CYSTEINE ENGINEERED ANTIBODY-DRUG CONJUGATES WITH PEPTIDE-CONTAINING LINKERS

§103 §112

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 . Status of Application, Amendments and/or Claims The amendment of 31 July 2026 has been entered in full. Claims 15, 23, and 53 are amended. Claims 1-14, 16-18, 24-28, 30, and 33 are cancelled. Claim 48 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 12 September 2024. Claims 15, 19-23, 29, 31, 32, and 34-47, and 49-53 are under consideration in the instant application. Information Disclosure Statement The information disclosure statement (IDS) submitted on 31 July 2026 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner. Withdrawn Objections and/or Rejections 1. The rejection of claim 53 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph as set forth at page 3 of the previous Office Action of 19 March 2026 is withdrawn in view of the amended claim (31 July 2026). 2. The rejection of claim 53 under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph as set forth at page 4 of the previous Office Action of 19 March 2026 is withdrawn in view of the amended claim (31 July 2026). 3. The rejection of claims 15, 19-23, 29, 31, 32, 34, 38-44, 46, 47, 49, and 50 on the ground of nonstatutory double patenting as being unpatentable over claims 1-8 of U.S. Patent No. 11,135,307 in view of Shen et al. (Nature Biotechnol 30(2): 184-191, 2012) as set forth at pages 14-15 of the previous Office Action of 19 March 2026 is withdrawn in view of the amended claims (31 July 2026). Specifically, the claims of the ‘307 patent do not recite wherein d13 is an integer from about 6 to about 13 or wherein d13 is 6 or 13. 4. The rejection of claims 51 and 52 on the ground of nonstatutory double patenting as being unpatentable over claims 1-8 of U.S. Patent No. 11,135,307 in view of Shen et al. (Nature Biotechnol 30(2): 184-191, 2012 as applied to claims 15, 19-23, 29, 31, 32, 34, 38-44, 46, 47, 49, and 50, and further in view of Yurkovetskiy et al. (US 2012/0321583) as set forth at pages 15-17 of the previous Office Action of 19 March 2026 is withdrawn in view of the amended claims (31 July 2026). Specifically, the claims of the ‘307 patent, Shen et al., and Yurkovetskiy et al. (US 2012/0321583) do not recite wherein d13 is an integer from about 6 to about 13 or wherein d13 is 6 or 13. New Claim Rejections - 35 USC § 112(a) The following is a quotation of the first paragraph of 35 U.S.C. 112(a): (a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention. The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112: The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention. 5. Claims 15, 19-23, 29, 31, 32, and 34-47, and 49-53 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a new matter rejection. Claim 15, for example, recites: PNG media_image1.png 183 535 media_image1.png Greyscale …wherein d13 is an integer from about 6 to about 13. Claim 23 recites the conjugate of claim 15, wherein d13 is 6 or 13. The specification as originally filed does not provide adequate written description for (i) d13 as being an integer from about 6 to about 13 or (ii) wherein d13 is 13. The limitations of wherein “d13 is an integer from about 6 to about 13” and “d13 is 13” as recited in claims 15 and 23, respectively, are not expressly asserted, nor do they flow naturally from the specification. At the top of the Remarks section at page 15 of the Response of 3l July 2026, Applicant states that the claim amendments are fully supported by the application as originally filed. However, upon the Examiner’s independent review of the specification, Figures, and originally filed claims, the specification of 16 June 2025 only teaches that d13 is an integer from about 1 to about 6 (page 4, [0014]; page 6, [0015]; page 9, [0038]; page 43, 44; page 45, [00167]). The specification also discloses that d13 is an integer from about 1 to about 4; about 4 to about 6; about 2 to about 4; and about 1 to about 2; about 2 to about 6; and about 3 to about 4 (page 9, [0039-0042]; page 45, [00168-00173]). The specification indicates that d13 is 1, 2, 3, 4, 5, or 6 (page 9, [0043]; page 46, [00174]). Therefore, the Examiner is unable to locate where the specification provides adequate written description of “d13 is an integer from about 6 to about 13” and “d13 is 13”. Maintained 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. 6. Claims 15, 19-23, 29, 31, 32, 34-47, and 49-53 are rejected under 35 U.S.C. 103 as being unpatentable over Yurkovetskiy et al. (WO 2018/098269 (cited on the IDS of 02 May 2022) or US 2018/0154018) and Shen et al. (Nature Biotechnol 30(2): 184-191, 2012 (cited on the IDS of 02 May 2022)). The basis for this rejection is set forth at pages 5-13 of the previous Office Action of 19 March 2026; at pages 4-14 of the Office Action of 24 September 2025; and at pages 23-24 of the Office Action of 18 December 2024. As both specifications of Yurkovetskiy et al. are the same, for brevity, the teachings will refer to WO 2018/098269. It is also noted that amended claim 53 is included in the rejection because the limitations of this claim are taught in Shen et al. (see pages 23-24 of the Office Action of 18 December 2024; see Shen et al., abstract; page 184, column 2, 2nd and 3rd full paragraphs; page 185). (i) At the top of page 16 of the Response of 31 July 2026, Applicant states that claim 15 has been amended to recite “d13 is an integer from about 6 to about 13”. Applicant asserts that neither Yurkovetskiy et al. nor Shen et al., when taken alone or in combination, provide the skilled artisan with a reasonable expectation of success in arriving at the claimed conjugate with the claimed d13. Applicant argues that the instant application provides examples of ADCs with the claimed d13 ([drug to antibody ratio] DAR about 6, see Example 3). Applicant submits that Shen et al. do not describe a V205C antibody or any antibody with a DAR greater than 2. At the middle of page 16 of the Response, Applicant continues to argue that a skilled artisan reading Shen et al. (alone or in combination with Yurkovetskiy) would not have a reasonable expectation of success to modify the V205C antibody of Shen et al. (or any antibody for that matter) to have the claimed d13. Applicant’s arguments have been fully considered but are not found to be persuasive. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Specifically, Yurkovetskiy et al. teach a conjugate comprising a targeting moiety and one or more linker-drug moieties covalently bonded to the targeting moiety (page 2, [0005]). Yurkovetskiy et al. disclose the same conjugate of Formula (I) as recited in instant claim 15 (see conjugate (I) of Yurkovetskiy et al.; page 3, [0007]; page 4, [0008]; pages 41-43, [00115]; pages 179). In particular, Yurkovetskiy et al. teach that d13 is an integer from 1 to about 14 (page 5, [0008]; page 40, [00114]). Yurkovetskiy et al. also state that d13 is an integer from 2 to 14, from 2 to 12, from 2 to 10, from 2 to 8, from 2 to 6, from 2 to 4, from 4 to 10, from 4 to 8, from 4 to 6, from 6 to 14, from 6 to 12, from 6 to 10, from 6 to 8, from 8 to 14, from 8 to 12, or from 8 to 10 (page 43, [00117]). Yurkovetskiy et al. disclose that d13 is 2, 3, 4, 5, 6, 7, 8, 9, or 10 (page 44, [00118-00122]). The teachings of Yurkovetskiy et al. meet the new d13 limitations recited in amended instant claim 15. Furthermore, Yurkovetskiy et al. teach that PBRM in the conjugate formula is a protein based recognition molecule, such as an antibody or antibody fragment (page 6, [0011]). Yurkovetskiy et al. state that the PBRM includes the anti-HER2 antibody, trastuzumab, and generate numerous conjugates with such antibody (page 26, [0072]; page 158, [00453, 00457]; pages 179-180, 184, 246, 248-252, 256, 258-261, 268-269). Yurkovetskiy et al. disclose different trastuzumab conjugates with a drug to trastuzumab (DAR) ratio of about 12.5; 2.8; 7.8; 7.6; 6.4, 6.3; 6.6, 6.5; 5.5; and 12.6 (see Example 7, conjugate 25, [00670]; Example 8, conjugate 28, [00673]; Example 11, conjugates 30A, 30B [00676]; Example 13, conjugates 34A, 34B [00679]; Example 18, conjugates 43A, 43B, [00688]); Example 20, conjugates 46A, 46B [00691]; Example 21, conjugate 48 [00693]; Example 23, conjugate 52 [00697]). Additionally, Yurkovetskiy et al. disclose that the drug conjugates have anti-proliferative properties in vitro and in vivo (pages 282-283, Tables I, II; Example 40; Figure 1). Therefore, contrary to Applicant’s arguments, one of ordinary skill in the art reasonably would have expected success with the d13 component of the conjugate formula being an integer from about 6 to about 13 because antibody conjugates (including trastuzumab) linked to chemotherapeutic drugs or other functional moieties with d13 as an integer from 1 to about 14 were already being successfully generated and shown to have anti-proliferative properties at the time the invention was made (see Yurkovetskiy et al. discussed in detail above). (ii) At the bottom of page 16 of the Response, Applicant asserts that the instant application describes increased efficacy of the claimed V205C ADCs with a DAR of about 6. Applicant states that Example 5 shows that Conjugate 4 (DAR 6, V205C) resulted in improved tumor growth response outcomes compared to Conjugate 2 (DAR 13, unmodified antibody) and Conjugate 3 (DAR 6, unmodified antibody). Applicant argues that the skilled artisan would appreciate that the relationship between DARs and efficacy is unpredictable. Applicant also submits that a person of skill in the art would not necessarily correlate ADC efficacy with a higher DAR, as higher DARs have been associated with faster clearance and increased toxicity, both of which are undesired effects in developing ADC drug candidates. In light of the unpredictability of the relationship between DAR and efficacy, Applicant contends that the instant application has demonstrated unexpected improvements in tumor growth response outcomes with the claimed ADC. Applicant’s arguments have been fully considered but are not found to be persuasive. First, regarding Applicant's discussion as to what a skilled artisan would have understood about the relationship between DARs and ADC (antibody drug conjugate) efficacy, the arguments of counsel cannot take the place of evidence in the record. In the instant case, Applicant is asserting that higher DARs have been associated with faster clearance and increased toxicity (both undesired effects in developing ADC drug candidates) while no provided data, information/evidence, or teaching supports such generalizations {see In re De Blauwe, 736 F.2d 699, 705, 222 USPQ 191, 196 (Fed. Cir. 1984; In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965); In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997) (“An assertion of what seems to follow from common experience is just attorney argument and not the kind of factual evidence that is required to rebut a prima facie case of obviousness.”) and MPEP § 716.01(c)(II), §2145(I)}. Second, it is noted that all conjugates in the instant specification (Conjugate 2 (trastuzumab, DAR 13.3), Conjugate 3 (trastuzumab, DAR 6.4, Example 2), and Conjugate 4 (V205C trastuzumab, DAR 6.6, Example 3)) have anti-proliferative properties and significantly reduce in vivo tumor size in mice as compared to control (page 2601, Table I; Figure 1). Conjugate 3 (trastuzumab, DAR 6.4) and Conjugate 4 (V205C trastuzumab, DAR 6.6) seem to have the greatest in vivo inhibitory growth effect, with similar growth responses to one another (see Example 5; Figure 1). Although Applicant argues that Conjugate 4 (V205C trastuzumab, DAR 6.6) results in improved tumor growth response outcomes as compared to Conjugate 2 and Conjugate 3 (trastuzumab, DAR 6.4), this improved response is not unexpected, especially when compared to Conjugate 3 (wherein the difference is simply the modified V205C in trastuzumab). Shen et al. indicate that the LC-205C conjugate has the greatest in vivo therapeutic activity as compared to other sites in trastuzumab modified with an engineered cysteine (that result in differences in solvent accessibility and charge) (abstract; page 185, column 1, 1st and 2nd full paragraphs; Figure 1d). Shen et al. teach that the LC-V205C-type conjugation sites that are surrounded by a positively charged environment might rapidly undergo succinimide ring hydrolysis in the linker, thereby preventing further linker-maleimide exchange and enabling stability (page 186, bottom of column 1 through the top of column 2). This stabilized conjugate shows improved efficacy (page 186, top of column 2; page 187, columns 1-2; Figure 1). In view of the teachings of Yurkovetskiy et al. and Shen et al., the results of the instant specification are not unexpected or unpredictable. In other words, upon reading the combined teachings of the prior art of Yurkovetskiy et al. and Shen et al., one of ordinary skill in the art would expect benefits of modifying the trastuzumab drug conjugates by engineering the light chain of trastuzumab with a cysteine at position 205 (V205C) of the instant claims. Again, Shen et al. teach that the V205C modification stabilizes the trastuzumab drug conjugates and enhances therapeutic efficacy (see page 185, column 1, 1st and 2nd full paragraphs; page 186, top of column 2; page 187, columns 1-2; Figure 1). Applicant is reminded that "[e]xpected beneficial results are evidence of obviousness of a claimed invention, just as unexpected results are evidence of unobviousness thereof." In re Gershon, 372 F.2d 535, 538, 152 USPQ 602, 604 (CCPA 1967); Ex parte Blanc, 13 USPQ2d 1383 (Bd. Pat. App. & Inter. 1989); MPEP § 716.02(c). Conclusion No claims are allowable. 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 BRIDGET E BUNNER whose telephone number is (571)272-0881. The examiner can normally be reached Monday-Friday 9:00 am-6:00 pm. 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, Joanne Hama can be reached at (571) 272-2911. 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. BEB Art Unit 1647 28 September 2026 /BRIDGET E BUNNER/Primary Examiner, Art Unit 1647