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.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 09 April, 2024 has been considered by the examiner.
Status of Application, Amendments, and/or Claims
The response filed on 06 December, 2023 has been entered in full. These are the amended claims of the original claim set received on 17 August, 2023. In the amendment, claims 4, 6, 8, 11, 13, 14, 17, 19, 22, 23, 26-28, 30, 32, 33, 37, 39, 40, 42, 44-46, 50, 55, 56, 59, 61, 64, 66-68, 70, and 72 are amended and claims 9, 12, 15, 18, 21, 24, 25, 29, 31, 38, 41, 43, 47-49, 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, 26-28, 30, 32-37, 39, 40, 42, 44-46, 50-52, 55-57, 59, 61, 64, 66-70, and 72 are pending and are the subject of this Office Action.
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, 37, 39, 40, 42, 44-46, 50, 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) and Kuball et al. (of record, IDS 04/09/2024).
In regards to claims 1, 37, 39, 40, and 50 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). Further Hayes 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 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: 45of 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 claims 42, 44, 45, and 46 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). Further, Hayes teaches the linkers of SEQ ID NOs: 18-25 (SEQ ID NOs: 30-37 of Hayes).
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 intratumoral injection (claim 36 of Hayes).
Hayes fails to teach the covalently linked antibody Fc domain of claims 1, 17, and 50, 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 expressed in SEQ ID NOs: 7, 13, 9, 14, 11, and 16 of the instant application claims 10, 11, 13, 14, and 16.
Lunde, however, 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 N-glycosylation site substitutions and further, the replacement of asparagine with glutamine, 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, 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, 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 and Kuball 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 stability, solubility, and avidity.
Claims 19, 20, 22, 23, 26-28, 30, 32-36, and 52 are rejected under 35 U.S.C. 103 as being unpatentable over Hayes in view of Lunde 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 UniPort 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 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. Further, Hayes in view of Lunde and Kuball fails to teach two IgG1 Fc domain regions with knob and hole mutations attached by one or more interchain disulfide bonds.
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 26, 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 so evidenced by the known sequence Merchant would predict these sequences (see Examiner Figure 1, below). Merchant fails to teach the hinge sequence of claims 26, 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).
PNG
media_image1.png
404
590
media_image1.png
Greyscale
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 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, 26-28, 30, 32-37, 39, 40, 42, 44, 45, 50-52, 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.
Claim 46 is 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 Chen, X. et al. (of record, IDS 04/09/2024).
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, glycosylation at the N18 residue of the alpha chain variable region as claimed in instant application claim 46 as outlined above.
The issued patent fails to recites the linkers of claim 46 of the instant application, however, Chen teaches the linkers claimed in SEQ ID NO: 18 (pg.4 , sec 3.1, lines 9-10) as well as teaches that linkers comprising glycine and serine are flexible (SEQ ID NOs: 19-21) (pg.4 , sec 3.1, lines 8-9), further Chen teaches, adding a glutamic acid can improve solubility (pg.4, sec 3.1, line 16) and adding a proline causes rigidity (pg.5, sec 3.2, line 29) allowing for fixed distance to maintain independent function (pg.5, sec 3.2, lines 10-12).
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. Chen teaches how to develop flexible or rigid linkers to maintain the function of the TCR fusion protein. Therefore, a person of ordinary skill in the art before the effectively filed date would have found it obvious to use the teachings to Chen to further modify the claimed fusion protein of the issued patent to get the TCR fusion protein of claim 46 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 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 Fc domain, and further where the domain is human IgG1. 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 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 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 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.
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 – Thursday from 7am to 4pm and Friday from 7am to 11am.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Joanne Hama, can be reached at telephone number (571)272-2911. The fax phone number for the organization where this application or proceeding is assigned is (571)273-8300.
Information regarding the status of an application may be obtained from Patent Center. Status information for published applications may be obtained from Patent Center. Status information for unpublished applications is available through Patent Center to authorized users only. Should you have questions about access to the USPTO patent electronic filing system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free).
Examiner interviews are available via a variety of formats. See MPEP § 713.01. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) Form at https://www.uspto.gov/InterviewPractice.
/D.A.A/Examiner, Art Unit 1647
/JOANNE HAMA/Supervisory Patent Examiner, Art Unit 1647