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 140-147 and 156-164 are pending and under consideration.
Rejections/Objections Withdrawn
The 35 USC 112(a) rejection of claims 152-154 is rendered moot by claim cancelation.
All 35 USC 103 and NSDP rejections have been withdrawn in view of claim amendments.
The terminal disclaimer filed on 04/01/2026 disclaiming the terminal portion of any patent granted on this application which would extend beyond the expiration date of US 12,248,477 B2 has been reviewed and is accepted. The terminal disclaimer has been recorded.
New Rejections Necessitated by Amendment
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.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 140-144, 146-147 and 158-164 is/are rejected under 35 U.S.C. 103 as being unpatentable over Vinstin (Vinstin, et al., Mol. Canc. Ther 2015 14(8):1868) in view of Fishkin (Fishkin, et al., WO 2021/198965 A1; Published 10/07/2021; Priority to 3/31/2020 by way of US 63/003,179) and Brun (Brun et al., WO 2021/174034A1; Published 9/2/2021; Priority to 02/28/2020 via US 62/982,943)
Vinstin teaches on the subject of anti-TM4SF1 ADCs as a therapeutic modality for cancer (Vinstin, Abstract). Vinstin teaches that TM4SF1 is an integral membrane glycoprotein related to tetraspanins that is abundantly expressed on cancer cells and on endothelial cells lining human cancer blood vessels but weakly expressed on endothelial cells of many normal tissues and organs, (Vinstin, p 1868, ¶ 2). Vinstin teaches that TM4SF1 being highly expressed by many human cancer cells and being associated with pathologic angiogenesis led to the hypothesis that targeting TM4SF1 would provide a dual anticancer mechanism: killing tumor cells directly and targeting the tumor vasculature (Vinstin, p 1869, ¶ 1). Vinstin teaches that the humanized anti-TM4SF1antibody v.1.10 was conjugated to ADC drug-linker moiety linker LP2, which comprises a dolastatin (a small molecule cytotoxic agent), which is depicted below (Vinstin, p 1869, ¶ 3):
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(Image: Vinstin, Supp. Fig. S1; Supplementary figures attached to Vinstin (2015) NPL reference)
Vinstin teaches that ADC v1.10-LP2 was able to induce complete tumor regression, defined as nonpalpable tumors in nearly all mice bearing NSCLC xenografts expressing high levels of TM4SF (Vinstin, p 1872, ¶ 2; Fig 3A) and that similar results were observed in human cancer xenografts for colon, prostate and pancreatic cancer cell lines, with complete regressions being achieved at a dose of 3 mpk (same as mg/kg) (Vinstin, p 1872, ¶ 3). Vinstin teaches that antibody v1.10 does not recognize murine TM4SF1, leading to the development of rabbit anti-mouse TM4SF1 antibody 2A7A that recognizes murine TM4SF1 but not human TM4SF1 and, when conjugated to LP2, was highly toxic to the murine microvascular endothelial cell line MS1 as well as 293 cells stably transfected to express murine TM4SF1 (Vinstin, p 1872, ¶ 4). Vinstin teaches that the combined therapy comprising administration the human TM4SF1-targeting ADC v1.10-LP2 and the murine TM4SF1-targeting ADC 2A7A-LP2 resulted in a significantly greater reduction in tumor volume compared to either ADC alone for both Calu-6 tumors and NCI-H460 tumors in murine xenograft studies (Vinstin, p 1874, ¶ 3-4; Fig. 6A,B).
Vinstin does not teach that the linker of the anti-TM4SF1 ADC comprises a reduction-sensitive cleavable 2-aminobenzene sulfonamide moiety. Vinstin does not teach that the anti-TM4SF1 antibody comprises an IgG4 Fc with an N297C mutation.
Fishkin teaches on the subject of neoDegrader conjugates as well as methods of treating cancer using such conjugates (Fishkin, Abstract). Fishkin teaches that bioreducible linkers take advantage of the reduction potential difference between the intracellular compartment vs plasma, with reduced being present in tumor cells’ cytoplasma being up to 1000-fold higher than in normal cells’ cytoplasma, leading to bioreducible linkers keeping conjugates intact during systemic circulation but are selectively cleaved by high intracellular glutathione, releasing active drug at tumor sites (Fishkin, ¶ 0413). Fishkin teaches that one bioreducible, cleavable linker suitable for ADC use comprises the following moiety (Fishkin, ¶ 0414):
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(Fishkin, ¶ 0414; q is in an integer from 2-10)
Brun teaches engineered antibodies suitable for use in antibody-ligand/drug conjugation (Brun, ¶ 001-007). Brun teaches that one of the engineered antibodies of Brun comprise IgG1 or IgG4 Fcs with N297 mutations, which decrease antibody N glycation (Brun, ¶ 0175), wherein the mutation is N297C mutation (Brun, ¶ 092; Fig 23)
It would be prima facie obvious to one of ordinary skill in the art to combine the anti-TM4SF1 ADC taught by Vinstin with the bioreducible 2-nitrobenzenesulfonamide linker component taught by Fishkin and the N297C IgG4 Fc of Brun and administer the resultant ADC in method of treating cancers expressing TM4SF1. One of ordinary skill in the art would be motivated to do this in order to form an improved anti-TM4SF1 ADC that is stable in circulation but selectively releases the cytotoxic payload in cellular cytosol upon internalization following binding to TM4SF1 on a tumor cell or tumor-associated endothelial cell. One of ordinary skill in the art would have a reasonable expectation of success combining the anti-TM4SF1 ADC taught by Vinstin with the bioreducible 2-nitrobenzenesulfonamide linker component taught by Fishkin and the N297C IgG4 Fc of Brun and administering the resultant ADC in method of treating cancers expressing TM4SF1 because: 1) Vinstin teaches that TM4SF1 targeting ADCs are capable of simultaneously targeting TM4SF1-expressing tumor cells and TM4SF1-expressing endothelial cells associated with tumor vasculature, 2) the ADC drug-linker utilized by Vinstin comprises a simple maleimide crosslinker linked to a dolastatin via a noncleavable C5 methylene linker, 3) Fishkin teaches that bioreducible linkers keep conjugates intact during systemic circulation but are selectively cleaved by high intracellular glutathione that is present in tumor cytosol, 4) Fishkin teaches that a 2-nitrobenzene sulfonamide moiety is an bioreducible linker that is suitable for use in antibody-drug conjugates, 5) Brun teaches antibodies comprising N297C IgG4 Fcs as suitable for antibody-ligand/drug conjugation, 6) it is within the purview of one of ordinary skill in the art to start with the anti-TM4SF1 ADC of Vinstin and add in an ADC linker moiety with known chemistry and 7) one of ordinary skill in the art would expect the resultant ADC to treat TM4SF1-expressing cancer because Vinstin teaches that TM4SF1 antibodies treat TM4SF1-expressing cancer by simultaneously targeting tumor cells and endothelial cells associated with the tumor vasculature.
Please note that the structure of the ADC drug-linker moiety would be—Maleimide—(CH2)2-NH-C(O)-(2-nitrobenzene)-S(O2)-NH-(CH2)5-Dolastatin, the two CH2 between the maleimide and the first amine are from the bioreducible linker taught by Fishkin (q =2), the sulfonamide is prepared by reacting an aryl sulfonyl chloride with an amide as also taught by Fishkin (see Fishkin, ¶ 0562), and the 5 CH2 between the bioreducible linker and the dolastatin drug are the original CH2 in the LP2 of Vinstin and this structure satisfies all of the structural limitations of instant claims 140-147. Regarding claim 143 specifically, the 5 CH2 between the bioreducible linker and the drug satisfy the first structure of claim 143 when m = 2, q = 0 and r =3). Additionally, the TM4SF1-expressing cancer taught by Vinstin are diseases characterized by abnormal endothelial cell interactions because endothelial cells forming tumor vasculature is abnormal. Regarding claim 162 specifically, one of ordinary skill in the art would reasonably expect that stem cells would be targeted as well because Vinstin teaches TM4SF1 is expressed during angiogenesis, which requires stem cells to produce the resultant vascular cells.
Response to Arguments
Applicant's arguments filed 4/1/2026 have been fully considered but they are not persuasive.
Applicant argued that the combined teachings of Vinstin and Fishkin do not teach all of the limitations of the claims as amended, as the combined teachings of Vinstin and Fishkin do not teach an IgG4 with an N297C mutation. Applicant also notes that previously applied publication WO2020176794A1 (The “794 publication), which does teach an IgG4 N297C mutation, is disqualified as prior art under 35 USC 102(b)(2) (see Section IV of Remarks). However, the claim amendments necessitated withdrawing all standing art rejections and making new ones and a new reference, Brun, has been applied, does meet the priority date and does teach IgG4 Fcs with N297C mutations.
Claim(s) 140-147 and 156-164 is/are rejected under 35 U.S.C. 103 as being unpatentable over Vinstin (Vinstin, et al., Mol. Canc. Ther 2015 14(8):1868, of record), Fishkin (Fishkin, et al., WO 2021/198965 A1; Published 10/07/2021; Priority to 3/31/2020 by way of US 63/003,179, of record) and Brun (Brun et al., WO 2021/174034A1; Published 9/2/2021; Priority to 02/28/2020 via US 62/982,943) as applied to claims 140-144, 146-147 and 158-164 above and in further view of Poon (Poon, et al., Toxicol. And App Pharmacol. 2013 273:298, of record).
The combined teachings of Vinstin, Brun and Fishkin are discussed above.
The combined teachings of Vinstin, Brun and Fishkin do not teach that the drug moiety of the anti-TM4SF1 ADC collectively taught by Vinstin, Brun and Fishkin is a maytansinoid moiety.
Poon teaches that trastuzumab emtansine (T-DM1) is an FDA-approved maytansinoid-comprising ADC targeting HER2 that is used for HER2 positive metastatic breast cancer (Poon, Abstract). Poon teaches that T-DM1 was tolerated in rats up to 40 mg/kg compared to 0.2 mg/kg for the maytansinoid DM1 alone, supporting the premise that ADCs improve the therapeutic index of the attached drug (Poon, Abstract).
It would be prima facie obvious to one of ordinary skill in the art to combine the anti-TM4SF1 ADC comprising a bioreducible cleavable linker and N297C IgG4 Fc collectively taught by Vinstin, Brun and Fishkin with the maytansinoid drug taught by Poon. The net result of this combination would be the anti-TM4SF1 ADC comprising a bioreducible cleavable linker with the maytansinoid of Poon as the cytotoxic drug. One of ordinary skill in the art would be motivated to do this in order to form an ADC comprising a cytotoxic drug that is FDA-approved for use treating cancer in humans. One of ordinary skill in the art would have a reasonable expectation of success combining the anti-TM4SF1 ADC comprising a bioreducible cleavable linker and N297C IgG4 Fc collectively taught by Vinstin, Brun and Fishkin with the maytansinoid drug taught by Poon to form an anti-TM4SF1 ADC comprising a bioreducible cleavable linker with the maytansinoid of Poon as the cytotoxic drug because: 1) the combined teachings of Vinstin, Brun and Fishkin collectively teach an anti-TM4SF1 ADC comprising a bioreducible linker and a dolastatin cytotoxic drug, 2) Poon teaches that the maytansinoid-comprising ADC T-DM1 is FDA-approved for treating cancer in humans, 3) Poon teaches that T-DM1 had a 2-fold reduction in toxicity compared to the maytansinoid alone, supporting the conclusion that attaching DM1 to an antibody increases the therapeutic index of that drug, 4) one of ordinary skill in the art would reasonably deduce that maytansinoid cytotoxin taught by Poon would also be capable of treating the TM4SF1-cancers because such cytotoxins work via general cytotoxicity mechanism that is toxic to cells in general and is not specific for a single type of cell.
Note: The complete structure of this resultant ADC would be identical to the second structure recited in instant claim 157 and additionally reads on instant claims 145, 156 and 157, which all recite ADCs comprising maytansinoid cytotoxins.
Response to Arguments
Applicant provided no arguments specific to this rejection
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 conflicting claims 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); 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 nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07€ and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) 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 www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claim 140-147 and 156-164 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 139-158 of copending Application No. 18/971,926 (Published as US 20250152730 A1 on 05/15/2025, of record) in view of Brun (Brun et al., WO 2021/174034A1; Published 9/2/2021; Priority to 02/28/2020 via US 62/982,943).
Although the claims at issue are not identical, they are not patentably distinct from each other because both the instant and copending claims are directed to anti-TM4SF1 antibodies comprising the same sugar-comprising cleavable linkers. Regarding instant claims 140-142 and 144, copending claim s 139-148 are directed to anti-TM4SF1 antibodies comprising the core sugar-comprising cleavable linker structure present in all of claims 140-142 and 144. Regarding instant claim 143, copending claims 149-150 are directed to linkers of the same general structure and permissible moieties. Regarding instant claim 145, the structures of copending claim 146 all comprise the sugar-comprising linker moiety of instant claim 145. Regarding instant claims 146-147 copending claim 151 is directed to ADCs with therapeutic molecules that are dolastatins and maytansinoids (both small molecules). Regarding instant claims 156-157, the structure of copending claim 143 reads on the bottom structure of claim 156 and the top structure of claim 157 when combined with the maytansinoid of copending claim 151. Regarding instant claim 158, copending claim 155 is directed to anti-TM4SF1 ADCs and pharmaceutically acceptable carriers. Regarding instant claims 159-154, copending claim 156 is directed to methods of treating diseases characterized by abnormal endothelial cell-cell interactions of all claimed cell pairings, said methods comprising administering anti-TM4SF1 ADCs.
The ‘926 application does not teach that the anti-TM4SF1 ADC of the ‘926 application comprises an N297C IgG4 Fc.
Brun teaches engineered antibodies suitable for use in antibody-ligand/drug conjugation (Brun, ¶ 001-007). Brun teaches that one of the engineered antibodies of Brun comprise IgG1 or IgG4 Fcs with N297 mutations, which decrease antibody N glycation (Brun, ¶ 0175), wherein the mutation is N297C mutation (Brun, ¶ 092; Fig 23).
It would be prima facie obvious to one of ordinary skill in the art to apply the N297C IgG4 Fc of Brun to the anti-TM4SF1 ADC of the ‘926 application. One of ordinary skill in the art would be motivated to do this in order to form the ADC of the ‘926 application with an Fc specifically engineered for antibodies in antibody-ligand/drug conjugates. One of ordinary skill in the art would have a reasonable expectation of success applying the N297C IgG4 Fc of Brun to the anti-TM4SF1 ADC of the ‘926 application because Brum teaches that the N297C IgG4 Fcs of Brum are antibodies specifically engineered to be used in antibody-ligand/drug conjugates.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
Applicant's arguments filed 4/1/2026 have been fully considered but they are not persuasive.
Applicant requested that the provisional rejections made in view of the ‘926 application be withdrawn pursuant to MPEP 804IB. This is not persuasive because the provisional NSDP rejection is not the last rejection still standing.
Claims 140-147 and 156-164 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 57-76 of copending Application No. 18/473,511 (Published as US 20240166759A1 on 05/23/2024, of record) in view of Vinstin (Vinstin, et al., Mol. Canc. Ther 2015 14(8):1868, of record), Fishkin (Fishkin, et al., WO 2021/198965 A1; Published 10/07/2021; Priority to 3/31/2020 by way of US 63/003,179, of record) and Brun (Brun et al., WO 2021/174034A1; Published 9/2/2021; Priority to 02/28/2020 via US 62/982,943).
The copending claims are directed to combinations comprising anti-TM4SF1 antibodies (copending claim 57) and ADCs comprising a TM4SF1 antibody or antigen-binding fragment conjugated to therapeutic molecules (copending claim 64) in combination with an immunotherapeutic agent. Regarding instant claims 146-147, copending claim 64 is directed to conjugates comprising maytansinoids (a small molecule class of drug).
The ‘511 application does not teach the antibody of the ADC of the ‘511 application is present in an ADC having a reduction-sensitive cleavable 2-aminobenzene sulfonamide moiety in the linker. The ‘511 application does not teach the resultant ADC is administered in methods of treating diseases characterized by abnormal endothelial cell-tumor cell interactions. The ‘511 Application does not teach the resultant ADC comprises an IgG4 Fc with N297C mutations.
Vinstin teaches on the subject of anti-TM4SF1 ADCs as a therapeutic modality for cancer (Vinstin, Abstract). Vinstin teaches that TM4SF1 is an integral membrane glycoprotein related to tetraspanins that is abundantly expressed on cancer cells and on endothelial cells lining human cancer blood vessels but weakly expressed on endothelial cells of many normal tissues and organs, (Vinstin, p 1868, ¶ 2). Vinstin teaches that TM4SF1 being highly expressed by many human cancer cells and being associated with pathologic angiogenesis led to the hypothesis that targeting TM4SF1 would provide a dual anticancer mechanism: killing tumor cells directly and id targeting the tumor vasculature (Vinstin, p 1869, ¶ 1). Vinstin teaches that the humanized anti-TM4SF1antibody v.1.10 was conjugated to ADC drug-linker moiety linker LP2, which comprises a dolastatin (a small molecule cytotoxic agent), which is depicted below (Vinstin, p 1869, ¶ 3):
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(Image: Vinstin, Supp. Fig. S1; Supplementary figures attached to Vinstin (2015) NPL reference)
Vinstin teaches that ADC v1.10-LP2 was able to induce complete tumor regression, defined as nonpalpable tumors in nearly all mice bearing NSCLC xenografts expressing high levels of TM4SF (Vinstin, p 1872, ¶ 2; Fig 3A) and that similar results were observed in human cancer xenografts for colon, prostate and pancreatic cancer cell lines, with complete regressions being achieved at a dose of 3 mpk (same as mg/kg) (Vinstin, p 1872, ¶ 3). Vinstin teaches that antibody v1.10 does not recognize murine TM4SF1, leading to the development of rabbit anti-mouse TM4SF1 antibody 2A7A that recognizes murine TM4SF1 but not human TM4SF1 and, when conjugated to LP2, was highly toxic to the murine microvascular endothelial cell line MS1 as well as 293 cells stably transfected to express murine TM4SF1 (Vinstin, p 1872, ¶ 4). Vinstin teaches that the combined therapy comprising administration the human TM4SF1-targeting ADC v1.10-LP2 and the murine TM4SF1-targeting ADC 2A7A-LP2 resulted in a significantly greater reduction in tumor volume compared to either ADC alone for both Calu-6 tumors and NCI-H460 tumors in murine xenograft studies (Vinstin, p 1874, ¶ 3-4; Fig. 6A,B).
Fishkin teaches on the subject of neoDegrader conjugates as well as methods of treating cancer using such conjugates (Fishkin, Abstract). Fishkin teaches that bioreducible linkers take advantage of the reduction potential difference between the intracellular compartment vs plasma, with reduced being present in tumor cells’ cytoplasma being up to 1000-fold higher than in normal cells’ cytoplasma, leading to bioreducible linkers keeping conjugates intact during systemic circulation but are selectively cleaved by high intracellular glutathione, releasing active drug at tumor sites (Fishkin, ¶ 0413). Fishkin teaches that one bioreducible, cleavable linker suitable for ADC use comprises the following moiety (Fishkin, ¶ 0414):
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(Fishkin, ¶ 0414; q is in an integer from 2-10)
Brun teaches engineered antibodies suitable for use in antibody-ligand/drug conjugation (Brun, ¶ 001-007). Brun teaches that one of the engineered antibodies of Brun comprise IgG1 or IgG4 Fcs with N297 mutations, which decrease antibody N glycation (Brun, ¶ 0175), wherein the mutation is N297C mutation (Brun, ¶ 092; Fig 23).
It would be prima facie obvious to one of ordinary skill in the art to combine the anti-TM4SF1 ADC taught by Vinstin with the bioreducible 2-nitrobenzenesulfonamide linker component taught by Fishkin, the N297C IgG4 of Brun and the anti-TM4SF1 antibody of the ‘511 application and administer the resultant ADC in method of treating cancers expressing TM4SF1. One of ordinary skill in the art would be motivated to do this in order to form an improved anti-TM4SF1 ADC that is stable in circulation but selectively releases the cytotoxic payload in cellular cytosol upon internalization following binding to TM4SF1 on a tumor cell or tumor-associated endothelial cell. One of ordinary skill in the art would have a reasonable expectation of success combining the anti-TM4SF1 ADC taught by Vinstin with the bioreducible 2-nitrobenzenesulfonamide linker component taught by Fishkin, the N297C IgG4 Fc of Brun and the anti-TM4SF1 antibody of the ‘511 application and administering the resultant ADC in method of treating cancers expressing TM4SF1 because: 1) Vinstin teaches that TM4SF1 targeting ADCs are capable of simultaneously targeting TM4SF1-expressing tumor cells and TM4SF1-expressing endothelial cells associated with tumor vasculature, 2) the ADC drug-linker utilized by Vinstin comprises a simple maleimide crosslinker linked to a dolastatin via a noncleavable C5 methylene linker, 3) Fishkin teaches that bioreducible linkers keep conjugates intact during systemic circulation but are selectively cleaved by high intracellular glutathione that is present in tumor cytosol, 4) Fishkin teaches that a 2-nitrobenzene sulfonamide moiety is an bioreducible linker that is suitable for use in antibody-drug conjugates, 5) Brun teaches antibodies comprising N297C IgG4 Fcs as suitable for antibody-ligand/drug conjugation, 6) it is within the purview of one of ordinary skill in the art to start with the anti-TM4SF1 ADC of Vinstin and add in an ADC linker moiety with known chemistry, 7) one of ordinary skill in the art would expect the resultant ADC to treat TM4SF1-expressing cancer because Vinstin teaches that TM4SF1 antibodies treat TM4SF1-expressing cancer by simultaneously targeting tumor cells and endothelial cells associated with the tumor vasculature and 8) the ‘511 application teaches that the anti-TM4SF1 antibody of the ‘511 application is capable of binding TM4SF1 and, as such, is a simple substitution for the antibody of Vinstin. Please also note that substituting the dolastatin cytotoxin of Vinstin for a maytansinoid would also be an obvious substitution in view of the ‘511 application as the ‘511 application teaches maytansinoid payloads.
Please note that the structure of the ADC drug-linker moiety would be—Maleimide—(CH2)2-NH-C(O)-(2-nitrobenzene)-S(O2)-NH-(CH2)5-Dolastatin, the two CH2 between the maleimide and the first amine are from the bioreducible linker taught by Fishkin (q =2), the sulfonamide is prepared by reacting an aryl sulfonyl chloride with an amide as also taught by Fishkin (see Fishkin, ¶ 0562), and the 5 CH2 between the bioreducible linker and the dolastatin drug are the original CH2 in the LP2 of Vinstin and this structure satisfies all of the structural limitations of instant claims 140-147 and when the maytansinoid of the ‘511 application is resulting in a structure identical to the second structure of claim 157 and reading on instant claims 145 and 156-157. Regarding claim 143 specifically, the 5 CH2 between the bioreducible linker and the drug satisfy the first structure of claim 143 when m = 2, q = 0 and r =3). Additionally, the TM4SF1-expressing cancer taught by Vinstin are diseases characterized by abnormal endothelial cell interactions because endothelial cells forming tumor vasculature is abnormal. Regarding claim 162 specifically, one of ordinary skill in the art would reasonably expect that stem cells would be targeted as well because Vinstin teaches TM4SF1 is expressed during angiogenesis, which requires stem cells to produce the resultant vascular cells.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
Applicant's arguments filed 4/1/2026 have been fully considered but they are not persuasive.
Applicant requested that the provisional rejections made in view of the ‘511 application be withdrawn pursuant to MPEP 804IB. This is not persuasive because the provisional NSDP rejection is not the last rejection still standing.
Claims 140-147 and 156-164 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-15 of U.S. Patent No. 11,208,495 B2 in view of Vinstin (Vinstin, et al., Mol. Canc. Ther 2015 14(8):1868, of record), Fishkin (Fishkin, et al., WO 2021/198965 A1; Published 10/07/2021; Priority to 3/31/2020 by way of US 63/003,179, of record) and Brun (Brun et al., WO 2021/174034A1; Published 9/2/2021; Priority to 02/28/2020 via US 62/982,943).
The patented claims are directed to anti-TM4SF1 antibodies (patented claim 1) and ADCs comprising a TM4SF1 antibody or antigen-binding fragment conjugated to therapeutic molecules (patented claims 9-10 and 15). Regarding instant claims 146-147, patented claim 15 is directed to conjugates comprising maytansinoids (a small molecule class of drug).
The ‘495 patent does not teach the antibody of the ADC of the ‘495 patent is present in an ADC having a reduction-sensitive cleavable 2-aminobenzene sulfonamide moiety in the linker. The ‘495 patent does not teach the resultant ADC is administered in methods of treating diseases characterized by abnormal endothelial cell-tumor cell interactions. The ‘495 patent does not teach the resultant ADC comprises an IgG4 Fc with N297C mutations.
Vinstin teaches on the subject of anti-TM4SF1 ADCs as a therapeutic modality for cancer (Vinstin, Abstract). Vinstin teaches that TM4SF1 is an integral membrane glycoprotein related to tetraspanins that is abundantly expressed on cancer cells and on endothelial cells lining human cancer blood vessels but weakly expressed on endothelial cells of many normal tissues and organs, (Vinstin, p 1868, ¶ 2). Vinstin teaches that TM4SF1 being highly expressed by many human cancer cells and being associated with pathologic angiogenesis led to the hypothesis that targeting TM4SF1 would provide a dual anticancer mechanism: killing tumor cells directly and id targeting the tumor vasculature (Vinstin, p 1869, ¶ 1). Vinstin teaches that the humanized anti-TM4SF1antibody v.1.10 was conjugated to ADC drug-linker moiety linker LP2, which comprises a dolastatin (a small molecule cytotoxic agent), which is depicted below (Vinstin, p 1869, ¶ 3):
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(Image: Vinstin, Supp. Fig. S1; Supplementary figures attached to Vinstin (2015) NPL reference)
Vinstin teaches that ADC v1.10-LP2 was able to induce complete tumor regression, defined as nonpalpable tumors in nearly all mice bearing NSCLC xenografts expressing high levels of TM4SF (Vinstin, p 1872, ¶ 2; Fig 3A) and that similar results were observed in human cancer xenografts for colon, prostate and pancreatic cancer cell lines, with complete regressions being achieved at a dose of 3 mpk (same as mg/kg) (Vinstin, p 1872, ¶ 3). Vinstin teaches that antibody v1.10 does not recognize murine TM4SF1, leading to the development of rabbit anti-mouse TM4SF1 antibody 2A7A that recognizes murine TM4SF1 but not human TM4SF1 and, when conjugated to LP2, was highly toxic to the murine microvascular endothelial cell line MS1 as well as 293 cells stably transfected to express murine TM4SF1 (Vinstin, p 1872, ¶ 4). Vinstin teaches that the combined therapy comprising administration the human TM4SF1-targeting ADC v1.10-LP2 and the murine TM4SF1-targeting ADC 2A7A-LP2 resulted in a significantly greater reduction in tumor volume compared to either ADC alone for both Calu-6 tumors and NCI-H460 tumors in murine xenograft studies (Vinstin, p 1874, ¶ 3-4; Fig. 6A,B).
Fishkin teaches on the subject of neoDegrader conjugates as well as methods of treating cancer using such conjugates (Fishkin, Abstract). Fishkin teaches that bioreducible linkers take advantage of the reduction potential difference between the intracellular compartment vs plasma, with reduced being present in tumor cells’ cytoplasma being up to 1000-fold higher than in normal cells’ cytoplasma, leading to bioreducible linkers keeping conjugates intact during systemic circulation but are selectively cleaved by high intracellular glutathione, releasing active drug at tumor sites (Fishkin, ¶ 0413). Fishkin teaches that one bioreducible, cleavable linker suitable for ADC use comprises the following moiety (Fishkin, ¶ 0414):
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126
237
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(Fishkin, ¶ 0414; q is in an integer from 2-10)
Brun teaches engineered antibodies suitable for use in antibody-ligand/drug conjugation (Brun, ¶ 001-007). Brun teaches that one of the engineered antibodies of Brun comprise IgG1 or IgG4 Fcs with N297 mutations, which decrease antibody N glycation (Brun, ¶ 0175), wherein the mutation is N297C mutation (Brun, ¶ 092; Fig 23).
It would be prima facie obvious to one of ordinary skill in the art to combine the anti-TM4SF1 ADC taught by Vinstin with the bioreducible 2-nitrobenzenesulfonamide linker component taught by Fishkin, the N297C IgG4 Fc of Brun and the anti-TM4SF1 antibody of the ‘495 patent and administer the resultant ADC in method of treating cancers expressing TM4SF1. One of ordinary skill in the art would be motivated to do this in order to form an improved anti-TM4SF1 ADC that is stable in circulation but selectively releases the cytotoxic payload in cellular cytosol upon internalization following binding to TM4SF1 on a tumor cell or tumor-associated endothelial cell. One of ordinary skill in the art would have a reasonable expectation of success combining the anti-TM4SF1 ADC taught by Vinstin with the bioreducible 2-nitrobenzenesulfonamide linker component taught by Fishkin, the N297C IgG4 Fc of Brun and the anti-TM4SF1 antibody of the ‘495 patent and administering the resultant ADC in method of treating cancers expressing TM4SF1 because: 1) Vinstin teaches that TM4SF1 targeting ADCs are capable of simultaneously targeting TM4SF1-expressing tumor cells and TM4SF1-expressing endothelial cells associated with tumor vasculature, 2) the ADC drug-linker utilized by Vinstin comprises a simple maleimide crosslinker linked to a dolastatin via a noncleavable C5 methylene linker, 3) Fishkin teaches that bioreducible linkers keep conjugates intact during systemic circulation but are selectively cleaved by high intracellular glutathione that is present in tumor cytosol, 4) Fishkin teaches that a 2-nitrobenzene sulfonamide moiety is an bioreducible linker that is suitable for use in antibody-drug conjugates, 5) Brun teaches antibodies comprising N297C IgG4 Fcs as suitable for antibody-ligand/drug conjugation 6) it is within the purview of one of ordinary skill in the art to start with the anti-TM4SF1 ADC of Vinstin and add in an ADC linker moiety with known chemistry, 7) one of ordinary skill in the art would expect the resultant ADC to treat TM4SF1-expressing cancer because Vinstin teaches that TM4SF1 antibodies treat TM4SF1-expressing cancer by simultaneously targeting tumor cells and endothelial cells associated with the tumor vasculature and 8) the ‘495 patent teaches that the anti-TM4SF1 antibody of the ‘495 patent is capable of binding TM4SF1 and, as such, is a simple substitution for the antibody of Vinstin. Please also note that substituting the dolastatin cytotoxin of Vinstin for a maytansinoid would also be an obvious substitution in view of the ‘495 patent as the ‘495 patent teaches maytansinoid payloads.
Please note that the structure of the ADC drug-linker moiety would be—Maleimide—(CH2)2-NH-C(O)-(2-nitrobenzene)-S(O2)-NH-(CH2)5-Dolastatin, the two CH2 between the maleimide and the first amine are from the bioreducible linker taught by Fishkin (q =2), the sulfonamide is prepared by reacting an aryl sulfonyl chloride with an amide as also taught by Fishkin (see Fishkin, ¶ 0562), and the 5 CH2 between the bioreducible linker and the dolastatin drug are the original CH2 in the LP2 of Vinstin and this structure satisfies all of the structural limitations of instant claims 140-147 and when the maytansinoid of the ‘495 patent is resulting in a structure identical to the second structure of claim 157 and reading on instant claims 145 and 156-157. Regarding claim 143 specifically, the 5 CH2 between the bioreducible linker and the drug satisfy the first structure of claim 143 when m = 2, q = 0 and r =3). Additionally, the TM4SF1-expressing cancer taught by Vinstin are diseases characterized by abnormal endothelial cell interactions because endothelial cells forming tumor vasculature is abnormal. Regarding claim 162 specifically, one of ordinary skill in the art would reasonably expect that stem cells would be targeted as well because Vinstin teaches TM4SF1 is expressed during angiogenesis, which requires stem cells to produce the resultant vascular cells.
Response to Arguments
Applicant's arguments filed 4/1/2026 have been fully considered but they are not persuasive.
Applicant argues that the instant claimed N297C IgG4 mutation differentiates the instant claimed subject matter from the combined teachings of the ‘495 patent, Vinstin and Fishkin. Applicant also notes that previously applied publication WO2020176794A1 (The “794 publication), which does teach an IgG4 N297C mutation, is disqualified as prior art under 35 USC 102(b)(2) (see Section IV of Remarks). However, the claim amendments necessitated withdrawing all standing art rejections and making new ones and a new reference, Brun, has been applied, does meet the priority date and does teach IgG4 Fcs with N297C mutations.
Conclusion
Claims 140-147 and 156-164 are rejected.
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
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