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 4/15/2026, are acknowledged and entered into the record. Applicants amended claims 1, 4-6, 8, 16-17 and 22, and added new claims 24-27, in the remarks of 4/15/2026.
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 a continuation of PCT/US2024/045722, filed 9/6/2024; and claims benefit under 35 U.S.C. 119(e) to U.S. Provisional application 63/536921, filed 9/6/2023.
Election/Restrictions
Applicant's election with traverse of Group I, encompassing claims 1-17 and 22, in the reply filed on 9/26/2025 is acknowledged. Examiner’s response to the traversal of 9/26/2025 is recited in the office action of 10/16/2025. In the remarks of 4/15/2026, applicants contend that because no prior art rejection under 35 U.S.C. 102 or 103 has been raised, the USPTO has established novelty and non-obviousness of the elected product claims, and therefore a rejoinder is requested pursuant to MPEP 821.04(b) and In re Ochiai 71 F.3d 1565 (Fed. Cir. 1995) because a process that employes a novel and non-obvious product must itself be novel and non-obvious (remarks, pg. 7, Election Restriction).
In response the examiner directs applicants to the requirement for restriction of 7/29/2005; section 8. Section 8 states “where applicant elects claims directed to the product and all product claims are subsequently found allowable, withdrawn process claims that include all the limitations of the allowable product claims should be considered for rejoinder.” In the instant case, the product claims are not deemed allowable. Thus the method claims do not include all the limitations of an allowable product. Therefore the restriction is maintained. Applicants are advised that if the product claims are ultimately deemed allowable, the withdrawn method claims will be eligible for rejoinder.
The requirement is still deemed proper and is therefore made FINAL. Claims 18 and 23, drawn to methods of treating cancer classified in A61K 39/00, are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Group II , there being no allowable generic or linking claim. Applicant’s election of the species of TSB being for EGFR and the ICB being for CD3, in the remarks of 9/26/2025 is acknowledged. Claim 15 is withdrawn as being directed to a non-elected species.
Status of Claims
Claims 1-18 and 22-27 are pending, claims 15, 18 and 23 are withdrawn, claims 1-14, 16-17, 22 and 24-27 are being examined on the merits.
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
This application contains sequence disclosures in accordance with the definitions for nucleotide and/or amino acid sequences set forth in 37 CFR 1.831(a) and 1.831(b). However, this application fails to comply with the requirements of 37 CFR 1.831-1.834.
The examiner has noted that amended claim 1 recites SEQ ID NO: 299. There is no SEQ ID NO: 299 recited in the specifications and no corresponding SEQ ID NO: 299 in the Sequence Listing. In the case that the recitation of “SEQ ID NO: 299” is a typographical error, applicants may amend claim 1 to remove recitation of “SEQ ID NO: 299”. In the case that “SEQ ID NO: 299” is an intended species of NBD of claim 1, Applicant must provide:
• A replacement “Sequence Listing XML” part of the disclosure, as described above in item 1. or 2., as well as
• A statement that identifies the location of all additions, deletions, or replacements of sequence information in the “Sequence Listing XML” as required by 1.835(b)(3);
• A statement that indicates support for the amendment in the application, as filed, as required by 37 CFR 1.835(b)(4);
• A statement that the “Sequence Listing XML” includes no new matter in accordance with 1.835(b)(5); and
• A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required incorporation by reference paragraph as required by 37 CFR 1.835(b)(2), consisting of:
o A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
o A copy of the amended specification without markings (clean version); and a statement that the substitute specification contains no new matter.
Claim Rejections – Withdrawn
Claim Rejections - 35 USC § 112
The rejection of claims 6, 17 and 22 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention, is withdrawn. Specifically, applicants amended the claims to remove reference to the trademark NANOBODY™ in claim 6, as well as removing the phrases “free of detectable pyrogens” and “an acceptable limit” from claims 17 and 22. Thus, obviating the indefiniteness issues.
Claim Rejections – New, necessitated by amendment
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
Claims 25-27 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claim 25, the phrase "such as" (or “e.g.”) renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d). Claims 26 and 27 depend from claim 25, but fail to rectify the issue of indefiniteness, thus claims 26-27 are also rejected. Further, claims 26-27 recite a stabilizing disulfide bond formed between a cysteine in the NBD amino acid sequence at position C735 or C662 and a cystine substitute at position R712 or Q580 (claim 26), or whereby the cysteines are substituted at positions L495 and E573 (claim 27). It is unclear what residues these positions are referring to. Claim 25 recites wherein the TAP1 NBD sequence may be that of any of SEQ ID NOs: 9, 12-14 or 291-294. However, none of the recited polypeptides are more than 300 residues in total length. Thus, in order for the skilled artisan to identify which amino acid residues correspond to the recited positions for a cysteine substitution, a specific NBD amino acid sequence must be claimed whereby the site of residue substitution may be mapped accordingly. Without proper reference to a polypeptide sequence comprising the recited residues, claims 26-27 are rendered indefinite.
Claim Rejections – Maintained, amended
Applicants amended the claims to add new limitations. Therefore the rejections of 10/16/2025 are maintained but amended to account for the new limitations of the amended claims.
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, 8 and 25 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 6-7, 10-12 and 14 of U.S. Patent No. 12,180,297; issued 12/31/2024 in view of Wu, (US 2019/0177439; published 6/13/2019).
Instant claim 1 is drawn to a construct comprising a first HC constant region polypeptide sequence, which comprises a NBD joined by a linker, and a second HC constant polypeptide sequence, whereby the first and second HC constant polypeptides form an IgFc. Under the broadest reasonable interpretation, claim 1 encompasses an antibody Fc with an NBD joined, directly or indirectly via a linker, to the N-terminus or the C-terminus of one HC constant domain of the antibody. See instant Fig. 1B, left, whereby the NBD is linked to the C-terminal of an antibody HC Fc domain, or Fig 1C, whereby the NBD is linked to the N-terminal of an antibody HC Fc domain.
US Patent ‘297 claims a polypeptide construct comprising a NBD and a tumor specific binder (TSB), wherein the NBD comprises an ATP binding site and can dimerize with a cognate non-identical NBD sequence in the presence of ATP, and the TSB comprises a sequence of an antibody or antigen binding fragment thereof, and has affinity for a tumor associated antigen (TAA) expressed on the surface of a tumor cell (claim 1). US ‘297 also claims wherein the polypeptide construct comprises a scaffold sequence (claim 2), and a composition comprising the first polypeptide construct (claim 3); and whereby the first polypeptide sequence, in the composition, comprises a TSB which is an anti-EGFR antibody (claim 5); whereby the scaffold comprises an immunoglobulin sequence (claim 6), whereby the scaffold is an IgFc sequence (claim 7), whereby the NBD comprises a TAP1 amino acid sequence of SEQ ID NOs: 10 or 88 (claims 10-12). US ‘297 also claims the polypeptide construct as a monomer or dimer, and whereby the construct also comprises an immune cell engager (ICE) domain having affinity for CD3 (claim 14).
The NBD of ‘297 SEQ ID NOs: 10 and 88 are 100% identical to the NBD of instant SEQ ID NOs: 16 and 294, respectively, wherein the X688 residue is N; and thereby possess the inherent properties of binding ATP and dimerizing around ATP of the NBD of the first polypeptide of the composition of US ‘297.
Therefore, US ‘297 claims a first polypeptide construct that may comprise an NBD, a scaffold, a TSB and an ICE domain (claims 1 and 14). In an embodiment the TSB is a full length anti-EGFR antibody, with the NBD linked to a heavy chain N- or C-terminal of the anti-EGFR antibody. Such an embodiment comprises a first polypeptide encoding a first HC Fc scaffold domain and a second polypeptide encoding a second HC Fc scaffold domain, and whereby the first and second Ig HC constant regions form an IgFc (e.g., of the full length anti-EGFR antibody).
However, US ‘297 does not claim whereby the polypeptide comprises one or more payloads, which may be a radiolabel, optical label or magnetic label.
Wu teaches asymmetric tandem Fab bispecific antibodies, which can bind two epitopes or two antigens (abstract). Wu teaches the asymmetric binders comprises an IgG CH2 and CH3 domain, whereby the CH3 domains have KiH mutations to promote heterodimerization between the CH3 domains of heavy chains from two different antibodies (pg. 1, para. 0006; pg. 12, para. 0115; see Fig. 1A). Wu teaches the MAT-Fab bispecific constructs may be conjugated to another compound, for example, within or at the C-terminus of either or both of the paired CH3m1 and CH3m2 domains; whereby the conjugated compound is a cytotoxic agent, an imaging agent or a therapeutic agent, and wherein the imaging agent is a radiolabel, such as 3H (pg. 5, para. 0052). See also, pg. 34, claims 1-2, 9 and 33-35. Specifically, Wu states “primarily owing to the presence of a dimerized Fc regions, a MAT-Fab bispecific antibody of the invention can be conjugated to any of a variety of agents that are currently conjugated to IgG antibodies”; and includes imagining agents, which may be attached with or without a linker to the CH3 domain (pg. 15, para. 0151). Thus, Wu teaches the art that attaching a radiolabel to an antibody-like construct, such as IgG Fc domain scaffolds comprising a KiH mutations to promote heterodimerization, whereby the radiolabel is conjugated to the CH3 domain, is common knowledge in the art.
It would have been obvious to one of skill in the art to add a radiolabel payload to the polypeptide construct comprising an IgFc scaffold domain of US ‘297. One would have been motivated to do so in order to improve the properties of the construct, including its use for therapeutic and/or diagnostic purposes. There would have been a reasonable expectation for success given that attaching a payload to the CH3 domain of an IgG Fc polypeptide is common knowledge in the art, as taught by Wu. Thus, the addition of a radiolabel payload was prima facie obvious to one of skill in the art at the time the invention was made.
US ‘297 claims polypeptide construct comprising one or more ATP-binding NBD sequences and a first and second IgG heavy chain Fc domain as scaffold domains, and Wu teaches it is obvious to add a radiolabel to the Fc CH3 domain. Therefore, US ‘297 claims 1-3, 6-7 and 10-12, in view of Wu, make obvious instant claims 1 (wherein the NBD is SEQ ID NO: 16) and 25 (wherein the NBD is SEQ ID NO: 294), and US ‘297 claims 1-3, 6-7, 10-12 and 14, in view of Wu, make obvious instant claim 8 (further comprising an ICB).
Claims 1-14, 16-17, 22 and 24-25 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 6-7, 10-12 and 14 of U.S. Patent No. 12,180,297 in view of Wu, (US 2019/0177439; published 6/13/2019) and Kontermann et al., (US 2022/0396635; published 12/15/2022).
The reasons why the combination polypeptides of US Patent ‘297 and Wu make obvious that of instant claims 1, 8 and 25 are described above. Briefly, US ‘297 claims a first polypeptide that may have an NBD amino acid sequence, a TSB domain, and a ICE domain, and whereby the TSB domain may be a full anti-TAA antibody comprising an Ig Fc domain as a scaffold, whereby the Fc domain is a functional Fc domain. For example, an anti-EGFR antibody with a NBD sequence linked to the C-terminal of one Fc domain anticipates the construct of instant claim 1 (see instant Fig. 1B, left). Wu teaches it is known in the art that a radiolabel can be conjugated to an Fc CH3 domain of antibody-like constructs comprising an IgG Fc domain. However, US ‘297 does not claim whereby the scaffold comprises an KiH sequence pair, or whereby the polypeptide comprises a therapeutic payload or label (i.e., claims 2, 4, 10-11, and dependents thereof).
Kontermann et al teaches trivalent binding molecules comprising a first polypeptide comprising two binding domains and a second polypeptide comprising a third binding domain (abstract). Kontermann teaches one binding domain is targeted to a tumor associated antigen, such as HER2, HER3 or EGFR (pg. 3, para. 0026), and the other binding domain targets the trigger molecule of the immune effector cell, for example, CD3 (pg. 2, para. 0025). Konetermann teaches that the binding molecules may also comprise one or more molecules that aid in purification, preferably a hexahistidyl-tag or FLAG-tag, and one or more co-stimulatory molecules, (pg. 3, paras. 0029-0030), including 4-1BBL (pg. 18, para. 0121), or one or more checkpoint inhibitors, including PD-L1 (pg. 18, para. 0121). Kontermann teaches the construct has heterodimerizing Fc, which includes “knob-into-hole” technology (pg. 15, para. 0092). Kontermann teaches the binding domains may be single-chain diabodies (scDb), which are 4 variable domains of two antibodies connected by 3 linkers, which can be employed for T-cell retargeting to tumor cells but also cells of the tumor microenvironment (pg. 18, para. 0122). Kontermann teaches one embodiment is a trivalent, bispecific anti-HER3 x anti-CD3 antibody (termed a scDb/scFv-Fc; Fig. 6), comprising a scDb molecule bispecific for HER3 (3-43) and CD3 (huU3, humanized version of UCHT1), and further comprising a scFv (or Fab) fragment specific for HER3 or CD3, and which utilized a heterodimerizing Fc part with knob-in-hole technology, of Fig. 6 (pg. 23, Example 5, para. 0205). Figure 6B displays the alternative formats of the two polypeptides of the construct; whereby one polypeptide comprises an Fc (hole) and the other polypeptide comprise an Fc (knob), such that the two polypeptides heterodimerize. The polypeptide with the Fc(hole) comprises a scDb with bispecific affinity for HER3 and CD3, while the polypeptide with the Fc(knob) comprises a N-terminal scFv directed at HER3. Kontermann teaches a similar embodiment which is an anti-EGFR x CD3 construct, whereby the EGFR-targeting antibody is centuximab, and follows the same format of the anti-HER3 x CD3 scDb/scFv-Fc construct; such that it comprises a scDb with binding affinity for EGFR and CD3 on one polypeptide with the Fc(hole), and an anti-EFGR scFv on the second polypeptide with the Fc(knob) mutation (pg. 24, Example 9, para. 0209). Kontermann teaches alternative formats including a trivalent, bispecific Fc fusion protein targeting EGFR, whereby the scDb may be monospecific for EGFR and the scFv (or Fab) for CD3 binding may be alternatively positioned as the scFv of the second polypeptide with the Fc(knob) mutation; with reference to Fig. 6 for an overview of formats (pg. 27, Example 11, para. 0217).
It would have been obvious to one of skill in the art to utilize the anti-EGFR/anti-CD3 construct of Kontermann as the TSB antibody domain of the first polypeptide construct of US ‘297. One would have been motivated to do so given that the anti-EGFR/anti-CD3 antibody targets the tumor associated antigen EGFR for the purpose of targeting the construct to the tumor or tumor microenvironment, as taught by Kontermann, where the NBD would bind (and dimerize around) the excessive ATP in the tumor microenvironment, as taught by US ‘297. There would have been a reasonable expectation for success given that US ‘297 teaches that the polypeptide comprising the NBD may also comprise the TSB amino acid sequence of an EGFR antibody, and that Kontermann teaches the anti-EGFR/anti-CD3 antibody construct successfully targets EGFR-expressing tumor cells. Thus, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made.
The combination construct of US ‘297, Wu and Kontermann would comprise a first polypeptide comprising a Fc (knob) and one or more of the NBD of US ‘297 linked, directly or via a linker, to the C-terminal and/or N-terminal of the Fc (knob), and a second polypeptide comprising an Fc (hole) and an anti-EGFR/anti-CD3 bispecific scDb at the N-terminus and a radiolabel at the C-terminus, whereby the Fc domains form a heterodimer IgFc as a single construct. The construct comprising two polypeptides includes the interspecific amino acid sequence pair of knob-in-hole (KiH) sequences (re. claims 2-3). The construct may also include a 4-1BBL, as taught by Kontermann (pg. 18, para. 0121), which is a therapeutic agent (re. claim 4) and/or a radiolabel payload, as taught by Wu. The construct comprises an additional anti-EGFR scFv on the first polypeptide chain (re. claim 6).
Thus, the construct of the combination of US ‘297, claim 1, and Wu and Kontermann makes obvious the construct of instant claim 1, comprising an NBD of SEQ ID NO: 16 and two heavy chain constant regions comprising an Fc; wherein the Fc have KiH mutations of instant claims 2-4; wherein the construct comprises an EGFR TSB of instant claims 5 and 7, which is an scFv of instant claim 6; whereby the construct comprises an NBD of US ‘297 SEQ ID NO: 88, which is 100% identical to instant SEQ ID NO: 294, wherein the X688 residue is N; and which can homodimerize and which comprises an anti-CD3 (ICB) of instant claim 8, whereby only one polypeptide comprises the NBD and the second polypeptide comprises the ICB of claim 9, with KiH mutations of instant claims 10 and 12, with a 4-1BBL therapeutic agent of claim 11, wherein the ICB targets CD3 of claims 13-14. The construct comprising one or two NBD at the N- and/or C-terminus of one polypeptide, when bound to ATP, makes obvious the bound complex of instant claims 16 and 24. Kontermann teaches the construct may be formulated in a pharmaceutical composition comprising a pharmaceutically acceptable carrier, and thus makes obvious instant claims 17 and 22.
Claims 1 and 25 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 5-7 and 10-12 of copending Application No. 18/989,938 in view of Wu, (US 2019/0177439; published 6/13/2019).
App ‘938 claims a polypeptide construct comprising a NBD and a tumor specific binder (TSB), wherein the NBD comprises an ATP binding site and can dimerize with a cognate non-identical NBD sequence in the presence of ATP (claim 1). App ‘938 also claims wherein the polypeptide construct comprises a scaffold sequence (claim 2), and a composition comprising the first polypeptide construct (claim 3); and whereby the first polypeptide sequence, in the composition, comprises a TSB which is an anti-EGFR antibody (claim 5); whereby the scaffold comprises an immunoglobulin sequence (claim 6), whereby the scaffold is an IgFc sequence (claim 7), whereby the NBD comprises a TAP1 amino acid sequence of SEQ ID NOs: 10 or 88 (claims 10-12).
The NBD of app ‘938 SEQ ID NOs: 10 and 88 (of claim 12) are 100% identical to the NBD of instant SEQ ID NOs: 16 and 294, respectively, wherein the X688 residue is N; and thereby possess the inherent properties of binding ATP and dimerizing around ATP of the NBD of the first polypeptide of the composition of app ‘938. Wu teaches that it is known in the art that a radiolabel may be conjugated to the CH3 region of an IgG Fc domain of antibody-like structures, as described above.
Therefore, app ‘938 claims a first polypeptide construct that may comprise an NBD, a scaffold, and a TSB (claims 1-3 and 5). In an embodiment the TSB is a full length anti-EGFR antibody, with the NBD linked to a heavy chain N- or C-terminal of the anti-EGFR antibody. Such an embodiment comprises a first polypeptide encoding a first HC Fc scaffold domain and a second polypeptide encoding a second HC Fc scaffold domain, and whereby the first and second Ig HC constant regions form an IgFc (e.g., of the full length anti-EGFR antibody). Thus, app ‘938 claims 1-3, 5-7 and 10-12, in view of Wu, make obvious instant claims 1 (wherein the NBD is SEQ ID NO: 16) and 25 (wherein the NBD is SEQ ID NO: 294).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-14, 16-17, 22 and 24-25 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 5-7 and 10-12 of copending Application No. 18/989,938 in view of Wu, (US 2019/0177439; published 6/13/2019) and Kontermann et al., (US 2022/0396635; published 12/15/2022).
The reasons why the polypeptides of application ‘938, in view of Wu, make obvious that of instant claims 1 and 25 are described above. App ‘938 claims a first polypeptide that may have an NBD amino acid sequence and a TSB domain, and whereby the TSB domain may be a full anti-TAA antibody comprising an Ig Fc domain as a scaffold, whereby the Fc domain is a functional Fc domain. For example, an anti-EGFR antibody with a NBD sequence linked to the C-terminal of one Fc domain anticipates the construct of instant claim 1 (see instant Fig. 1B, left). App ‘938 also claims a polypeptide construct with a NBD (of TAP1 or TAP2) and further comprising an immune cell engager (ICE) domain (claim 18), with a scaffold aa sequence (claim 19); and a composition comprising the first and second polypeptide constructs wherein the TSB of the first polypeptide binds EGFR and the ICE of the second polypeptide is a Fab or scFv with affinity for CD3 (claim 20). Wu teaches the art that it is obvious to conjugate a radiolabel to the CH3 region of an IgG Fc domain of an antibody-like construct. However, app ‘938 does not claim whereby the scaffold comprises an KiH sequence pair, or whereby the polypeptide comprises a payload or label (i.e., instant claims 2, 4, 8, 10-11, and dependents thereof).
Kontermann et al teaches trivalent binding molecules comprising a first polypeptide comprising two binding domains and a second polypeptide comprising a third binding domain (abstract). Kontermann teaches one binding domain is targeted to a tumor associated antigen, such as HER2, HER3 or EGFR (pg. 3, para. 0026), and the other binding domain targets the trigger molecule of the immune effector cell, for example, CD3 (pg. 2, para. 0025). Konetermann teaches that the binding molecules may also comprise one or more molecules that aid in purification, preferably a hexahistidyl-tag or FLAG-tag, and one or more co-stimulatory molecules, (pg. 3, paras. 0029-0030), including 4-1BBL (pg. 18, para. 0121), or one or more checkpoint inhibitors, including PD-L1 (pg. 18, para. 0121). Kontermann teaches the construct has heterodimerizing Fc, which includes “knob-into-hole” technology (pg. 15, para. 0092). Kontermann teaches the binding domains may be single-chain diabodies (scDb), which are 4 variable domains of two antibodies connected by 3 linkers, which can be employed for T-cell retargeting to tumor cells but also cells of the tumor microenvironment (pg. 18, para. 0122). Kontermann teaches one embodiment is a trivalent, bispecific anti-HER3 x anti-CD3 antibody (termed a scDb/scFv-Fc; Fig. 6), comprising a scDb molecule bispecific for HER3 (3-43) and CD3 (huU3, humanized version of UCHT1), and further comprising a scFv (or Fab) fragment specific for HER3 or CD3, and which utilized a heterodimerizing Fc part with knob-in-hole technology, of Fig. 6 (pg. 23, Example 5, para. 0205). Figure 6B displays the alternative formats of the two polypeptides of the construct; whereby one polypeptide comprises an Fc (hole) and the other polypeptide comprise an Fc (knob), such that the two polypeptides heterodimerize. The polypeptide with the Fc(hole) comprises a scDb with bispecific affinity for HER3 and CD3, while the polypeptide with the Fc(knob) comprises a N-terminal scFv directed at HER3. Kontermann teaches a similar embodiment which is an anti-EGFR x CD3 construct, whereby the EGFR-targeting antibody is centuximab, and follows the same format of the anti-HER3 x CD3 scDb/scFv-Fc construct; such that it comprises a scDb with binding affinity for EGFR and CD3 on one polypeptide with the Fc(hole), and an anti-EFGR scFv on the second polypeptide with the Fc(knob) mutation (pg. 24, Example 9, para. 0209). Kontermann teaches alternative formats including a trivalent, bispecific Fc fusion protein targeting EGFR, whereby the scDb may be monospecific for EGFR and the scFv (or Fab) for CD3 binding may be alternatively positioned as the scFv of the second polypeptide with the Fc(knob) mutation; with reference to Fig. 6 for an overview of formats (pg. 27, Example 11, para. 0217).
It would have been obvious to one of skill in the art to utilize the anti-EGFR/anti-CD3 construct of Kontermann as the TSB antibody domain of the first polypeptide construct of app ‘938. One would have been motivated to do so given that the anti-EGFR/anti-CD3 antibody targets the tumor associated antigen EGFR for the purpose of targeting the construct to the tumor or tumor microenvironment, as taught by Kontermann, where the NBD would bind (and dimerize around) the excessive ATP in the tumor microenvironment, as taught by app ‘938. There would have been a reasonable expectation for success given that app ‘938 teaches that the polypeptide comprising the NBD may also comprise the TSB amino acid sequence of an EGFR antibody, and that Kontermann teaches the anti-EGFR/anti-CD3 antibody construct successfully targets EGFR-expressing tumor cells. Thus, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made.
The combination construct of app ‘938 and Wu and Kontermann would comprise a first polypeptide comprising a Fc (knob) and the NBD of app ‘938 linked, directly or via a linker, to the C-terminal or N-terminal of the Fc (knob), and a second polypeptide comprising an Fc (hole) and an anti-EGFR/anti-CD3 bispecific scDb at the N-terminus, whereby the Fc domains form a heterodimer IgFc as a single construct. The construct comprising two polypeptides includes the interspecific amino acid sequence pair of knob-in-hole (KiH) sequences (re. claims 2-3). The construct may also include a 4-1BBL, as taught by Kontermann (pg. 18, para. 0121), which is a therapeutic agent (re. claim 4), and/or a radiolabel payload, as taught by Wu. The construct comprises an additional anti-EGFR scFv on the first polypeptide chain (re. claim 6).
Thus, the construct of the combination of app ‘938, claim 1, and Wu and Kontermann makes obvious the construct of instant claim 1, comprising an NBD of SEQ ID NO: 16 and two heavy chain constant regions comprising an Fc; wherein the Fc have KiH mutations of instant claims 2-4; wherein the construct comprises an EGFR TSB of instant claims 5 and 7, which is an scFv of instant claim 6; whereby the construct comprises an NBD of US ‘297 SEQ ID NO: 88, which is 100% identical to instant SEQ ID NO: 294, wherein the X688 residue is N; and which can homodimerize and which comprises an anti-CD3 (ICB) of instant claim 8, whereby only one polypeptide comprises the NBD and the second polypeptide comprises the ICB of claim 9, with KiH mutations of instant claims 10 and 12, with a 4-1BBL therapeutic agent of claim 11, wherein the ICB targets CD3 of claims 13-14. The construct comprising one or two NBD at the N- and/or C-terminus of one polypeptide, when bound to ATP, makes obvious the bound complex of instant claims 16 and 24. Kontermann teaches the construct may be formulated in a pharmaceutical composition comprising a pharmaceutically acceptable carrier, and thus makes obvious instant claims 17 and 22.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
Applicant's arguments filed 4/15/2026 have been fully considered but they are not persuasive. Applicants contend that instant claim 1 is amended to further comprise a specific payload, such as a radiolabel. Applicants contend that none of the cited art teaches or fairly suggests labeling the constructs with such labels, and that any suggestion or motivation to do so would originate with applicant’s disclosure, and therefore would be impermissible in the formulation of an obviousness type double patenting rejection (remarks, pg. 9, para. 6). Applicants also contend that claim 8 is limited to a capped NBD sequence, such as instant SEQ ID NO: 294, which are not taught or suggested by the prior art (remarks, pg. 9, para. 7).
Examiner’s response is that the amendments to instant claim 1 requires an amended rejection. Wu teaches adding a radiolabel to an antibody-like structure comprising an IgG Fc domain is common knowledge in the art, and the radiolabel may be conjugated, with or without a linker, to the CH3 region of the IgG Fc domain. This is consistent with applicant’s description of attaching a payload, as depicted in Figure 1 (pg. 2). The constructs of Wu are also bispecific and comprise KiH mutations to pair heterodimeric Fc domains. The suggestion is made by Wu and the motivation is that which is common to the art of labeling a construct; that is to enhance the properties of the construct for therapeutic or diagnostic purposes. Thus, Wu makes obvious the addition of a radiolabel, and such an addition does not patentably distinguish the constructs of US ‘297 nor that of application ‘938 from the instant product. Rather this is an obvious modification to the known constructs. Regarding instant claim 8, both US ‘297 and application ‘938 teach wherein the NBD may be that of SEQ ID NO: 88 (identical in ‘297 and ‘938), which is 100% identical to the capped NBD of instant SEQ ID NO: 294, whereby the X residue is N. Thus, the NBD constructs of US ‘297 and application ‘938 meet the limitations of amended claim 8. The rejections for non-statutory double patenting 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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