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 .
Application Status
Claims 1-23 are pending and examined on the merits herein.
Grounds of Rejection Withdrawn
Previous rejection of claims 2 and 4-5 under 35 U.S.C. 112(b) are withdrawn in view of claim amendments.
Previous rejection of claims 1-3 and 10-22 under 35 U.S.C. 102 are withdrawn in view of the common ownership statement in the arguments filed 08/18/2026 under the 102(b)(2) exception.
Previous rejection of claims 4 and 6-9 under 35 U.S.C. 103 are withdrawn in view of the common ownership statement in the arguments filed 08/18/2026 under the 102(b)(2) exception.
Double Patenting
New Rejection Necessitated by Amendment
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.
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Claims 1-3 and 10-23 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1, 11-19, 27-33, and 35 of copending Application No. 17/760,394 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other.
Regarding claims 1-3, the copending claims teach an isolated multi-specific antibody (claim 11 and 1), wherein the multi-specific antibody is a bispecific antibody (claim 12), wherein the first antigen-binding arm (Abl) comprises HI and LI and a second antigen-binding arm (Ab2) comprises H2 and L2, wherein
(a) HI and H2 each comprises a CHI region of human IgGl, IgG2, IgG3, or IgG4; and
(b) LI and L2 each comprises a CL region of a human kappa light chain or a human lambda light chain;
wherein HILI and H2L2 each comprise a charge pair selected from the group consisting of the following amino acid substitutions:
(1) Gl66D/E in CHI of HI and S114K/R in CL of LI, respectively, and Gl66K/R in CHI of H2 and SI 14D/E in CL ofL2, respectively;
(2) Tl87D/E in CHI of HI and DINI 70K/R in CL of LI, respectively, and Tl87K/R in CHI ofH2 and DINI 70D/E in CL ofL2, respectively;
(3) Sl31D/E in CHI of HI and Pl 19K/R in CL of LI, respectively, and Sl31K/R in CHI of H2 and Pl 19D/E in CL ofL2, respectively;
(4) Al29D/E in CHI of HI and Sl21K/R in CL of LI, respectively, and Al29K/R in CHI of H2 and Sl21D/E in CL ofL2, respectively;
(5) K/R133D/E in CHI of HI and K207K/R in CL of LI, respectively, and K/R133K/R in CHI ofH2 and K207D/E in CL ofL2, respectively;
(6) K/R133D/E in CHI of HI and I/LI l 7K/R in CL of LI, respectively, and K/R133K/R in CHI ofH2 and I/LI l 7D/E in CL ofL2, respectively;
(7) K/R133D/E in CHI of HI and F/V209K/R in CL of LI, respectively, and K/R133K/R in CHI ofH2 and F/V209D/E in CL ofL2, respectively;
(8) Gl66D/E in CHI ofH2 and S114K/R in CL ofL2, respectively, and Gl66K/R in CHI of HI and SI 14D/E in CL of LI, respectively (claim 17).
Regarding claims 10-11 and 13, the copending claims teach the isolated bispecific antibody or antigen-binding fragment thereof of claim 12, wherein Ab I binds an immune cell modulator (ICM) (claim 13), wherein the ICM is CD3 (claim 14), the isolated bispecific antibody or antigen-binding fragment thereof of claim 12, wherein Ab2 binds a tumor-associated antigen (TAA) (claim 15), wherein the TAA is DLL3 (claim 16).
Regarding claims 12 and 14, the copending claims teach the isolated bispecific antibody or antigen binding fragment thereof comprising 1) a first antigen-binding arm (Abl) comprising a VH region having the polypeptide sequence of SEQ ID NO: 15, a VL region having the polypeptide sequence of SEQ ID NO: 17, a CHI region having [[a]] the polypeptide sequence of SEQ ID NO: 16, and a CL region having the polypeptide sequence of SEQ ID NO: 18; 2) a first antigen-binding arm (Abl) comprising a VH region having [[a]] the polypeptide sequence of SEQ ID NO: 19 (claim 18). SEQ ID NO: 19, 16, 17 and 18 having 100% sequence identity to the instant claimed SEQ ID NO: 9, 10, 11 and 12 respectively.
Regarding claim 14, the copending claims teach he isolated bispecific antibody or antigen-binding fragment thereof of claim 18, wherein the second antigen-binding arm (Ab2) comprises a VH region having the polypeptide sequence of SEQ ID NO:23, a VL region having the polypeptide sequence of SEQ ID NO:25, a CHI region having the polypeptide sequence of SEQ ID NO:24, and a CL region having the polypeptide sequence of SEQ ID NO:26 (claim 19). SEQ ID NO: 23-26 have 100% sequence identity to the instant claimed SEQ ID NO: 13-16 respectively.
Regarding claim 15, the copending claims teach an isolated nucleic acid encoding the isolated antibody or antigen-binding fragment thereof of claim 1 (claim 27).
Regarding claim 16, the copending claims teach A vector comprising the isolated nucleic acid of claim 27 (claim 28).
Regarding claim 17, the copending claims teach An isolated host cell comprising the vector of claim 28 (claim 29).
Regarding claim 18, the copending claims teach A pharmaceutical composition comprising the isolated antibody or antigen-binding fragment thereof of claim of 1, and a pharmaceutically acceptable carrier (claim 30).
Regarding claims 19-20 and 23, the copending claims teach a method of treating a cancer in a subject in need thereof, the method comprising administering to the subject the pharmaceutical composition of claim 30 (claim 31), wherein the cancer is selected from the group consisting of a lung cancer, a gastric cancer, an esophageal cancer, a bile duct cancer, a cholangiocarcinoma, a colon cancer, a hepatocellular carcinoma, a renal cell carcinoma, a bladder urothelial carcinoma, a metastatic melanoma, a breast cancer, an ovarian cancer, a cervical cancer, a head and neck cancer, a pancreatic cancer, a glioma, a glioblastoma, and other solid tumors, and a non-Hodgkin's lymphoma (NHL), an acute lymphocytic leukemia (ALL), a chronic lymphocytic leukemia (CLL), a chronic myelogenous leukemia (CML), a multiple myeloma (MM), an acute myeloid leukemia (AML), and other liquid tumors (claim 32).
Regarding claim 21, the copending claims teach a method of producing the isolated antibody or antigen-binding fragment thereof of claim 1, the method comprising culturing a cell comprising a nucleic acid encoding the antibody or antigen-binding fragment thereof under conditions to produce the antibody or antigen-binding fragment thereof, and recovering the antibody or antigen-binding fragment thereof from the cell or culture (claim 33).
Regarding claim 22, the copending claims teach a method of producing a pharmaceutical composition comprising the isolated antibody or antigen-binding fragment thereof of claim 1, the method comprising combining the antibody or antigen-binding fragment thereof with a pharmaceutically acceptable carrier to obtain the pharmaceutical composition (claim 35).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim 4 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 11-19, 27-33, and 35 of copending Application No. 17/760,394 (reference application) as applied to claims 1-3 and 10-23 above and further in view of Dillon (mAbs, 9(2), 213–230; cited in OA 05/12/2026).
The teachings of the copending claims regarding claims 1-3 and 10-23 are detailed above.
The copending claims do not teach that the VL region of L1 have a Q39E and a Q38K substitution respectively and the VL region of L2 have a Q39K and a Q38E substitution mutation respectively.
Dillon teaches that bispecific IgG production in single host cells has been a much sought-after goal to support the clinical development of these complex molecule (abstract). Dillon further teaches that for efficient orthogonal Fab pairing changes, it can be advantageous to combine variable and constant domain mutations such as a conserved hydrogen bond between the variable domains involving VH Q39 and VL Q38 (page 218, col 1, para 2) and further that as these residues are distal to the complementary-determining regions (CDRs), little effect upon antigen binding affinity was seen (table 4). Dillon further teaches that these positions minimize LC homodimer and improve orthogonal Fab designs for single-cell BsIgG (page 218, col 1, para 2). Dillon further teaches that the variant, VL Q38E, negatively affected antibody assembly (Fig. 2D) but that this assembly defect was rescued with the VH Q39K variant (page 218, col 1, para 2).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application to add charge pair mutations in the VL region of the bispecific as taught by Dillon to the bispecific antibody with engineered charge pair mutations in the constant regions as taught by the copending claims. The ordinary artisan would have been motivated to do so because Dillon teaches that it is advantageous to combine variable and constant domain mutations such as a conserved hydrogen bond between the variable domains involving VH Q39 and VL Q38 to support bispecific IgG production in single host cells. The ordinary artisan has a reasonable expectation of success to add Q39E and Q38K mutations in the VL of L1 and L2 to improve bispecific antibody production in a single cell.
The rationale to apply a technique taught by the prior art as improving the therapeutic and production characteristics of a similar construct is to predictably obtain an improvement to the second construct and is consistent with the exemplary rationales provided by the Supreme Court in KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385, 1395-97 (2007) and discussed in M.P.E.P. § 2143. For these reasons, the invention as a whole would have been prima facie obvious to one ordinary skill in the art before the effective filing date of the claimed invention.
Claim 5 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 11-19, 27-33, and 35 of copending Application No. 17/760,394 (reference application) as applied to claims 1-3 and 10-23 above and further in view of Li (US 2022/0411497 A1; PTO-892) and Magrolimab (KeggDrug; no date available; PTO-892).
The applied reference has a common assignee and inventor with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2). This rejection under 35 U.S.C. 102(a)(2) might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C. 102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B) if the same invention is not being claimed; or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed in the reference and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement.
The teachings of the copending claims regarding claims 1-3 and 10-23 are detailed above.
The copending claims do not teach the sequences of CH1 and CL comprise SEQ ID NO: 17-20 or 21-22 respectively or that the specific substitutions as recited in claim 5, options (1)-(4).
Magrolimab is an IgG4 monoclonal antibody that targets CD47. The sequence of magrolimab has 100% sequence identity to the instant claimed SEQ ID NO: 20 and 21.
Li teaches an isolated bispecific antibody or antigen-binding fragment thereof comprising: a. a first heavy chain, H1; b. a second heavy chain, H2; c. a first light chain, L1; and d. a second light chain, L2; wherein there are amino acid substitutions in the CH1 and CL regions are selected from: (1) K133C and C220X in CH1, and F209C and C214X in CL; (18) R133C and C131X in CH1, and F209C and C214X in CL; (19) R133C and C131X in CH1, and V209C and C214X in CL; or (20) K133C and C220X in CH1, and V209C and C214X in CL; wherein X is selected from S, A or G (claim 1). Li further teaches that these engineered bispecific antibodies have a shifted interchain disulfide bond on one arm while maintaining the native interchain disulfide bond on the second arm, and further have stability and production advantages to be used for therapeutic purposes (para 0002).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application to add shifted interchain disulfide bond on one arm of the bispecific as taught by Li with an established IgG4 sequence as taught by magrolimab, to the bispecific antibody with engineered charge pair mutations in the constant regions as taught by the copending claims. The ordinary artisan would have been motivated to do so because Li teaches bispecific antibodies with a shifted interchain disulfide bond on one arm have stability and production advantages. The ordinary artisan has a reasonable expectation of success to add a shifted interchain disulfide bond to improve bispecific antibody production and stability.
Claims 6-9 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 11-19, 27-33, and 35 of copending Application No. 17/760,394 (reference application) as applied to claims 1-3 and 10-23 above and further in view of Wang (WO 2019/217145 A1; cited in OA 05/21/2026), Wang hereafter “Zou” for clarity of the record (WO 2019/173420 A1; cited in OA 05/21/2026).
The teachings of the copending claims regarding claims 1-3 and 10-22 are detailed above.
The copending claims do not teach that the ICM target is CD47 or that the TAA is CLDN18.2.
Regarding claims 6 and 8, Wang teaches that an anti-CD47 antibody can be used to induce macrophage-mediated phagocytosis of cancer cells that express both a TAA and CD47 (para 0031). Wang further teaches an isolated anti-CD47 monoclonal antibody or antigen-binding fragment thereof comprising a humanized heavy chain variable region of an anti-CD47 monoclonal antibody and a humanized light chain variable region of an anti-DLL3 monoclonal antibody, wherein the anti-CD47 monoclonal antibody or antigen-binding fragment thereof comprises: (e) a heavy chain variable region having the polypeptide sequence of SEQ ID NO: 176, and a light chain variable region having the polypeptide sequence of SEQ ID NO: 172 (claim 9). SEQ ID NO: 176 has 100% sequence identity to the instant claimed SEQ ID NO: 1 and SEQ ID NO: 172 has 100% sequence identity to the instant claimed SEQ ID NO: 2.
Regarding claims 7 and 9, Zou teaches that CLDN18.2 is an ideal target for precision-guided, anti-cancer biologics to CLDN18.2-positive tumors, as CLDN18.2 is not expressed in any normal tissue other than the differentiated gastric epithelial cells, which are unreachable by large molecule compounds administrated intravenously (para 0005). Zou further teaches an isolated monoclonal antibody or antigen-binding fragment thereof wherein the antibody or antigen-binding fragment thereof specifically binds claudin 18.2 (CLDN18.2), preferably human CLDN18.2 (claim 1), wherein the isolated humanized antibody or antigen-binding fragment thereof comprises: (k) a heavy chain 4variable region having the polypeptide sequence of SEQ ID NO: 151, and a light chain variable region having the polypeptide sequence of SEQ ID NO: 153 (claim 8). SEQ ID NO: 151 and 153 have 100% sequence identity to the instant claimed SEQ ID NO: 3 and 4 respectively.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application to use CD47 as the ICM as taught by Wang and CLDN18.2 as taught by Zou in the bispecific antibody with engineered charge pair mutations in the constant regions as taught by the copending claims. The ordinary artisan would have been motivated to do so because the engineered charge pairs in the constant region of the bispecific can be applied to any ICM/ TAA targets to improve immunotherapy production, Wang teaches that an anti-CD47 antibody can be used to induce macrophage-mediated phagocytosis of cancer cells and Zou teaches that CLDN18.2 is an ideal target for precision-guided, anti-cancer biologics to CLDN18.2-positive tumors. The ordinary artisan has a reasonable expectation of success use CD47 x CLDN18.2 to produce a bispecific immunotherapy with engineered charge pairs in the constant domain.
Response to Arguments
Applicant's arguments filed 08/18/2026 have been fully considered but they are not persuasive.
Applicant submits: Since this rejection is only provisional at this stage, as none of the allegedly conflicting claims have been patented or allowed, Applicant defers substantively addressing the obviousness type double patenting rejection at this stage of prosecution. However, in the event that the obviousness type double patenting rejection is maintained, Applicant reserves the right to amend or cancel the pending claims, or file a Terminal Disclaimer, once the rejection is no longer provisional or once the rejection is the last remaining rejection.
In Response: The double patenting rejection is maintained.
Applicant should submit an argument under the heading “Remarks” pointing out disagreements with the examiner’s contentions. Applicant must also discuss the references applied against the claims, explaining how the claims avoid the references or distinguish from them.
Conclusion
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 AMBER K FAUST whose telephone number is (703)756-1661. The examiner can normally be reached Monday - Thursday 9:00am-6:00pm EST.
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/AMBER K FAUST/Examiner, Art Unit 1643
/GARY B NICKOL/Primary Examiner, Art Unit 1643
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