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 the Claims
Applicant’s cancelation of claim 31 in the response filed on November 19th 2025 is acknowledged. Claims 27-30 and 32-36 are pending and are examined on their merits.
Information Disclosure Statement
The Information Disclosure Statements received September 21, 2021 (68 references), May 26, 2022 (14 references) and January 20, 2023 (18 references) are in compliance with the provisions of 37 CFR 1.97 and have been considered in full. A signed copy of references cited from the IDS is included with this Office Action.
Rejections & Objections Overcome by Amendment
Nucleotide and/or Amino Acid Sequence Disclosures
Applicant submitted a substitute specification in both clean and marked-up versions including additions of sequence identifiers at original claims 11 and 12, page 15, 1l. 18 and 22, page 36, I1. 22, 23, and 25, and page 112, Il. 10-15. The substitute specification also includes a paragraph at page 1, 11. 3-6, identifying the Sequence Listing. Applicants note that since the substitute specification does not include the claims and that the application now comprises the substitute specification and the claims presented with the amendment. The objection is withdrawn.
35 U.S.C. § 112(b) Rejections for Claims 28-30 and 32 Overcome by Amendment
Applicant submitted amended claims 28, 29, 30, and 32 to specify a single definition range for the recited variables a, b1, b2 and d that do not include a narrower range of or limitation that falls within a broader range of the claims. The rejection is withdrawn.
35 U.S.C. § 112(d) Rejections for Claim 31 Overcome by Amendment
Applicant has canceled claim 31. The rejection is now considered moot and the rejection is withdrawn.
Nonstatutory Double Patenting Rejections Overcome by Terminal Disclaimer
Applicant filed a Terminal Disclaimer over U.S. Patent No. 11,446,292 in the response filed on May 28th, 2025. The terminal disclaimer is sufficient to overcome the nonstatutory double patenting rejections over U.S. Patent No. 11,446,292. Accordingly, the rejection is withdrawn.
Respons to Applicants Arguments under 35 US§ 103 Rejections
Applicant’s arguments in the response filed November 19th, 2025 assert that based on the teachings in Nakada, a person skilled in the art would have been motivated to include a spacer between the peptidic group and the drug unit, and would have been led away from directly linking the peptidic group to the drug unit as claimed in the present application. Suggesting that ADCs lacking a spacer (i.e., where the peptidic group is directly linked to the drug unit) show decreased cytotoxicity.
Contrary to the applicant’s remarks, the applicant would have reasonable expectation of success utilizing the core compound of Nakada, with or without, the spacer utilizing variations of the core compound as taught by Nakida because the ADCs 1-7 identified in Figure 1 all are considered effective ADCs and exhibit cytotoxicity. The core compound taught by Nakada and the core compound of the instant application are functional equivalents.
The applicant further asserts that Sugimori teaches various camptothecin analogs as small molecule anti-tumor agents but fails to teach or suggest that any of its anti-tumor agents, let alone compound 34, would be suitable for use as a drug unit in a conjugate.
The applicant’s argument is not convincing because even if compound 34 was not specifically identified as a suitable as camptothecin molecule to explore for use as a drug conjugate, as described by the applicant’s argument, the use of the compound 34 as small molecule anti-tumor agent would be obvious to explore.
35 U.S.C. § 103 Rejections Maintained
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 rejection of claims 27-36 under 35 U.S.C. 103 as being unpatentable over Nakada (Nakada, et al.; Bioorganic & Medicinal Chemistry Letters, v26, pp.1542-1545; 2016) in view of Sugimori (Sugimori, et al.; Journal of Medicinal Chemistry, v41, pp.2308-2318; 1998) is maintained.
35 U.S.C. § 103 Rejections for Claims 27-36 Reiterated
Claim 27 is directed to a method of treating cancer in a patient, comprising administering to the patient a ligand-drug conjugate of formula IV: L- (DL)p, or a pharmaceutically acceptable salt or solvate thereof, wherein L is a Ligand unit (e.g., an antibody), which is covalently linked to D¹, where D¹ is a Drug Linker unit that is a linker-camptothecin compound of formula III:
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where RLL is selected from a Markush group of variable length chemical linkers that are covalently attached to the camptothecin compound of formula III (e.g., the particular hexacyclic camptothecin drug analog). One of the Markush group members of linkers defined by claim 27 is a succinimidyl-alkyl-Gly-Gly-Phe-Gly-linker component that links the antibody to the camptothecin (i.e., RLL and the variables listed as GLL-x)
Similar to Applicant’s claimed invention, Nakada also teaches the use of antibody-drug-conjugates (ADCs) composed of an antibody-linker-camptothecin conjugates (i.e., a trastuzumab antibody-variable length chemical linker-camptothecin analogs), in cytotoxicity against breast cancer cells in mouse cell model (see Abstract), that are both potent and water soluble. Nakada’s drug-linker compounds contain peptidic segments that act as the variable length chemical linker, including a succinimide-C5-alkl-Gly-Gly-Phe-Gly connector subunit withing the scope of claim 27.
The molecule of Nakada is nearly identical to the applicant’s claimed compound, except for the variation in the CPT (highlighted as ADC (1) and the differences from the claimed core compound, circled). However, one of ordinary skill in the art would have had a reasonable expectation of success arriving at the applicant’s core CPT compound in place of the one selected by Nakada because both are, for all practical purposes, functional equivalents. For example, see Sugimori.
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Sugimori teaches the synthesis of a series of hexacyclic camptothecin analogues can also be potent topoisomerase inhibitors with an amino group at the 4 position. The compounds were evaluated for cytotoxicity against murine and human tumor cell lines as topoisomerase inhibitors, including compound 34; that has the same core feature of the claimed compound of formula III (shown below).
Claim Number(s) of Instant Application
Instant Application
Sugimori
27
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Sugimori’s compound 34 is racemic at the chiral 9-position rather than being the S-enantiomer; however, Sugimori teaches the preparation of both racemic and 9S-enantiomeric hexacyclic camptothecin analogues, via a Friedlander condensation of a bicyclic amino-ketone precursor with a tricyclic ketone, as shown below in Sugimori’s Scheme 1. Control over the stereochemistry is made by the choice of tricyclic ketone product (7a or 7b) independently of the desired substituents and the resulting 4-position and 5-position in the hexacyclic product.
Applicant’s invention is unpatentable over the disclosure of Nakada and further in view of Sugimori, because a person of ordinary skill in the art, at the effective time of filing, would have a reasonable expectation of success in combining the drug-linker containing peptidic segments with a succinimide-based connector in antibody-drug-conjugates (ADCs) with a hexacyclic camptothecin analogue as described by Nakada, with Sugimori, that teaches the core feature of the instant compound of formula III in compound 34.
Claims 28-36 further limit claim 27, each to a compound or a narrower genus of compounds that is met by the rejection above.
Applicant’s arguments in the response filed November 19th, 2025 are found to be unpersuasive because the teaching of the ADC combining the drug-linker containing peptidic segments with a succinimide-based connector in antibody-drug-conjugates (ADCs) with a hexacyclic camptothecin analogue as described by Nakada, with Sugimori, that teaches the core feature of the instant compound of formula III in compound 34. Applicant does not show any unexpected results that suggest that the claimed compound is more effective than the drug-linker containing peptidic segments with a succinimide-based connector in antibody-drug-conjugates (ADCs) with a hexacyclic camptothecin analogue as described by Nakada, with Sugimori, that teaches the core feature of the instant compound of formula III in compound 34. See, MPEP 716.02(d), Unexpected Results Commensurate in Scope with Claimed Invention, the nonobviousness of a broader claimed range can be supported by evidence based on unexpected results from testing a narrower range if one of ordinary skill in the art would be able to determine a trend in the exemplified data which would allow the artisan to reasonably extend the probative value thereof. In re Kollman, 595 F.2d 48, 201 USPQ 193 (CCPA 1979).
Conclusion
THIS ACTION IS MADE FINAL. 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 PAUL RANDALL GAUGER whose telephone number is (571)272-1325. The examiner can normally be reached M-F 7:30-5:00.
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/P.R.G./ Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/ Supervisory Patent Examiner, Art Unit 1629
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