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 .
Claims Status
The Amendment filed on 25Nov2025 in which claims 1-65 were canceled by Applicant and claims 66-120 are new is acknowledged.
The reply filed on 25Nov2025 is acknowledged, in which Applicant elected without traverse:
a modified T cell receptor comprising a TCR α chain, and a TCR β chain, wherein
the first antigen-binding region comprises a heavy chain variable region amino acid sequence as shown in SEQ ID NO: 50,
the first constant region comprises the amino acid sequence shown in SEQ ID N0:41,
the second antigen-binding region comprises a light chain variable region amino acid sequence as shown in SEQ ID NO: 51 and
the second constant region comprises the amino acid sequence shown in SEQ ID N0:6 (see new claim 50);
For the costimulatory molecule endodomain, Applicant elects OX40
For the immune cell type comprising the modified TCR, Applicant elects a T cell.
Claim(s) 66-120 is/are currently pending and presented for examination on the merits.
Drawings
The drawings are objected to because:
Figs. 1-5, 34, 36-40, 47, 53, 58, 60: are not legible.
Fig. 11: legend patterns vs. bar graph patterns are not clear matches (e.g., the αβ-OX40).
Fig. 35: unclear which survival plot line is mock vs. STAR vs. αβ-OX40.
Fig. 49: unclear which survival plot line is mut-ohmE141 vs. mut-ohmE141-αβ-OX40.
Fig. 55: unclear which survival plot line is PBS vs. CD3γ-ICOS cysE141.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
The use of trade name(s) or mark(s) used in commerce (e.g., Invitrogen, Promega), has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code (e.g., pg. 7, ¶ 1). Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Claim Objections
Claim(s) 70 and 76 are objected to because of the following informalities: “where n is an integer from 1 to 10 (respectively comprising the amino acid sequences of SEQ ID NO: 16-25).” should be “where n is an integer from 1 to 10 (, respectively).” for clarity of the record. Appropriate correction is required.
Claim(s) 102 is objected to because of the following informalities: “of any claim 66” should be “of . Appropriate correction is required.
Claim(s) 103 (and dependent claim 104) is objected to because of the following informalities: “of any one of claim 66” should be “of . Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
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(s) 66-120 is/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(s) 66-120, recites the phrase "the target binding region". There is insufficient antecedent basis for this limitation in the claim. For the purposes of compact prosecution, the phrase “the target binding region…” in line 7 is considered to mean the first and second target binding regions together form an antigen-binding region (based on Applicant election of a VH and VL). This rejection may be overcome by amending claim 66 to recite (1) recite “…the target binding region, comprising the first target binding region and the second binding region, is…”, (2) replace “the target binding region” with “wherein the first and second target binding regions comprise an antigen-binding domain”, or (3) otherwise clearly recite the intended limitations of the instant invention. Dependent claims 67-120 can overcome this rejection by amending claim 66 as described above.
Regarding claim 67, the phrase "such as" 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). For the purposes of compact prosecution the limitations following the phrase are not considered part of the claimed invention. This rejection may be overcome by amending claim 67 to remove the phrase “such as” and the limitations following the phrase.
Regarding claim 104, the phrases “(UNIPROT Q02223)”, “(UNIPROT Q9NQ25)”, “(UNIPROT Q9NZD1)”, “(UNIPROT Q9NYL4)”, “(UNIPROT P53708)”, and “(UNIPROT Q68SN8)” are not defined in the terms preceding it. Thus, the phrases renders the claim indefinite because it is unclear whether the limitation(s) in the parentheses are a part of the claimed invention. See MPEP 2173.05(d). Specifically, the phrases inside parenthesis appear to correspond to a UNIPROT sequence for a specific isoform of a cancer-associated antigen. Therefore, it is unclear if “(UNIPROT Q02223)”, “(UNIPROT Q9NQ25)”, “(UNIPROT Q9NZD1)”, “(UNIPROT Q9NYL4)”, “(UNIPROT P53708)”, and “(UNIPROT Q68SN8)” are limitations or merely provided as examples. To promote compact prosecution, the phrases “(UNIPROT Q02223)”, “(UNIPROT Q9NQ25)”, “(UNIPROT Q9NZD1)”, “(UNIPROT Q9NYL4)”, “(UNIPROT P53708)”, and “(UNIPROT Q68SN8)” are not considered a limitation of the claim(s). This rejection may be overcome by amending claim 104 to delete the phrases “(UNIPROT Q02223)”, “(UNIPROT Q9NQ25)”, “(UNIPROT Q9NZD1)”, “(UNIPROT Q9NYL4)”, “(UNIPROT P53708)”, and “(UNIPROT Q68SN8)”.
Regarding claim(s) 105, recites the limitations "the first antigen-binding region" in lines 1, 4 and “the second antigen-binding region” in lines 3, 5-6. There is insufficient antecedent basis for this limitation in the claim. For the purposes of compact prosecution, the “first antigen-binding region” is considered to mean the “first target binding region” of claim 66, and the “second antigen-binding region” is considered to mean the “second target binding region” of claim 66. This rejection may be overcome by amending claim 105 as described above.
Regarding claim(s) 106, recites the limitations "the first antigen-binding region" in lines 1-2 and “the second antigen-binding region” in line 3. There is insufficient antecedent basis for this limitation in the claim. For the purposes of compact prosecution, the “first antigen-binding region” is considered to mean the “first target binding region” of claim 66, and the “second antigen-binding region” is considered to mean the “second target binding region” of claim 66. This rejection may be overcome by amending claim 106 as described above.
Regarding claim(s) 114, recites the limitations "the first antigen-binding region" in lines 2, 5, 9, 11-12, 16, 19, 23, 26, 30, 32, and “the second antigen-binding region” in lines 3, 6, 10, 13, 17, 20, 24, 27, 31, 33. There is insufficient antecedent basis for this limitation in the claim. For the purposes of compact prosecution, the “first antigen-binding region” is considered to mean the “first target binding region” of claim 66, and the “second antigen-binding region” is considered to mean the “second target binding region” of claim 66. This rejection may be overcome by amending claim 106 as described above.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 66-69, 72-75, 78-80, 83-88, 88-91, 97-98, 103-112, and 114-120 is/are rejected under 35 U.S.C. 102(a)(2) as being anticipated by WO2021188599-A1 (hereinafter “WO599”).
Regarding instant claim(s) 66-67, 103-110, 114-115, WO599 teaches synthetic antigen receptors (SARs) wherein the SAR is an engineered (e.g., modified) TCR [e.g., title, abstract; ¶ 0002, 0007]. WO599 teaches the TCR comprises an alpha chain and a beta chain [e.g., ¶ 0127, 00158, 00225, 00227], wherein the engineered TCR binding domain(s) comprises an anti-CD19 antibody scFv antigen binding domain known as FMC63 [e.g., pg. 87, ¶ 00210, 00249], which comprises a VH and VL joined by a (G4S)3 linker, and is the same as the instant claimed TCR binding domain of SEQ ID NOs: 50-51 and (G4S)3 linker SEQ ID NO: 18 (see alignment below). WO599 further teaches the SAR (e.g., engineered TCR) comprises an OX40 costimulatory molecule [e.g., ¶ 00160-00161, 0680-0681] and that the first and/or second target binding region of the engineered TCR may comprise an scFv or a scTFv (single chain fragment comprising two variable fragments of a TCR, e.g., Va and Vb) that is optionally linked to an AABD domain which may comprise a VHH antibody that may recognize the same antigen (e.g., CD19) [e.g., ¶ 0019, 00126-00127, 0143, 0202, 0212, 0216; fig. 1].
Alignment of elected binding domain (SEQ ID NOs: 50-51) with WO599 anti-CD19 FMC63 sequence(SAR construct related polypeptide, SEQ ID 1228):
Query Match 99.0%; Score 1183.5; Length 297;
Best Local Similarity 93.8%;
Matches 227; Conservative 0; Mismatches 0; Indels 15; Gaps 1;
(G4S)3 linker
Qy 1 DIQMTQTTSSLSASLGDRVTISCRASQDISKYLNWYQQKPDGTVKLLIYHTSRLHSGVPS 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 22 DIQMTQTTSSLSASLGDRVTISCRASQDISKYLNWYQQKPDGTVKLLIYHTSRLHSGVPS 81
Qy 61 RFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPYTFGGGTKLEIT------------- 107
|||||||||||||||||||||||||||||||||||||||||||||||
Db 82 RFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPYTFGGGTKLEITGGGGSGGGGSGGG 141
Qy 108 --EVKLQESGPGLVAPSQSLSVTCTVSGVSLPDYGVSWIRQPPRKGLEWLGVIWGSETTY 165
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 142 GSEVKLQESGPGLVAPSQSLSVTCTVSGVSLPDYGVSWIRQPPRKGLEWLGVIWGSETTY 201
Qy 166 YNSALKSRLTIIKDNSKSQVFLKMNSLQTDDTAIYYCAKHYYYGGSYAMDYWGQGTSVTV 225
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 202 YNSALKSRLTIIKDNSKSQVFLKMNSLQTDDTAIYYCAKHYYYGGSYAMDYWGQGTSVTV 261
Qy 226 SS 227
||
Db 262 SS 263
Regarding instant claim(s) 68-69, 72-75, 78-80, 83-85, 88, WO599 further teaches TRAC truncation (e.g., TCR α natural endodomain deletion) and/or TRBC truncation (e.g., TCR β natural endodomain deletion) of the modified TCR at the C terminus of each chain, respectively [e.g., ¶ 00226]. WO599 further teaches that the costimulatory domain (CSD, or CD) and/or an activating domain (AD; e.g., functional domain) may be attached at the c-terminal end of TCR chain(s) (e.g., TCRa and/or TCRb) [e.g., ¶ 00161, 00259, 0276;tbls. A1-6, A1-9 SAR class 4, 12, 29].
Regarding instant claim(s) 89-90, WO599 further teaches WT hTCRa, hTCRb, mTCRa, and mTCRb [e.g., ¶ 00148, 00259; tbls. 12]. WO599 further teaches that the costimulatory domain (CSD, or CD) and/or an activating domain (AD; e.g., functional domain) may be attached at the c-terminal end of TCR chain(s) (e.g., TCRa and/or TCRb) [e.g., ¶ 00161, 00259, 0276;tbls. A1-6, A1-9 SAR class 4, 12, 29].
Regarding instant claim(s) 91, WO599 further teaches a mouse TCRa constant chain and a T48C mutation therein [e.g., ¶ 00148].
Regarding instant claim(s) 97-98, WO599 further teaches human and mouse TCRb constant chains and modifications thereto [e.g., ¶ 00148].
Regarding instant claim(s) 111-112, WO599 further teaches that the SAR (e.g., engineered TCR) binds to one or two or more epitopes of one or more antigens [e.g., ¶ 0008-0009, 0021, 0023, 0025, 0033, 0073].
Regarding instant claim(s) 116, WO599 further teaches sorting (e.g., isolating) immune cells comprising the SARs (e.g., modified TCRs) [e.g., ¶ 00611-00614, 0620-0621].
Regarding instant claim(s) 117, WO599 further teaches the immune cell is a T cell or a NK cell [e.g., ¶ 00642, 00648, 00653, 00655, 00658, 00659, 00661, 0675, 0689, 00700].
Regarding instant claim(s) 118-120, WO599 further teaches methods of treating cancer in a subject in need thereof comprising administering a pharmaceutical composition comprising the modified T cell and a suitable carrier (e.g., pharmaceutically acceptable) [e.g., ¶ 00720-00733].
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 69-71 and 75-77 is/are rejected under 35 U.S.C. 103 as being unpatentable over WO2021188599-A1 (hereinafter “WO599”) as applied to claim(s) 66, 68-69, and 72-75 above, and further in view of WO599.
The teachings of WO599 as recited above apply for claims 66, 68-69, and 72-75.
WO599 does not expressly teach that the a (G4S)3 linker joining the C-terminus of the TCRa and/or TCRb chain with the costimulatory domain.
Regarding claim(s) 69-71 and 75-77, WO599 further teaches the C-terminal end of the SAR (e.g., TCR) is connected to an intracellular domain (IC) [e.g., ¶ 00127; tbl. A1-2, A1-6, A1-7], intracellular costimulatory domains [e.g., ¶ 00161, 00259, 0276;tbls. A1-6, A1-9], and G4Sx3 linkers [e.g., ¶ 00258; tbl. 11]. WO599 further teaches that SARs with CAR, TCR, or hybrid backbones [e.g., tbls. A1-2 through A1-9], and that CAR-derived backbones include CAR generations 1-3 [e.g., ¶ 00212]. While not expressly stated, one of ordinary skill in the art would understand that CARs commonly employ (G4S)x3 linker domains between domains, including between the intracellular costimulatory domain and the transmembrane domain.
It would have been prima facie obvious to a person having ordinary skill in the art (PHOSITA) before the effective filing date of the claimed invention to substitute the intracellular domain of the engineered TCR taught by WO559, with the CAR intracellular domain as taught by WO599, in the context of designing and developing engineered TCR comprising a intracellular costimulatory domain. A PHOSITA would have been motivated to substitute the intracellular domain of the engineered TCR taught by WO599 with the CAR intracellular domain as taught by WO599, because WO599 teaches that engineered TCRs may be connected to hybrid backbones, to costimulatory domains, or to intracellular domains, and WO599 further teaches the invention reads on CAR generations 1-3, which are commonly known in the art to comprise G4Sx3 linking domains between intracellular domains. There would have been a reasonable expectation of success for a PHOSITA to substitute the intracellular domain of the engineered TCR as taught by WO599 with CAR intracellular domain as taught by WO599 because WO599 teaches engineered TCRs further comprising hybrid backbones, intracellular domains, or costimulatory domains, and additionally teaches backbones (including intracellular domains thereof) of CARs, which are known in the art to comprise G4Sx3 linkers between costimulatory domains. This rationale aligns with the principle of simple substitution of one known element for another to obtain predictable results, supporting a conclusion of obviousness (see MPEP § 2141).
Thus, the invention as a whole is prima facie obvious over the references, especially in the absence of evidence to the contrary.
Claim(s) 113 is/are rejected under 35 U.S.C. 103 as being unpatentable over WO2021188599-A1 (hereinafter “WO599”) as applied to claim(s) 66 above, and further in view of WO2014127261-A1 (hereinafter “WO261”).
The teachings of WO599 as recited above apply for claim 66.
WO599 does not expressly teach the OX40 costimulatory domain sequence.
Regarding claim(s) 113, WO261 teaches chimeric receptors in T cells, B cells, or NK cells [e.g., title, abstract; ¶ 0004, 0047], and the OX40 costimulatory domain of SEQ ID: 65 [e.g., ¶ 00107], that is the same as the instant claimed OX40 of SEQ ID NO: 11 (see alignment below).
Alignment of instant claimed OX40 (SEQ ID NO: 11) with WO261 (Human OX40 intracellular chain polypeptide, SEQ ID:65):
Query Match 100.0%; Score 198; Length 37;
Best Local Similarity 100.0%;
Matches 37; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 RRDQRLPPDAHKPPGGGSFRTPIQEEQADAHSTLAKI 37
|||||||||||||||||||||||||||||||||||||
Db 1 RRDQRLPPDAHKPPGGGSFRTPIQEEQADAHSTLAKI 37
It would have been prima facie obvious to a person having ordinary skill in the art (PHOSITA) before the effective filing date of the claimed invention to substitute the general OX40 costimulatory domain of the modified TCR comprising an OX40 costimulatory domain as taught by WO599, with the OX40 costimulatory domain sequence taught by WO261, in the context of designing and developing a modified TCR therapeutic. A PHOSITA would have been motivated to substitute the general OX40 costimulatory domain of the modified TCR comprising an OX40 costimulatory domain as taught by WO599 with the OX40 costimulatory domain sequence taught by WO261, because both WO599 and WO261 teach an OX40 costimulatory domain, and OX40 teaches the sequence (WO599 doesn’t). There would have been a reasonable expectation of success for a PHOSITA to substitute the general OX40 costimulatory domain of the modified TCR comprising an OX40 costimulatory domain as taught by WO599 with the OX40 costimulatory domain sequence taught by WO261, because both WO599 teaches the modified TCR structure comprises an OX40 costimulatory domain and WO621 teaches the OX40 sequence. This rationale aligns with the principle of simple substitution of one known element for another to obtain predictable results, supporting a conclusion of obviousness (see MPEP § 2141).
Thus, the invention as a whole is prima facie obvious over the references, especially in the absence of evidence to the contrary.
Free From the Prior Art
During the course of examination, the elected anti-CD19 modified TCR comprising:
(1) a TCRa constant domain comprising one or more modifications selected from: S112L, M114I, G115V, 6ED, K13R, residue 18 deletion, or residue 18 deletion;
(2) a TCRa constant region comprising any one of SEQ ID NOs: 1, 3, 5, 7, 8, 26, 41, 42, 56;
(3) a mTCRb constant domain comprising one or more modifications selected from: S56C, R3K, T6F, K9E, S11A, L12V, residue 17 deletion, or residues 21-25 deletion; or
(4) a TCRa constant region comprising any one of SEQ ID NOs:2, 4, 6, 9, 27, 43, 57,
was found to be non-obvious in view of the prior art. Briefly, for (1) and (3) while one or more of the mutations listed exist in the prior art, not all were found, and no rationale to make the substitutions to arrive at the instant invention were found in the prior art; and (2) and (4) while the TCRa and TCRb constant domain sequences are well-known in the prior art, no rationale was found in the art to specifically substitute one of the instant claimed constant domains in place of the taught constant domain sequences of WO599 to arrive at the instant invention.
Conclusion
No claims are currently allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to AMY M CHATTIN whose telephone number is (571)270-0646. The examiner can normally be reached T-F 0600-1600 PST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Julie Wu can be reached at (571) 272-5205. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/AMY M. CHATTIN/Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643