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 .
DETAILED ACTION
Claims 1, 38, 43, 52, 54-55, 68-70, 73, 77, 81, 87, 89, 92-100 are pending.
Claim 100 is new.
Claim 93 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 2/5/2025.
Claims 70, 73, 77, 81, and 98 were previously withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse.
Claims 1, 38, 43, 52, 54-55, 68-69, 87, 89, 92, 94-97, and 99-100 are pending.
Species Under Examination
Applicant previously elected Group I, and species of (i) the target antigen BCMA, (ii) L-D of Formula (D)
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and a single species of:
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in the reply filed on 2/5/2025 is acknowledged.
Claims 1, 38, 43, 52, 54-55, 68-69, 87, 89, 92, 94-97, and 99-100 read on the elected species and are under examination.
The elected species of:
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only has non-statutory double patenting rejections.
The Examiner previously rejoined three additional species for examination that are now outside of the amended claimed subject matter.
The next Examiner elected species is an antibody-drug conjugate of Formula (1) with (i) the target antigen BCMA; and (ii) L-D of
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.
The Examiner elected species is present in claim 100. The Examiner notes while instant claim 93 contains an embodiment wherein the antibody-drug conjugate of claim 1, wherein R03 is the formula
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wherein R027 is a hydrogen atom and R028 is a -(CH2)p0-SO2-OR030 group, the independent claim 1 does not recite these R027 and R028 as selectable options. Thus, instant claim 93 is an expansion of scope of independent claim 1 and is not present for the Examiner elected species.
Objections and Rejections Withdrawn
The rejection of claims 52, 89, and 92-93 under 35 USC §112(b) are withdrawn in view of claim amendment.
The rejections to claims 1, 43, 52, 54-55, 68-69, 87, 93, 95-97, and 99 under 35 USC §112(a) are withdrawn in view of claim amendment.
The rejection of claims 1, 38, 43, 52, 54-55, 68-69, 87, 92, 94-97, and 99 under Nonstatutory Double Patenting of 17/613,020 is withdrawn in view of a Terminal disclaimer approved on 6/26/2026.
The rejection of claims 1, 38, 43, 52, 54-55, 68-69, 87, 92, 94-97, and 99-100 under Nonstatutory Double Patenting of 18/038,437 is withdrawn in view of claim amendment.
New Rejections Necessitated by Amendment
Regarding the species of
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Claim Rejections - 35 USC § 112(a)
Claim 100 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Regarding instant claim 100, the Applicant does not have possession of antibody-drug conjugates that include payload P2 that are effective antibody drug conjugates as seen in Tables 28-29 or Figs 6-7. Payload P2 is compound C2 and the IC50 cytotoxic response in cancer cells is about 10 µM, which is the least effective Mcl-1 inhibitor of the 14 inhibitors tested in the instant specification in Table 23 on page 568. Further, the elected species L12-P2 did not converge when conjugated to a BCMA antibody in Table 29 and is ineffective.
Scope of the claimed genus
Regarding claim 100, an antibody-drug conjugate is claimed of formula Ab-(L-D), wherein the a) L-D under examination is:
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, wherein the drug is attached to the linker at the R09 position, and wherein p is an integer from 1 to 16.
Summary of Species disclosed in the original specification
The instant specification tests antibody drug conjugates wherein the Mcl-1 inhibitors tested are payloads P1-P2 and C1-C14 and P15-P17, wherein P1 has the structure of compound 1 and P2 has the structure of C2.
The structure of compounds C1-C14 are:
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;
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;
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;
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;
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;
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;
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;
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;
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;
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;
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;
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;
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; and
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, respectively (specification page 532-550).
The structure of compounds P15-P17 are:
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;
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;
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Specification pages 551-552.
Table 23 shows inhibition of Mcl-1 by Fluorescence Polarization (FP} and cancer cell cytotoxicity IC50 values, wherein compound C2 has a cancer cell cytotoxicity IC50 value of about 10 µM and is the highest value of all the compounds tested.
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Antibody-drug conjugates comprising compound C2 which is present in P2 in Tables 28-29 or Figs 6-7 do not show activity against cancer cells.
Linker L24, which is labeled as (14) in instant claim 1, was active when conjugated to compounds C1 and C6-C7, and anti-CD33 and anti-HER2 antibodies (Fig 8A, 9A and 19B). Compounds C1 and C6-C7 have cancer cell IC50 values from about 2 to 3 nM, which is about 3,000 times more potent against cancer cells when compared to compound C2.
The Applicant does not have possession of an effective antibody drug conjugate comprising compound C2. Only compounds C1, C3-C14 and P15-P17 showed activity in antibody-drug conjugates.
Further, testing of the L12-P2 antibody drug conjugate with a BCMA antibody was shown in the specification to be ineffective when tested in Table 29 on page 572 of the specification.
State of the Relevant Art
EP2886545 (Kotschy A et al. IDS reference) taught the Mcl-1 inhibitor of Example 30 with the structure:
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(page 115) was an effective Mcl-1 inhibitor and cytotoxic to cancer cells (page 262, Table 1). Kotschy taught the compounds may be linked to monoclonal antibodies or fragments thereof (page 17, paragraph 45).
Li taught antibody-drug conjugates (ADC) comprise targeting antibodies armed with potent small-molecule payloads (Li F et al. Cancer Res (2016) 76 (9): 2710–2719 reference of record, abstract). Li taught membrane permeability and the ability of the released payload to diffuse through the tumor are required for bystander killing and it is important to evaluate engineered payload for their membrane permeability and bystander killing (page 2717, left column, second to last paragraph). Li taught intertumoral release of membrane permeable MMAE released from cAC10-vcMMAE kills both CD30+ cells and CD30− cells in vivo, whereas another auristatin payload that is impermeable, MMAF, lacked such capacity (page 2717, left column, second to last paragraph).
Dal Corso A et al. (Journal of Controlled Release 2017 264 211-218 reference of record) taught that the Val-Cit linker, connecting the F16 antibody to PNU159682, is cleaved by proteases that are intracellular (e.g., cathepsin B), but that are also released in the extracellular space upon tumor cell death, wherein the acidic tumor microenvironment may facilitate the activation of these hydrolytic enzymes, triggering drug release by proteolysis (page 217, left column, second paragraph). Dal Corso taught hydrophilic or charged drugs released in the extracellular environment fail to subsequently cross the tumor cell membrane (page 217, left column, third paragraph). Thus, ADCs comprising Val-Cit linkers can be cleaved extracellularly to release payloads wherein cell permeability is important for activity.
One of skill in the art would reasonably conclude that applicant was not in possession of an antibody-drug conjugate of a BCMA antibody with L12-P2 that was effective. Further, the P2 payload was not identified as effective in an antibody drug conjugate. Mcl-1 variants that were shown to be effective include Mcl-1 inhibitors with the structure of C1, C3-C14 and P15-P17, wherein the Mcl-1 inhibitor connection point is shown in the Examples in the specification.
Summary
A genus of species is not present in the instant specification that would demonstrate a structure activity relationship would be known for Mcl-1 inhibitors other than Mcl-1 inhibitors with the structure of C1, C3-C14 and P15-P17. Applicant does not have possession of an antibody-drug conjugate of L12-P2 or a payload P2 that are effective antibody drug conjugates as seen in Tables 28-29 or Figs 6-7, wherein payload P2 is compound C2. No linkers within the application show the compound is effective as an antibody-drug conjugate.
Response to Arguments
Independent claim 1 has been amended.
Applicant argues solely to advance prosecution and without acquiescing to the merits of the rejection, claim 1 is amended to further define variables "R028" and "R030." As amended, claim 1 no longer encompasses ADCs having P2 as a payload.
In response, Applicant's arguments filed 6/26/2026 have been fully considered
but they are not persuasive. In response to amended claim 1, the updated rejection is above. The payload P2 is present in the anti-body-drug conjugate in instant claim 100.
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.
Regarding the elected species of
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Claims 1, 38, 43, 52, 54-55, 68-69, 87, 92, 94-97, and 99-100 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 8, 12-13, 18, 22-23, 25-26, 37-38, 40-41, 43-51, 61-62, and 66-69 of copending Application No. 18/038,437 in view of WO 2019025983 (Kinneer K et al. reference of record) and Staben LR et al. (ACS Med. Chem. Lett. 2017, 8, 1037−1041 reference of record).
‘437 taught an antibody drug conjugate, wherein Ab is an anti-CD48 antibody, p is an integer from 1 to 16 and D is a Mcl-1 inhibitor in copending claim 1, wherein the structure was:
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in copending claim 22, the Mcl-1 inhibitor D was
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in copending claim 38, and a pharmaceutical composition comprising the antibody-drug conjugate and a pharmaceutically acceptable carrier in copending claim 43.
The claims of ‘437 did not teach: 1) the antibody target as BCMA and a single embodiment of the elected species, but this is obvious in view of Staben and Kinneer.
Staben taught a quaternary ammonium salt peptide linker that is amenable to the stable connection and traceless release of tertiary amines for antibody drug conjugates (page 1038, left to right column, bridging paragraph). Staben taught that traceless release avoids potential loss of drug potency (page 1038, left to right column, bridging paragraph). Staben taught an effective pharmaceutical composition with a vehicle carrier of an anti-CD22 antibody drug conjugate with a maleimide- valine-citrulline- self-immolative group linked to a toxic payload via a tertiary amine that was effective against cancer in vivo (Fig. 4A-C)
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Staben taught the antibody drug conjugate in a liquid composition of 20 mM histidine acetate and sucrose as a carrier (Supp page 3, Supp Materials and Methods, preparation of conjugates). Staben taught the antibody had a drug to antibody ratio of 2 (page 1039).
Kinneer taught BCMA protein has been detected on the surface of plasma cells from multiple myeloma patients and has been investigated as a possible therapeutic target for multiple myeloma (page 1 paragraph 3). Kinneer taught an anti-BCMA antibody drug conjugate of 15B2GL-SG3249 which comprised a protease cleavable linker and self-immolative group (page 14, paragraph 43) and a monoclonal anti-BCMA antibody (page 23, paragraph 70), with a drug to antibody ratio of about 2 (page 27, Table 2), which effectively killed cancer cells in a pharmaceutical composition in vivo (Fig 4) with a pharmaceutically acceptable carrier (page 17, paragraph 51). Kinneer taught conjugation of the anti-BCMA antibody drug conjugate comprising reacting an antibody with a cleavable linker joined to a payload under conditions that allow conjugation (page 25, paragraph 74).
Regarding instant claims 1, 38, 43, 52, 54-55, 68-69, 92, 94-97, and 99-100, it would have been obvious for a person having ordinary skill in the art to take the antibody drug conjugate of copending claim 1 wherein, p is an integer from 1 to 16 and D is a Mcl-1 inhibitor with the linker if copending claim 22 and the Mcl-1 inhibitor of copending claim 38 in a pharmaceutical composition with a carrier in copending claim 43 – and 1) connect the tertiary amine of the Mcl-1 inhibitor of copending claim 38 to the linker via the tertiary amine via a bond as taught by Staben, which would make A a bond; and 2) exchange the targeting antibody for the an anti-BCMA antibody 15B2GL of Kinneer.
This is obvious because: 1) the Mcl-1 inhibitor contains a tertiary amine that could be linked to the antibody drug conjugate of Staben in a traceless manner, wherein traceless release avoids potential loss of drug potency; and 2) 15B2GL was effective at targeting an antibody drug conjugate to cancer cells and killing them in vivo in a pharmaceutical composition with a pharmaceutically acceptable carrier in an antibody drug conjugate comprising a protease cleavable linker and self-immolative group.
This would produce a pharmaceutical composition with a pharmaceutical carrier and an anti-BCMA antibody drug conjugate of the elected species with the structure
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,wherein the antibody is the BCMA targeting antibody 15B2GL which targets BCMA on cancer cells, and wherein the drug to antibody ratio is about 1 to 16. This meets the claim limitations of instant claims 1, 38, 43, 52, 54-55, 68-69, 92, 94-97, and 99.
There is a reasonable expectation of success because: 1) attachment to an antibody with the effective val-cit- self-immolative benzene linked tertiary amine causes traceless release of the toxic payload which would be targeted to cancer cells; and 2) 15B2GL was effective at targeting an antibody drug conjugate to cancer cells and killing them in vivo in a pharmaceutical composition with a pharmaceutically acceptable carrier in an antibody drug conjugate comprising a protease cleavable linker and self-immolative benzene and would target the Mcl-1 inhibitor to BCMA expressing cancer cells.
Regarding instant claim 87, it would have been obvious for a person having ordinary skill in the art to use the method of Kinneer for conjugation of the anti-BCMA antibody drug conjugate comprising reacting an antibody with a cleavable linker joined to a payload under conditions that allow conjugation – and to connect the linker payload of ‘437, Staben, and Kinneer.
This is obvious with a reasonable expectation of success because the maleimide group of ‘437, Staben, and Kinneer that attaches the cleavable linker to the antibody is the same.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
Applicants disagree with the merit of the rejection, The instant application is a US national stage application of International Patent Application PCT/US2020/033615, filed on May 19, 2020. Therefore, the instant application has a patent term filing date of May 19, 2020. The '437 application is a US national stage application of International Patent Application PCT/US2021/060560, filed on November 23, 2021. Thus, the '437 application has a patent term filing date of November 23, 2021. Accordingly, the instant application has an earlier patent term filing date than the '437 application and the provisional double patent rejection should be withdrawn. See MPEP §804.Il(b)(i).
In response, Applicant's arguments filed 6/26/2026 have been fully considered
but they are not persuasive. Section 804 1.(b).i. of the M.P.E.P. sates if a provisional nonstatutory double patenting rejection is the only rejection remaining in an application having the earlier patent term filing date, the examiner should withdraw the rejection in the application having the earlier patent term filing date and permit that application to issue as a patent, thereby converting the provisional nonstatutory double patenting rejection in the other application into a nonstatutory double patenting rejection upon issuance of the patent. The instant application still has pending rejections.
Conclusion
Claims 1, 38, 43, 52, 54-55, 68-69, 87, 92, 94-97, and 99-100 are rejected.
Claim 89 is objected to because all other species in the application are not allowable.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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 JOHN J SKOKO III whose telephone number is (571)272-1107. The examiner can normally be reached M-F 8:30 - 5:00.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Julie Z 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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/J.J.S./Examiner, Art Unit 1643
/Karen A. Canella/ Primary Examiner, Art Unit 1643
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