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 .
DETAILED ACTION
The amendment filed February 10, 2026 in response to the Office Action of November 12, 2025 is acknowledged and has been entered.
Claims 40-43, 46, 48, 50, and 55 have been amended.
Claims 37-39 have been cancelled.
Claims 40-56 are pending.
Claims 55 and 56 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected inventions or species, there being no allowable generic or linking claim.
Claims 40-54 are currently under consideration as drawn to the elected invention.
Claim objections set forth in the previous Office Action of November 12, 2025 are hereby withdrawn in view of the claim amendments.
In view of cancelation of claims 37-39, the 112(b) rejection set forth in the previous Office Action of November 12, 2025 is hereby withdrawn.
In view of cancelation of claims 37-39, the 112(d) rejection set forth in the previous Office Action of November 12, 2025 is hereby withdrawn.
Because the amended claims now depend on claim 40, the 112(a) rejection set forth in the previous Office Action of November 12, 2025 is hereby withdrawn.
MAINTAINED/MODIFIED REJECTION
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.
Claims 40-53 are rejected under 35 U.S.C. 103 as being unpatentable over Sommermeyer (Sommermeyer et al., The Journal of Immunology, 2010, 184: 6223-6231, Publication Date: 06/01/2010, cited in IDS of 11/25/2024, of record) in view of Haga-Friedman (Haga-Friedman et al., The Journal of Immunology, 2012, 188: 5538-5546, Publication Year: 2012, cited in IDS of 11/25/2024, of record).
It is noted that the amino acid sequence of human TCRβ chain constant domain cited by Sommermeyer (see Fig. 2A) and the amino acid sequence of human TCRβ chain constant domain disclosed by the instant specification (SEQ ID NO: 2 or SEQ ID NO: 3) have different starting amino acid. Sequence of Sommermeyer has one more amino acid compared to the sequence of the instant application. However, in the claims, the position numbers appear to be based on the sequence of Sommermeyer. This is why the position numbers for human TCRβ chain constant domain recited by the instant claims appear off by one according to SEQ ID NO: 2 or SEQ ID NO: 3.
Sommermeyer teaches that one critical prerequisite for TCR gene therapy is sufficient expression of transferred TCRs. Several strategies to achieve optimal expression were developed, including “murinization”, which replaces the human TCRα and TCRβ constant regions by their murine counterparts (Abstract).
Sommermeyer teaches that nine amino acids are sufficient for the improved expression of human TCRs, including a human TCRβ chain with K-18, A-22, I-133, A-136, and H-139 (Fig. 3E; and page 6226, col. 2, para. 2) and a human TCRα chain with S-90, D-91, V-92 and P-93 (Fig. 4C; and page 6227, col. 1, para. 2-3). As evidenced by Fig. 2A, human TCRβ chain with K-18, A-22, I-133, A-136, and H-139 would comprise substitutions of E18K, S22A, F133I, E136/A and Q139H. As evidenced by Fig. 4A, human TCRα chain with S-90, D-91, V-92 and P-93 would comprise substitutions of P90S, E91D, S92V, S93P.
Sommermeyer teaches that the TCR targets NYESO-1 (not binding to MAGEA4) (page 6225, col. 1, para. 3). Sommermeyer teaches that TCR with mutations has increased expression (Fig. 5, page 6227, col. 2, para. 2; and results from pages 6227-6228).
Sommermeyer teaches mmTCR chains with the substitutions preferentially pair to each other (46% vs 27%) and result in more stable TCR complex (page 6228, col. 2, paras. 2-3).
Sommermeyer teaches mmTCR chains with the substitutions enhances IFNγ secretion significantly (Fig. 6B).
Sommermeyer teaches that nine amino acid derived from murine TCR C region are sufficient to significantly improve the cell surface expression of human TCRs and the function of TCR gene modified T cells (page 6224, col. 1, para. 3).
Sommermeyer teaches as set forth above, however, Sommermeyer does not teach hydrophobic amino acid substitution at position 115, 118, and 119 of constant domain of TCRα chain.
Haga-Friedman teaches that TCR exhibits a lack of stability associated with the presence of positively charged residues in its transmembrane (TM) region. Incorporation of hydrophobic residues at evolutionarily permissive positions resulted in an enhanced surface expression of the TCR chains, leading to an improved cellular avidity and anti-tumor TCR activity (Abstract).
Haga-Friedman teaches human TCRα chain TM region mutants with S115L, G118V and F119L substitutions (see Fig. 1A, α-LVL mutant).
Haga-Friedman teaches that TCR with α-LVL mutations have significant higher surface expression, and higher IFN-γ secretion (Fig. 3).
Haga-Friedman teaches that the combination of murinization and LVL mutations can noticeably improve TCR surface expression and function (§ Combining LVL mutations with other variable and constant region TCRs, on pages 5544-5545).
It would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to combine the teaching of Sommermeyer with the teaching of Haga-Friedman by combining the substitutions taught by Sommermeyer and Haga-Friedman, since both relate to the same problem of increasing expression and activity of TCRs and the two sets of substitutions can enhance surface expression and TCR activity. Furthermore, one of ordinary skill in the art would have had a reasonable expression of success because Haga-Friedman teaches the combination of murinization and LVL mutations may further improve TCR surface expression and function (§ Combining LVL mutations with other variable and constant region TCRs, on pages 5544-5545). The motivation would be to generate a TCR with better therapeutic activity.
Regarding claim 38-40, as evidenced by Fig. 2A of Sommermeyer, engineered human TCRβ chain with K-18, A-22, I-133, A-136, and H-139 would comprise substitutions of E18K, S22A, F133I, E136/A and Q139H. As evidenced by Fig. 4A of Sommermeyer, engineered human TCRα chain with S-90, D-91, V-92 and P-93 would comprise substitutions of P90S, E91D, S92V, S93P. Haga-Friedman further teaches TCRα chain TM region mutants with S115L, G118V and F119L substitutions (see Fig. 1A, α-LVL mutant). Sommermeyer and Haga-Friedman combined would teach an engineered TCR comprising (a) an engineered human TCRα chain constant domain comprises amino acid substitutions, P90S, E91D, S92V, S93P, S115L, G118V, and Fl19L; and (b) an engineered human TCRβ chain constant domain comprises amino acid substitutions E18K, S22A, F133I, E136A, and Q139H. As shown below, SEQ ID NO: 4 comprises 7 substitutions (P90S, E91D, S92V, S93P, S115L, G118V, and Fl19L) in human TCRα chain constant domain and SEQ ID NO: 5 comprises 5 substitutions (E18K, S22A, F133I, E136A, and Q139H based on Sommermeyer’s numbering) in human TCRβ chain constant domain:
SEQ ID NO: 1 (human TCRα chain constant domain ) vs SEQ ID NO: 4:
Query Match 94.4%; Score 676; DB 1; Length 140;
Best Local Similarity 95.0%;
Matches 133; Conservative 1; Mismatches 6; Indels 0; Gaps 0;
Qy 1 IQNPDPAVYQLRDSKSSDKSVCLFTDFDSQTNVSQSKDSDVYITDKTVLDMRSMDFKSNS 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 IQNPDPAVYQLRDSKSSDKSVCLFTDFDSQTNVSQSKDSDVYITDKTVLDMRSMDFKSNS 60
Qy 61 AVAWSNKSDFACANAFNNSIIPEDTFFPSSDVPCDVKLVEKSFETDTNLNFQNLLVIVLR 120
||||||||||||||||||||||||||||| : ||||||||||||||||||||| || |
Db 61 AVAWSNKSDFACANAFNNSIIPEDTFFPSPESSCDVKLVEKSFETDTNLNFQNLSVIGFR 120
Qy 121 ILLLKVAGFNLLMTLRLWSS 140
||||||||||||||||||||
Db 121 ILLLKVAGFNLLMTLRLWSS 140
SEQ ID NO: 2 (human TCRβ chain constant domain) vs SEQ ID NO: 5:
Query Match 97.6%; Score 906; DB 1; Length 176;
Best Local Similarity 97.2%;
Matches 171; Conservative 2; Mismatches 3; Indels 0; Gaps 0;
Qy 1 DLNKVFPPEVAVFEPSEAEISHTQKATLVCLATGFFPDHVELSWWVNGKEVHSGVSTDPQ 60
||||||||||||||||:|||:|||||||||||||||||||||||||||||||||||||||
Db 1 DLNKVFPPEVAVFEPSKAEIAHTQKATLVCLATGFFPDHVELSWWVNGKEVHSGVSTDPQ 60
Qy 61 PLKEQPALNDSRYCLSSRLRVSATFWQNPRNHFRCQVQFYGLSENDEWTQDRAKPVTQIV 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 PLKEQPALNDSRYCLSSRLRVSATFWQNPRNHFRCQVQFYGLSENDEWTQDRAKPVTQIV 120
Qy 121 SAEAWGRADCGFTSVSYQQGVLSATILYEILLGKATLYAVLVSALVLMAMVKRKDF 176
||||||||||| || || ||||||||||||||||||||||||||||||||||||||
Db 121 SAEAWGRADCGITSASYHQGVLSATILYEILLGKATLYAVLVSALVLMAMVKRKDF 176
Thus, as set forth above, Sommermeyer and Haga-Friedman combined teach the TCR of claim 40.
Regarding claim 41, Sommermeyer teaches that mmNY-TCR binds to NY-ESO-1 peptide pulsed cells (Fig. 5B; and page 6227, col. 2, para. 2).
Regarding claim 42, Sommermeyer teaches that nine amino acid derived from murine TCR C region are sufficient to significantly improve the cell surface expression of human TCRs and the functional avidity of TCR gene modified T cells (page 6224, col. 1, para. 3; last paragraph of Discussion). Thus, one of ordinary skill in the art would have a reasonable expectation that TCRs with nine amino acid substitutions derived from murine TCR C region and hydrophobic amino acid substitutions in TM region would have higher surface expression and increased avidity compared to TCRs with only hydrophobic amino acid substitutions in TM region.
Regarding claim 43-45, Sommermeyer teaches that mmTCR chains were combined by a 2A peptide linker sequence (P2A) (§ Construction of retroviral vectors). Sommermeyer teaches that mmTCR chains of NY-TCR were linked via the P2A element to ensure simultaneous expression of both TCR chains (§ Primary human T cells modified with mmTCRs show increased multimer binding compared with cells transduced with wtTCRs, on page 6227). As evidenced by paragraph [0158-0160] of the instant publication US 2023/0124640, 2A peptide is a viral self-cleaving peptide. Thus, the mmNY-TCR expressed in primary human T cells would read on the claimed fusion protein.
Regarding claims 46-49, Sommermeyer teaches mmTCR chain genes were combined by a 2A peptide linker sequence (P2A) to generate MP71 vector expressing both TCR chains simultaneously. Thus, MP71 would read on an expression vector comprising a nucleic acid encoding the claimed TCR or fusion protein as instantly claimed.
Regarding claims 50-53, the human PBL cells transduced with mmNY-TCR (see § Primary human T cells modified with mmTCRs show increased multimer binding compared with cells transduced with wtTCRs, on page 6227). Because PBL cells contain immune effector cells such as T cell and NK cells, PBL cells transduced with mmNY-TCR would read on claims 50-53.
Claim 54 is rejected under 35 U.S.C. 103 as being unpatentable over Sommermeyer (Sommermeyer et al., The Journal of Immunology, 2010, 184: 6223-6231, Publication Date: 06/01/2010, cited in IDS of 11/25/2024, of record) in view of Haga-Friedman (Haga-Friedman et al., The Journal of Immunology, 2012, 188: 5538-5546, Publication Year: 2012, cited in IDS of 11/25/2024, of record), as applied to claims 40-53 above, and further in view of Brandt (Brandt et al., WO2019/070541, cited in IDS of 11/25/2024).
Sommermeyer and Haga-Friedman teach the TCR of claim 37 and the cell of claim 51 as set forth above. Sommermeyer further teaches that TCR-gene modified T cells into tumor patients (TCR gene therapy) is a novel approach to treat cancer (Abstract). Sommermeyer further teaches that the human TCRs with substitutions led to increase functional avidity of TCR gene-modified T cells which could be selected for use in TCR gene therapy (the last paragraph of Discussion).
However, Sommermeyer and Haga-Friedman do not explicitly teach a pharmaceutical composition comprising a pharmaceutically acceptable carrier and the cell of claim 51.
Brandt teaches binding molecules such as T cell receptors (TCRs) ([0161], claims 1).
Brandt teaches genetically engineered cells expressing the binding molecules, wherein the cells are T cells and/or NK cells ([0495], claims 255, 272, 273).
Brandt teaches treating diseases such as cancers with the genetically engineered cells expressing the binding molecules, wherein the cells are T cells and/or NK cells (claims 296, 298).
Brandt teaches TCRs binding to tumor associated antigens, such as NYESO-1 ([0840]).
Brandt teaches pharmaceutical composition including engineered cells expressing TCR, and the composition includes one or more optional pharmaceutically acceptable carrier, and components of a pharmaceutical composition ([0922]-[0925]).
It would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to generate immune effector cell expressing the TCR of instant claim 37 as taught by Sommermeyer and Haga-Friedman, and to use it in a pharmaceutical composition further comprising a pharmaceutically acceptable carrier, because Sommermeyer and Haga-Friedman teach the modified TCRs could be used in TCR therapy for treating cancers and Brandt teaches making the pharmaceutical composition comprising TCR-expressing T cells and components in a pharmaceutical composition. Given that the components are well known in the art, as evidenced by Brandt, one of ordinary skill in the art would have had reasonable expectation of success to reach the claimed pharmaceutical composition. The motivation would have been to develop a pharmaceutical composition for therapeutical applications.
Response to Arguments
For the 103 rejections applicant first argues:
Sommermeyer is a research article that mentions examples of the "minimal murinization" of the constant region of the alpha- and beta-chains of TCRs. The authors of Sommermeyer emphasize throughout the document that only nine specific amino acid substitutions are required to achieve the desired result of minimal murinization-five substitutions in the alpha chain and four substitutions in the beta chain.
Sommermeyer specifically teaches away from any more than these nine substitutions. Indeed, Sommermeyer specifically teaches away from further murinizing or modifying any additional TCRa residues. Thus, Sommermeyer fails to teach or suggest engineered TCRs as required by the presently amended claims, which comprise, inter alia, a TCRa constant region comprising SEQ ID NO: 4 and a TCRβ constant region comprising SEQ ID NO: 5 or SEQ IDNO: 6-sequences that comprise additional modifications as compared to those taught in Sommermeyer. Indeed, the TCRβ chain of Sommermeyer comprises an E (glutamic acid; Glu) residue at position 10 (see, for example Figure 2A of Sommermeyer), while claimed SEQ ID NO: 6 comprises a (lysine; Lys) residue at that same position (corresponds to position 9 in SEQ ID NO: 6). Moreover, and as acknowledged by the Office, Sommermeyer does not teach or suggest any of the claimed additional mutations of S115L, G118V, or F119L that are present in the claimed SEQ ID NOs.
Accordingly, one of skill in the art would not be motivated by the teachings of Sommermeyer to further modify the TCRa/~ chains to arrive at the pending claims.
Applicant’s arguments have been fully considered but they are not persuasive. It is acknowledged that that the nine amino acid substitutions are sufficient to significantly improve the cell surface expression of human TCRs and the function of TCR gene-modified T cells. By only using these substitutions, it is possible to achieve levels of TCR expression and functional avidity in rec1p1ent T cells that are comparable to fully mu TCRs (as pointed out by Applicant). However, Sommermeyer’s results and statement only indicate minimal murinization (9 amino-acid substitutions) are enough for achieve most advantages through murinization. This would not prevent one ordinary skill in the art to further improve TCR through other modifications. In particular, Haga-Friedman explicitly teaches that the combination of murinization and LVL mutations can noticeably improve TCR surface expression and function (§ Combining LVL mutations with other variable and constant region TCRs, on pages 5544-5545). As set forth above, one of ordinary skill in the art would combine the teaching of Sommermeyer with the teaching of Haga-Friedman by combining the substitutions taught by Sommermeyer and Haga-Friedman, since both relate to the same problem of increasing expression and activity of TCRs and the two sets of substitutions can enhance surface expression and TCR activity. Furthermore, one of ordinary skill in the art would have had a reasonable expression of success because Haga-Friedman teaches the combination of murinization and LVL mutations may further improve TCR surface expression and function (§ Combining LVL mutations with other variable and constant region TCRs, on pages 5544-5545).
Applicant further argues the specific sequences represented by SEQ ID NOs: 4-6:
Indeed, the TCRβ chain of Sommermeyer comprises an E (glutamic acid; Glu) residue at position 10 (see, for example Figure 2A of Sommermeyer), while claimed SEQ ID NO: 6 comprises a (lysine; Lys) residue at that same position (corresponds to position 9 in SEQ ID NO: 6). Moreover, and as acknowledged by the Office, Sommermeyer does not teach or suggest any of the claimed additional mutations of S115L, G118V, or F119L that are present in the claimed SEQ ID NOs.
Applicant’s arguments have been fully considered but they are not persuasive. Although SEQ ID NO: 6 comprises a Lys residue at position 9, but SEQ ID NO: 5 comprises a Glu at position 9, which is the same as shown in Fig 2A of Sommermeyer. Thus, as set forth above, by incorporating substitutions taught by Sommermeyer and Haga-Friedman, one of ordinary skill in the art would reach SEQ ID NO: 4 and SEQ ID NO: 5 as set forth above.
Applicant further argue that the claimed TCRs show the surprising and unexpected results.
TCR with the claimed combination of minimal murine amino acid substitutions and hydrophobic amino acid substitutions in the TCRa transmembrane domain synergistically increases TCR stability, expression, specific pairing and functional avidity. Moreover, the present inventors have surprisingly discovered that engineering the TCR constant domains can imbue many TCRs (both high affinity and low affinity) with the foregoing characteristics; thus, making them a more tractable immunotherapy strategy….
For example, Example 1 demonstrates that lentiviral vectors encoding engineered TCRs comprising both murinization and hydrophobic substitutions show a synergistic 4-fold increase in TCR expression in T cells, compared to T cells transduced with a lentiviral vector encoding wild-type TCR (FIG. 1 and Example 1 at pages 69-70 of the PCT application, as published).
Examples 2 and 5 further demonstrates this synergistic result. For example, Example 2 (FIGs. 2A-2B) provides experimental evidence demonstrating a 4-fold increase in T cells transduced with engineered TCRs as compared to wild-type TCRs. Example 5 (FIGs. 5A-5B and 6) provides additional evidence that engineered TCRs demonstrated increased specific pairing in transduced T cells.
In Example 3, Applicant surprisingly shows that TCR mispairing is eliminated when T
cells are transduced with engineered TCRs compared to wild-type TCRs (FIGs. 3A-3B). This
result is surprising, as TCR mispairing is a significant obstacle facing other TCR gene therapies.
Furthermore, the engineered TCRs demonstrate potent anti-tumor properties, as evidenced in
IFNy and cytotoxicity assays in Example 4 (FIGs. 4A and 4B) compared to wild-type TCRs.
Applicant’s arguments have been fully considered but they are not persuasive. First, the Examples shows the results for two TCRs with claimed substitutions: MAGEA4 TCR and NYESO-1 TCR without disclosing the sequence of TCRα and TCRβ chain constant domains. It is not clear whether the two TCRs comprise the a TCRα chain constant domain comprising SEQ ID NO: 4 and a TCRβ chain constant domain comprising SEQ ID NO: 5 or SEQ ID NO: 6.
Regarding “unexpected” increased cell surface expression level, Sommermeyer teaches that TCR with mutations has increased expression (Fig. 5, page 6227, col. 2, para. 2; and results from pages 6227-6228). Haga-Friedman teaches that TCR with α-LVL mutations have significant higher surface expression (Fig. 3). Haga-Friedman further teaches that the combination of murinization and LVL mutations can noticeably improve TCR surface expression and function (§ Combining LVL mutations with other variable and constant region TCRs, on pages 5544-5545). Thus, an increased expression is expected based on the teachings of Sommermeyer and Haga-Friedman. Fig. 1 and Example 1 of the instant specification shows an additive effects of combining the substitutions in MAGEA4 TCR. The increased level for NYESO-1 TCR was less significant (FIGS. 5A-5B and 6). Taken together, the results of the specification are not unexpected.
Regarding improved pairing with claimed TCRs, Sommermeyer teaches mmTCR chains with the substitutions preferentially pair to each other (46% vs 27%) and result in more stable TCR complex (page 6228, col. 2, paras. 2-3). Thus, an improved pairing for the claimed TCRs is also expected by Sommermeyer.
Regarding increased IFNγ secretion and cytotoxicity (Example 4, FIGS 4A and 4B, all based on MAGEA4 TCR), Sommermeyer teaches mmTCR chains with the substitutions enhances IFNγ secretion significantly (Fig. 6B). Haga-Friedman teaches that TCR with α-LVL mutations have significant higher surface expression, and higher IFN-γ secretion (Fig. 3). Thus, the results of increased IFNγ secretion and cytotoxicity are not unexpected.
Additionally, the evidence of nonobviousness must be commensurate in scope with the claims to rebut the prima facie case of obviousness. See MPEP 716.02 (d). In this case, the claims are not limited to the specific TCRs tested in the specification. The claims are not limited to these configurations, i.e. TCRβ chain can be either SEQ ID NO: 5 or SEQ ID NO: 6; the TCR can target different antigens. The effects of the substitutions on different TCRs are different: ~3 fold for expression of MAGEA4 TCR (Fig. 1) vs. less than 2 fold for expression of NYESO-1 TCR (Fig. 5A). The effects of substitutions are context dependent. Thus, the examples are not commensurate in scope with the claimed invention and is not probative on the non-obviousness of the claimed invention.
Regarding rejection to claim 54, Applicant is reiterating similar arguments set forth above. Thus for the reasons set forth above the rejection is maintained.
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 40-41 and 43-52 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 5, 10, 12, 15, 16, 20, 21, 28, 34, 37, 38, 46, 47, 49, 50, 52, 54, 60, 62, 67, 69, 71, 73, 77, 78, 85, 98, 101, 103, 104, 106, 107, 109, 111, 112, 116-119, 123-128, 134-141 and 143 of copending Application No. 18/578,367 (hereinafter Appl. 367, US 2024/0342215 A1). Although the claims at issue are not identical, they are not patentably distinct from each other because:
The claims of Appl. 367 teach an engineered T cell receptor (TCR) comprising: a) a TCRα polypeptide comprising a TCRα variable domain; b) a TCRβ polypeptide comprising a TCRβ variable domain; and c) one or more antigen-binding domains linked to the TCRα variable domain and/or TCRβ variable domain, … (claim 1); engineered TCR of claim 1, wherein the TCRα polypeptide comprises a TCRα constant domain, the TCRP polypeptide comprises a TCRβ constant domain (claim 3).
The claims of Appl. 367 teach that the engineered TCR of claim 1, wherein: the TCRα constant domain comprises an amino acid sequence at least 90% identical to an amino acid sequence as set forth in SEQ ID NOs: 82 or 88, and/or the TCRβ constant domain comprises an amino acid sequence at least 90% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 80, 81, 86, or 87, …. (claim 50). As shown below, SEQ ID NO: 88 of Appl. 367 is identical to SEQ ID NO: 4 of the instant application:
Query Match 100.0%; Score 716; Length 140;
Best Local Similarity 100.0%;
Matches 140; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 IQNPDPAVYQLRDSKSSDKSVCLFTDFDSQTNVSQSKDSDVYITDKTVLDMRSMDFKSNS 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 IQNPDPAVYQLRDSKSSDKSVCLFTDFDSQTNVSQSKDSDVYITDKTVLDMRSMDFKSNS 60
Qy 61 AVAWSNKSDFACANAFNNSIIPEDTFFPSSDVPCDVKLVEKSFETDTNLNFQNLLVIVLR 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 AVAWSNKSDFACANAFNNSIIPEDTFFPSSDVPCDVKLVEKSFETDTNLNFQNLLVIVLR 120
Qy 121 ILLLKVAGFNLLMTLRLWSS 140
||||||||||||||||||||
Db 121 ILLLKVAGFNLLMTLRLWSS 140
SEQ ID NO: 86 of Appl. 367 is identical to SEQ ID NO: 5 of the instant application:
Query Match 100.0%; Score 929; Length 176;
Best Local Similarity 100.0%;
Matches 176; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 DLNKVFPPEVAVFEPSKAEIAHTQKATLVCLATGFFPDHVELSWWVNGKEVHSGVSTDPQ 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 DLNKVFPPEVAVFEPSKAEIAHTQKATLVCLATGFFPDHVELSWWVNGKEVHSGVSTDPQ 60
Qy 61 PLKEQPALNDSRYCLSSRLRVSATFWQNPRNHFRCQVQFYGLSENDEWTQDRAKPVTQIV 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 PLKEQPALNDSRYCLSSRLRVSATFWQNPRNHFRCQVQFYGLSENDEWTQDRAKPVTQIV 120
Qy 121 SAEAWGRADCGITSASYHQGVLSATILYEILLGKATLYAVLVSALVLMAMVKRKDF 176
||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 SAEAWGRADCGITSASYHQGVLSATILYEILLGKATLYAVLVSALVLMAMVKRKDF 176
Thus, as set forth above, TCR comprising SEQ ID NO: 86 and 88 taught by of claims 1, 3 and 50 of Appl. 367 reads on TCRs of instant claims 37-40 of the instant applications.
Regarding claim 41, the claims of Appl. 367 teach that the TCR binds to a target antigen, such as NYESO-1 (claim 16).
The claims of Appl. 367 teach a fusion polypeptide comprising: a) a TCRβ polypeptide comprising a TCRβ variable domain; b) a polypeptide cleavage signal; and b) a TCRα polypeptide comprising one or more antigen-binding domains, a polypeptide linker, and a TCRα variable domain; or …. (claim 54); the fusion protein of claim 54 wherein the TCRβ polypeptide comprising a TCRβ constant domain, and the TCRα polypeptide comprising TCRα domain,… (claim 60).
The claims of Appl. 367 teach that the engineered TCRs of claim 54, wherein: the TCRα constant domain comprises an amino acid sequence at least 90% identical to an amino acid sequence as set forth in SEQ ID NOs: 82 or 88, the TCRβ constant domain comprises an amino acid sequence at least 90% identical to an amino acid sequence as set forth in any one of SEQ ID NOs: 80, 81, 86, or 87, …. (claim 107).
The claims of Appl. 367 teach the fusion polypeptide of claim 54 wherein the fusion polypeptide further comprising a polypeptide cleavage signal (claim 111); wherein the cleavage signal is a viral 2A peptide (claim 112).
Thus, claims 54, 60, 107, 111, 112 of Appl. 367, teach the fusion proteins of instant claims 43-45.
Regrading instant claims 46-52, the claims of Appl. 367 teach a polynucleotide encoding the engineered TCR (claim 124); a vector comprising the polynucleotide (claim 125); the vector is an expression vector, retroviral vector, or a lentiviral vector (claim 126); a cell comprising the engineered TCR (claim 127); wherein the cell is a T cell, NK cell or NKT cell (claim 128).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim 42 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 5, 10, 12, 15, 16, 20, 21, 28, 34, 37, 38, 46, 47, 49, 50, 52, 54, 60, 62, 67, 69, 71, 73, 77, 78, 85, 98, 101, 103, 104, 106, 107, 109, 111, 112, 116-119, 123-128, 134-141 and 143 of copending Application No. 18/578,367 (hereinafter Appl. 367, US 2024/0342215 A1), as applied to claims 37-41 and 43-52, and further in view of Sommermeyer (Sommermeyer et al., The Journal of Immunology, 2010, 184: 6223-6231, Publication Date: 06/01/2010, cited in IDS of 11/25/2024, of record).
The claims of Appl. 367 teach the TCR of instant claim 37. However, the claims of Appl. 367 do not teach that (a) the TCR expression and avidity is increased compared to a TCR that comprises a minimally murinized TCRα chain and a minimally murinized TCRβ chain but wherein the TCRα chain transmembrane domain does not comprise hydrophobic amino acid substitutions; and/or (b) wherein the TCR expression and avidity is increased compared to a TCR that does not comprise a minimally murinized TCRα chain and a minimally murinized TCRβ chain but wherein the TCRα chain transmembrane domain comprises hydrophobic amino acid substitutions.
Sommermeyer’s teachings are described above. In particular, Sommermeyer teaches that nine amino acid derived from murine TCR C region are sufficient to significantly improve the cell surface expression of human TCRs and the functional avidity of TCR gene modified T cells (page 6224, col. 1, para. 3; last paragraph of Discussion). As set forth above, the claims of Appl. 367 teach TCRs comprising a minimally murinized TCRα chain and a minimally murinized TCRβ chain, as taught by Sommermeyers. Thus, one of ordinary skill in the art would have a reasonable expectation that TCRs with nine amino acid substitutions derived from murine TCR C region and hydrophobic amino acid substitutions in TM region would have higher surface expression and increased avidity compared to TCRs with only hydrophobic amino acid substitutions in TM region.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 53-54 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 5, 10, 12, 15, 16, 20, 21, 28, 34, 37, 38, 46, 47, 49, 50, 52, 54, 60, 62, 67, 69, 71, 73, 77, 78, 85, 98, 101, 103, 104, 106, 107, 109, 111, 112, 116-119, 123-128, 134-141 and 143 of copending Application No. 18/578,367 (hereinafter Appl. 367, US 2024/0342215 A1), as applied to claims 37-41 and 43-52, and further in view of Brandt (Brandt et al., WO2019/070541, cited in IDS of 11/25/2024).
The claims of Appl. 367 teach T cells expressing the TCR which comprising the TCRα and TCRβ constant domains of instant claim 50. However, the claims of Appl. 367 do not teach a composition of instant claim 53, or a pharmaceutical composition of instant claim 54.
Brandt teaches binding molecules such as T cell receptors (TCRs) ([0161], claims 1).
Brandt teaches genetically engineered cells expressing the binding molecules, wherein the cells are T cells and/or NK cells ([0495], claims 255, 272, 273).
Brandt teaches treating diseases such as cancers with the genetically engineered cells expressing the binding molecules, wherein the cells are T cells and/or NK cells (claims 296, 298).
Brandt teaches TCRs binding to tumor associated antigens, such as NYESO-1 ([0840]).
Brandt teaches pharmaceutical composition including engineered cells expressing TCR, and the composition includes one or more optional pharmaceutically acceptable carrier ([0922]-[0925]).
It would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to generate immune effector cell (e.g. T cells) expressing the TCR of instant claim 51 as taught by the claims of Appl. 367, and to use it in a pharmaceutical composition further comprising a pharmaceutically acceptable carrier, because Brandt teaches making the pharmaceutical composition comprising TCR-expressing T cells for treating various diseases including cancers. One of ordinary skill in the art would have had reasonable expectation of success to make a pharmaceutical composition comprising the T cells expressing the engineered TCRs (e.g. comprising SEQ ID NOs 86 and 88), and a pharmaceutically acceptable carrier, because Brandt teach the components for making pharmaceutical compositions, and the components are well known in the art. The motivation would have been to make a composition for therapeutical applications.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
For the Double Patenting rejections applicant argues:
Appl. 367 (the later-filed application) has a patent term filing date of July 14, 2022, while
the instant application (the earlier filed application) has a patent term filing date of March 26,
2021. Applicants respectfully submit that the foregoing provisional nonstatutory obviousness
Type double patenting rejection is the only rejection remaining in the instant application, the
earlier filed application. Moreover, Appl. 367, the later-filed application, has not yet been
examined. Accordingly, Applicants respectfully request that the Examiner withdraw the foregoing provisional nonstatutory obviousness-type double patenting rejection in the present
application. If appropriate, the issue of obviousness-type double-patenting can then be addressed in the later filed Appl. 367.
Applicant’s arguments have been fully considered but they are not persuasive because the claims of the instant application are still obvious in view of the co-pending claims and a terminal disclaimer has not been filed. In addition, the rejection is not the only rejection remained. MPEP 804 I-B states: “The “provisional” double patenting rejection should continue to be made by the examiner in each application as long as there are conflicting claims in more than one application unless that “provisional” double patenting rejection is the only rejection remaining in at least one of the applications.” Therefore, the rejections above are maintained for the reasons of record.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHENG LU whose telephone number is (571)272-0334. The examiner can normally be reached Monday-Friday 8-5.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Samira Jean-Louis can be reached at (571)270-3503. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/CHENG LU/Examiner, Art Unit 1642
/PETER J REDDIG/Primary Examiner, Art Unit 1646
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