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, 3-4, 6, 8, 10, 12, 14, 16, 42, 44-45, 47, 49, and 51 are pending and examined on the merits herein.
Grounds of Rejection Withdrawn
All previous rejections of claims 2, 5, 7, 24-25 are rendered moot by claim cancellation.
Previous rejection of claims 1, 3-4, 6, 8, 10, 12, 14, 16, 42, 44-45, 47, 49, and 51 under U.S.C. 112(a) is withdrawn in view of claim amendments.
Previous rejection of claims 1, 3-4, 6, 8, 10, 12, 14, and 16 under U.S.C. 102 is withdrawn in view of claim amendments.
Previous rejection of claims 42, 44-45, 47, 49, and 51 under U.S.C. 103 is withdrawn in view of claim amendments.
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, 3-4, 6, 8, 10, 12, 14, 16, 45, and 47 are rejected under 35 U.S.C. 103 as being unpatentable over Blein (US 2015/0133640 A1; IDS entered 07/19/2023) and Moore (US 2016/0355600 A1; PTO-892).
Regarding claims 1, 3, 8, and 10, Blein teaches a hetero-dimeric immunoglobulin or fragment thereof, comprising: (a) a first polypeptide that binds to Protein A comprising an epitope binding region that binds a first epitope and an immunoglobulin constant region; and (b) a second polypeptide that does not bind to Protein A comprising an epitope binding region, that binds a second epitope and an immunoglobulin constant region; wherein the epitope binding region of the first polypeptide binds the CD3 protein complex and the epitope binding region of the second polypeptide binds a disease associated antigen (claim 1), the hetero-dimeric immunoglobulin or fragment thereof of claim 1, wherein the epitope binding region of the first polypeptide is a scFv and the epitope binding region of the second polypeptide is a FAB (claim 11). Blein further teaches a hetero-dimeric immunoglobulin or fragment thereof that binds to: ii) the CD3 protein complex and HER2, wherein the first polypeptide has an amino acid sequence of SEQ ID NO: 161 and is assembled with a cognate light chain of amino acid sequence of SEQ ID NO: 3 and binds HER2, and wherein the second polypeptide has an amino acid sequence of SEQ ID NO: 162 and binds CD3 epsilon (claim 12). SEQ ID NO: 161 has 100% sequence identity to the instant claimed SEQ ID NO: 10-12. SEQ ID NO: 3 has 100% sequence identity to the instant claimed SEQ ID NO: 13-15. Blein further teaches that the hetero-dimeric antibodies were produced based on BEAT® technology as described in WO 2012/131555, to generate a CD3-antigen epitope in an scFv-Fab format (para 0184).
Regarding claims 4, 12, 14, and 16 Blein teaches a hetero-dimeric immunoglobulin or fragment thereof that binds to: xii) the CD3 protein complex and CD20, wherein the first polypeptide has an amino acid sequence of SEQ ID NO: 180 and is assembled with a cognate light chain of amino acid sequence of SEQ ID NO: 181 and binds CD20, and wherein the second polypeptide has an amino acid sequence of SEQ ID NO: 177 and binds CD3 epsilon (claim 12). SEQ ID NO: 177 has 100% sequence identity to the instant claimed SEQ ID NOs: 1-9. Blein further teaches the anti-human CD3 epsilon arm of the hetero-dimeric immunoglobulin consisted of a BEAT heavy chain (SEQ ID NO: 177) encompassing a scFv fragment (para 0373).
Regarding claim 6, Blein teaches a hetero-dimeric immunoglobulin or fragment thereof that binds to: x) the CD3 protein complex and CD38, wherein the first polypeptide has an amino acid sequence of SEQ ID NO: 178 and is assembled with a cognate light chain of amino acid sequence of SEQ ID NO: 128 and binds CD38, and wherein the second polypeptide has an amino acid sequence of SEQ ID NO: 179 and binds CD3 epsilon (claim 12). SEQ ID NO: 179 has 100% sequence identity to the instant claimed SEQ ID NO: 24-29.
Blein does not specifically teach that the linker is fused to the C -terminus of the scFv.
Regarding claims 1, 42, and 44, Moore teaches that FIG. 3C depicts a format wherein the scFvs are at the N-terminus of the heavy chain and further that as will be appreciated by those in the art, this covalent linkage can be direct (e.g. no exogenous linker amino acid sequences used), or indirect, using a linker (e.g. a linker at the C-terminus of the scFv sequence) which can be a standard glycine-serine linker (para 0089). Moore further teaches In some embodiments, the linker is a “domain linker”, used to link any two domains as outlined herein together, which utilizes a glycine-serine polymer, (GGGGS)n (SEQ ID NO: 241), where n is an integer of at least one (para 0206). SEQ ID NO: 241 has 100% sequence identity to the instant claimed sequence SEQ ID NO: 18.
Regarding claim 45, as seen in the alignment below, instant SEQ ID NO: 34 is comprised of the CD3 scFv from residues 1-250 of SEQ ID NO: 177 (Blein), identical to instant claimed SEQ ID NO: 9; a linker comprising SEQ ID NO: 141 (Moore) identical to instant claimed SEQ ID NO: 18; and the HER2 Fab from SEQ ID NO: 161 (Blein), identical to the instant claimed SEQ ID NO: 17. SEQ ID NO: 3 (Blein) has 100% sequence identity to the instant claimed SEQ ID NO: 33 (claim 12).
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Regarding claim 47, as seen in the alignment below, instant SEQ ID NO: 35 (Blein) is comprised of the CD3 scFv from residues 1-250 of SEQ ID NO: 177, identical to instant claimed SEQ ID NO: 9; a linker comprising SEQ ID NO: 141 (Moore) identical to instant claimed SEQ ID NO: 18; and the HER2 Fab from SEQ ID NO: 3 (Blein) identical to the instant claimed SEQ ID NO: 17. SEQ ID NO: 5 (Blein) has 100% sequence identity to the instant clamed SEQ ID NO: 36 (claim 12).
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It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application apply a (Gly4Ser)n linker between the scFv-Fab as well as orientation to the N terminus as taught by Moore to the CD3 scFv-HER2 Fab as taught by Blein. The ordinary artisan would have been motivated to do so because Moore teaches the specific orientation of a Fab linked to the C terminus of an scFv and that the ordinary artisan would know that the linkage can be done via a glycine serine linker. The ordinary artisan has a reasonable expectation of success to use a (G4S)n linker and orient the heterodimeric molecule as CD3 scFv-GGGGS- HER2 Fab.
Claims 49 and 51 are rejected under 35 U.S.C. 103 as being unpatentable over Blein (US 2015/0133640 A1; IDS entered 07/19/2023) and Moore (US 2016/0355600 A1; PTO-892) as applied to claims 1, 3-4, 6, 8, 10, 12, 14, 16, 45, and 47 above, and further in view of Kischel (US 2013/0129729 A1; cited in OA 12/23/2025).
The teachings of Blein and Moore regarding claims 1, 3-4, 6, 8, 10, 12, 14, 16, 45, and 47 are detailed above.
Blein and Moore do not teach the HER2 Fab comprising SEQ ID NO: 20-21 or 22-23.
Kischel teaches a bispecific single chain antibody with comprises (i) a first binding domain binding to an epitope of human and non-chimpanzee primate CD3, and (ii) a second binding domain binding to a cell surface antigen (claim 1). Kischel further teaches that SEQ ID NO. 194 corresponds to the amino acid sequence of the anti-CD3 VL-VH scFv comprising the human-like VL (SEQ ID NO. 168) and the human-like VH (SEQ ID NO. 110) (para 0243). Kischel further teaches that only when the safety in animals and possible effectiveness of the drug candidate has been established in preclinical testing will this drug candidate be approved for clinical testing in humans (para 0002).
Regarding claim 49, as seen in the alignment below, instant SEQ ID NO: 21 is comprised of the CD3 scFv from Kischel SEQ ID NO: 194, identical to instant claimed SEQ ID NO: 32; a linker comprising GGGGS identical to instant claimed SEQ ID NO: 18; and the HER2 Fab from Blein SEQ ID NO: 161 residues 1-223, identical to the instant claimed SEQ ID NO: 17. SEQ ID NO: 3 from Blein has 100% sequence identity to the instant clamed SEQ ID NO: 20 (claim 12).
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Regarding claim 51, as seen in the alignment below, instant SEQ ID NO: 22 is comprised of the CD3 scFv from Kischel, SEQ ID NO: 194, identical to instant claimed SEQ ID NO: 32; a linker comprising GGGGS identical to instant claimed SEQ ID NO: 18; and the HER2 Fab from Blein SEQ ID NO: 3, identical to the instant claimed SEQ ID NO: 17. SEQ ID NO: 5 from Blein has 100% sequence identity to the instant clamed SEQ ID NO: 23 (claim 12).
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It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application substitute the CD3 scFv as taught by Kischel into the CD3 scFv-GGGGS-HER2 FAB as taught by Blein and Moore. The ordinary artisan would have been motivated to do so because Kischel teaches a CD3 scFv that binds to both human and non-chimpanzee primate CD3 and further that only when the safety in animals and possible effectiveness of the drug candidate has been established in preclinical testing will this drug candidate be approved for clinical testing in humans. The ordinary artisan has a reasonable expectation of success to substitute the CD3 scFv with cross species binding into the CD3 scFv- GGGGS-HER2 Fab heterodimeric bispecific molecule to facilitate clinical safety and efficacy testing.
Response to Arguments
Applicant's arguments filed 03/23/2026 have been fully considered but they are not persuasive.
Applicant submits: Applicant has amended claim 1 to recite the limitation of claim 24. Amended claim 1 recites, in part, "L comprises a linker that connects A to B, wherein the linker connects the C-terminus of A to the N-terminus of B." (Emphasis added). Applicant notes that former claim 24 was not rejected as being anticipated by Blein as evidenced by Wassman. Accordingly, Applicant submits that amended claim 1 is not anticipated Blein as evidenced by Wassman.
In Response: Although Blein does not explicitly teach that the linker is bound to the c-terminus of the scFv, Blein does teach that the hetero-dimeric antibodies were produced based on BEAT® technology as described in WO 2012/131555, to generate a CD3-antigen epitope in an scFv-Fab format or vice versa and further that these can be connected directly or via a linker. The ordinary artisan would understand that the order of the construct is N terminus to C-terminus.
Further this limitation is explicitly taught by Moore in the new 103 rejection detailed above.
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, 3-4, 8, 10, and 16 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 9-11, 36 and 130 of copending Application No. 18/256,278 in view of Blein (US 2015/0133640 A1; IDS entered 07/19/2023) as evidenced by Blein (hereafter referenced as “Wassman” for clarity of the record; WO 2012/131555 A2; cited in OA 12/23/2025).
Regarding claim 1, the copending claims teach an isolated polypeptide or polypeptide complex comprising an anti-CD3 binding domain to CD3 (claims 9-11).
Regarding claims 3-5, the copending claims teach the isolated polypeptide or polypeptide complex of claim 9, wherein the anti-CD3 binding domain is a single chain variable fragment (scFv) comprising HCDRs comprising SEQ ID NOs: 3-5 and LCDRs comprising SEQ ID NOs: 6-8 (claim 36). SEQ ID NOs: 3-5 have 100% sequence identity to the instant claimed SEQ ID NOs: 1-3. SEQ ID NOs: 6-8 have 100% sequence identity to the instant claimed SEQ ID NOs: 4-6.
Regarding claim 16, the copending claims teach the isolated polypeptide or polypeptide complex of claim 9, wherein the anti-CD3 binding domain comprises the amino acid sequence of SEQ ID NO: 9 (claim 130). SEQ ID NO: 9 has 100% sequence identity to the instant claimed SEQ ID NO: 9.
The copending claims do not teach a bispecific polypeptide targeting HER2 and CD2.
Regarding claims 1-3, 8, and 10, Blein teaches a hetero-dimeric immunoglobulin or fragment thereof, comprising: (a) a first polypeptide that binds to Protein A comprising an epitope binding region that binds a first epitope and an immunoglobulin constant region; and (b) a second polypeptide that does not bind to Protein A comprising an epitope binding region, that binds a second epitope and an immunoglobulin constant region; wherein the epitope binding region of the first polypeptide binds the CD3 protein complex and the epitope binding region of the second polypeptide binds a disease associated antigen (claim 1), the hetero-dimeric immunoglobulin or fragment thereof of claim 1, wherein the epitope binding region of the first polypeptide is a FAB and the epitope binding region of the second polypeptide is a scFv or wherein the epitope binding region of the first polypeptide is a scFv and the epitope binding region of the second polypeptide is a FAB (claim 11). Blein further teaches a hetero-dimeric immunoglobulin or fragment thereof that binds to: ii) the CD3 protein complex and HER2, wherein the first polypeptide has an amino acid sequence of SEQ ID NO: 161 and is assembled with a cognate light chain of amino acid sequence of SEQ ID NO: 3 and binds HER2, and wherein the second polypeptide has an amino acid sequence of SEQ ID NO: 162 and binds CD3 epsilon (claim 12). SEQ ID NO: 161 has 99.6% sequence identity to the instant claimed SEQ ID NO: 17 and 100% sequence identity to the instant claimed SEQ ID NO: 10-12. SEQ ID NO: 3 has 100% sequence identity to the instant claimed SEQ ID NO: 13-16. Blein further teaches that the hetero-dimeric antibodies were produced based on BEAT® technology as described in WO 2012/131555, to generate a CD3-antigen epitope in an scFv-Fab format (para 0184).
Regarding claim 1, as evidenced by Wassman (WO 2012/131555) the heterodimeric immunoglobulin wherein at least one additional polypeptide is fused to the first engineered immunoglobulin and is selected from a Fab or scFv, wherein fusion is achieved by genetic engineering as known to the skilled person and may involve amino acid sequence linkers which do not form part of the amino acid sequences to be fused (page 192, line 31-page 193, line 6). This results in a CD3 scFv-linker-HER2 Fab.
Blein further teaches that T cell redirected killing is a desirable mode of action in therapy mediated by bispecific antibodies and that the human CD3 is the most targeted to redirect T cell killing (para 0002). Blein further teaches bispecific formats that will encompass a human Fc region will have longer circulation half-lives which may result in enhanced efficacy and/or less frequent dosing regimens including Fab (para 0003)
It would have been obvious to one of ordinary skill in the art to add an antigen targeting moiety with a linker as taught by Blein to the CD3 targeting scFv as taught by the copending claims. The ordinary artisan would have been motivated to do so because Blein teaches that T cell redirected killing is a desirable mode of action in therapy mediated by bispecific antibodies and that the human CD3 is the most targeted to redirect T cell killing. Blein further teaches a bispecific polypeptide based of a known cancer target HER2 with a previously developed antibody trastuzumab and CD3. The ordinary artisan has a reasonable expectation of success to use combine CD3 and HER2 to generate the CD3 scFv-linker-HER2 Fab heterodimeric bispecific molecule to improve T cell mediated killing in therapeutic use.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
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.
Applicant submitted no arguments other than patent term filing date in regards to provisional NSDP rejections. As the application is not in condition for allowance at this time the rejection is maintained.
Conclusion
No claims 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.
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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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Julie 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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/AMBER K FAUST/Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643
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