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 .
Response to Election/Restrictions
Applicant’s election without traverse of the species of D1 in claim 18 in the reply filed on May 12th, 2026 is acknowledged. The elected species are read on claims 1, 8, 12, 17, 18, 19, 26, 34, 36,51, 52, 53, 60, 88, 89, 90, 91, 93, 100, 128, 129, 132, 137, 141, 142, 144, 145, 146, 147, 150, 151, and 152. Claim 143 is drawn to a non-elected species, but is reconsidered because prior art was found against Claim 143.
Priority
The instant application, filed July 26th, 2023, claims domestic benefit to US provisional application 63/392,806, filed July 27, 2022.
Status of Claims/Application
The preliminary amendment of May 12th, 2026 is acknowledged. Claim 143 is withdrawn. Claims 1, 8, 12, 17-19, 26, 34, 36, 51-53, 60, 88-91, 93, 100, 128-129, 132, 137, 141, 142, 143, 144, 145, 146, 147, 150-152 are pending in the application and examined on the merits herein.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on March 24, 2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement has been considered by the examiner.
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.
Claims 1,8,12,17-19,34,36,51-53,60,88-91,93,100,128-129,132,137,141-147 and 150-152 are rejected under 35 U.S.C. 103 as being unpatentable over Li (Li W, Veale KH, Qiu Q, et al. Synthesis and Evaluation of Camptothecin Antibody-Drug Conjugates. ACS Med Chem Lett. 2019;10(10):1386-1392. Published 2019 Sep 6. doi: 10.1021/acsmedchemlett.9b00301) and in further view of Yamazaki (Yamazaki, C.M., Yamaguchi, A., Anami, Y. et al. Antibody-drug conjugates with dual payloads for combating breast tumor heterogeneity and drug resistance. Nat Commun 12, 3528 (2021). https://doi.org/10.1038/s41467-021-23793-7, listed in the IDS Cite No. 91), Wikipedia for mertansine (Wikipedia for mertansine, published January 20, 2022; website:web.archive.org/web/20220120142348/http://en.wikipedia.org/wiki/Mertansine#cite_note-1, accessed on July 17, 2026) and Strickley (Strickley RG, Lambert WJ. A review of Formulations of Commercially Available Antibodies. J Pharm Sci. 2021 Jul;110(7):2590-2608.e56. doi: 10.1016/j.xphs.2021.03.017. Epub 2021 Mar 28. PMID: 33789155) and as evidenced by Gemmete (Gemmete JJ, Mukherji SK. Trastuzumab (Herceptin). AJNR Am J Neuroradiol. 2011 Sep;32(8):1373-4. doi: 10.3174/ajnr.A2619. Epub 2011 Aug 4. PMID: 21816914; PMCID: PMC7964332).
Regarding instant claims 1, 8, 12, 17, 18, 19, 26, 34, 36, 51, 52, 53, 60, 88, 89, 90, 91, 141, Yamazaki teaches the elected species of D1 which is monomethyl auristatin E (MMAE) that is capable of binding to an antibody trastuzumab(page 3, fig. 1, or figure 1 of this office action).
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Figure 1. Yamazaki teaches trastuzumab and MMAE in a dual drug ADC conjugation (page 3, Fig 1)
However, Yamazaki does not teach the thiol group that is linked to the MMAE as the elected species D1. Wikipedia Mertansine teaches a thiol group that is attached to a cytotoxic compound maytansinoid which helps to attach a monoclonal antibody to the drug (page 1, paragraph 1, “Mertansine, also called DM1 (and in some of its forms emtansine), is a thiol-containing maytansinoid that for therapeutic purposes is attached to a monoclonal antibody through reaction of the thiol group with a linker structure to create an antibody-drug conjugate (ADC)” and page 4, see the C-C-S group linked to maytansine, figure 3 of this office action). Therefore, it would have been obvious to the person of ordinary skill in the art to substitute the same C-C-S linker as shown for mertansine which is a known effective ADC, to conjugate with MMAE to produce a thiol containing MMAE to link to antibodies.
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Figure 2. Wikipedia for mertansine, posted on Jan 2022 (page
However, Yamazaki and Wikipedia for Mertansine do not teach the linkers between the antibody and the thiol containing MMAE. Li teaches an antibody drug conjugate using the linker of the claimed invention (page 1388, fig.3, see figure 3 of this office action). Li further teaches different linkers that has the group glucamine as recited in instant claim 36 (page 1389, column 1, paragraph 1, “ADCs that are highly hydrophobic can form aggregates and are potentially cleared from circulation in vivo faster than more hydrophilic conjugates.27 Adding a polar moiety to the linker was therefore desired, but preferably at a location that would not affect the hydrophobicity of an ADC’s released metabolite. Consequently, a more hydrophilic derivative, bearing a polyhydroxyl moiety and a maleimide, to enable conjugation was prepared. Z-LGlutamic acid benzyl ester 23 was coupled to N-methyl-D glucamine (24) using DMTMM to give 25, which was deprotected by hydrogenation in methanol/water to 26. The heterobifunctional linker 27 was then coupled to 26 to give 28. To prepare a sulfide-bearing payload, 16 was reacted with 14a in dilute acid to give 29. Deprotection of 29 with morpholine, followed by coupling to 28 using DMTMM gave 21c.”). For instant claim 90, Li teaches drug to antibody ratios at 7.3 (see figure 3 of this office action, “The value n indicates the drug per antibody ratio (DAR)”).
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Figure 3. Li teaches the antibody linked with the linker, a payload. Li further teaches n is a drug to antibody ratio (DAR) ranging from 7-8 (page 1388, figure 3 and scheme 2 showing what AAA is which is the peptide linker recited in the instant claims)
Li further discloses the ADCs that could efficiently release the cytotoxic drug metabolites that contain sulfide and thiol moiety since they can be inactivated in the liver (page 1387, column 2). Therefore, it would have been obvious to the person of ordinary skill in the art to use the same linker that can link with thiol-containing drug payloads to efficiently release them and reduce drug toxicities.
Regarding instant claims 137 and 144, Li and Yamazaki teach a dual load antibody drug conjugate where Li teaches the trastuzumab antibody is attached to the linker and camptothecin (see Figure 1 of this office action and described above) and Yamazaki further teaches the trastuzumab can have dual payload cytotoxic drugs MMAE and MMAF (page 3, Fig 1., Molecular Design and Conjugation strategy for generating dual-drug ADCs) and teaches that the dual payload strategy helps to overcome breast tumor HER2 heterogeneity and drug resistance (page 8, column 2, paragraph 2). A skilled artisan would have been able to use the antibody taught by Li with the linker and camptothecin to add another drug conjugate using the same linker taught by Li and expect a reasonable expectation of success at creating a dual payload ADC as claimed in instant claim 137 and 144.
Further, for claim 144, Yamazaki that possible drug-to antibody ratios that can be up to 6 (page 4, figure 2b, showing 4+2, 2+2, 2+4 and up to 6 attachment sites, etc.). Yamazaki discloses that higher numbers of total payload modules and higher numbers of MMAE modules are correlated with higher ADC hydrophobicity (page 3, column 1, paragraph 1).
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For claim 137, Li teaches DARs with average numbers ranging from 1-7 (page 1388, fig.3, see figure 3 of this office action).
Regarding instant claims 93, 100, 128, 129, and 132, as described above, Li and Yamazaki teach the combination of two drug payload structures linked to a cell binding agent (C) which is an antibody like trastuzumab taught by Yamazaki and W is the camptothecin taught by Li (page 1386, column 1, paragraph 2, “Camptothecin (1) and its derivatives bind to the TOPO 1/DNA complex to prevent reannealing, which can cause cell death due to the accumulation of partially cleaved DNA”) or MMAE or MMAF as taught by Yamazaki. D as recited in claim 128, is the MMAE with the thiol group attached which is described above in view of Yamazaki and Wikipedia Mertansine. The structures recited in claim 129, mainly the elected species MMAE is taught in Yamazaki and the linker structure is taught by Li as described prior. For instant claim 132, both Yamazaki, Wikipedia for Mertansine and Li teach the combination of structures with the linker and MMAE and MMAF that one person of ordinary skill in the art is able to combine based on Yamazaki’s teaching that the combinations are possible (page 4, fig 2, and see above).
Regarding instant claim 141 and 142, Yamazaki teaches trastuzumab (page 3, Fig. 1) which is a monoclonal antibody as evidenced by Gemmete (page 1, abstract, “Herceptin (trastuzumab) is a human monoclonal antibody”).
Regarding instant claim 145 and 150, Li, Yamazaki, and Wikipedia do not teach a pharmaceutical composition comprising the compound of either 53 or 93. Strickley discloses commercially available antibodies and their pharmaceutical formulations (page 2604, Table 6, trastuzumab, see figure 4 of this office action).
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Figure 4. Strickley teaches commercially available Trastuzumab and biosimilars that have different excipients formulated into a pharmaceutical composition (page 2604, Table 6).
Further, Strickley teaches that the antibody formulations can be a good starting point in formulation development of a new antibody formulation (page 2607, column 1, paragraph 1). Therefore, it would have been obvious to the person of ordinary skill in the art to formulate the single load and dual ADC (MMAE with or without camptothecin) taught by Yamazaki, Li and Wikipedia and formulate these in the excipients disclosed by Strickley as they are commercially already approved and are a good starting point to develop new antibody formulations.
Regarding instant claim 146, 147, 151, and 152, Yamazaki teaches a method of treating a cell proliferative disease or disorder or inhabiting abnormal cell growth, said method comprising administering the compound of claim 53 or of claim 93 to a subject in need thereof (page 1, Title and page 7, figure 5 showing in vivo antitumor activity in a JIMT-1/MDA-MB-231 admixed model). Li teaches antitumor activity of the ADC with the claimed linker structure that is linked to camptothecin (page 5, figure 4).
Regarding instant claim 143, as it is drawn to a non-elected species, D2 or MMAF is taught in Yamazaki (see figure 1 of this office action) in combination with Li and Wikipedia for mertansine as described above.
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(e) 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.
Claims 1,8,12,17-19,34,36,51-53,60,88-91,93,100,128-129,132,137,141-147 and 150-152 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1, 2, 3, 4, 5, 8, 9, 11, 12, 13, 14, and 15 of U.S. Patent No. 12,521,444, issued on January 13th, 2026, herein “Pat444” in view of Yamazaki (cited previously) and Wikipedia for mertansine (cited previously).
Regarding instant claims 19, 26, 34, 36, 52, 53, 60, 89, 90, 91, 93, 100, 129, 137, 141, 142, 143, and 144, Pat444 claims 1,2, and 3 recite a compound, or a pharmaceutically acceptable salt thereof, selected from:
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wherein p is 4-8, or 7-8.
Pat444 claim 8 and 9 recite a compound having the following structure:
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or a pharmaceutically acceptable salt thereof, wherein p is the drug to antibody ratio (DAR), which is an average number that is 7-8.
Pat444 claim 12 recite a compound having the following structure:
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or a pharmaceutically acceptable salt thereof, wherein p is the drug to antibody ratio (DAR), which is an average number that is 7-8; and C is an anti-HER2 antibody comprising the following CDRs: a HCDR1 having the sequence GFNIKDTYIH (SEQ ID NO:3); a HCDR2 having the sequence RIYPTNGYTRYADSVKG (SEQ ID NO: 4); a HCDR3 having the sequence WGGDGFYAMDY (SEQ ID NO:5); a LCDR1 having the sequence RASQDVNTAVA (SEQ ID NO:6); a LCDR2 having the sequence SASFLYS (SEQ ID NO:7); and a CCDR3 having the sequence QQHYTTPPT (SEQ ID NO:8).
Pat444 claim 13 recites the compound of claim 12, wherein C is trastuzumab, trastuzumab-dkst, trastuzumab-pkrb, trastuzumab-dttb, trastuzumab-qyyp, or trastuzumab-anns and/or p is 8.
However, Pat444 claims do not recite the MMAE and thiol group or D1 structure as recited in 1, 8, 12, 17, 18, 19, 26, 34, 36, 51, 52, 53, 60, 88, 89, 90, 91, 143, and 144. Yamazaki teaches the elected species of D1 which is monomethyl auristatin E (MMAE) linked to antibody trastuzumab that is capable of dual payload of MMAE and MMAF and has remarkable therapeutic effect in mouse models of refractory breast cancer with heterogeneous HER2 expression (page 3, fig. 1, or figure 1 of this office action, and page 2, column 1, paragraph 3, “We also demonstrate that a homogeneous anti-HER2 ADC containing both MMAE and MMAF exerts remarkable therapeutic effect in two mouse models of refractory breast cancer with heterogeneous HER2 expression”). However, Yamazaki does not teach the thiol group that is linked to the MMAE as the elected species D1 in the instant claim. Wikipedia Mertansine teaches a thiol group that is attached to a cytotoxic compound maytansinoid which helps to attach a monoclonal antibody to the drug (page 1, paragraph 1, “Mertansine, also called DM1 (and in some of its forms emtansine), is a thiol-containing maytansinoid that for therapeutic purposes is attached to a monoclonal antibody through reaction of the thiol group with a linker structure to create an antibody-drug conjugate (ADC)” and page 4, see the C-C-S group linked to maytansine, figure 3 of this office action). Therefore, it would have been obvious to the person of ordinary skill in the art to substitute the same C-C-S linker as shown for mertansine which is a known effective ADC, to conjugate with MMAE to produce a thiol containing MMAE to link to antibodies.
However, Pat444 claims do not teach dual payload linkage to trastuzumab as recited in claims 132, 137, 143, and 144. Yamazaki teaches dual payload capabilities of the trastuzumab (see figure 1 of this office action), and further teaches that the therapeutic potential of the homogeneous dual-drug ADC format to overcome breast tumor HER2 heterogeneity and drug resistance. In particular, our data demonstrate the advantages of dual-drug ADCs for treating low-HER2 breast tumors over co-administration of two single drug ADCs carrying the same payloads, which one may think would be as effective as the former approach” (page 8, column 2, paragraph 2). Therefore, it would have been obvious to the person of ordinary skill in the art to use Pat444 trastuzumab structure and added the additional MMAE thiol linker with the same linker as Pat444 and expected an improved antibody drug conjugate that can overcome drug resistance and heterogeneity of HER2 expression.
Regarding instant claims 145 and 150, Pat444 claim 4 recites a pharmaceutical composition comprising the compound of claim 1, or a pharmaceutically acceptable salt thereof.
Regarding instant claims 146, 147, 151, and 152, Pat444 claim 5 recites a method of treating cancer comprising administering to a subject in need thereof the compound of claim 1, or a pharmaceutically acceptable salt thereof. Pat444 claim 10 and 11 recite a method of treating cancer comprising administering to a subject in need thereof the compound of claim 9 and 8, or a pharmaceutically acceptable salt thereof, and wherein the cancer is breast cancer, gastric cancer, lung cancer, or ovarian cancer. Pat444 claim 14 and 15 recite a method of treating cancer comprising administering to a subject in need thereof the compound of claim 13 and 12, or a pharmaceutically acceptable salt thereof, and wherein the cancer is breast cancer, gastric cancer, lung cancer, or ovarian cancer.
Conclusion
Claims 1,8,12,17-19,34,36,51-53,60,88-91,93,100,128-129,132,137,141-147 and 150-152 are not allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Lam Thuy Vi Tran Ho whose telephone number is (571)272-9135. The examiner can normally be reached Monday-Friday 7:30-3.
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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.
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/LAM THUY VI TRAN HO/Examiner, Art Unit 1647 /L.T./Examiner, Art Unit 1647 /JOANNE HAMA/Supervisory Patent Examiner, Art Unit 1647
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