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 .
Applicant’s remarks, filed 5/13/2026, are acknowledged and entered into the record. Applicants amended claims 1, 5, 7, 17 and 21-26, and canceled claims 2, 13 and 16, in the remarks of 5/13/2026.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. The present application is drawn from PCT/US2020/036464, filed 6/5/2020; and claims benefit under 35 U.S.C. 119(e) to U.S. Provisional applications 62/858509, filed 6/7/2019, and 62/858630, filed 6/7/2019.
Election/Restrictions
Applicant’s election without traverse of Group I, encompassing claims 1-23, in the reply filed on 10/24/2025 is acknowledged. Claims 24-25 and 27 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Groups II-IV, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 6/21/2024. Applicant’s election of species, whereby the linker L3 is at least 10 amino acids, whereby the VH1 and VL1 comprise SEQ ID NOs: 44 and 45, respectively, whereby linkers L1, L2 and L3 are different lengths, and whereby L1 and L3 are the same length, is acknowledged.
Applicants amended the claims in the remarks of 5/13/2026. It is noted that applicants canceled the previously elected species of linkers of claim 1, whereby the minimum length of the linkers is “at least 10” amino acids (versus “at least 15” amino acids); and amended the claims to require linkers with “at least 25” amino acids, which are a different species. For the purposes of compact prosecution, the examiner will examiner the amended claims. However the elected species regarding claims 9-10 and 12, and the restriction requirement of 4/25/2025, are maintained. Claims 9-10, 12, 24-25 and 27 are withdrawn.
Status of Claims
Claims 1, 3-12, 14-15 and 17-27 are pending; claims 9-10, 12, 24-25 and 27 are withdrawn; claims 1, 3-8, 11, 14-15, 17-23 and 26 are being examined on the merits.
Claim Objections-Withdrawn
The previous objections to claims 5, 17, 21-22 and 26 are withdrawn in view of applicant’s amendments to the claims to correct the cited informalities.
Claim Rejections – Maintained, amended
The following rejections are maintained from the office action of 11/13/2025, but are amended in view of applicant’s amendments to the claims. Specifically, applicants amended claim 1 to require alternative, further limited, linker species from what was previously claimed, and amended claim 7 to remove species of VH and VL that were previously claimed, and which were cited in the rejections of 11/13/2025.
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, 3-8, 11, 14-15, 17-23 and 26 is/are rejected under 35 U.S.C. 103 as being unpatentable over Ghayur et al., (from IDS of 6/9/2025, FOR Cite No. 1; WO 2014/106015; published 7/3/2014) and Hanzatian et al., (WO 2015/191934; published 12/17/2015) and Amgen (from IDS of 10/6/2023, FOR Cite No. 13; WO 2017/0029502; published 2/2/2017).
Ghayur teaches multivalent binding proteins that specifically bind to one or more target antigens, as well as nucleic acids, vectors and host cells encoding the binding proteins and methods of using the binding proteins (abstract). Ghayur teaches making single-chain dual variable domain immunoglobulin molecules, termed scDVD, which have the general formula of VH1-X1-VH2-X2-VL1-X3-VL2; whereby X1, X2 and X3 are linkers (pg. 12, last paragraph – pg. 13, top). In example 17 (pg. 98), Ghayur teaches the design of an exemplary scDVD molecule, which is schematically depicted in FIG. 4. Ghayur teaches the X2 linker, which links the VH1/VH2 to the VL1/VL2, is a (G4S)n peptide linker of 30, 35, 40 or 45 amino acids in length (pg. 98, para. 1).
However, Ghayur does not teach a scDVD wherein the linker X1 binding the VH1 and VH2, or the linker X3 binding the VL1 and the VL2, are at least 25 amino acids.
Hanzatian et al. teaches scDVD format bispecific antibodies with the format VH1-X1-VH2-X2-VL1-X3-VL2 (pg. 39, para. 0192). Hanzatian teaches the length and sequence of the linkers linking the variable domains may be optimized for each format to achieve desirable properties (pg. 42, para. 0202). Hanzatian teaches the linkers connecting the variable domains may be a G4S repeat, or ASTKGPSVFPLAPASTKGPSVFPLAP of SEQ ID NO: 28, which is 26 amino acids in lenth (pg. 55, para. 0246). For example, Hanzatian claims an scDVD (pg. 120, claim 7), wherein the DVD comprises a VH1-X1-VH2 (pg. 121, claim 8) or a VL1-X1-VL2 (pg. 122, claim 10), whereby the linker X1 of either claim 8 or 10 is SEQ ID NO: 28 (pg. 124, claim 13). Thus, Hanzatian teaches scDVD bispecific antibodies may comprise a 26 amino acid linker (of SEQ ID NO: 28) between the VH1-VH2 domains and the VL1-VL2 domains. Hanzatian also claims the linker may be G4S repeats, although does not specifically define a (G4S)5 sequence.
It would have been obvious to one of skill in the art to substitute the linkers X1 and X3 of the scDVD format VH1-X1-VH2-S2-VL1-X3-VL2 of Ghayur with the linkers X1 and X3, of SEQ ID NO: 28, of Hanzatian, whereby the linker X2 is a (G4S)n peptide linker of 30, 35, 40 or 45 amino acids in length as taught by Ghayur. One would have been motivated to do so in order to optimize the scDVD for desirable properties as taught by Hanzatian et al. There would have been a reasonable expectation for success given that the 26 amino acid linker of Hanzatian is a suitable linker for linking the variable domains (VD) VD1-VD2 of a scDVD as taught by Hanzatian et al. Thus, the invention was prima facie obvious to one of skill in the art at the time the invention was made.
Amgen teaches a bispecific antibody construct comprising a first binding domain which binds to human MSLN on the surface of a target cell and a second binding domain which binds to human CD3 on the surface of a T cell (abstract). Amgen teaches MSLN is over-expressed on cancer cells, such as ovarian, pancreatic, lung and breast cancers (pg. 1, para. 0008). Amgen teaches the anti-CD3 binding domain of I2C, which comprises the VH and VL of SEQ ID NOs: 98-99, respectively (pg. 50); and the anti-MSLN binding domain of MS_4, which comprises the VH and VL of SEQ ID NOs: 187-188, respectively (pg. 57). Amgen also teaches the bispecific molecule of SEQ ID NO: 280, which comprises the MS_4 VH/VL and the I2C VH/VL of SEQ ID NOs: 187-188 and 98-99. Thus, Amgen teaches anti-MSLN/anti-CD3 bispecific antibodies and the VH and VL domains of each of the anti-MSLN and anti-CD3 binding domains.
The anti-MSLN “MS_4” VH and VL of Amgen SEQ ID NOs: 187-188 are 100% identical to that of instant SEQ ID NOs: 48-49, respectively. The anti-CD3 “I2C” VH and VL of Amgen SEQ ID NOs: 98-99 are 100% identical to instant SEQ ID NOs: 50-51, respectively.
It would have been obvious to one of skill in the art to modify the TNF/SOST scDVD binding protein format of Ghayur to instead comprise the MSLN/CD3 variable domains of Amgen et al. One would have been motivated to do so given that each combination results in a bispecific binding protein that targets an immune effector cell and a target cell for the purpose of treating cancer; and that scDVD format, VH1-X1-VH2-X2-VL1-X3-VL2, provides an improved multispecific binding protein format, as taught by Ghayur et al. There would have been a reasonable expectation of success given that various corresponding VH/VL domains may be used in the scDVD format, and that the linkers, specifically the longer X2 linker, are what imparts the ability of the corresponding VH1/VL1 and VH2/VL2 pairs to form their functional binding domains at the level of the target antigen, as taught by Ghayur et al. Ghayur demonstrates the success of the scDVD format with 2 separate embodiments, one a TNF/SOST bispecific molecule, the other a DLL4/VEGF bispecific molecule, thus providing a reasonable expectation for success of scDVD formats when incorporating VH/VL domains with distinct target specificity. Thus, the invention was prima facie obvious to one of skill in the art at the time the invention was made.
Thus, the combination of Ghayur, Hanzatian and Amgen teach a bispecific scDVD construct comprising the anti-MSLN VH and VL of instant SEQ ID NOs: 48-49, respectively, and the anti-CD3 VH and VL of instant SEQ ID NOs: 50-51, respectively; whereby the format of the scDVD is VH1-X1-VH2-X2-VL1-X3-VL2, the X1 and X3 linkers are the 26 amino acid long linker of SEQ ID NO: 28 of Hanztian et al., and the X2 linker is the longer (G4S)n peptide linker of 30, 35, 40 or 45 amino acids in length of Ghayur et al.
Regarding claim 1, 6-8, 11, 14-15 and 17; the combination scDVD is bispecific anti-MSLN/anti-CD3 construct, targeting the CD3 epsilon chain of a T cell and the MSLN expressed on a cancer cell, whereby the linkers X1-X3 are all at least 25 amino acids in length, and therefore makes obvious instant claim 1; and wherein the VH1, VL1, VH2 and VL2 are identical to instant SEQ ID NOs: 49-51, respectively, and thus makes obvious instant claims 6-7. Further, the linkers X1-X3 (i.e., L1-L3) are different lengths but X1 and X3 are the same length (for example X1=26 aa, X2=30 aa, X3=26 aa), and therefore makes obvious instant claims 8 and 11. As the scDVD format of Ghayur, Hanzatian and Amgen makes obvious the format of the instant binding constructs of claim 1, it necessarily possesses the inherent properties of instant claims 14-15 and 17.
Regarding claims 18-21 and 26; Ghayur teaches polynucleotides encoding the binding protein, expression vectors comprising the polynucleotides, host cells expressing the binding protein, and methods of manufacturing the binding protein (pg. 211, claims 37-40; see also pg. 49, section IV). Therefore, the combination of Ghayur, Hanzatian and Amgen makes obvious instant claims 18-21. Ghayur also teaches pharmaceutical compositions comprising the binding protein (pg. 211, claim 35; see also pg. 58, section VI); thus the combination of Ghayur, Hanzatian and Amgen makes obvious instant claim 26.
Regarding claims 22-23; Amgen teaches methods of treatment comprising administering the bispecific anti-MSLN/anti-CD3 construct binding protein, whereby the antibody can be used for treating various types of cancers (pg. 72, claims 20-21). Thus, the combination of Ghayur, Hanzatian and Amgen make obvious instant claim 22. Further, Ghayur teaches combination therapy (pg. 60, section VII), whereby the binding protein is administered with one or more additional therapeutic agents including antineoplastic agents or radiotherapy (pg. 60, para. 3). Thus, the combination of Ghayur, Hanzatian and Amgen make obvious instant claim 23.
Regarding claims 3-5. Amgen teaches examples for means to extend serum half-life include fusion of the constant regions of immunoglobulins (i.e. Fc domains); whereby such variants of Fc domains may be optimized or modified in order to abolish Fc receptor binding (pg. 15, para. 0177). Amgen teaches a “mono Fc” polypeptide of SEQ ID NO: 150 (pg. 56) as well as the scFc-1 dual Fc monomer construct of SEQ ID NO: 260 (pg. 61). Specifically, Amgen teaches the anti-MSLN/anti-CD3 bispecific construct of SEQ ID NO: 280, which comprises a G4 linker at the C-terminal end followed by the scFc-1 sequence of SEQ ID NO: 260. For example, this is identical to the scFc of the anti-MSLN/anti-CD3 construct of instant SEQ ID NO: 31 (specs, pg. 66, para. 00234). As described above, Amgen SEQ ID NO: 280 also comprises identical anti-MSLN and anti-CD3 VHs and VLs to instant SEQ ID NOs: 48-51. Thus, the anti-MSLN/anti-CD3 construct of Amgen SEQ ID NO: 280 comprises the anti-MSLN VH/VL of instant SEQ ID NOs: 48-49, the anti-CD3 VH/VL of instant SEQ ID NOs: 50-51, a G4 linker and the scFc-1, with 100% identity to the anti-MSLN/anti-CD3 construct of instant SEQ ID NO: 31; with the difference being the construct is re-formatted from a VH1-X1-VL1-X2-VH2-X3-VL2-X4-scFc (i.e. HLHL format) to a scDVD having the format VH1-X1-VH2-X2-VL1-X3-VL2-X4-scFc (i.e. HHLL format). Thus, the anti-MSLN/anti-CD3 constructs of Amgen, in the format of Ghayur, with the linkers of Hanzatian, and the scFcs of Amgen make obvious instant claims 3-4.
Amgen also teaches an alternative mono Fc polypeptide of SEQ ID NO: 149. The polypeptide of SEQ ID NO: 149 is identical to the mono Fc of SEQ ID NO: 150, except that it includes the hinge region (i.e. residues 216-230 of instant SEQ ID NO: 36, specs., pg. 19-20, para. 0076), and it has 3 residue substitutions, including LALA mutations at residues 234-235 (residues according to the full IgG1; corresponding to residues 4-5 of SEQ ID NO: 150). This modification is consistent with the modifications taught in the instant specifications, (see pg. 22, para. 0082, L234A/L235A). Therefore, Amgen teaches a mono Fc polypeptide, with LALA mutations, which may be attached to the bispecific molecule for the purposes of extending half-life; and thus the combination of Ghayur, Hanzatian and Amgen make obvious instant claim 5.
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.
Claims 1, 3-8, 11, 14-15, 17-23 and 26 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 8-13, 16-21 and 24-31 of copending Application No. 17/616,575 in view of Ghayur et al., (from IDS of 6/9/2025, FOR Cite No. 1; WO 2014/106015; published 7/3/2014) and Biontech (US 2016/0272711; published 9/22/2016).
Application ‘575 claims a bispecific construct with the format of VH1-L1-VH2-L2-VL1-L3-VL2, with linkers L1, L2 and L3, whereby L1 is 10 aa, L2 is at least 15 aa, and L3 is at least 10 aa, wherein L1 or L3 comprises a protease cleavage site (claim 1), or wherein the protein also comprises a scFc subdomain (claim 2), wherein L1 and L3 each comprise a protease cleavage site (claim 3), whereby the protein further comprises a half-life extending moiety (claim 8), which is a single chain Fc (scFc) from IgG1, and an additional linker (claim 9), whereby the additional linker comprises a cleavage site (claim 10), wherein the scFc polypeptide comprises an alteration (claim 11), whereby the VH1, VH2, VL1 and VL2 have different sequences (claim 12), whereby the linkers are of different length (claim 17), wherein the L1 and L3 linkers are the same length (claim 20), whereby the effector cell expresses a protein that is part of a TCR (claim 23), wherein the protein is CD3ε (claim 24), including nucleic acids, vectors and host cells (claims 25-27), as well as a method for manufacturing the protein (claim 28) and a method for treating cancer (claim 29), including an additional chemotherapeutic agent (claim 30); as well as a pharmaceutical composition comprising the protein (claim 31). Application ‘575 dependent claims 16, 18-19 and 21 also encompass the limitations cited above, and thus also read on the instant claims.
Further, application ‘575 claims wherein the VH1 and VL1 are that of SEQ ID NOs: 65-66, respectively; and the VH2 and VL2 are that of SEQ ID NOs: 75-76, respectively (claim 13). App ‘575 SEQ ID NOs: 65-66 are 100% identical to the anti-CD3 VH and VL of instant SEQ ID NOs: 50-51, respectively; and app ‘575 SEQ ID NOs: 75-76 are 100% identical to the anti-MSLN VH and VL of instant SEQ ID NOs: 48-49, respectively. Thus, app ‘575 claims an anti-MSLN/anti-CD3 scDVD which is the same as the instant claims. The difference is that app ‘575 claims shorter linkers with a protease cleavage site.
Ghayur et al. teaches bispecific scDVD molecules as described above. Ghayur teaches the linker connecting the VH1-VH2 domain to the VL1-VL2 domain (i.e. X2) should be longer, and teaches wherein the linker X2 is a (G4S)n peptide linker of 30, 35, 40 or 45 residue length. Ghayur also teaches whereby the linkers between the VH1-VH2 (i.e. X1) or the VL1-VL2 (i.e. X3) can be (G4S)n where N= 1-3 (see Fig. 5). However, Gayur does not teach wherein the linkers are (G4S)5, thus comprising at least 25 amino acid residues.
Biontech teaches a bispecific binding domain which binds CD3 on T cells and a second domain which binds a tumor associated claudin molecule, for use in treating cancers (abstract). Biontech teaches the bispecific is in the VH1-X1-VL1-X2-VH2-X3-VL2 format (i.e. HLHL), see Fig. 1. Biontech teaches that the linkers X1 and X3 may be 20 or 25 amino acids and preferably are connected via a peptide linker comprising the amino acid sequence (GGGGS)5 (pg. 3, para. 0025).
It would have been obvious to one of skill in the art to substitute the linkers of the bispecific construct of app ‘575 with those of Ghayur and Biontech. One would have been motivated to do so in order to optimize the scDVD for desirable properties. There would have been a reasonable expectation for success given that the 30, 35, 40 or 45 residue length X2 linker is preferred for scDVD molecules, as taught by Ghayur; and that (G4S)5 linkers, totaling 25 amino acid residues, are suitable for the X1 and X3 linkers, for linking tandem variable domains in single chain molecules such as scFvs, as taught by Biontech. Thus, the invention was prima facie obvious to one of skill in the art at the time the invention was made.
Thus, the combination of app ‘575, comprising the anti-MSLN/anti-CD3 binding domains in a scDVD format, with the 30 aa linker X2 of Ghayur and the 25 aa linkers X1 and X3 of Biontech, make obvious the construct of instant claims 1 and 7 and the inherent properties of instant claims 14-15. App ‘575 claims 8-11 make obvious instant claims 3-5; app ‘575 claim 12 makes obvious instant claim 6; app ‘575 claims 17 and 20 make obvious instant claims 8 and 11; app ‘575 claims 23-24 make obvious instant claims 17; app ‘575 claims 25-28 make obvious instant claims 18-21; and app ‘575 claims 29-31 make obvious instant claims 22-23 and 26.
This is a provisional nonstatutory double patenting rejection.
Claims 1, 3-8, 11, 14-15, 17-23 and 26 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 2, 4-6, 8, 11, 14-17, 21-23 and 26 of copending Application No. 18/038,886 in view of Ghayur et al., (from IDS of 6/9/2025, FOR Cite No. 1; WO 2014/106015; published 7/3/2014) and Biontech (US 2016/0272711; published 9/22/2016) and Raum et al., (US Patent 10294300; issued 5/21/2019).
Application ‘886 claims a molecule having the structure VH1-L1-VH2-L2-VL1-L3-VL2-L4-Half-Life Extending moiety-L5-VH3-L1-VH4-L2-VL3-L3-VL4; wherein each linker (L1-L3) are at least 10 amino acids and total at least 35 amino acids, and wherein the half-life extending moiety is a single chain Fc (scFc) region (claim 2); wherein the half-life moiety is an scFc from IgG1 (claim 4); wherein the scFc comprises alterations that inhibit Fcγ binding (claim 5); wherein the VH1, VH2, VL1 and VL2 all have different sequences (claim 6); wherein the L1, L2 and L3 are different lengths (claim 8); wherein the L1 and L3 are the same length (claim 11); whereby the molecule exhibits enhanced stability (claim 14), and exhibits enhanced in vitro expression (claim 15); whereby the effector cell expresses a TCR (claim 16); wherein the effector cell protein is CD3ε (claim 17). App ‘886 also claims a method of manufacturing comprising nucleic acids encoding the molecule in a host cell expressing the molecule (claim 21), a method of treating a cancer patient (claim 22); whereby an additional chemotherapeutic agent is administered (claim 23); and a pharmaceutical composition comprising the molecule (claim 26).
While the construct of app ‘886 includes additional variable domain moieties beyond what is required in the instant claims, it nonetheless comprises the VH1-L1-VH2-L2-VL1-L3-VL2 format of the instant bispecific binding construct; it comprises the format twice in the same construct (with or without a half-life extending moiety).
However, app ‘886 does not claim wherein the linkers are each at least 25 amino acid residues in length.
Ghayur et al. teaches bispecific scDVD molecules as described above. Ghayur teaches the linker connecting the VH1-VH2 domain to the VL1-VL2 domain (i.e. X2) should be longer, and teaches wherein the linker X2 is a (G4S)n peptide linker of 30, 35, 40 or 45 residue length. Ghayur also teaches whereby the linkers between the VH1-VH2 (i.e. X1) or the VL1-VL2 (i.e. X3) can be (G4S)n where N= 1-3 (see Fig. 5). However, Gayur does not teach wherein the linkers are (G4S)5, thus comprising at least 25 amino acid residues.
Biontech teaches a bispecific binding domain which binds CD3 on T cells and a second domain which binds a tumor associated claudin molecule, for use in treating cancers (abstract). Biontech teaches the bispecific is in the VH1-X1-VL1-X2-VH2-X3-VL2 format (i.e. HLHL), see Fig. 1. Biontech teaches that the linkers X1 and X3 may be 20 or 25 amino acids and preferably are connected via a peptide linker comprising the amino acid sequence (GGGGS)5 (pg. 3, para. 0025).
It would have been obvious to one of skill in the art to substitute the linkers of the bispecific construct of app ‘886 with those of Ghayur and Biontech. One would have been motivated to do so in order to optimize the scDVD for desirable properties. There would have been a reasonable expectation for success given that the 30, 35, 40 or 45 residue length X2 linker is preferred for scDVD molecules, as taught by Ghayur; and that (G4S)5 linkers, totaling 25 amino acid residues, are suitable for the X1 and X3 linkers, for linking tandem variable domains in single chain molecules such as scFvs, as taught by Biontech. Thus, the invention was prima facie obvious to one of skill in the art at the time the invention was made.
Thus, the combination of app ‘886, comprising the 30 aa linker X2 of Ghayur and the 25 aa linkers X1 and X3 of Biontech, make obvious the format of the binding construct of instant claim 1; however, the combination does not teach wherein the binding domains are CD3 and MSLN or DLL3.
Raum et al. teaches bispecific binding proteins with the (scFv)2 format, as described above. Raum teaches one such format is SEQ ID NO: 438, which is a DLL3/CD3 bispecific binding construct. SEQ ID NO: 438 of Raum comprises the DLL3 VH and VL domains of instant SEQ ID NOs: 44-45, respectively, and also comprises the CD3 VH and VL domains of instant SEQ ID NOs: 50-51, respectively, with 100% sequence identity, as described above.
It would have been obvious to one of skill in the art to utilize the DLL3 VH1 and VL1, and the CD3 VH2 and VL2, of Raum et al., in the binding construct format of app ‘886. One would be motivated to do so in order to target the binding construct to CD3 on an immune effector cell and to DLL3 on a target cell, as taught by Raum et al. There would have been a reasonable expectation for success given that the linkers, L1-L3, and specifically the long L2 linker, allows the corresponding VH1/VL1 and VH2/VL2 domains to form a functional binding domain at the level of the target antigen, and that variable domains, with different target specificities, are substitutable in a bispecific construct with the VH1-L1-VH2-L2-VL1-L3-VL2 format. Thus, the invention was prima facie obvious to one of skill in the art at the time the invention was made.
As such, the VH1, VL1, VH2, VL2 binding domains of Raum, in the format of the bispecific binding protein of app ‘886 claim 1, and comprising the linkers of Ghayur and Biontech, makes obvious instant claims 1 and 7. Further, the combination of Raum, Ghayur and Biontech and app ‘886 claims 2 and 4-6 make obvious instant claims 1 and 3-6; app ‘886 claims 8, 11 and 14-15 make obvious instant claims 8, 11 and 14-15; app ‘886 claims 16-17 make obvious instant claim 17; the method of manufacturing of app ‘886 claim 21 make obvious the nucleic acids and the methods of instant claims 18 and 21; the methods of treating cancer of app ‘886 claims 22-23 make obvious the methods of instant claims 22-23; and app ‘886 claim 26 make obvious instant claim 26. Ghayur teaches polynucleotides encoding the binding protein, expression vectors comprising the polynucleotides, host cells expressing the binding protein, and methods of manufacturing the binding protein (pg. 211, claims 37-40). Thus, the combination of app ‘886, Ghayur, Biontech and Raum make obvious instant claims 19-20.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
Applicant's arguments filed 5/13/2026 have been fully considered but they are not persuasive. Applicants contend that amended the claims to require each linker to be at least 25 amino acids in length obviates the reference of Ghayur, as Ghayur doesn’t teach each linker being 25 residues long (remarks, pg. 7, top). Applicants contend that Raum also fails to overcome the deficiencies of Ghayur because Raum doesn’t teach the requisite linkers and Raum doesn’t teach the scDVD format, which has improved properties (remarks, pg. 8). Applicants recite that the HHLL format has improved properties compared to a HLHL format (pg. 9), thus the rejection for obviousness over Ghayur and Raum should be withdrawn (pg. 9). Applicants contend that the lack of teaching the 25 residue length linkers also obviates the rejections for double patenting (pg. 10).
In response the examiner states that the length of the linkers was changed in the amended claims, and therefore required the amended rejections above. Examiner highlights that Amgen teaches an anti-MSLN/anti-CD3 bispecific construct, including a scFc (Amgen SEQ ID NO: 280) which incorporates each component of the instant claims. The difference is that the construct of Amgen is in the HLHL format, whereas that of the instant claims is in the HHLL format. Nonetheless, Ghayur teaches sdDVDs, which are the HHLL format; thus the HHLL format is not novel over the prior art. Ghayur teaches that the X2 linker should be a long linker for sdDVD formats, and thus proposes linkers > 30 residues for the X2 linker. Regarding the X1 and X3 linkers, Ghayur teaches that (G4S) repeats may be used. Alternatively, Ghayur teaches linkers derived from the first residues of a CH1 region, which may also be N=2, such that they are over 25 amino acids in length. Likewise Hanzatian teaches X1 and X3 linkers over 25 amino acids in length. Further, Biontech teaches scFvs can have X1 and X3 linkers of 25 amino acids. Thus, Hanzatian and Biontech teach the art that single chain molecules can have X1 and X3 linkers that are longer. Ghayur teaches the necessary long X2 linker in scDVD formats. Thus, reformatting the construct of Amgen to a scDVD format does not present novelty over the art. The data applicants rely on for improved properties is a comparison of a HHLL construct versus an HLHL construct. However, Ghayur already teaches HHLL constructs were known. Thus, if applicants contend that the length of the linkers (i.e. each at least 25 residues) is critical for imparting an advantageous property to the construct, the comparison should be between scDVDs with linkers of different lengths, and not an scDVD format versus a bispecific scFV or BiTE format, as the scDVD format is not novel. The examiner maintains that the combination of Ghayur, Hanzatian and Biontech make obvious the binding domains of Amgen and/or Raum in scDVD formats. Thus, the rejections are maintained.
Conclusion
No claims are allowed.
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.
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/JAMES RYLAND MELCHIOR/Examiner, Art Unit 1644
/NELSON B MOSELEY II/Primary Examiner, Art Unit 1642
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