-8). Basran teaches that the anti-PD-L1 affimer of Basran comprises the general formula (Basran, p 40, ¶ 6, p 41-, ¶3):
MIPRGLSEAKPATPEIQEIVDKVKPQLEEKTNETYGKLEAVQYKTQVLA-(Xaa)nSTNYYIKVRAGDNKYMHLKVFNGP-(Xaa)m-ADRVLTGYQVDKNKDDELTGF
wherein (Xaa)n is selected from instant Basran’s SEQ ID NOs:6-40 (Same as instant SEQ ID NOs 6-40) (Basran, p 41, ¶ 2; Table-Loop2 sequences) and (Xbb)m is selected from Basran’s SEQ ID NOs: 42-77 (Basran’s SEQ ID NOs: 42-76 are the same as instant SEQ ID NOs: 41-75) (Basran, p 45, ¶ 3; Table-Loop 4 sequences).
It would be prima facie obvious to one of ordinary skill in the art to combine the drug-linker technology taught by Jeffries, the Val-boroPro drug and proline-specific cleavage taught by Adams and a PD-L1 affimer of Basran in view of the teachings of Bertucci to arrive at an antibody drug conjugate with the linker structure of Jeffries with PT-100 as the drug, the Val-Cit replaced with Ala-Pro and attached to a PD-L1 affimer of Basran. One of ordinary skill would further be motivated to administer the resultant ADC to a patient having fibrosarcoma as part of a pharmaceutical composition. One of ordinary skill would be motivated to do this in order to better treat fibrosarcomas. Jeffries teaches of ADCs with polyethylene glycol moieties in the linker to allow for high DAR loading with minimal to no aggregation, wherein said ADCs further comprise a Val-Cit-PABC motif that is specifically cleaved by lysosomal proteases leading to the release of the original drug due to the self-immolative property of the PABC spacer. Therefore, one of ordinary skill would have a reasonable expectation of success making high DAR conjugates using this technology. Adams teaches that the drug Val-boroPro is potent immunomodulator capable of both retarding tumor growth as well as establishing specific tumor resistance to fibrosarcomas. Adams also teaches that FAP is differentially expressed in the tumor microenvironment in and around fibrosarcoma cells and that FAP selectively cleaves peptides having a Xaa-Pro motif, wherein Xaa is any naturally found amino acid. The teachings of Adams provide sufficient teaching, suggestion and motivation that would lead one of ordinary skill in the art to make two changes to the work of Jeffries. First, the PT-100 of Jeffries is able to retard the growth of tumor cells as well as foment immunological resistance to subsequent tumors and this would lead one of ordinary skill to use PT-100 as the drug in the drug-linker technology of Jeffries with a reasonable expectation of success. Second, Adams teaches that expression of the extracellular protease FAP is expressed at markedly higher levels in tumor microenvironments compared to normal tissue and that FAP selectively cleaves dipeptide motifs of the form Xaa-Pro, wherein Xaa is any naturally occurring amino acid. This would lead one of skill in the art to replace the Val-Cit motif of Jeffries with an Ala-Pro motif, which reads on the SRS structure of claims 1 and 23. One of ordinary skill in the art would do this because Adams teaches that FAP is differentially expressed in the tumor microenvironments targeted by the Val-boroPro of Adams and the addition of an Ala-Pro motif would cause one of ordinary skill to have a reasonable expectation of success with respect to the PT-100 not being cleaved until it reaches its target environment. Additionally, though the lysosomal enzymes that cleave the Val-Cit motif of Jeffries and the FAP taught by Adams recognize different peptidic motifs, they both still work via the hydrolysis of an amide bond adjacent to a PABC moiety, meaning that one of ordinary skill would reasonably expect the PABC moiety to retain its self-immolative function. Since the FAP of Adams will cleave any dipeptide of the form Xaa-Pro, one of ordinary skill could pick any amino acid for Xaa including proline and have a reasonable expectation of success. Finally, the teachings of Bertucci provide sufficient motivation to use an PD-L1-targeting polypeptide as the antibody in this type of ADC because Bertucci teaches that a significant percentage of fibrosarcomas express high levels of PD-L1 and that PD-L1 acts to suppress immunological activity against tumors. The PD-L1-binding affimer of Basran therefore would perform two important function in the modified ADC. First, targeting PD-L1 would localize the Val-boroPro in and around the target tissue due to the differential expression. Second, Bertucci teaches that antibody blockade of PD-1/PD-L1 interaction attenuates the immunosuppressive property of this pathway and Adams teaches that Val-boroPro performs poorly in immunosuppressed organisms. One of ordinary skill in the art would have a reasonable expectation of success using an anti-PD-L1 antibody because Bertucchi teaches that PD-L1 is expressed highly in fibrosarcoma cells and blockade of this pathway attenuates the immunosuppressive property of PD-1/PD-L1 signaling, which could prevent the Val-boroPro from having its desired effect. Regarding the DPP8/DPP8 inhibiting limitation of claim 85, Stallard provides sufficient evidence to establish that administration of the Val-boroPro of Adams would inherently inhibit DPP8 and DPP9 (Stallard, Summary).
Response to Arguments
Applicant provided no unique set of arguments regarding this combination of references
Claim(s) 1-2, 13-15, 23-24, 28, 78-79, 85-86 and 94-98 is/are rejected under 35 U.S.C. 103 as being unpatentable over Jeffries (Jeffries, et al., J. Med. Chem. 2005 48:1344, of record) in view of Adams (Adams, et al.., Cancer Research 2004 64:5471, of record), Bertucci (Bertucci, et al., Oncoimmunology 2017 Vol. 6, No. 3; article ID e1278100, of record) Basran (Basran, et al., WO2019197583; Published 10/17/2019; Priority to 4/11/2018 via GB1805963.4) and as evidenced by Stallard (Stallard, “Researchers Gain Insight into How a Drug Fires up an Immune Response to Cancer” 12/19/2016; Memorial Sloan Kettering Cancer Center; URL = https://www.mskcc.org/news/researchers-gain-insight-how-drug-fires-immune-response-cancer Accessed 11/12/2024, , of record) as applied to claims 1-2, 13-15, 23-24, 28, 78-79 and 85-86 above and in further view of SigmaAldrich (SigmaAldrich.com; URL: https://www.sigmaaldrich.com/US/en/product/mm/573114?srsltid=AfmBOooOl-VC8cCohfCFMSMX6UqDM5BUwo8gIAb5rF6sw-Qvy9cIBoEv ; Date: 01/09/2004; Accessed 11/29/2024), SigmaAldrich (SigmaAldrich.com; URL: https://www.sigmaaldrich.com/US/en/product/aldrich/803669?srsltid=AfmBOoowhJ3cGXxeX1yPLsh85t2lRcRUUwPoaKLggOTi6hUggxyJHQYtB ; Date: 5/6/2012; Accessed 12/22/2025)and AbCaM (AbCam.com; URL: https://www.abcam.com/en-us/products/biochemicals/spdp-crosslinker-cysteine-and-primary-amine-reactive-short-chain-crosslinker-ab145613 ; Date: 8/28/2014; Accessed 12/22/2025).
The teachings of Jeffries, Adams and Bertucci are discussed above. In addition to the teachings discussed above, Jeffries also teaches that the final step required to make the linker-drug motif used to make the cAC10-29 of Jeffries comprised the addition of the maleimidocaproyl crosslinker by deprotection of a terminal Fmoc protecting group in piperidine followed by reacting a maleimidocaproyl succimidyl ester with the resultant primary amino group (Jeffries, p 1349, Scheme 5):
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The teachings of Jeffries, Adams and Bertucci do not teach that the crosslinker in the linker motif of Jeffries comprised a SMCC adduct, an SIAB adduct or a
Sigma-Aldrich teaches that the linker SMCC was commercially available in 2004 and has the structure, which comprises a thiol-reactive maleimide end and an amine-reactive-NHS ester end (Sigma-Aldrich, p 1):
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Abcam teaches that the linker SPDP was commercially available in 2014 and has the structure, which comprises a thiol-reactive pyridyldithiol end and an amine-reactive-NHS ester end (Sigma-Aldrich, p 1):
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Sigma-Aldrich teaches that the linker SIAB was commercially available in 2004 and has the structure, which comprises a thiol-reactive halogen end and an amine-reactive-NHS ester end (Sigma-Aldrich, p 1):
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It would be prima facie obvious to one of ordinary skill in the art to modify the ADC in the combined method of Jeffries, Adams, Bertucci and Basran discussed above to comprise any one of the following for L1: 1) the SPDP of Abcam (adduct- claim 96) 2) SMCC of Sigma-Aldrich (Adduct-claim 97) or the SIAB or Sigma-Aldrich (adduct- Claim 98) . One of ordinary skill in the art would be motivated to do this to create an art One of ordinary skill in the art would be motivated to do this in order to use an L1 linker that is art equivalent crosslinker to the maleimidocaproyl crosslinker of Jeffries. One of ordinary skill in the art would have a reasonable expectation of success doing this because both the maleimodocaproyl-OSu crosslinker of Jeffries as well as the SMCC Sigma-Aldrich, the SIAB of Sigma-Aldrich and the DPDP of Abcam share the same teneral qualities: they are all short, mostly hydrophobic heterobifunctional linkers comprising one end that is thiol-reactive and another end that is amine-reactive.
Response to Arguments
Applicant provided no unique set of arguments regarding this combination of references
Conclusion
Claims 1-2, 13-15, 23-24, 28, 78-79, 85-86 and 94-98 are rejected.
Claims 1 and 95 are objected to.
No claims are allowed.
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.
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/SYDNEY VAN DRUFF/Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643