DETAILED ACTION
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
2. Applicant's preliminary amendment filed on 12/29/2023 is acknowledged.
Claims 1, 8, 16-17, 26, 34-35, 37-39, 41-42, 77, 94, 96-99, 107 and 139 are pending.
3. Applicant’s attention is drawn to the form of subclause (ii) of claim 34, specifically the recitation “an LFR4 comprising the amino acid sequence set forth in SEQ ID NO: 33,” where it appears that “the LFR4 comprising an amino acid sequence set forth in SEQ ID NO: 33” may have been intended.
4. 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.
5. Claims 1, 8, 16-17, 26, 34-35, 37-39, 41-42, 77, 94, 96-99, 107 and 139 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
(i) Claim 1 is indefinite in the recitation of “an expression or activity” of the respective genes, because it is unclear what type(s) of gene “activity,” other than gene expression, are within the scope of the claim.
(ii) Claim 37 is indefinite because of the following inconsistency:
Claim 37 depends on claim 1, which recites a targeting moiety comprising a VH and a VL. Claim 37 recites a targeting moiety which “further” comprises “the” VH and “the” VL. The use of definite article “the” indicates that the VH and VL referred to in claim 37 are the same as the VH and VL recited in claim 1, whereas the expression “further comprises” indicates that the targeting moiety of claim 37 comprises a VH and a VL in addition to the VH and VL of claim 1. Therefore, the relationship between the VH and VL of claim 37 to those of claim 1 is unclear, as is the number of different VH regions and VL regions in the targeting moiety of claim 37.
(iii) Claims 94 and 96 are indefinite, because the use of an indefinite article in the phrase “a modification” creates ambiguity as to the relationship of the modifications of claims 94 and 96 to the “modified” immune effector cell of claim 1, on which claims 94 and 96 depend.
(iv) Claim 94 is further indefinite in the generic recitations of “an antisense RNA, an siRNA, an shRNA, and a CRISPR/Cas9 system,” because the “targets” of these reagents are unknown.
(v) Claim 107 is indefinite in the recitation of a “method for preparing an immune effector cell” comprising “modifying the immune effector cell,” for the following reasons:
(a) Recitation of “the” immune effector cell in the phrase “modifying the immune effector cell” lacks proper antecedent basis in the preceding part of the claim. The recitation of “preparing an immune effector cell” in the preamble of the claim describes the result of performing the method, and as such cannot provide an antecedent basis for starting material of the method.
(b) In practicing the step of “modifying” an immune effector cell, an immune effector cell must be already present prior to being modified; therefore, it is unclear what is being “prepared” as a result of practicing the method.
(vi) Claim 107 is further indefinite in the recitation of “the immune cell” at the very end of the claim, because it is unclear whether it refers to the immune effector cell recited in the preceding pars of the claim, or to a broader genus of immune cells.
(vii) Claims 8, 16-17, 26, 34-35, 37-39, 41-42, 77, 94, 96-99, 107 and 139 are indefinite, because they encompass the indefinite limitations of the claim(s) on which they depend.
In view of the above, a person of ordinary skill in the art cannot unequivocally interpret the metes and bounds of the claims so as to understand how to avoid infringement. Applicant is reminded that any amendment must point to a basis in the specification so as not to add New Matter. See MPEP 714.02 and 2163.06.
6. 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 of this title, 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.
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.
7. Claims 1, 8, 16-17, 26, 34-35, 37-39, 41-42, 94, 96-99, 107 and 139 are rejected under 35 U.S.C. 103 as being unpatentable over the combined teachings of O'Rourke et al. (US 20210128617) and Shang et al. (US 20220193135).
O'Rourke reviews that IL13Rα2 is expressed in a variety of human tumor types but not on normal human tissues except adult testes, and IL13 signaling through IL13Rα2 plays a critical role in tumor cell migration and invasion (e.g. [0002]-[0004]). Promising preliminary results were reported with anti-IL13Rα2 antibodies and IL13Rα2 based tumor vaccine (Id). In particular, redirecting T cells to IL13Rα2-expressing tumor cells with IL13-CD3-zeta fusion induced a clinical response which was limited by binding to IL13Rα1 expressed in normal tissues (Id).
O'Rourke addressed these limitations by constructing anti-IL13Rα2 CAR-T cells, wherein the antigen-binding domain (i.e. targeting moiety) is humanized scFv Hu08 comprising CDRs of SEQ ID NOS: 12-14 and 16-18 (e.g. [0011] and Table 1). The latter are identical to instant SEQ ID NOS: 1-3 and 19-21, respectively (see SCORE). O'Rourke found that Hu08 anti-IL13Rα2 CAR-T cells have potent antitumor activity in a mouse model of human glioma (Example 2 at [0478]-[0481] and Fig. 2).
Shang reviews the difficulties and limitations inherent in using autologous T cells for CAR-T cell therapy, which may be overcome by utilizing allogeneic T cells for this purpose (e.g. [0003]). The latter present a different set of issues, most notably (i) graft-versus-host disease caused by recognition of host antigens by endogenous TCR of allogeneic T cells, and (ii) recognition of HLA antigens on allogeneic T cells by the host immune system, leading to elimination of allogeneic cells (Id). Shang overcomes these issues by eliminating the expression of endogenous TCR and HLA antigens, respectively.
Specifically, Shang teaches a modified immune effector cell wherein, compared with the expression and/or activity of the corresponding gene in a corresponding unmodified cell, the expression and/or activity of the TRAC gene and the HLA-A gene are down-regulated, and the expression and/or activity of the CIITA or the B2M gene is not down-regulated. Also provided is a method for preparing the modified immune effector cell (e.g. the Abstract).
In particular, Shang teaches a working example of “CAR-T Cells in which the TRAC Gene and the HLA-A Gene were Dual Knockout” (e.g. Example 13 at [0313]-[0324]), and exemplifies CARs targeting IL13Rα2 (e.g. [0025], [0242]). See also claims 1, 3, 5, 8 and 10.
Before the effective filing date of the claimed invention, a person of ordinary skill in the art would have been motivated to inactivate TRAC and HLA-A genes in O'Rourke’s Hu08 anti-IL13Rα2 CAR-T cells to prevent recognition of host antigens by endogenous TCR and to prevent elimination of CAR-T cells by host immune system, as taught by Shang. One of ordinary skill in the art would have an expectation of success, based on O'Rourke’s data that Hu08 anti-IL13Rα2 CAR-T cells have potent antitumor activity.
Therefore, the invention as a whole recited in claim 1 was prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, as evidenced by the references, especially in the absence of evidence to the contrary.
Claims 8, 16-17, 26, 34-35, 37-39 and 41-42 are included in the rejection, because instant SEQ ID NOS: 16, 34, 39 and 42 are identical to O'Rourke’s SEQ ID NOS: 96, 103, 131 and 129, respectively (see SCORE).
Limitations of instant claims 94, 96 and 98 are taught by Shang e.g. in claims 8 and 10.
Claims 97 and 99 are included, because the recited sgRNA sequences are taught by Shang, e.g. instant SEQ ID NOS: 186, 200, 201 and 241 are identical to Shang’s SEQ ID NOS: 1, 15, 16 and 54 (taught e.g. in claim 12), respectively (see SCORE).
Claim 107 is included, because methods of preparing modified cells are inherent in teachings of modified cells.
Claim 139 is included, because CAR-T cells are intended for administration to patients, as taught by both O'Rourke and Shang.
8. 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 §§ 706.02(l)(1) - 706.02(l)(3) 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 USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The 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/process/file/efs/guidance/eTD-info-I.jsp.
9. Claims 1, 8, 16-17, 26, 34-35, 37-39, 41-42, 94, 96-99, 107 and 139 are rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of U.S. Patent No. 12133890 in view of O'Rourke et al. (US 20210128617).
Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims are obvious over the claims of US ‘890 in view of O'Rourke.
US ‘890 claims recite an immune effector cell expressing a CAR modified to down-regulate expression of TRAC and HLA-A to reduce immune rejection in allogeneic cell therapy (claims 13-16). As addressed in section 7 above, a person of ordinary skill in the art before the effective filing date of the claimed invention would have had both the motivation and an expectation of success in producing an immune effector cell modified as recited in US ‘890 and expressing an anti-IL13Rα2 CAR taught by O'Rourke, thereby arriving at the invention of instant claim 1, 8, 16-17, 26, 34-35, 37-39 and 41-42.
US ‘890 further recites that the modification further comprises administering to the immune effector cell an sgRNA of SEQ ID NO: 157 to SEQ ID NO: 171 targeting an exon portion of the TRAC gene, and an sgRNA of SEQ ID NO: 172 to SEQ ID NO: 212 targeting an exon portion of the HLA-A gene (claims 18-21). Instant SEQ ID NO: 186 is identical to US ‘890 SEQ ID NO: 157, and instant SEQ ID NO: 201 is identical to US ‘890 SEQ ID NO: 172 (see SCORE), i.e. limitations of instant claims 94 and 96-99 are recited in US ‘890 claims 18-21.
Limitations of instant claim 107 are inherent in US ‘890 claims, and limitations of instant claim 139 are recited in US ‘890 claims 24-26.
10. Claims 1, 8, 16-17, 26, 34-35, 37-39, 41-42, 94, 96-99, 107 and 139 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of copending application USSN 17/563804 (published as US 20220193135 described in section 7 above) in view of O'Rourke et al. (US 20210128617).
Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims are obvious over the claims of USSN ‘804 in view of O'Rourke.
USSN ‘804 claims recite an immune effector cell modified to down-regulate expression of TRAC and HLA-A but not CIITA or B2M (claims 1 and 3), wherein the cell expresses a CAR (claims 17-22). The subject matter of instant claims 1, 8, 16-17, 26, 34-35, 37-39 and 41-42 would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention over the above USSN ‘804 claims in view of O'Rourke for the same reasons as presented in sections 7 and 9 above.
TRAC-targeting sgRNA of SEQ ID NO: 1 recited in USSN ‘804 claim 1 is identical to instant SEQ ID NO: 186, and HLA-A-targeting sgRNA of SEQ ID NO: 17 recited in USSN ‘804 claim 12 is identical to instant SEQ ID NO: 202 (see SCORE) , i.e. limitations of instant claims 94 and 96-99 are recited in USSN ‘804 claims 1 and 12.
Limitations of instant claim 107 are inherent in USSN ‘804 claims, and limitations of instant claim 139 are recited in USSN ‘804 claims 43-44.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
11. Claims 1, 8, 16-17, 26, 34-35, 37-39, 41-42, 94, 96-99, 107 and 139 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of copending application USSN 18/575451 (published as US 20240139321) in view of O'Rourke et al. (US 20210128617).
USSN ‘451 recites a CAR-expressing immune effector cell modified to down-regulate expression of TRAC and HLA-A (claim 51).
The subject matter of instant claims 1, 8, 16-17, 26, 34-35, 37-39 and 41-42 would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention over USSN ‘451 claim 51 in view of O'Rourke for the same reasons as presented in sections 7 and 9 above.
TRAC-targeting sgRNA of SEQ ID NO: 144 recited in USSN ‘451 claim 65 is identical to instant SEQ ID NO: 186, and HLA-A-targeting sgRNA of SEQ ID NO: 159 recited in USSN ‘451 claim 67 is identical to instant SEQ ID NO: 201 (see SCORE) , i.e. limitations of instant claims 94 and 96-99 are recited in USSN ‘451 claims 65 and 67.
Limitations of instant claims 107 and 139 are recited in USSN ‘451 claims 75 and 107.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
12. The following prior art references, which teach various aspects of the claimed invention, are cited of record but not presently relied upon:
Eyquem et al. (2017) Targeting a CAR to the TRAC locus with CRISPR/Cas9 enhances tumour rejection. Nature 543: 113-118.
Lee et al. (2020) Abrogation of HLA surface expression using CRISPR/Cas9 genome editing: a step toward universal T cell therapy. Scientific Reports 10: 17753, p. 1-10.
Torikai et al. (2013) Toward eliminating HLA class I expression to generate universal cells from allogeneic donors. Blood (2013) 122 (8): 1341–1349.
Tampella et al. (US 20210000875, US 12152079) teach anti-IL13Rα2 CAR comprising the same amino acid sequences as presently recited.
“Universal,” “hypoimmunogenic,” or "off-the-shelf" CAR-T cells with disruptions of TRAC and/or HLA-A genes are taught e.g. in the following documents:
US 20230265154
US 20170152526
US 20210308183
US 20150037304
US 20220227865
The following documents teach anti-IL13Rα2 CAR-T cells with disruptions of TRAC and/or HLA-A genes:
US 20200392473
US 20220251572
US 20200149009
US 20180362975
13. Conclusion: no claim is allowed.
14. Any inquiry concerning this communication or earlier communications from the examiner should be directed to ILIA I OUSPENSKI whose telephone number is (571)272-2920. The examiner can normally be reached 9 AM - 5:30 PM.
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/ILIA I OUSPENSKI/ Primary Examiner, Art Unit 1644
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