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 .
Application Status
The Response to the non-final Office Action filed June 22, 2026 is acknowledged. Claims 1-2, 9, 11, 14, 32, and 34-35 are considered to be pending. Claim 1 has been amended. Claims 16-17, 22, 24-25, 27-28, and 31 are considered to be canceled. Claims 32 and 34-35 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Claims 1-2, 9, 11, and 14 are under examination herein.
Notice Regarding Non-Compliant Claim Amendments
It is noted that claims 15-31 are annotated as canceled in the amended claims filed June 22, 2026, but that claims 16-17, 22, 24-25, 27-28, and 31 also remain in the claim set and are annotated as “withdrawn”. It is further noted that Applicant's Remarks filed June 22, 2026 state that claims 16-17, 22, 24-25, 27-28, and 31 have been canceled.
In the interest of compact prosecution, these claims will be considered canceled as attested by Applicant in the Remarks filed June 22, 2026 (see page 5).
Applicant is advised to follow the rules of MPEP § 714 (in particular section (II)(C)) in future amendment submissions.
WITHDRAWN REJECTIONS
The rejection of claims 1, 9, 11, and 14 under 35 U.S.C. § 112(b) is withdrawn in view of Applicant's amendments to claim 1.
The rejection of claim 2 under 35 U.S.C. § 112(d) is withdrawn in view of Applicant's amendments to claim 1.
The rejection of claim 11 under 35 U.S.C. § 112(a) for failing to satisfy the written description requirement is withdrawn in view of Applicant's amendments to the claim.
The rejection of claims 1-2 and 9 under 35 U.S.C. § 102 as being anticipated by Zhou ‘802 (WO 2022/095802 A1; cited in IDS) is withdrawn in view of Applicant's amendment to claim 1.
The rejection of claims 1 and 14 under 35 U.S.C. § 103 as being unpatentable over Zhou ‘802 (WO 2022/095802 A1) in view of Liu (Cell Research (2017) 27: 154-157) is withdrawn in view of Applicant's amendment to claim 1.
The prior grounds of rejection of claims 1-2, 9, and 14 under 35 U.S.C. § 103 as being unpatentable over Zhou ‘591 (WO 2022/012591 A1; cited in IDS) in view of Kim (Nature Biotechnology (2017) 35(8): 722-723) and Zhou ‘802 (WO 2022/095802 A1), and of claims 1 and 11 further in view of Perez (US 2020/0246382 A1; cited in IDS), are withdrawn in view of Applicant's amendment to claim 1.
The prior provisional grounds of rejection of claims 1-2, 9, and 11 on the grounds of non-statutory double patenting over U.S. Patent Application No. 18/639,066, and of claims 1 and 14 further in view of Liu (Cell Research (2017) 27: 154-157), are withdrawn in view of Applicant's amendment to claim 1.
NEW REJECTIONS NECESSITATED BY CLAIM AMENDMENT
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.
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.
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.
(1)
Claims 1-2, 9, and 14 are rejected under 35 U.S.C. 103 as being unpatentable over Zhou (WO 2022/012591 A1; cited in IDS; hereafter “Zhou ‘591”) in view of Kim (Nature Biotechnology (2017) 35(8): 722-723; cited in PTO-892) and Zhou ‘802 (WO 2022/095802 A1; cited in IDS). This is a new grounds of rejection necessitated by claim amendment.
Zhou ‘591 describes engineered immune cells in which the expression of at least one MHC-related gene (e.g., RFX5, TAP1, or B2M), at least one NK activating receptor binding molecule, and at least one TCR/CD3 gene (e.g., TRAC) are suppressed or silenced, wherein said cells also express a chimeric antigen receptor that binds to a target selected from CD19, CD20, and others, “and any combination thereof” (e.g., Abstract; Invention Summary, ¶ 0006-0019; claims 1-13 of machine translation), pertinent to claims 1 and 9. Relevant to claim 2, Zhou ‘591 teaches that the immune cells are T cells or NK cells (e.g., ¶ 0019-0020; claims 13-14 of machine translation). Relevant to claim 14, Zhou ‘591 discloses that CRISPR/Cas9 was used to generate T cells having reduced expression of B2M, RFX5, and TRAC according to the invention, for which the NK cell killing effect was inhibited (e.g., Detailed Implementation/Examples, ¶ 0114-0119; Figure 3 of machine translation). Zhou ‘591 acknowledges that “since MHC molecules are key molecules for NK cells to recognize ‘autologous cells’, the complete inactivation of MHC class I molecules such as B2M will cause NK cells to regard the reinfused engineered immune cells as ‘foreign’ and kill them, ultimately affecting the survival and persistence of the reinfused cells, and thus affecting the treatment effect” (machine translation, ¶ 0004).
However, Zhou ‘591 does not expressly teach an embodiment in which expression of endogenous B2M is not engineered or otherwise altered in the engineered immune cell.
Kim discusses strategies for engineering pluripotent stem cells (PSCs), which can differentiate into any cell type, to avoid immune detection and rejection (page 722). Kim teaches that cell surface expression of MHC-I molecules requires association with B2M (page 722). Kim further teaches that while donor PSC lines deficient in B2M expression have the disadvantage of remaining susceptible to lysis by host NK cells, this effect can be overcome by engineering forced expression of HLA-E at the locus of a disrupted B2M gene (page 722; Figure 1).
However, Kim also notes that while lack of MHC class I expression may be beneficial for preventing rejection or recurrence of autoimmune or genetic diseases, there may also be some unintended consequences – for example, the development of immunologic “blind spots” where reservoirs of viral infection or tumors could go undetected (page 722). Kim also notes that other non-classic MHC-I or MHC-I-like molecules require B2M for their expression, and knocking out B2M can lead to unforeseen deleterious effects (page 723).
Zhou ‘802 discloses engineered immune cells expressing a chimeric antigen receptor (CAR) comprising an anti-CD7 antigen-binding domain in which the expression of endogenous CD7, at least one TCR/CD3 gene, and at least one MHC-II related gene is suppressed or silenced, which are useful for treating diseases associated with CD7 expression (e.g., Abstract). Zhou ‘802 describes engineered immune cells (e.g., T cells and NK cells) that express an anti-CD7 CAR and have suppressed or silenced expression of endogenous CD7, TRAC, and RFX5 (e.g., Summary of the Invention, ¶ 0007-0021; Invention details, ¶ 0051-0063; claims 1-11 of machine translation). Suppressing or silencing endogenous TCR/CD3 genes (e.g., TRAC) reduces risk of graft-versus-host disease (GVHD), while inhibiting or silencing the expression of endogenous MHC-II related genes (e.g., RFX5) in the CAR-T cells of the invention minimizes killing of the exogenous CAR-T cells by the patient’s endogenous CD4+CD7 T cells (e.g., Invention details, ¶ 0053-0060 of machine translation). Zhou ‘802 further states that in one embodiment, endogenous B2M in the CAR-T cells of the invention is functional (e.g., Invention Details, ¶ 0060 of machine translation). The antigen-binding domain of the CAR may comprise an antibody targeting a second antigen such as CD19 (e.g., Summary of the Invention, ¶ 0010; claims 4-5 of machine translation).
Based on the teachings of Kim and Zhou ‘802, it would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to modify the engineered CAR-T cells described by Zhou ‘591 such that endogenous B2M is not suppressed. The skilled artisan would have been motivated to do so because Zhou ‘591 and Kim both set forth that suppression of B2M expression in allogeneic cells results in increased host NK cell-mediated elimination, which would not be advantageous for cell therapy. Furthermore, Kim also sets forth that B2M expression is required for the expression of other classic MHC-I or MHC-I-like molecules and that knocking out B2M can lead to unforeseen deleterious effects, providing an additional “teaching away” from knocking out endogenous B2M expression. There would have been a reasonable expectation of success because Zhou ‘802 sets forth a proof-of-concept of an engineered CAR-T cell in which expression of multiple genes, including RFX5 and TRAC, are inactivated or deficient, while retaining endogenous B2M expression.
(2)
Claims 1 and 11 are rejected under 35 U.S.C. 103 as being unpatentable over Zhou ‘591 (WO 2022/012591 A1; supra) in view of Kim (Nature Biotechnology (2017) 35(8): 722-723; supra) and Zhou ‘802 (WO 2022/095802 A1; supra) as applied to claims 1-2, 9, and 14 above, further in view of Perez (US 2020/0246382 A1; cited in IDS). This is a new grounds of rejection necessitated by claim amendment.
The teachings of Zhou ‘591 are recited in the 35 U.S.C. § 103 rejection above. While Zhou ‘591 does teach that the engineered immune cells of the invention may comprise a CAR against CD19 and/or CD20, Zhou ‘591 does not teach that said engineered immune cells express a CAR comprising the amino acid sequence of instant SEQ ID NO: 26.
The teachings of Kim and Zhou ‘802 are recited in the 35 U.S.C. § 102 and 103 rejections above.
Perez discloses CARs and TCRs comprising one or more antigen binding motifs, including against CD19 and CD20 (e.g., Abstract). In an exemplary embodiment, Perez discloses an anti-CD20/anti-CD19 bicistronic CAR having the amino acid sequence of SEQ ID NO: 292 (which shares 100% sequence identity to instant SEQ ID NO: 26) (e.g., ¶ 0183; Example 21 at ¶ 0361). Perez teaches that the anti-CD20/anti-CD19 bicistronic CAR constructs of the invention are well-tolerated and elicit anti-tumor activity (e.g., Example 10 at ¶ 0327-0330).
Taken together, it would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to substitute into the engineered immune cell described by Zhou ‘591 an anti-CD20/anti-CD19 bicistronic CAR such as that taught by Perez. The skilled artisan would have been motivated to do so because the bicistronic CAR constructs taught by Perez (e.g., the CAR construct comprising the amino acid sequence of SEQ ID NO: 292) are well tolerated and show anti-tumor activity. There would have been a reasonable expectation of success because the CAR constructs described by Zhou ‘591 and Perez are functional equivalents (i.e., capable of binding CD19 and/or CD20) and possess utility for the same purpose (i.e., treating a CD19- and/or CD20-expressing tumor).
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.
(1)
Claims 1-2, 9, 11, and 14 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 10, 19, 24, 27, 34, 43, 52, 57, 60, 65, 67-71, 74, 76-77, and 82 of co-pending Application No. 18/639,066 (reference application) in view of Zhou ‘591 (WO 2022/012591 A1; supra).
The co-pending reference application recites an isolated immune cell (human T cell or NK cell) engineered to have lower or eliminated activity or expression of RFX5 and TRAC, and further expressing an anti-CD19 CAR comprising the amino acid sequence of SEQ ID NO: 26 (which shares 100% sequence identity to instant SEQ ID NO: 26), wherein endogenous B2M expression is not engineered or altered (e.g., co-pending claims 71, 74, 76-77, and 82).
The co-pending claims do not recite that the isolated immune is cell further engineered to have an inactivated or deficient endogenous gene of TAP1, or that the endogenous gene of RFX5 or TRAC is edited by CRISPR/Cas9. However, these deficiencies are remedied by the teachings of Zhou ‘591 as set forth in the 35 U.S.C. § 103 rejection above.
It would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to use CRISPR/Cas9-mediated gene editing to suppress or silence TRAC, TAP1, and RFX5 expression in the engineered immune cells claimed in the co-pending reference application. The skilled artisan would have been motivated to do so because the combination knockout approach used by Zhou reduces risk of immune rejection caused by allogeneic transplantation. There would have been a reasonable expectation of success because Zhou ‘591 provides a proof-of-concept that the expression of at least two or three TCR/CD3- and/or HLA-I-related genes may be silenced or suppressed in a CAR-T cell.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Elizabeth A Shupe whose telephone number is (703) 756-1420. The examiner can normally be reached Monday to Friday, 9:30am - 6:00pm EST.
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/ELIZABETH A SHUPE/Examiner, Art Unit 1643
/Brad Duffy/Primary Examiner, Art Unit 1643
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