ANTIBODY DRUG CONJUGATE INTERMEDIATE CONTAINING SN38 AND ITS PREPARATION METHOD

§103 §112

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 . DETAILED ACTION Claims 1-18 and 23-25 are pending in the instant application. Claims 24-25 are new. Claim Status Applicant’s election without traverse of Group I, an antibody-drug conjugate intermediate represented by formula (I) and the species represented by formula (4) PNG media_image1.png 239 578 media_image1.png Greyscale in the reply filed on 3/2/2026 was previously acknowledged in the Office action filed 5/19/2026. The elected species in present in instant claims 1-2, 5, and 24-25. Claims 6-18 and 23 were previously withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim in the Office action filed 5/19/2026. Election was made without traverse in the reply filed on 3/2/2026. Claims 3-4 were previously withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim in the Office action filed 5/19/2026. Election was made without traverse in the reply filed on 3/2/2026. Claim Rejections Withdrawn The rejection of claim 2 under 35 U.S.C. 112(b) is withdrawn in view of claim amendment. Claim Rejections Maintained or Necessitated by Amendment 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. Claim 24 is 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. Regarding instant claim 24, the antibody-drug conjugate intermediate according to claim 1 is claimed as m is 5 and/or p is 2, but m and p are not selectable variables present in claim 1. Thus, the claim is indefinite because the metes and bounds are unclear. To promote compact prosecution, “claim 1” will be interpreted as ---claim 2---. 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. 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. 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. The rejection of claims 1-2 and 5 under 35 U.S.C. 103 as being unpatentable over WO 2021/225892 (Zhu T et al. priority date 5/3/2020) and Elgersma RC et al. (Mol. Pharmaceutics 2015, 12, 6, 1813–1835) is maintained. Zhu taught an effective method of treatment of a subject with a Trop-2 expressing cancer comprising administering an anti-Trop-2 ADC comprising compound 1 (page 85, Table 2 and Fig. 6), wherein the structure of antibody drug intermediate compound 1 is: PNG media_image2.png 30 443 media_image2.png Greyscale (page 77). Zhu did not teach the elected species of: PNG media_image3.png 264 598 media_image3.png Greyscale , but this is obvious in view of Elgersma. Elgersma taught an ADC Linker-drug 2 was selected based on the properties of the corresponding trastuzumab conjugate, SYD983, which showed subnanomolar potencies against multiple human cancer cell lines, was highly efficacious in a BT-474 xenograft model, and had a long half-life in cynomolgus monkeys, in line with high stability in monkey and human plasma (abstract). Elgersma taught the ADC Linker-drug 2 comprised the structure of: PNG media_image4.png 203 410 media_image4.png Greyscale (abstract). Elgersma taught the self-elimination module in the ADC releases the cytotoxic agent following proteolytic cleavage of the linker (scheme 5). Elgersma taught the less lipophilic nature of the substituents in the cyclization spacer led to lower levels of high-molecular weight ADC species (page 1821, right column, third paragraph). Regarding instant claims 1-2 and 5, it would have been obvious for a person having ordinary skill in the art to take the effective anti-Trop-2 ADC for treating cancer comprising the antibody drug conjugate intermediate compound 1 with the structure: PNG media_image2.png 30 443 media_image2.png Greyscale – and: Exchange one self-immolative self-elimination module of PNG media_image5.png 75 149 media_image5.png Greyscale for PNG media_image6.png 94 214 media_image6.png Greyscale in view of Elgersma. This is obvious because: 1a) Elgersma taught an ADC Linker-drug 2 was effective and had a long half-life in cynomolgus monkeys, in line with high stability in monkey and human plasma and the self-elimination module in the ADC effectively releases the cytotoxic agent following proteolytic cleavage of the linker; and 1b) Elgersma taught the less lipophilic nature of the substituents in the cyclization spacer led to lower levels of high-molecular weight ADC species. There is a reasonable expectation of success because: 1a) Elgersma taught an ADC Linker-drug 2 was effective and had a long half-life in cynomolgus monkeys, in line with high stability in monkey and human plasma and the self-elimination module in the ADC effectively releases the cytotoxic agent following proteolytic cleavage of the linker; and 1b) Elgersma taught the less lipophilic nature of the substituents in the cyclization spacer led to lower levels of high-molecular weight ADC species. Thus, exchange of one effective self-immolative self-elimination module in an effective antibody drug conjugate for another would have a reasonable expectation of success. This would produce an effective anti-Trop-2 ADC for treating cancer comprising an antibody drug conjugate intermediate with the structure: PNG media_image7.png 282 454 media_image7.png Greyscale . Response to Arguments Applicant argues: 1) Elgersma fails to provide a reasonable motivation to combine. Applicant argues The Action's position argument relies primarily on replacing the self-eliminating module in Zhu with the self-eliminating module in Elgersma. However, this simple "module substitution" argument has the following flaws. Differences in technical fields. Elgersma's ADC (SYD985) is a duocarmycin-type ADC, while the present application involves an SN38 ADC. There are significant differences at least in payload type (alkylating agent versus topoisomerase I inhibitor), and linker design (branched PEG2-tertiary amine-X2 motif that is not present in SYD985). There is no reasonable basis for a person skilled in the art to migrate the linker design for the duocarmycin ADC to an ADC comprising SN38. Payload differences. Elgersma uses a duocarmycin-type payload (seco-DUBA), while in the present application SN38 is adopted. These two payloads differ in chemical structure and water solubility and therefore require different linker designs. Elgersma aims to develop a novel class of linker-payload compounds using duocarmycin as the parent skeleton. The ADC constructed using this linker-payload design, as described in Elgersma, exhibits pharmacological efficacy through the synergistic effect of both the linker and the payload, rather than a single technical feature. For example, Elgersma explicitly states the following contents: -This duocarmycin was incorporated into novel linker duocarmycin constructs using linkers optimized to provide a perfect synergy with the drug; -SYD985 was selected as lead clinical candidate following extensive linker-duocarmycin structure-activity studies, in which both drug and linker components were optimized and the composition of the ADC in terms of average DAR and DAR species was improved; -We set out to develop a new class of linker-drugs based on duocarmycins; -Linker-drug 2 was eventually selected based on the properties of the corresponding trastuzumab conjugate, SYD983; and -We developed a linker-drug technology based on the duocarmycin class of compounds. Furthermore, Elgersma failed to provide any inspiration for adapting the linker and its technical features to other drugs or drug types as payloads. Throughout the patent application of Elgersma, it consistently emphasizes defining the linker-drug combination as a complete "technology," rather than a simple combination of two independent elements. Therefore, the linker-payload compound in the present application should similarly not be understood as a simple combination of dispersed technical features, but rather as a highly synergistically adapted linker-payload compound obtained through optimized design. Lack of motivation. Elgersma fails to teach or inspire the use of its self-eliminating module in SN38-loaded ADCs. The examiner's argument of "replacing one effective self-eliminating module with another" is overly simplistic and ignores the impact of different payloads and targets on linker design. The purpose of the presently claimed subject matter is not merely to replace the self-eliminating module, but also to introduce PEG chains into the linker and perform specific structural modifications, thereby solving at least one of the following key problems in the prior art: (i) Avoiding heavy metal ion contamination: The prior art CL2A-SN38 requires the use of a Click reaction in its synthesis, resulting in Cu2+ in the product that is difficult to remove. The preparation method of the present application avoids the Click reaction and does not introduce heavy metal ions. (ii) Systematic linker design: The presently claimed subject matter achieves higher stability through a specific linker (including the introduction of Xl). This represents a systematic linker design improvement, rather than a simple module replacement. In addition, due to the excessively high lipophilicity of Seco-DUBA in Elgersma (leading to poor water solubility, easy aggregation, and the need to reduce DAR), it is necessary to reduce the lipophilicity of the substituents in the cyclized spacer. SN-38 is less lipophilic than Seco-DUBA 1, therefore there is no incentive to further reduce lipophilicity, and it is difficult to expect that a linker suitable for Seco-DUBA would also be suitable for SN-38 given such a large difference in lipophilicity. In response, Applicant's arguments filed 8/14/2026 have been fully considered but they are not persuasive. Regarding differences in technical field and payload differences, both Zhu and Elgersma teach antibody drug conjugates wherein the linker comprises a valine citrulline cleavage peptide conjugated to a self-immolative elimination moiety further conjugated to a cytotoxic payload. Elgersma taught the self-elimination module in the ADC releases the cytotoxic agent following proteolytic cleavage of the linker (scheme 5). Exchange of one self-immolative self-elimination module of PNG media_image5.png 75 149 media_image5.png Greyscale of Zhu for PNG media_image6.png 94 214 media_image6.png Greyscale of Elgersma is within the skill of a person having ordinary skill in the art. Elgersma described antibody-drug conjugates wherein the self-immolative self-elimination module was PNG media_image5.png 75 149 media_image5.png Greyscale in compound 29 in Chart 1. Thus, exchange of one self-immolative self-elimination module for another is within the technical field. Further, Elgersma taught the antibody-drug conjugates SYD983 and SYD985 comprised the self-immolative self-elimination module of PNG media_image6.png 94 214 media_image6.png Greyscale and were identified to have subnanomolar potencies against multiple human cancer cell lines, was highly efficacious in a BT-474 xenograft model, and had a long half-life in cynomolgus monkeys, in line with high stability in monkey and human plasma (abstract). Elgersma taught SYD985 was selected for further development and recently entered clinical Phase I evaluation (abstract). Thus, utilization of the self-immolative self-elimination module of PNG media_image6.png 94 214 media_image6.png Greyscale would be expected to be effective for a cytotoxic payload whether it is a duocarmycin-type of Elgersma or the SN38 payload of Zhu. The effective release of the payload via a linker comprising a valine citrulline cleavage peptide conjugated to a self-immolative elimination moiety taught by Elgersma would effectively release SN38 through the same mechanism. Regarding Elgersma failed to provide any inspiration for adapting the linker and its technical features to other drugs or drug types as payloads and lack of motivation: Elgersma described antibody-drug conjugates wherein the self-immolative self-elimination module was PNG media_image5.png 75 149 media_image5.png Greyscale in compound 29 in Chart 1 and the ADC Linker-drug 2 comprised the structure of: PNG media_image4.png 203 410 media_image4.png Greyscale (abstract). Thus, exchange of one self-immolative self-elimination module for another in an ADC was known to the art. Exchange of one effective self-immolative self-elimination module for another is within the skill of a person having ordinary skill in the art and would be expected to effectively release SN38 as seen for a duocarmycin-type payload of Elgersma. The known effectiveness of the self-immolative self-elimination module would provide motivation for its use. Elgersma taught the antibody-drug conjugates SYD983 and SYD985 comprised the self-immolative self-elimination module of PNG media_image6.png 94 214 media_image6.png Greyscale and were identified to have subnanomolar potencies against multiple human cancer cell lines, was highly efficacious in a BT-474 xenograft model, and had a long half-life in cynomolgus monkeys, in line with high stability in monkey and human plasma (abstract). Elgersma taught SYD985 was selected for further development and recently entered clinical Phase I evaluation (abstract). Thus, the self-immolative self-elimination module of PNG media_image6.png 94 214 media_image6.png Greyscale was known to be effective and its usage would be obvious with a reasonable expectation of success. Regarding heavy contamination and click reaction, a click reaction is not necessary for Zhu or Elgersma. Regarding systematic linker design, Elgersma taught an ADC comprising a linker comprising PNG media_image8.png 183 241 media_image8.png Greyscale was previously known to the prior art as to release a payload with subnanomolar potencies against multiple human cancer cell lines, was highly efficacious in a BT-474 xenograft model, and had a long half-life in cynomolgus monkeys, in line with high stability in monkey and human plasma (abstract). Regarding lipophilicity differences between the payloads, it is known in the prior art that antibody drug conjugates comprising SN38 can have short PEG linkers included in the ADC to aid in solubility (Goldenberg DM et al. Antibody-drug conjugates targeting TROP-2 and incorporating SN-38: A case study of anti-TROP-2 sacituzumab govitecan (MAbs 2019 Jul 18;11(6):987–995.) (Fig. 2 and Fig. 2 legend)). Thus, the self-immolative self-elimination module of PNG media_image6.png 94 214 media_image6.png Greyscale would be further expected to be beneficial and would give a person having ordinary skill in the art a further incentive for an ADC comprising SN38. Applicant argues: 2) The presently claimed subject matter achieves unexpected technical effects. According to the experimental data in the specification, the antibody-drug conjugate intermediate of the presently claimed subject matter exhibits significantly superior technical effects compared to the cited art, effects that could not be expected by the posited prior art combination (Zhu plus Elgersma) cited in the Action. Significantly Improved Stability (Example 6 in the Specification). The stability of the compound of formula (1) of the present application was compared with that of the commercially available reference standard CL2A-SN38 (the linker-payload of Sacituzumab govitecan): PNG media_image9.png 242 728 media_image9.png Greyscale As can be seen from the above data, the intermediate of the present application exhibits significantly better stability than CL2A-SN38 under weakly acidic conditions (pH=6, simulating a lysosomal environment). This significant difference in stability is unexpected from the teachings of Zhu and Elgersma. Improved Stability While Maintaining Comparable Efficacy (Examples 5 and 7 of the Specification). Cell inhibition experiments (NCI-N87 cells) showed that the IC50 of ADC-1 (the ADC of the present application, prepared from intermediate compound 1 of the present application) was 251 nglml, and the IC50 of ADC-17 (control, HER2-CL2A-SN38) was 210 nglml, indicating comparable inhibitory effects. In addition, in vivo antitumor experiments (BT474 breast cancer model) showed that the T/C of ADC-1 was 62.48%, and the T/C of ADC-17 was 49.30%, both significantly inhibiting tumor growth. However, the ADC-1 of the present application showed a significantly higher TIC value. Therefore, the ADC of the presently claimed subject matter significantly improves stability while maintaining efficacy comparable to the control. Such a combination of the results of significantly improved stability while maintaining comparable efficacy is unexpected. In response, Applicant's arguments filed 8/14/2026 have been fully considered but they are not persuasive. The claimed stability differences do not identify the compound structure in comparison to CLA2-SN38. Further, the control ADC-17 which comprises CLA2-SN38 (instant specification, page 30) is more effective at treating cancer in Table 6 and does not show higher levels of weight loss in vivo in comparison to ADC-12 (Experimental Group 4) in Fig. 1. While ADC-12 comprises the elected species and is effective at inhibiting cancer cell growth in Table 6 on page 42 of the instant specification, the claims are not commensurate with the unexpectedly effective ADC. Unexpected results are required to be commensurate in scope with claimed invention. MPEP 716.02(d) states, “Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support. In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range." The claims would require the complete structure of ADC-12 to be commensurate in scope with the unexpected results. Claims 1-2, 5, and 24-25 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2021/225892 (Zhu T et al. priority date 5/3/2020) and Elgersma RC et al. (Mol. Pharmaceutics 2015, 12, 6, 1813–1835) as applied to claims 1-2 and 5 above. Zhu and Elgersma are described above. The elected species of PNG media_image1.png 239 578 media_image1.png Greyscale is further present in new instant claim 25 and the interpretation for compact prosecution of new instant claim 24. The elected species is obvious with a reasonable expectation of success as discussed above. Conclusion Claims 1-2, 5, and 24-25 are rejected. 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 JOHN J SKOKO III whose telephone number is (571)272-1107. The examiner can normally be reached M-F 8:30 - 5:00. Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Julie Z Wu can be reached at (571)272-5205. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300. Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000. /J.J.S./Examiner, Art Unit 1643 /Karen A. Canella/Primary Examiner, Art Unit 1643