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 .
The rejections under sections 112(a) and 112(b) are withdrawn in view of Applicant’s amendments and remarks in connection with these grounds of rejection.
The rejection under section 102 is moot since the rejected claims has been canceled.
The rejection under section 103 is withdrawn in favor of the following new ground of rejection under this section:
Claim Rejections - 35 USC § 103
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 1-10, 12-30 are rejected under 35 U.S.C. 103 as being unpatentable over CN 110577600 (CN 600) as evidenced by English Translation of Written Opinion of counterpart PCT application PCT/CN2021/121825 (previously cited) or WO 20180954221 (WO 221) in view of Tumey et al., Bioconjugate Chem. 2014, 25, 1871−1880 (previously cited) (Tumey) and Christie et al., Journal of Controlled Release 220 (2015) 660–670 (Christie).
CN 600 discloses a reaction route of antibody-drug conjugates:
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See Written Opinion of counterpart PCT application PCT/CN2021/121825, providing a partial translation, wherein CN 600 is Document D1:
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The hydrolyzed open-loop structure is also depicted in the preferred embodiments, which also cover those conjugates in the rejected claims:
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Moreover, as admitted in the specification at page 8, WO 221 teaches the following reaction:
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The primary references may not explicitly teach the required hydrolysis step. However, maleimide hydrolysis in Antibody-Drug Conjugates (ADCs) involves opening the thiosuccinimide ring formed after conjugation to cysteine residues. This process stabilizes the ADC by preventing the reverse Michael reaction (retro-Michael), which causes premature payload loss in circulation. It is for that proposition that the rejection joins the secondary references:
Tumey teaches that hydrolysis is used in the preparation of antibody-drug conjugates (ADCs) to stabilize the conjugate by converting a labile thiosuccinimide or maleimide linkage into a more stable form, preventing the premature release of the drug. Specifically, Tumey teaches that the stability of the connection between the antibody and the toxin can have a profound impact on ADC safety and efficacy. There has been increasing evidence in recent years that maleimide-based ADCs are prone to payload loss via a retro-Michael type reaction. Herein, we report a mild method for the hydrolysis of the succinimide-thioether ring which results in a “ring-opened” linker. ADCs containing this hydrolyzed succinimide linker show equivalent cytotoxicity, improved in vitro stability, improved PK exposure, and improved efficacy as compared to their nonhydrolyzed counterparts. This method offers a simple way to improve the stability, exposure, and efficacy of maleimide-based ADCs. See Abstract:
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Also, Christie teaches that cysteine-linked ADCs prepared with N-aryl maleimides exhibited less than 20% deconjugation in both thiol-containing buffer and serum when incubated at 37°C over a period of 7 days, whereas the analogous ADCs prepared with N-alkyl maleimides showed 35–67% deconjugation under the same conditions. ADCs prepared with the anticancer drug N-phenyl maleimide monomethyl-auristatin-E (MMAE) maintained high cytotoxicity following long-term exposure to serum whereas the N-alkyl maleimide MMAE ADC lost potency over time, see Abstract. Christie teaches that concept of resonance-promoted thiosuccinimide hydrolysis in the following figure:
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In this way, those of ordinary skill could have applied the recited hydrolysis in the manner required and in a predictable fashion for the purposes of obtaining providing a stable ADC. As outlined above, the primary references teach the recited conjugation steps. The secondary references are added for the proposition that the recited hydrolysis step is applicable to this process of conjugation. Specifically, the secondary references teach that the particular known technique of stabilizing ADC’s by hydrolysis after cysteine-conjugation was recognized as part of the ordinary capabilities of one skilled in the art. In this manner, those of ordinary skill would have recognized that applying the known technique to cysteine-conjugated methods, such as taught by the primary references, would have yielded predictable results. Accordingly, using hydrolysis for the purposes of providing stable cysteine-conjugated ADC’s would have been prima facie obvious.
The claims recite hydrolysis methods and reaction parameters. However, these parameters are results-effective variables, and therefore, are subject to routine optimization in the absence of unexpected results.
Notwithstanding Applicant’s remarks, CN 600 teaches the recited compounds. This reference teaches the ring-open maleimides, and therefore, a hydrolysis step has taken place, as recited in the claims.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KARL J PUTTLITZ whose telephone number is (571)272-0645. The examiner can normally be reached on Monday to Friday from 9 a.m. to 5 p.m.
If attempts to reach the examiner by telephone are unsuccessful, the examiner's acting supervisor, Gregory Emch, can be reached at telephone number 571-272-8149. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/KARL J PUTTLITZ/ Primary Examiner, Art Unit 1646