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 .
Priority
The instant application, filed on 17 August, 2023, claims domestic benefit to US provisional application no. 63/399,095, filed on 18 August, 2022.
Status of Application, Amendments, and/or Claims
The response filed on 20 May, 2026 has been entered in full. The response is an amendment to a Non-Final Rejection to the claim set filed on 06 December, 2023. In the amendment claims 1, 6, 11, 13, 27, 28, 30, 32-36, 40, 51, 52, 56, and 59 are amended, claims 4, 8, 14, 17, 19, 22, 23, 55, 61, 64, 66-68, 70, and 72 are previously presented, and claims 9, 12, 15, 18, 21, 24-26, 29, 31, 37-39, 41-50, 53, 54, 58, 60, 62, 63, 65, 71, and 73-76 are cancelled. Therefore, claims 1-8, 10, 11, 13, 14, 16, 17, 19, 20, 22, 23, 27, 28, 30, 32-36, 40, 51, 52, 55-57, 59, 61, 64, 66-70, and 72 are pending and are the subject of this office action.
Status of Objections and Rejections
In the office action of 02/20/2026
Claims 37, 39, 42, 44-46, and 50 were rejected under 35 U.S.C. 103 over Hayes et al. in view of Lunde et al. and Kuball et al. The cancellation of these claims has rendered the rejections moot and the rejections have been withdrawn.
Claim 26 was rejected under 35 U.S.C. 103 over Hayes et al. in view of Lunde et al. and Kuball et al. and further in view of Armour et al and Merchant et al. as evidenced by UniProt and Chiu et al. The cancellation of the claim has rendered the rejection moot and the rejection has been withdrawn.
Claims 1-8 10, 11, 13, 14, 16, 17, 40, 51, 55, 61, 64, 67-70, and 72 were rejected under 35 U.S.C. 103 over Hayes et al. in view of Lunde et al. and Kuball et al. The amendment of claim 1 necessitates a modified form of the 103 rejection over Hayes et al., Lunde et al., Xu et al., and Kuball et al.
Claims 19, 20, 22, 23, 27, 28, 30, 32-36, and 52 were rejected under 35 U.S.C. 103 over Hayes et al. in view of Lunde et al. and Kuball et al. and further in view of Armour et al. and Merchant et al. as evidenced by UniProt and Chiu et al. The amendment of claim 1 necessitates a modified form of the 103 rejection over Hayes et al., Lunde et al., Xu et al., Kuball et al., Armour et al., and Merchant, further evidenced by Uniprot and Chiu et al.
Claims 1-11, 13, 14, 16, 17, 19, 20, 27, 28, 30, 32-36, 40, 51, 52, 55-57, 59, 61, 64, 66-70, and 72 were rejected on the ground of nonstatutory double patenting over U.S. Patent No. 12,065,475. The rejection is maintained.
Claims 22 and 23 were rejected on the ground of nonstatutory double patenting over U.S. Patent No. 12,065,475 in view of Armour et al. The rejection is maintained.
Claims 1-8, 10, 11, 13, 14, 16, 37, 39, 42, 44-46, 55, 61, 64, 67, 68, and 72 are rejected on the ground of nonstatutory double patenting over claims U.S. Patent No. 11,505,590 (of record, IDS 04/09/2024) in view of Lunde and Kuball. The amendment of the claims necessitates the modified DP rejection of U.S. Patent No. 11,505,590 in view of Lunde et al., Xu et al., and Kuball et al.
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.
Claim 27 rejected under 35 U.S.C. 112(b), as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor, regards as the invention. Claim 27 recites dependence on claim 26, however claim 26 is cancelled, thus rendering the claim unclear. For the purpose of further examination, the claim will be interpreted to be dependent up claim 1.
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 1-8, 10, 11, 13, 14, 16, 17, 40, 51, 55, 61, 64, 67-70, and 72 are rejected under 35 U.S.C. 103 as being unpatentable over Hayes et al. (WO2017175006 of record, IDS 04/09/2024) in view of Lunde et al. (2010) Stabilizing mutations increase secretion of functional soluble TCR-Ig fusion proteins BMC Biotechnology (10) 61 (hereafter Lunde), Xu et al. (2015) Production of bispecific antibodies in “knobs-into-holes” using a cell-free expression system mAbs 7:1, 231-242 (hereafter Xu), and Kuball et al. (of record, IDS 04/09/2024).
In regards to claims 1 and 40, Hayes teaches a TCR fusion protein in which the soluble TCR contains the CDRs of SEQ ID NOs: 1, 2, and 3 in the alpha chain variable region and the CDRs of SEQ ID NOs: 4, 5, and 6 in the beta chain variable region (claim 12, Table 6 of Hayes). Hayes also teaches the fusion of the TCR to a CD3 scFv (T cell engaging domain) of SEQ ID NO: 35 (claim 20/ claim 21 SEQ ID NO: 42 residues 1-253 of Hayes). In addition, Hayes teaches covalently linking the CD3 scFv with the TCR via a linker in which the C Terminus of the CD3 is linked to the N terminus of the beta chain (claim 21 of Hayes), and further, Hayes teaches the linkers of SEQ ID NOs: 18-25 (SEQ ID NOs: 30-37 of Hayes).
In regards to claims 6, 7, and 51 Hayes teaches the cystine substitution in the alpha and beta chain constant regions and further the beta chain cystine substitution at position 57 to form a non-native disulfide bond between the alpha and beta chain constant domains (claim 17 of Hayes).
In regards to claims 8 and 10 Hayes teaches the alpha chain variable region of SEQ ID NO: 7 but with unsubstituted glycosylation sites (SEQ ID NO: 24 of Hayes). Similarly, Hayes teaches the beta chain variable region of SEQ ID NO: 13 with unsubstituted glycosylation sites (SEQ ID NO:29 of Hayes).
In regards to claims 11, 13, 14, and 16 Hayes teaches the alpha chain of SEQ ID NO: 11 (SEQ ID NO: 40 of Hayes) and the beta chain of SEQ ID NO: 16 (SEQ ID NO: 45 of Hayes) without the glycosylation site substitutions which further encompass the unsubstituted alpha chain constant region of SEQ ID NO: 9 and beta chain constant region of SEQ ID NO:14.
In regards to claim 55-57, and 59 Hayes teaches a polynucleotide (claim 26 of Hayes) and a vector (claim 27 of Hayes) encoding the fusion proteins. Instant claims 56 and 59 refer to kits to use the polynucleotide and vector of claims 55 and 57 without listing other components therefore the kits do not preclude the compositions.
In regards to claims 67-70 and 72 Hayes teaches using a pharmaceutical composition of the TCR fusion protein for treating cancer in a human subject who expresses of MAGE-A4 and/or are the HLA*02 subtype (claims 32, 33, 35 of Hayes). Hayes also teaches that the administration of the fusion protein or composition is intravenously or by intertumoral injection (claim 36 of Hayes).
Hayes fails to teach the covalently linked antibody Fc domain and the three polypeptide configurations of claim 1, and the glycosylation at N18 of the alpha chain variable region and N-glycosylation site substitutions of all other potential N-glycosylation site of claims 1-5 and further seen in SEQ ID NOs: 7, 13, 9, 14, 11, and 16 of the instant application claims 10, 11, 13, 14, and 16.
Lunde, however, in regards to claim 1 and 17 teaches attaching a human IgG1 Fc domain to the extracellular region of a TCR (pg.2, col 2, lines 14-18) for improved solubility and stability (pg.2, col 1, lines 24-28), further Lunde teaches that the attachment of an Ig Fc region to a TCR may provide the targeting TCRs with effector function in vivo (pg.2, col 1, lines 32-37).
Lunde fails to teach the three polypeptide configurations of claim 1, N-glycosylation site substitutions and further, the replacement of asparagine with glutamine of claims 1-5.
Xu, however, in regards to claim 1 teaches attachment of bispecific antibodies (Bite) to an Fc domain comprising a Fc with a knob and hole design can be done in various formats including a single arm formation in which one scFv antibody is bound by the C terminus to the N terminus of another scFv binding antibody which is bound to the N terminus of a Fc domain and wherein a second Fc domain is bound to the first Fc domain (Figure 1). Further Xu teaches attaching these Fc domains to the bispecific antibodies increased their half-life without impacting their function (pg.235, col 2, lines 20-24). This structure while not exactly encompassing the three polypeptide chains of the instant application, present the same single armed three chain structure that is being described by the instant application.
Xu fails to teach the N-glycosylation site substitutions and the replacement of asparagine with glutamine of claims 1-5.
Kuball teaches that the selective removal of N glycosylation sites in the TCR results in increased TCR mobility at the cell surface, enhanced recruitment to the synapse, improved engagement, and enhanced functional avidity of the T cells (pg. 464, col. 1, lines 42-47). Further Kuball teaches changing N to Q by site directed mutagenesis (pg. 464, col. 1, lines 49-53).
Thus, Hayes discloses the claimed sequences of the alpha chain, beta chain, and scFv of a CD3-TCR fusion protein, Lunde teaches the benefit of adding a IgG1 Fc domain to the TCR fusion protein for increased solubility and stability, Xu teaches attaching a bispecific antibody with Fc domains in a single arm configuration, and Kuball teaches specific N glycosylation site substation and replacing the asparagine with glutamine for improved functions such as enhanced functional avidity. Therefore, a person of ordinary skill in the art before the effective filing date of the claimed invention would have found it obvious to combine the teachings of Hayes with the teachings of Lunde, Xu, and Kuball with a reasonable expectation of success to develop a TCR fusion protein wherein the TCR and CD3 scFv are simply substituted for the two Bite scFvs of Xu to increase the half-life of the fusion protein and impart effector function to the TCR in vivo and further wherein the N glycosylation sites are removed according to the teaching of Kuball to improve the fusion protein’s engagement and functional avidity in T cells, for an improved bi-specific antibody fusion protein.
Claims 19, 20, 22, 23, 27, 28, 30, 32-36, and 52 are rejected under 35 U.S.C. 103 as being unpatentable over Hayes in view of Lunde, Xu, and Kuball as applied to claims 1 and 17 above, and further in view of Armour et al. (1999) Recombinant human IgG molecules lacking Fc receptor binding and monocyte triggering activities Eur. J. Immunol (29) 2613 – 2624 (hereafter Armour), Merchant et al. (1998) An efficient route to human bispecific IgG Nature Biotechnology (16) 677-681 (hereafter Merchant) as evidenced by UniProt P0DOX5 (first entered in 2017), and Chiu et al (2019) Antibody Structure and Function: The Basis for Engineering Therapeutics Antibodies (8) 55 (hereafter Chiu).
Hayes in view of Lunde, Xu, and Kuball fails to teach the point mutations in the IgG1 Fc region to modulate effector function including a domain comprising mutations N297G, E233P, L234V, L235A, and a deletion at G236 or a domain comprising mutations L234A, L235A, and P329G of claims 19, 20, 22, and 23. Hayes in view of Lunde Xu, and Kuball also fails to reach the hinge sequences of claims 27, 32, and 52. Further, Hayes in view of Lunde, Xu, and Kuball fails to teach two IgG1 Fc domain regions with knob and hole mutations attached by one or more interchain disulfide bonds of claims 28, 30, and 33-36.
Armour, however in regards to claims 19, 20, 22, and 23 teaches the substitution of residues at positions of 233-236 (pg.2614 col 1, lines 11-16) and further teaches the N297G, E233P, L234V, L235A and the G236 deletion of claim 23 (Table 1) to block effector activity (pg.2619 col 1, lines 12-14). Armour fails to teach the two IgG1 Fc domains with mutations to form knob and hole and attached by one or more interchain disulfide bond of claims 28, 30 and 33-36. Armour also fails to teach the hinge sequence of claims 27, 32, and 52.
However, Merchant teaches in regards to claims 28, 30, and 33-36 the mutations to form knob and hole Fc domains of IgG1 (Table 1) to support efficient antibody dependent cell-mediated cytotoxicity (ADCC) (pg.697, col 2, lines 42-45) and further teaches interchain disulfide bonds to control heterodimerization and mobility (pg.679, col 1, lines 4-5 / pg.679, col 2, lines 23-24). It is also noted the SEQ ID NO: 26 and SEQ ID NO: 27 of the instant application are the known sequence of the IgG1 (P0DOX5) FC domain with the listed mutations as taught in Merchant, therefore evidenced by the known sequence Merchant would predict these sequences (see Examiner Figure 1, below).
Merchant fails to teach the hinge sequence of claims 27, 32, and 52, however, Chiu teaches the hinge sequence of SEQ ID NO: 31 of the instant application is part of the native hinge domain of human IgG1 (figure 6) and is the attachment point of the antibody region of IgG1 to the Fc region and further teaches it allows for a large degree of conformational flexibility (pg.9, lines 1-2).
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Examiner Figure 1: SEQ ID NO: 26 of instant application aligned to the SEQ of IgG 1 Fc region. (Mutations circled)
Thus, Hayes in view of Lunde, Xu, and Kuball discloses a TCR fusion protein linked to an antibody Fc domain, and a T cell engaging domain in which all but one N-glycosylation site is substituted and the T cell engaging domain is CD3, Armour teaches mutations of the IgG1 Fc domain to modulate effector function, Merchant teaches the hole and knob mutations for efficient ADCC support and Interchain disulfide bonds for improved heterodimerization and mobility, and Chiu teaches the hinge sequence of IgG1 and further teaches that it allows for a large degree of conformational flexibility. Therefore, a person of ordinary skill in the art before the effective filing date of the claimed invention would have found it obvious to combine the teachings of Hayes in view of Lunde and Kuball with the teachings of Armour, Merchant and informed by the teachings of Chiu with a reasonable expectation of success to develop a TCR fusion protein linked to an antibody Fc domain, and a T cell engaging domain with enhanced conformational flexibility, efficient ADCC support, and modulated effector function.
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 1-11, 13, 14, 16, 17, 19, 20, 27, 28, 30, 32-36, 40, 51, 52, 55-57, 59, 61, 64, 66-70, and 72 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6, 9, 11-17, and 19-21 of U.S. Patent No. 12,065,475. Although the claims at issue are not identical, they are not patentably distinct from each other.
Claims 1 and 19-21 of the issued patent and claims 1-11, 13, 14, 16, 17, 19, 20, 26-28, 30, 32-37, 39, 40, 42, 44, 45, and 50-52 of the instant application both recite claim to a TCR fusion protein which binds to HLA-A*02 wherein the TCR is covalently linked to a T cell engaging domain and an antibody Fc domain of human IgG1. Comprising the claimed CDRs of the instant application, glycosylation at the N18 residue of the alpha chain variable region, substitutions of the N residues with Q in the alpha and beta chains as outlined in claims 2-5 of the instant application and the disulfide bond linkers.
SEQ ID NO: 34 of the issued patent and SEQ ID NO: 34 of the issued patent are identical.
SEQ ID NO: 29 of the issued patent recites a polypeptide which contains the alpha chain components of SEQ ID NOs: 1, 2, 3, 7, 9, and 11 of the instant application as well as the antibody FC domain with the hole mutation of SEQ ID NO: 27 of the instant application and the hinge sequence of SEQ ID NO: 31 of the instant application.
SEQ ID NO: 30 of the issued patent recites a polypeptide which contains the beta chain components of SEQ ID NOs: 4, 5, 6, 13, 14, and 16 of the instant application which includes an engineered cystine reside at the 57 position of the beta chain constant domain as well as the anti CD3 scFv of SEQ ID NO: 17 of the instant application and the hinge sequence of SEQ ID NO: 31 of the instant application.
SEQ ID NO: 28 of the issued patent recited a polypeptide which contains the antibody domain with the knob mutation of SEQ ID NO: 26 of the instant application.
Though Claim 1 of the issued patent does not explicitly state the TCR is soluble because the TCR structure of the instant application and the issued patent are the same it is reasonable to interpret that the TCR of the instant application is soluble.
Claims 2-6 and 11-17 of the issued patent and claims 55-57, 59, 61, 64, 66-70, and 72 of the instant application both recite claim to the methods of making, use of, and kits containing the TCR fusion protein.
Claims 22 and 23 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 19 of U.S. Patent No. 12,065,475 in view of Armour.
Claim 9 of the issued patent recites a TCR fusion protein which binds to HLA-A*02 wherein the TCR is covalently linked to a T cell engaging domain and an antibody Fc domain of human IgG1. Comprising the claimed CDRs of the instant application, and glycosylation at the N18 residue of the alpha chain variable region as claimed in instant application claims 22 and 23 as outlined above.
The issued patent fails to recite the mutations at the E233, L324, L235, G236 and the P329 residues of the IgG1 Fc domain. Armour however teaches the substitution of residues at positions of 233-236 (pg.2614 col 1, lines 11-16) and further teaches the N297G, E233P, L234V, L235A and the G236 deletion of claim 23 (Table 1) to block effector activity (pg.2619 col 1, lines 12-14).
Thus, the issued patent recites claim to a TCR fusion protein which binds to HLA-A*02 wherein the TCR is covalently linked to a T cell engaging domain and an antibody Fc domain of human IgG1. Comprising the claimed CDRs of the instant application and glycosylation at the N18 residue of the alpha chain variable region. Armour teaches the substitution of residues at the specific positions of the IgG1 FC domain to modulate it effector activity. Therefore, a person of ordinary skill in the art before the effectively filed date would have found it obvious to use the teachings to Armour to further modify the claimed fusion protein of the issued patent to get the TCR fusion protein of claims 22 and 23 of the instant application.
Claims 1-8, 10, 11, 13, 14, 16, 37, 39, 42, 44-46, 55, 61, 64, 67, 68, and 72 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4, 6, and 34 - 45 of U.S. Patent No. 11,505,590 (of record, IDS 04/09/2024) in view of Lunde, Xu, and Kuball.
Claims 1, 4, 6, and 34-39 of the issued patent and claims 1-8, 10, 11, 13, 14, 16, 37, 39, 42, and 44-46, of the instant application both recite claim to a fusion protein, comprising a soluble TCR with CDRs 1,2 and 3 for the alpha chain variable region, and the beta chain variable region, as well as an alpha and a beta chain constant region fused to a anti CD3 binding motif via linkers. Further the issued patent and instant application recite claim to engineered cystine residue in the alpha and beta chain and at position 57 of the beta chain to form a non-native disulfide bond between the chains.
The CDRs of the alpha chain variable region SEQ ID NOs: 6, 83, and 87 of the issued patents are the identical sequences of the alpha chain variable region CDRs of SEQ ID NOs: 1, 2, and 3 of the instant application respectively. Further the CDRs of the beta chain variable region SEQ ID NOs: 90, 88, and 89 of the issued patents are the identical sequences of the alpha chain variable region CDRs of SEQ ID NOs: 4, 5, and 6 of the instant application respectively.
The alpha chain variable region of SEQ ID NO: 24 in the issued patent is almost identical to the alpha chain variable region of SEQ ID NO: 7 of the instant application without the N to Q substitutions of claims 2-5 of the instant application. The beta chain variable region of SEQ ID NO: 29 in the issued patent is almost identical to the alpha chain variable region of SEQ ID NO: 13 of the instant application without the N to Q substitutions of claims 2-5 of the instant application.
The alpha chain of SEQ ID NO: 40 in the issued patent is almost identical to the alpha chain of SEQ ID NO: 11 which encompasses the alpha chain constant region of SEQ ID NO: 9 without the N to Q substitutions of claims 2-5 of the instant application. The beta chain of SEQ ID NO: 45 in the issued patent is almost identical to the beta chain of SEQ ID NO: 16 which encompasses the beta chain constant region of SEQ ID NO: 14 without the N to Q substitutions of claims 2-5 of the instant application.
The linkers of SEQ ID NOs: 30-37 in the issued patent are identical to the linkers of SEQ ID NOs: 18-25 of the instant application.
The issued patent fails to recite the N site glycosylation mutations and replacement of asparagine (N) with Glutamine (Q) as well as the attachment of an antibody human Fc domain, and the orientation of polypeptides are recited in claim 1. Lunde, however, teaches that the attachment of an Ig molecules to TCR acquire increased stability and binding avidity upon dimerization while still maintaining solubility (pg.2, col 1, lines 21-26). Lunde fails to teach the orientation of polypeptides Xu, however, teaches attachment of bispecific antibodies (Bite) to an Fc domain comprising a Fc with a knob and hole design can be done in various formats including a single arm as discussed above to increase half-life without impacting function (pg.235, col 2, lines 20-24). Both Lunde and Xu fail to teach N site glycosylation mutation and replacement of N with Q, however, Kuball teaches that the selective removal of N glycosylation sites in the TCR results in increased TCR mobility at the cell surface, enhanced recruitment to the synapse, improved engagement, and enhanced functional avidity of the T cells (pg. 464, col. 1, lines 42-47). Further, Kuball teaches changing N to Q by site directed mutagenesis (pg. 464, col. 1, lines 49-53).
Thus, the issued patent recites claim to a TCR fusion protein which binds to HLA-A*02 wherein the TCR is covalently linked to a T cell engaging domain of CD3 . Comprising the claimed CDRs of the instant application and a disulfide bond between the alpha and beta chains of the fusion protein. Lunde teaches the attachment of an IgG molecule for increased stability and binding avidity, Xu teaches single arm attachment of a bispecific antibody with a Fc domain, and Kuball teaches controlled replacement of N glycosylation sites with Q for increase TCR mobility and functional avidity. Therefore, a person of ordinary skill in the art before the effectively filed date would have found it obvious to use the teachings to Lunde, Xu, and Kuball to further modify the claimed fusion protein of the issued patent to get the TCR fusion protein of claims 1-8, 10, 11, 13, 14, 16, 37, 39, 42, and 44-46 of the instant application.
Claims 40-45 of the issued patent and claims 55, 61, 64, 67, 68, and 72 refer to methods of use and methods of making and expressing the claimed TCR fusion proteins outlined above.
Response to Arguments
Applicant's arguments filed 20 May, 2026 have been fully considered but they are not persuasive.
In response to applicants’ argument that Lunde fails to teach or suggest TCR fusion proteins comprising three polypeptides with the specific domain and domain orientations that are required by claim 1 (remarks 05/20/2026, pg.13, lines 23-27) with respect to the 35 U.S.C. 103 rejection of claim 50, of which the subject matter has been moved into claim 1 by recent amendment has been fully considered and is persuasive. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground of rejection is made over Hayes in view of Lunde, Xu, and Kuball.
In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references (remarks 05/20/2026, pg.14, lines 10-26), the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case the applicant's argument is against the Lunde reference individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). The soluble TCR is taught in Hayes by specific sequences which are present in the instant application, while Lunde’s support teaches IgG attachment to TCRs which one of the art would have been motivated to try the combination to support improved solubility and stability of the TCR as discussed above in the rejection of claim 1. Further the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981).
In response to applicant’s argument that the TCR fusion protein exhibit superior and unexpected properties that could not have been predicted from the cited combination of references (remarks 05/20/2026, pg. 15, lines 13-14), the examiner recognizes “any differences between the claimed invention and the prior art may be expected to result in some differences in properties. The issue is whether the properties differ to such an extent that the difference is really unexpected” (See MPEP 716.02). Expected beneficial results are evidence of obviousness (see MPEP 716.02(c)), the current examples demonstrate the TCR fusion protein is modified in way to induce expected improvements to the pharmacodynamics of the protein. It is the applicant’s burden to show evidence of a greater than expected result, a superior property, the presence of an unexpected property, or the absence of an expected property (MPEP 716.02(a) / MPEP 716.02(b)).
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DASIA A ALDARONDO whose telephone number is (571)272-1977. The examiner can normally be reached on Monday – Friday from 8:30am to 4:30pm.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Joanne Hama, can be reached at telephone number (571)272-1977. The fax phone number for the organization where this application or proceeding is assigned is (571)273-8300.
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/D.A.A/Examiner, Art Unit 1647 /JOANNE HAMA/Supervisory Patent Examiner, Art Unit 1647
Prosecution Insights