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 .
Acknowledgement is made of applicant’s election without traverse of the species of P-III and P-IV in the paper filed 11/14/2025.
Claims 27, 30 and 42 have been amended. Claims 1, 2, 5, 6, 8, 11-13, 16, 18-20, 22-24, 27-31, 37-40, 42, 44, 45, 50 and 51 are pending and will be examined on the merits to the extent that they encompass the elected species of P-III and P-IV.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 119(e) as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, Application No. 63/298,786, fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application.
The provisional application provides a written description of the exatecan derivatives P-I and P-II but fails to provide any written description of the instant camptothecin derivatives P-III and P-IV. Thus, benefit of earlier priority is not extended to the instant claims requiring the camptothecin derivatives P-III and P-IV. The claims will be considered to have the priority date of 1/10/2023.
Claim Objections
Claims 27, 30 and 42 are objected to because of the following informalities:
the incorporation of an extraneous “_” before the recitation of “claim 1” in claims 27 and 30, and between “claim” and “40” in claim 42;
the word-processing error of “any one of claims 18” in claim 19 as opposed to “claim 18”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
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.
Claims 18-20, 28, 44 and 45 are 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.
It is unclear how a “second spacer unit” in claim 18 differs from the SP2.
Claim 28 is vague and indefinite because it lacks definitions for the “R” substituents. For purpose of examination, R4, R5, R6 and R7 will be considered to have the limitations of the corresponding R substituents in claim 1.
Claims 44 and 45 are vague and indefinite in the lack of any active, positive steps that define the claimed method. See MPEP 2173.05(q).
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.
Claims 50 and 51 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of making a triazole comprising the cycloaddition of azide to
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or
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, does not reasonably provide enablement for the cycloaddition of tetrazine to
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or
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. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
The factors considered when determining if the disclosure satisfies the enablement requirement and whether any necessary experimentation is undue include, but are not limited to: 1) nature of the invention, 2) state of the prior art, 3) relative skill of those in the art, 4) level of predictability in the art, 5) existence of working examples, 6) breadth of claims, 7) amount of direction or guidance by the inventor, and 8) quantity of experimentation needed to make or use the invention. In re wands, 858 F.2d 731, 737.8 USPQ2d 1400, 1404 (Fed. Cir. 1988).
Claim 50 is directed in part to the use of ,
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, as opposed to N3, in the formation of a triazole when paired with
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The art teaches the well-known Huisgen 1,3-dipolar cycloaddition of azido and alkynes to yield triazoles
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(Gil et al, Synthesis, 2007, No. 11, pp. 1589-1620, see page 1594). However, the art teaches that tetrazines and alkynes undergo cycloaddition to extrude N2 producing an addition product which is not a triazole
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(Chen et al, Chemical communications, 2012, Vol. 48, pp. 1736-1738, see Figure 1, A and B on page 1737). The specification fails to provide and teachings or guidance for forming a triazole from a tetrazine and an alkyne. Thus, one of skill in art would be subject to undue experimentation in order to carry out the broadly claimed method of producing the compound BA-(L1-B-L2-P) using a reaction between an alkyne and a tetrazine wherein B was a triazole.
Claim 51 is included with this rejection to the extent that the compound s a compound of Formula (A).
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 37 and 39 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Rougier et al (Journal of clinical Oncology, 1997, Vol. 15, pp. 251-260).
Rougier et al disclose the treatment of patients with advanced colorectal cancer comprising the administration of irinotecan, which meets the limitation of compound
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in claim 37 and the method of claim 39.
Claims 37 and 39 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Adams et al (Cancer Chemotherapy and Pharmacology, 2006, Vol. 57, pp. 135-144).
Adams et al disclose the camptothecin derivatives of
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and
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(page 138, Table 1: 10-OH, no 7-alkyl and 10-OMe, no 7-alkyl) having 51 fold and 44 fold greater activity against MCF-7 breast cancer cells in vitro relative to unmodified camptothecin.
Claim 37 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Dallavalle et al (Journal of Medicinal chemistry, 2000, vol. 43, pp. 3963-3969).
Dallavalle et al disclose intermediate compound 2c (page 3964, Scheme I)
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which meets the limitations of claim 37.
Claims 37 and 39 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Kim et al (Journal of Thoracic Oncology, 2012, Vol. 7, pp. 731-736).
Kim et al disclose the treatment of patients with small cell lung cancer by administration of Belotecan (title) which meets the limitations of claims 37 and 39 for
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,
Claims 37 and 39 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Cabri et al (WO96/37496).
Cabri et al disclose compound 101’ (page 25) which meets the limitations of
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in claim 37. Cabri et al disclose that the compounds of the invention have anti leukemic activity ad anti-tumor activity against colon and rectal tumors (page 30, line 26 to page 31 line 2) which meets the limitations of claim 39.
Claim 1, 2, 5, 6, 8, 12, 13, 16, 19, 24, 30, 31, 38, 44, 45 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Woo et al (WO2024/005460, priority to KR-2022-78448, pages 25, 39, 40, 141, 167 and 179) as evidenced by US2025/0121072 (English Language version) and Lu et al (U.S. 2018/0055944).
Woo et al disclose antibody-drug conjugates comprising an antibody joined to a drug moiety by means of a linker/spacer linking the antibody to a triazole which is attached by a linker/spacer to the drug, “PL” (bottom of page 28 and top of page 29) wherein the drug, PL, is a camptothecin moiety:
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(page 12), which meets the limitation of claim 1 for P-III, wherein R5 is H and R4 is -N(C1-C6alkyl) and (CH2)2. Woo et al disclose an embodiment wherein the linker-drug may be bound to an antibody through the -c(=O)NH2 of glutamine (page 26, lines 20-33) which meets the limitations of claim 2. Woo et al disclose that the antibody is Trastuzumab (paragraph [0139]) which meets the limitations of an anti-Her2 antibody in claim 6. Lu et al provide evidence that trastuzumab targets breast, lung and ovarian and prostate tumors (Table 2). Thus, the trastuzumab of Woo et al meets the limitation of claim 8. Woo et al disclose linker-drugs of “DAR4 type” in Table C, which meet the limitations of claims 30 and 31 for a DAR of about 0.5-about 12 and a DAR of 2, 4 or 8, as well as the limitations of claim 24 wherein n is 2 or 4. Woo et al disclose pharmaceutical compositions of the inventive conjugates in a pharmaceutically acceptable carrier or excipient (paragraph [0212]) which meets the limitations of claim 38. Woo et all disclose that the composition can be used for the treatment of cancers or tumors (paragraph [0219]) which meets the limitations of claim 39, as well as claims 44 and 45 because trastuzumab will target Her2 expressed o cancer cells and after receptor internalization, the conjugate will be taken up in the lysosomes for release of the camptothecin into the cell.
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Woo et al disclose the linker-drug:
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in Table B as of the DAR2 type (heading page 218 and structure page 222), which also meets the limitations of claims 30 and 31. After reaction with the antibody at the maleimide, the structures meet the limitations of having a first linker, L1, and a second linker, L2 joined together at the triazole. Wherein L1 comprises C1-C6 alkyl in claim 12;
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and
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in claim 13;
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in claim 16, and SP2 is
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which meets the limitations of claim 18, wherein SP1 and AA are absent. Alternatively, with regard to claim 18, SP1 can be
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and AA and SP2 can be considered as “absent”; which thus meets the limitations of claim 22 wherein SP2 is absent.
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.
Claims 1, 2, 5, 6, 8, 12, 13, 16, 19, 24, 30, 31, 38, 40, 44, 45, are rejected under 35 U.S.C. 103 as being unpatentable over Woo et al (WO2024/005460) as evidenced by US2025/0121072 (English Language version) and as evidenced by Lu et al (U.S. 2018/0055944) in view of Goldenberg and Sharkey (Expert Opinion on Biological therapy, 2020, Vol. 20, pp. 871-885)..
Woo et al teach that the compositions of the invention can be used to treat cancers and tumors (paragraph [0219]). Woo et al do not specifically tech that the cancers and tumors are in a subject in need thereof, or that the cancers include breast cancers.
Goldberg and Sharkey teach an ADC comprising an anti-TROP2 monoclonal antibody and govitecan, a semi-synthetic camptothecin (page 873, first column, second paragraph under section 2.2). Goldberg and Sharkey teach that the ADC was used to treat patients with breast cancers and lung cancers (page 876, Table 1).
It would have been prima facie obvious to use the drug-linkers of Woo et al having the camptothecin derivatives, wherein the drug linkers were conjugated to a TROP-2 antibody for the treatment of patients with breast cancers or lung cancers. One of skill in the art would have been motivated to dos o because Woo et al teach that the compounds of the invention can be used in the treatment of cancers and tumors and Goldenberg and Sharkey teach ADCs having a structurally similar drug moiety, thus rendering obvious claims 40 and 42.
Claims 1, 6, 8, 12, 13, 16, 19, 24, 28, 30, 31, 38, 44, 45, are rejected under 35 U.S.C. 103 as being unpatentable over Woo et al (WO2024/005460) as evidenced by US2025/0121072 (English Language version) and as evidenced by Lu et al (U.S. 2018/0055944) in view of Gil et al (Synthesis, 2007, No. 11, pp. 1589-1620).
Claim 28 requires a compound having the formula Alkyne-L2-P. Woo et al teach
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having an azido group rather than an alkyne group.
Gil et al teach the Huisgen 1,3-dipolar cycloaddition for formation of a triazole from an azido group and an alkyne (page 1594, section 4).
It would have been prima facie obvious at the time prior to the effective filing date to swap the azido group on the end of the L2-P for
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wherein R1 was L2-P. One of skill in the art would have been motivated to do so because the formation of the tetrazole resulted from the interaction of the pi bonds of the alkyne and the azido group which would be expected to produce the same product if the two moieties were attached to either L1 and L2. Thus, switching the azido group for
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represents an art recognized equivalent for the precursors of the cycloaddition and results in the compound of claim 28.
Claims 1, 2, 5, 6, 8, 11, 12, 13, 16, 19, 24, 30, 31, 38, 44, 45, 50 and 51 are rejected under 35 U.S.C. 103 as being unpatentable over Woo et al (WO2024/005460) as evidenced by US2025/0121072 (English Language version) and as evidenced by Lu et al (U.S. 2018/0055944) in view of Dickgiesser et al (Bioconjugate Chemistry, 2020, Vol. 31, pp. 1070-1076).
Claim 2 requires that that the first linker is connected to a side-chain of a glutamine residue I the antibody of claim 1. Claim 5 specifies, in part, that the glutamine residue in claim 2 is naturally present in the antibody. Claim 11 specifies, in part, that the glutamine residue of claim 2 is Q395.
Claim 50 is drawn to a method of making a compound of formula A wherein formula (A) has the same requirements as the compound of claim 1 except L1 is covalently bound to the side chain of a glutamine residue of the antibody, formed from contacting the antibody with L1-B in the presence of a transglutaminase, wherein B’ is N3 and B’’ is
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Woo et al teach preparation of Linker P-1 having an azido group (page 43) and the preparation of linker P-2 having a
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(page 44 (example 2).
Woo et al teach that the antibody may be bound to the linker through the -c(=O)NH2 of glutamine (paragraph [0135]), which meets the limitations of claim 2. Woo et al do not specifically teach that the glutamines are naturally present in the antibody or are Q295.
Dickgiesser et al teach the site-specific conjugation of native antibodies using engineered microbial transglutaminases (title).
Dickgiesser et al teach that the resulting ADCs have excellent stability in vitro as well as in vivo (abstract).
It would have been prima facie obvious at the time prior to the effective filing date to attach the L1-B’, wherein the B’ was either N3 or
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, to the Q295 residue of the native antibody, BA by means of the engineered microbial transamidase, and then to carry out a 1, 3 cyclo addition with B’’-L2 having either
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or N3 as B’’ to complement B’ and provide for the formation of the triazole. One of skill in the art would have been motivated to do so because Woo et al teach the conjugation of L1 and L2 though a linker ending in
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with a linker ending in N3 to form a triazole and couple both of the linkers. One of skill in the art would have been motivated to attach the L1 linker to the antibody at Q295 using the microbial transamidase because Dickgiesser et al teach that ADC conjugates attached to the antibody through Q295 glutamine exhibit excellent stability in vitro as well as in vivo.
Allowable Subject Matter
Claims 23, 27, and 29 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KAREN A CANELLA whose telephone number is (571)272-0828. The examiner can normally be reached M-F 10-6:30.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Julie 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.
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KAREN A. CANELLA
Examiner
Art Unit 1643
/Karen A. Canella/ Primary Examiner, Art Unit 1643