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 .
Claims 1-20 are pending and will be examined on the merits.
Claim Objections
Claims 19 and 20 are objected to under 37 CFR 1.75(c) as being in improper form because a multiple dependent claim must refer to a preceding claims in the alternative only. See MPEP § 608.01(n). Accordingly, the claims not been further treated on the merits.
Claims 6, 7, 19 and 20 objected to under 37 CFR 1.75(c) as being in improper form because a multiple dependent claim cannot depend on other multiple dependent claims. See MPEP § 608.01(n). Accordingly, the claims not been further treated on the merits.
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.
Claim(s) 1-2 and 8 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Coumans (Coumans, et al., WO 2017/137628 A1; Published 08/17/2017).
Regarding claims 1-2 Coumans teaches that DPPBS (Reducing agent (I)) selectively reduces engineered cysteines in an antibody while leaving the interchain native cysteines intact (Coumans, Abstract; Coumans, p 12, lines 20-22). One of ordinary skill in the art would reasonably conclude that the engineered cystines in the positions taught by Coumans are unpaired because they have no counterpart on the opposite chain. Regarding claim 8, Coumans teaches a method of preparing an antibody-drug conjugate comprising reduction of engineered cysteines of an antibody by contacting the antibody with DPPBS followed by contacting the reduced antibody with a crosslinker-linker-drug moiety comprising a thiol-reactive maleimide crosslinker to form an ADC (Coumans, p 13, lines 4-21).
Claim Rejections - 35 USC § 102/103
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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.
Claim(s) 9-10 is/are rejected under 35 U.S.C. 102(a)(1) as anticipated by or, in the alternative, under 35 U.S.C. 103 as obvious over (Coumans, et al., WO 2017/137628 A1; Published 08/17/2017).
The ADC production method comprising selective reduction of antibodies with DPPBS followed by contacting the reduced antibody with a crosslinker-linker-drug moiety of Coumans is discussed above.
Regarding claims 9-10, Coumans is silent that the method of Coumans would result in an ADC population wherein more than about 80% of the ADCs have a DAR of 2. However, as evidenced by the instant Specification, it would be expected that performing the method of Coumans (Specification, ¶ 0042) would inherently result in an ADC population wherein more than about 80% of the ADCs have a DAR or 2 (Specification, ¶ 0047).
Claim Rejections - 35 USC § 103
Claim(s) 1-5, and 8-12 is/are rejected under 35 U.S.C. 103 as being unpatentable over Arathoon (Arathoon, et al., WO 2015/031698 A1; Published 03/05/2015) in view of Coumans (Coumans, et al., WO 2017/137628 A1; Published 08/17/2017).
Arathoon teaches on the subject of site-specific antibody conjugation methods (Arathoon, Abstract). Arathoon teaches that unpaired cysteines were generated in the hinge region by mutating the cysteines at positions C220 and C214 to replace the cysteines with serines (Arathoon, Table 11). Arathoon teaches that cytotoxic drugs were conjugated to the hinge regions in a three-step process: 1) complete reduction, 2) re-oxidation of the paired interchain thiols and 3) conjugation of the drug-linker to the free unpaired cysteines, which resulted in a DAR of 2 (Arathoon, p115, line 24 – p116, line 23; Arathoon, p113, Table 11; Arathoon; Fig. 1; Arathoon; Fig. 9).
Arathoon does not teach that the antibodies comprising the C214S and C220S mutations were selectively reduced using 3-(diphenylphosphino)benzenesulfonic acid (hereinafter “DPPBS”).
Coumans teaches that DPPBS (Reducing agent (I)) selectively reduces engineered cysteines in an antibody while leaving the interchain native cysteines intact (Coumans, Abstract; Coumans, p 12, lines 20-22). One of ordinary skill in the art would reasonably conclude that the engineered cystines in the positions taught by Coumans are unpaired because they have no counterpart on the opposite chain. Coumans teaches a method of preparing an antibody-drug conjugate comprising reduction of engineered cysteines of an antibody by contacting the antibody with DPPBS followed by contacting the reduced antibody with a crosslinker-linker-drug moiety comprising a thiol-reactive maleimide crosslinker to form an ADC (Coumans, p 13, lines 4-21).
It would be prima facie obvious to one of ordinary skill in the art to combine the site-specific conjugation scheme taught by Arathoon with the DPPBS selective reduction taught by Coumans. The net result of this combination would be a method of generating site-specific ADCs, said method comprising: 1) introduction of C220S or C214S mutations into the antibody, 2) selective reduction of the unpaired cysteines with DPPBS and 3) conjugation of reduced antibody to a concentration of drug-linker moiety comprising a maleimide sufficient to yield an ADC with a DAR of 2. One of ordinary skill in the art would be motivated to make such a combination in order to arrive at a more efficient method of generating site-specific conjugates. The conjugation scheme taught by Arathoon comprises reduction of all of the cysteines in the antibody followed by selective re-oxidation, which selectively re-forms the interchain disulfides whilst leaving the engineered, unpaired cysteines in the reduced form and therefore able to participate in a reaction with maleimide moieties. The selective reduction using DPPBS taught by Coumans is a simpler and more efficient way of selectively reducing the cystines because only the unpaired, engineered cysteines are reduced. One of ordinary skill in the art would have a reasonable expectation of success making such a combination because: 1) Arathoon teaches of site-specific conjugation scheme utilizing an antibody with a C220S or C214S mutation, 2) preparing the selectively reduced antibody via the method of Arathoon involves reduction followed by partial re-oxidation and 3) the DPPBS-base selective reduction taught Coumans is a simpler selective reduction method that involves one step instead of two and does not affect interchain disulfide bonds. Regarding claims 9 and 10 specifically, the DAR of this ADC is 2 (see line 5 of this page). This means 100% of the ADCs have a DAR of 2, satisfying claims 9-10.
This fully satisfies the limitation s of claims 1-5 and 8-12.
Claim(s) 1-5 and 8-18 is/are rejected under 35 U.S.C. 103 as being unpatentable over Arathoon (Arathoon, et al., WO 2015/031698 A1; Published 03/05/2015) and Coumans (Coumans, et al., WO 2017/137628 A1; Published 08/17/2017) as applied to claims 1-5, and 8-12 above and in further view of Levengood (Levengood, et al., Angew. Chem. Int. Ed. (2017) 56:733-737) and Hamblett (Hamblett, et al., Clin. Cancer Research (2004) 10:7063-7070).
The combined teachings of Arathoon and Coumans are discussed above.
The combined teachings of Arathoon and Coumans do not teach that the selectively reduced ADC is then capped with a maleimide-comprising first drug-linker moiety, the remaining disulfides are reduced with TCEP and then is reacted with a second maleimide-comprising second drug-linker moiety to yield a dual drug-linker ADC with a DAR of the first drug-linker moiety of 2 and a DAR of the second drug-linker moiety of 2 for a total DAR of 4.
In addition to the teachings of Coumans discussed above, Coumans also teaches that the reducing agent TCEP is used in making ADCs and is capable of reducing disulfides of native cysteines making them available for conjugation (Coumans, p 2, lines 9-25).
Levengood teaches on the subject of ADCs comprising two different toxins (Levengood, Abstract). Levengood teaches that the ADCs comprising two different toxins had superior IC50 values when compared to ADCs having only one toxin (Levengood, Fig. 3; Levengood; Fig. 4).
Hamblett teaches that ADCs having a DAR of 4 had a comparable in vivo antitumor activity with ADCs having a DAR of 8 but that the maximum tolerated dose of the ADC with the DAR of 4 was double the maximum tolerated dose of ADCs with DAR of 8 (Hamblett, Abstract).
It would be prima facie obvious to one ordinary skill in the art to combine the selectively reduction of antibodies that are C220 or C214 mutants to form ADCs taught by Arathoon, the DPPBS selective reducing agent of Coumans, the TCEP non-selective reducing agent of Coumans ADC, the dual drug teachings of Levengood and the DAR4 teachings of Hamblett. The net result of this combination would be a method of producing a dual-drug linker ADC, said method comprising: 1) selective reduction of a C220 or C214 mutant antibody with the DPPBS of Coumans, 2) reacting the selectively reduced ADC with a maleimide-comprising first drug-linker moiety, 3) reducing the remaining disulfides are reduced with TCEP and 4) attaching a second maleimide-comprising drug-linker moiety to form a dual drug-linker ADC with a DAR of 4. One of ordinary skill in the art would be motivated to do this to improve the efficacy of the ADC of Arathoon and Coumans by making it a dual-drug ADC, which Levengood teaches have enhanced IC50 compared to single drug ADCs. One of skill in the art would have a reasonable expectation of success making such a combination because: 1) the combined teachings of Arathoon and Coumans teach a method of producing ADCs via selective reduction of engineered antibodies with DPPBS, which reduces introduced cysteines but not native cysteines, 2) Levengood teaches that ADCs comprising two different drug moieties possess enhanced IC50 compared to single drug ADCs, 3) it is within the purview of one of skill in the art to realize that if an ADC comprises linker-drug moieties at positions that are selectively reduced by DPPBS addition of a second drug-linker moiety would be possible by reduction of the native disulfides (not reduced by DPPBS) with standard TCEP and allow for the addition of a second-drug linker and 4) Hamblett teaches that a DAR of 4 is as effective as DAR 8 antibody (the maximum loading with cysteine chemistry) but had double the maximum tolerated dosage.
Conclusion
Claims 1-5 and 8-18 are rejected.
Claims 6-7 and 19-20 are objected to.
No claims are allowed.
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/SYDNEY VAN DRUFF/Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643
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