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 .
Continued Examination Under 37 CFR 1.114
Applicants’ reply to the October 17, 2025 Office Action, filed January 7, 2026, is acknowledged. Applicants previously canceled claims 1-155, 158, 165, and 171-174. Applicants amend claim 156. Claims 156-157, 159-164, and 166-170 are pending and under examination.
Any objection or rejection of record in the previous Office Action, mailed October 17, 2025, which is not addressed in this action has been withdrawn in light of Applicants’ amendments and/or arguments. This action is FINAL.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 119(e) as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of 35 U.S.C. 112 (pre-AIA ). See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, Application No. 62/376,372, fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112 (pre-AIA ), first paragraph for one or more claims of this application. The application fails to provide support for the claims under examination, since there is no disclosure therein of the claimed specific candidate target sequences or removal of such candidate target sequences in haplotypes that occur in at least 0.1% of a population. Although the application discloses CRISPR complexes that have reduced capability of modifying off-target loci, the application does not disclose the claimed candidate target sequences or determination of haplotypes that occur in at least 0.1% of a population. Therefore, the effective filing date of claims 156—157, 159-164, and 166-170 is deemed to be December 20, 2016, the filing date of U.S. Provisional Patent Application No. 62/437,031.
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 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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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 156-157, 159-164, 166-170, and 175 are rejected under 35 U.S.C. 103 as being unpatentable over Zhang et al. (Zhang I, U.S. Patent Application Publication No. 2019/0010471, published January 10, 2019, and claiming priority to PCT Patent Application No. PCT/US2016/038034, filed June 17, 2016, and U.S. Provisional Patent Application Nos. 61/181,453; 62/207,312; 62/237,360; 62/255,256; and 62/269,876, filed June 18, 2015; August 19, 2015; October 5, 2015; November 13, 2015; and December 18, 2015, respectively) in view of Mandal et al. (15 Cell Stem Cell 643-652 (2014), and cited in the Information Disclosure Statement filed January 14, 2021), Chen (36(11) Trends in Immunology 667-669 (2015)), and Knipping et al. (24(Supplement 1) Molecular Therapy S50 (2016)). This rejection is modified as necessitated by Applicants’ amendments, and is maintained.
It is noted that claims 156-157, 159-164, 166-170, and 175 are product-by-process claims. Therefore, the claims are being interpreted as encompassing a modified eukaryotic cell prepared by any method that reduces off-target effects of a CRISPR-Cas9 system.
Regarding claims 156-157, Zhang I discloses a CRISPR-Cas9 system where the Cas9 can be guided to specific locations within genomes (abstract and paragraph [0076]). Zhang I discloses that off-target effects can be seen where the Cas9 can bind to off-target loci (abstract and paragraph [0076]). Zhang I discloses that these off-target effects can be computationally determined (paragraph [0632]). Zhang I discloses modified cells where off-target effects are reduced (paragraph [1180]). Zhang I discloses that the modified cells can have altered expression of PDCD1, CTLA4, and TRAC (i.e., TCRA) (paragraph [1566]). Zhang I also discloses that CD52 can be targeted (paragraph [1567]). Zhang I further discloses that the off-target candidates include HBB (Table B). Zhang I discloses that additional off-target candidates include LC2A2, GLUT2, G6PC, G6PT, G6PT1, GAA, LAMP2, LAMPB, AGL, GDE, GBE1, GYS2, PYGL, PFKM (Table B). Zhang I discloses that Cas9 target recognition is dictated by base-pairing interactions of the guide with the DNA target, and that the degree of complementarity between the guide and the target is greater than 94.5% (paragraphs [0076] and [0298]). Zhang I discloses that the cells can be human cells, including lymphocytes, which encompasses T cells (paragraphs [0089] and [0988]).
Regarding claims 159-160 and 175, Zhang I discloses that the cells can be human cells, including lymphocytes, which encompasses T cells (paragraphs [0089] and [0988]).
Regarding claims 161-164 and 170, Zhang I discloses that the CRISPR-Cas9 system can provide for modified cells where the cells are associated with a genetic disease or disorder, including sickle-cell anemia (a blood disorder) and cancer, where the cells can be prepared ex vivo and reinfused into a patient, which is interpreted as being a pharmaceutical composition (paragraphs [0365] and [0414]). Zhang I discloses that the modified cells can be administered to a patient, which is also interpreted as being a pharmaceutical composition of the modified cells (paragraph [1691]).
Regarding claims 166-167, Zhang I discloses that the Cas9 can be from either Streptococcus pyogenes or Staphylococcus aureus (paragraphs [0303] and [0386]). Zhang I discloses that the PAM sequence for S. pyogenes is NGG (paragraph [0579]).
Regarding claim 168, Zhang I discloses that the guide RNA can be a chimeric sgRNA, which comprises the crRNA (guide) and the tracr linked together (paragraphs [0106]-[0108] and [0116]).
Regarding claim 169, Zhang I discloses that CRISPR-Cas9 systems can be applied to stem cells (paragraph [0166]).
Zhang I fails to explicitly disclose or suggest that the expression of B2M is altered.
Mandal discloses CRISPR/Cas9 targeting of the B2M gene in human primary T cells (abstract). Mandal discloses that CRISPR/Cas9 can efficiently ablate genes with minimal off-target mutagenesis abstract). Mandal discloses that the B2M (beta-2 microglobulin) encodes the accessory chain of the major histocompatibility complex (MHC) Class I molecules and that deletion or alteration of B2M is well-known to ablate MCH class ( surface expression (paragraph bridging pages 643 and 644). Mandal discloses that ablation of the B2M gene is useful in transplantation and adoptive immunotherapy (paragraph bridging pages 643 and 544).
Chen discloses using CRISPR-Cas9 to delete a variety of genes, including CTLA-4 (page 669, paragraph bridging columns 1 and 2). Chen discloses T-cell therapy can be used for cancer, viral infections, and autoimmune diseases (abstract). Chen also discloses that blocking CTLA-4 and PD-1 signaling have shown marked efficacy in treating melanoma (paragraph bridging pages 667 and 668).
Knipping discloses that adoptive transfer of T cells with transgenic high avidity T cell receptors (TCR) is a promising therapeutic approach (abstract). Knipping discloses that CRISPR/Ca9 can be used with guide RNAs targeting the constant region of the TCR α-chain (TRAC) (abstract). Knipping discloses that this leads to successful elimination of surface TCR expression, which can be used for T cell engineering (abstract).
It would have been obvious to one with ordinary skill in the art before the effective filing date of the claimed invention to alter the expression of B2M, CTLA-4, and/or TRAC as disclosed by Mandal, Chen, and Knipping for the eukaryotic cells of Zhang I because this provides a mechanism to create eukaryotic cells with altered B2M and CTLA-4 expression, which cells can then be used in cancer therapy and immunotherapy without the potential issue of off-target effects and increased potential for unwanted surface molecules to be expressed. One of ordinary skill in the art would have had a predictable and reasonable expectation of success in using Zhang’s CRISPR-Cas9 to alter the expression of both CTLA-4 and B2M, as disclosed by Mandal, Chen, and Knipping in order to produce eukaryotic cells for use in cancer therapy and immunotherapy.
Claims 156-157, 159-164, 166-170, and 175 are rejected under 35 U.S.C. 103 as being unpatentable over Hsu et al. (157(6) Cell 1262-1278 (2014), and cited in the Information Disclosure Statement filed March 9, 2020) or Zhang et al. (Zhang II, PCT Patent Application Publication No. WO 2015/089364, published June 18, 2015, and cited in the Information Disclosure Statement filed February 15, 2019); or Wang et al. (U.S. Patent Application Publication No. 2016/0251648, published September 1, 2016, filed April 28, 2016, and claiming priority to PCT Patent Application No. PCT/US14/62558, filed October 28, 2014 and U.S. Provisional Patent Application Nos. 61/961,980; 61/963,643; and 62/069,243, filed October 28, 2013; December 9, 2013; and October 27, 2014, and cited in the Information Disclosure Statement filed March 9, 2019) in view of Zhang et al. (Zhang I, U.S. Patent Application Publication No. 2019/0010471, published January 10, 2019, and claiming priority to PCT Patent Application No. PCT/US2016/038034, filed June 17, 2016, and U.S. Provisional Patent Application Nos. 61/181,453; 62/207,312; 62/237,360; 62/255,256; and 62/269,876, filed June 18, 2015; August 19, 2015; October 5, 2015; November 13, 2015; and December 18, 2015, respectively), Mandal et al. (15 Cell Stem Cell 643-652 (2014), and cited in the Information Disclosure Statement filed January 14, 2021), Chen (36(11) Trends in Immunology 667-669 (2015)), and Knipping et al. (24(Supplement 1) Molecular Therapy S50 (2016)). This rejection is modified as necessitated by Applicants’ amendments, and is maintained.
It is noted that claims 156-157, 159-164, 166-170, and 175 are product-by-process claims. Therefore, the claims are being interpreted as encompassing a modified eukaryotic cell prepared by any method that reduces off-target effects of a CRISPR-Cas9 system.
Regarding claims 156-157, Hsu discloses a CRISPR-Cas9 system where the Cas9 can be guided to specific locations within genomes (abstract). Hsu discloses that off-target effects can be seen where the Cas9 can bind to off-target loci (page 1270, column 1, second full paragraph). Hsu discloses that these off-target effects can be computationally determined (page 1270, column 2, first full paragraph). Hsu discloses modified cells where off-target effects are reduced (page 1269, column 2, second full paragraph and paragraph bridging pages 1270 and 1271). Hsu discloses that Cas9 target recognition is dictated by base-pairing interactions of the guide with the DNA target (page 1270, column 1, first full paragraph).
Regarding claims 159-160, Hsu discloses that the cells can be human cells, including lymphocytes (page 1269, column 2, second full paragraph and page 1274, column 2, final full paragraph).
Regarding claims 161-164 and 170, Hsu discloses that the CRISPR-Cas9 system can provide for modified cells where the cells are associated with a genetic disease or disorder, including sickle-cell anemia (a blood disorder) and cancer, where the cells can be prepared ex vivo and reinfused into a patient, which is interpreted as being a pharmaceutical composition (page 1274, column 2 to page 1275 column 1).
Regarding claims 166-167, Hsu discloses that the Cas9 can be from either Streptococcus pyogenes or Staphylococcus aureus (Figure 5). Hsu discloses that the PAM sequence for S. pyogenes is NGG (page 1269, column 1, final full paragraph).
Regarding claim 168, Hsu discloses that the guide RNA can be a chimeric sgRNA, which comprises the crRNA (guide) and the tracr linked together (page 1270, column 2).
Regarding claim 169, Hsu discloses that CRISPR-Cas9 systems can be applied to human pluripotent stem cells (page 1269, column 1, final full paragraph).
Regarding claims 156-157, Zhang II discloses modified eukaryotic cells having reduced off-target effects (paragraph [0416]). Zhang II discloses that the selected parameters or variables are selected from the group comprising CRISPR effector specificity, gRNA specificity, CRISPR-Cas complex specificity, PAM restrictiveness, PAM type (natural or modified), PAM nucleotide content, PAM length, CRISPR effector activity, gRNA activity, CRISPR-Cas complex activity, target cleavage efficiency, target site selection, target sequence length, ability of effector protein to access regions of high chromatin accessibility, degree of uniform enzyme activity across genomic targets, epigenetic tolerance, mismatch/budge tolerance, CRISPR effector stability, CRISPR effector mRNA stability, gRNA stability, CRISPR-Cas complex stability, CRISPR effector protein or mRNA immunogenicity or toxicity, gRNA immunogenicity or toxicity, CRISPR-Cas complex immunogenicity or toxicity, CRISPR effector protein or mRNA dose or titer, gRNA dose or titer, CRISPR-Cas complex dose or titer, CRISPR effector protein size, CRISPR effector expression level, gRNA expression level, CRISPR-Cas complex expression level, CRISPR effector spatiotemporal expression, gRNA spatiotemporal expression, CRISPR-Cas complex spatiotemporal expression, as well as the effect of sgRNA mutations on the ability to induce indels (paragraphs [0047] and [00195] and Figures 11A-D). Zhang II further discloses, selecting one or more CRISPR-Cas system delivery vehicle or expression system, and optimization of selected parameters or variables associated with the CRISPR-Cas system and/or its functionality, wherein specificity, efficacy, and/or safety are optimized, which is achieved using systems arranged to have a high degree of sequence specificity for the target DNA, and removing off target binding and effects thereof (paragraphs [0066] and [0077]). Zhang II discloses that Cas9 target recognition is dictated by base-pairing interactions of the guide with the DNA target, and that the degree of complementarity between the guide and the target is greater than 94.5% (paragraph [0061]).
Regarding claims 159-160, Zhang II discloses that the cells can be human cells (paragraphs [0009] and [0059]).
Regarding claims 161 and 170, Zhang II discloses that the CRISPR-Cas9 system can provide for modified cells where the cells are associated with a genetic disease or disorder, where the cells can be prepared ex vivo and reinfused into a patient, which is interpreted as being a pharmaceutical composition (paragraph [0075]). Zhang II discloses that the modified cells can be administered to a patient, which is also interpreted as being a pharmaceutical composition of the modified cells (paragraph [0075]).
Regarding claims 166-167, Zhang II discloses that the Cas9 can be from either Streptococcus pyogenes or Staphylococcus aureus (paragraphs [0012] and [0096]). Zhang II discloses that the PAM sequence for S. pyogenes is NGG (paragraph [0045] and [0068]).
Regarding claim 168, Zhang II discloses that the guide RNA can be a chimeric sgRNA, which comprises the crRNA (guide) and the tracr linked together (paragraphs [0065]).
Regarding claim 169, Zhang II discloses that CRISPR-Cas9 systems can be applied to stem cells (paragraph [0075]).
Regarding claims 156 and 157, Wang discloses a CRISPR-Cas9 system where the Cas9 can be guided to specific locations within genomes (paragraph [0045]). Wang discloses that off-target effects can be seen where the Cas9 can bind to off-target loci (paragraphs [0087]-[0092]). Wang discloses that these off-target effects can be computationally determined (paragraph [0011]). Zhang I discloses modified cells where off-target effects are reduced (paragraph [0089]). Wang discloses that the degree of complementarity between the guide and the target is greater than 94.5% (paragraphs [0140]).
Regarding claims 159-160, Wang discloses that the cells can be human cells, including lymphocytes (paragraphs [0028] and [0121]).
Regarding claims 161 and 164, Wang discloses that the CRISPR-Cas9 system can provide for modified cells where the cells are associated with a genetic disease or disorder, including cancer (paragraph [0130]
Regarding claims 166-167, Wang discloses that the Cas9 can be from either Streptococcus pyogenes or Staphylococcus aureus (paragraphs [0045] and [0129]). Wang discloses that the PAM sequence for S. pyogenes is NGG (paragraph [0045]).
Regarding claim 168, Wang discloses that the guide RNA can be a chimeric sgRNA, which comprises the crRNA (guide) and the tracr linked together (paragraphs [0016] and [0104]).
Regarding claim 169, Wang discloses that CRISPR-Cas9 systems can be applied to human embryonic stem cells (paragraphs [0090] and [0138].
Hsu fails to explicitly disclose or suggest the degree of complementarity between the guide and the target sequence. Hsu fails to disclose specifically modified genes. Hsu fails to explicitly disclose that the cells can be a pharmaceutical composition.
Zhang II fails to disclose that the cells can be lymphocytes, or that the genetic disease or disorder can be a blood disorder or cancer. Zhang II fails to disclose specifically modified genes.
Wang fails to disclose that the cells can be lymphocytes, or that the genetic disease or disorder can be a blood disorder or cancer. Wang fails to disclose specifically modified genes. Wang fails to disclose or suggest that the cells can be a pharmaceutical composition.
Regarding claims 156-157, Zhang I discloses a CRISPR-Cas9 system where the Cas9 can be guided to specific locations within genomes (abstract and paragraph [0076]). Zhang I discloses that off-target effects can be seen where the Cas9 can bind to off-target loci (abstract and paragraph [0076]). Zhang I discloses that these off-target effects can be computationally determined (paragraph [0632]). Zhang I discloses modified cells where off-target effects are reduced (paragraph [1180]). Zhang I discloses that the modified cells can have altered expression of PDCD1, CTLA4, and TRAC (i.e., TCRA) (paragraph [1566]). Zhang I also discloses targeting CD52 (paragraph [1567]). Zhang I further discloses that the off-target candidates include HBB (Table B). Zhang I discloses that additional off-target candidates include LC2A2, GLUT2, G6PC, G6PT, G6PT1, GAA, LAMP2, LAMPB, AGL, GDE, GBE1, GYS2, PYGL, PFKM (Table B). Zhang I discloses that Cas9 target recognition is dictated by base-pairing interactions of the guide with the DNA target, and that the degree of complementarity between the guide and the target is greater than 94.5% (paragraphs [0076] and [0298]). Zhang I discloses that the cells can be human cells, including lymphocytes, which encompasses T cells (paragraphs [0089] and [0988]).
Regarding claims 156-157 and 159-160, Zhang I discloses that the cells can be human cells, including lymphocytes, which encompasses T cells (paragraphs [0089] and [0988]).
Regarding claims 161-164 and 170, Zhang I discloses that the CRISPR-Cas9 system can provide for modified cells where the cells are associated with a genetic disease or disorder, including sickle-cell anemia (a blood disorder) and cancer, where the cells can be prepared ex vivo and reinfused into a patient, which is interpreted as being a pharmaceutical composition (paragraphs [0365] and [0414]). Zhang I discloses that the modified cells can be administered to a patient, which is also interpreted as being a pharmaceutical composition of the modified cells (paragraph [1691]).
Regarding claims 166-167, Zhang I discloses that the Cas9 can be from either Streptococcus pyogenes or Staphylococcus aureus (paragraphs [0303] and [0386]). Zhang I discloses that the PAM sequence for S. pyogenes is NGG (paragraph [0579]).
Regarding claim 168, Zhang I discloses that the guide RNA can be a chimeric sgRNA, which comprises the crRNA (guide) and the tracr linked together (paragraphs [0106]-[0108] and [0116]).
Regarding claim 169, Zhang I discloses that CRISPR-Cas9 systems can be applied to stem cells (paragraph [0166]).
Mandal discloses CRISPR/Cas9 targeting of the B2M gene in human primary T cells (abstract). Mandal discloses that CRISPR/Cas9 can efficiently ablate genes with minimal off-target mutagenesis abstract). Mandal discloses that the B2M (beta-2 microglobulin) encodes the accessory chain of the major histocompatibility complex (MHC) Class I molecules and that deletion or alteration of B2M is well-known to ablate MCH class ( surface expression (paragraph bridging pages 643 and 644). Mandal discloses that ablation of the B2M gene is useful in transplantation and adoptive immunotherapy (paragraph bridging pages 643 and 544).
Chen discloses using CRISPR-Cas0 to delete a variety of genes, including CTLA-4 (page 669, paragraph bridging columns 1 and 2). Chen discloses T-cell therapy can be used for cancer, viral infections, and autoimmune diseases (abstract). Chen also discloses that blocking CTLA-4 and PD-1 signaling have shown marked efficacy in treating melanoma (paragraph bridging pages 667 and 668).
Knipping discloses that adoptive transfer of T cells with transgenic high avidity T cell receptors (TCR) is a promising therapeutic approach (abstract). Knipping discloses that CRISPR/Ca9 can be used with guide RNAs targeting the constant region of the TCR α-chain (TRAC) (abstract). Knipping discloses that this leads to successful elimination of surface TCR expression, which can be used for T cell engineering (abstract).
Thus, it would have been obvious to one with ordinary skill in the art before the effective filing date of the claimed invention to alter the expression of B2M, as disclosed by Mandal, CTLA-4, as disclosed by Chen, and/or TRAC, as disclosed by Knipping, for the eukaryotic cells disclosed and suggested by Hsu, Zhang II, Wang, and Zhang I because this provides eukaryotic cells because this provides a mechanism to create eukaryotic cells with altered B2M and CTLA-4 expression, which cells can then be used in therapy without the potential issue of off-target effects and increased potential for unwanted surface molecules to be expressed. One of ordinary skill in the art would have had a predictable and reasonable expectation of success in using Hsu’s, Zhang II’s, Wang’s, and Zhang I’s CRISPR-Cas9 to alter the expression of CTLA-4, B2M, and/or TRAC, as disclosed by Mandal, Chen, and Knipping, in order to produce eukaryotic cells for use in cancer therapy and immunotherapy.
It would have been obvious to one with ordinary skill in the art before the effective filing date of the claimed invention to modify the eukaryotic cells of Hsu, Zhang II, or Wang with the characteristics of the eukaryotic cells of Zhang II because each of Hsu, Zhang II, Wang, Zhang, Mandal, Chen, and Knipping all related to the use of CRISPR-Cas9 to prepare eukaryotic cells having reduced off-target effects. As such, one of ordinary skill in the art would be motivated to incorporate all of Zhang I’s characteristics in the cells of Hsu, Zhang II, Wang, or Zhang I in order to arrive at eukaryotic cells that can be used to treat genetic diseases and disorders. Further, one of ordinary skill in the art would have had a predictable and reasonable expectation of success in incorporating Zhang I’s characteristics into the modified eukaryotic cells of Hsu, Zhang II, Wang, in view of Zhang I, Mandal, Chen, and Knipping.
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 §§ 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.
Claims 156-157, 159-164, 166-170, and 175 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 14-17 of U.S. Patent No. 10,494,621 in view of Zhang et al. (Zhang I, U.S. Patent Application Publication No. 2019/0010471, published January 10, 2019, and claiming priority to PCT Patent Application No. PCT/US2016/038034, filed June 17, 2016, and U.S. Provisional Patent Application Nos. 61/181,453; 62/207,312; 62/237,360; 62/255,256; and 62/269,876, filed June 18, 2015; August 19, 2015; October 5, 2015; November 13, 2015; and December 18, 2015, respectively), Mandal et al. (15 Cell Stem Cell 643-652 (2014), and cited in the Information Disclosure Statement filed January 14, 2021, Chen (36(11) Trends in Immunology 667-669 (2015)), and Knipping et al. (24(Supplement 1) Molecular Therapy S50 (2016)). This rejection is modified as necessitated by Applicants’ amendments, and is maintained.
It is noted that claims 156-157, 159-164, 166-170, and 175 are product-by-process claims. Therefore, the claims are being interpreted as encompassing a modified eukaryotic cell prepared by any method that reduces off-target effects of a CRISPR-Cas9 system.
Although the claims at issue are not identical, they are not patentably distinct from each other because the ‘621 patent claims a method of developing or designing a CRISPR-Cas system-based therapy/therapeutic by selecting target sequences that are not off-target sites. While the ‘621 patent does not specifically claim a cell made by a method of reducing off-target effects, it discloses such cells. However, it would have been obvious to one with ordinary skill in the art before the effective filing date of the claimed invention that the method claimed by the ‘621 patent would result in modified eukaryotic cells with reduced off-target effects. Furthermore, the ‘621 patent disclosed, but did not claim the modified eukaryotic cells made by a method where off-target effects were reduced. The instant case is analogous to Sun Pharmaceutical Industries, Ltd. v. Eli Lilly and Company (Fed. Cir. July 28, 2010), where the courts ruled that obviousness-type double patenting exist between previously-disclosed, but newly-claimed utility.
The ‘621 patent fails to claim specific candidate target sequences or altered expression of the B2M gene.
Regarding claims 156-157, Zhang I discloses a CRISPR-Cas9 system where the Cas9 can be guided to specific locations within genomes (abstract and paragraph [0076]). Zhang I discloses that off-target effects can be seen where the Cas9 can bind to off-target loci (abstract and paragraph [0076]). Zhang I discloses that these off-target effects can be computationally determined (paragraph [0632]). Zhang I discloses modified cells where off-target effects are reduced (paragraph [1180]). Zhang I discloses that the modified cells can have altered expression of PDCD1, CTLA4, and TRAC (i.e., TCRA) (paragraph [1566]). Zhang I also discloses that CD52 can be targeted (paragraph [1567]). Zhang I further discloses that the off-target candidates include HBB (Table B). Zhang I discloses that additional off-target candidates include LC2A2, GLUT2, G6PC, G6PT, G6PT1, GAA, LAMP2, LAMPB, AGL, GDE, GBE1, GYS2, PYGL, PFKM (Table B). Zhang I discloses that Cas9 target recognition is dictated by base-pairing interactions of the guide with the DNA target, and that the degree of complementarity between the guide and the target is greater than 94.5% (paragraphs [0076] and [0298]). Zhang I discloses that the cells can be human cells, including lymphocytes, which encompasses T cells (paragraphs [0089] and [0988]).
Regarding claims 159-160, Zhang I discloses that the cells can be human cells, including lymphocytes, which encompasses T cells (paragraphs [0089] and [0988]).
Regarding claims 161-164 and 170, Zhang I discloses that the CRISPR-Cas9 system can provide for modified cells where the cells are associated with a genetic disease or disorder, including sickle-cell anemia (a blood disorder) and cancer, where the cells can be prepared ex vivo and reinfused into a patient, which is interpreted as being a pharmaceutical composition (paragraphs [0365] and [0414]). Zhang I discloses that the modified cells can be administered to a patient, which is also interpreted as being a pharmaceutical composition of the modified cells (paragraph [1691]).
Regarding claims 166-167, Zhang I discloses that the Cas9 can be from either Streptococcus pyogenes or Staphylococcus aureus (paragraphs [0303] and [0386]). Zhang I discloses that the PAM sequence for S. pyogenes is NGG (paragraph [0579]).
Regarding claim 168, Zhang I discloses that the guide RNA can be a chimeric sgRNA, which comprises the crRNA (guide) and the tracr linked together (paragraphs [0106]-[0108] and [0116]).
Regarding claim 169, Zhang I discloses that CRISPR-Cas9 systems can be applied to stem cells (paragraph [0166]).
Mandal discloses CRISPR/Cas9 targeting of the B2M gene in human primary T cells (abstract). Mandal discloses that CRISPR/Cas9 can efficiently ablate genes with minimal off-target mutagenesis abstract). Mandal discloses that the B2M (beta-2 microglobulin) encodes the accessory chain of the major histocompatibility complex (MHC) Class I molecules and that deletion or alteration of B2M is well-known to ablate MCH class ( surface expression (paragraph bridging pages 643 and 644). Mandal discloses that ablation of the B2M gene is useful in transplantation and adoptive immunotherapy (paragraph bridging pages 643 and 544).
Chen discloses using CRISPR-Cas9 to delete a variety of genes, including CTLA-4 (page 669, paragraph bridging columns 1 and 2). Chen discloses T-cell therapy can be used for cancer, viral infections, and autoimmune diseases (abstract). Chen also discloses that blocking CTLA-4 and PD-1 signaling have shown marked efficacy in treating melanoma (paragraph bridging pages 667 and 668).
Knipping discloses that adoptive transfer of T cells with transgenic high avidity T cell receptors (TCR) is a promising therapeutic approach (abstract). Knipping discloses that CRISPR/Ca9 can be used with guide RNAs targeting the constant region of the TCR α-chain (TRAC) (abstract). Knipping discloses that this leads to successful elimination of surface TCR expression, which can be used for T cell engineering (abstract).
It would have been obvious to one with ordinary skill in the art before the effective filing date of the claimed invention to modify the claims of the ‘621 patent by employing the candidate genes of Zhang and/or to alter the expression of CD52, PDCD1B2M, CTLA-4, and/or TRAC as disclosed by Mandal, Chen, and Knipping for the eukaryotic cells of Zhang I because this provides a mechanism to create eukaryotic cells with altered B2M and CTLA-4 expression, which cells can then be used in cancer therapy and immunotherapy without the potential issue of off-target effects and increased potential for unwanted surface molecules to be expressed. One of ordinary skill in the art would have had a predictable and reasonable expectation of success modifying the ‘621 patent claims with Zhang’s CRISPR-Cas9 to alter the expression of CD52, PDCD1, B2M, CTLA-4, and/or TRAC as disclosed by Mandal, Chen, and Knipping, in order to produce eukaryotic cells for use in cancer therapy and immunotherapy.
Claims 156-157, 159-164, 166-170, and 175 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 27 and 29 of U.S. Patent No. 10,876,100 in view of Zhang et al. (Zhang I, U.S. Patent Application Publication No. 2019/0010471, published January 10, 2019, and claiming priority to PCT Patent Application No. PCT/US2016/038034, filed June 17, 2016, and U.S. Provisional Patent Application Nos. 61/181,453; 62/207,312; 62/237,360; 62/255,256; and 62/269,876, filed June 18, 2015; August 19, 2015; October 5, 2015; November 13, 2015; and December 18, 2015, respectively), Mandal et al. (15 Cell Stem Cell 643-652 (2014), and cited in the Information Disclosure Statement filed January 14, 2021), Chen (36(11) Trends in Immunology 667-669 (2015)), and Knipping et al. (24(Supplement 1) Molecular Therapy S50 (2016)). This rejection is modified as necessitated by Applicants’ amendments, and is maintained.
It is noted that claims 156-157, 159-164, 166-170, and 175 are product-by-process claims. Therefore, the claims are being interpreted as encompassing a modified eukaryotic cell prepared by any method that reduces off-target effects of a CRISPR-Cas9 system.
Although the claims at issue are not identical, they are not patentably distinct from each other because the ‘100 patent and the instant application both claim modified eukaryotic cells made by a method that provides for reduced off-target effects.
The ‘100 patent fails to claim specific candidate target sequences or altered expression of the B2M gene.
Regarding claims 156-157, Zhang I discloses a CRISPR-Cas9 system where the Cas9 can be guided to specific locations within genomes (abstract and paragraph [0076]). Zhang I discloses that off-target effects can be seen where the Cas9 can bind to off-target loci (abstract and paragraph [0076]). Zhang I discloses that these off-target effects can be computationally determined (paragraph [0632]). Zhang I discloses modified cells where off-target effects are reduced (paragraph [1180]). Zhang I discloses that the modified cells can have altered expression of PDCD1, CTLA4, and TRAC (i.e., TCRA) (paragraph [1566]). Zhang I also discloses that CD52 can be targeted (paragraph [1567]). Zhang I further discloses that the off-target candidates include HBB (Table B). Zhang I discloses that additional off-target candidates include LC2A2, GLUT2, G6PC, G6PT, G6PT1, GAA, LAMP2, LAMPB, AGL, GDE, GBE1, GYS2, PYGL, PFKM (Table B). Zhang I discloses that Cas9 target recognition is dictated by base-pairing interactions of the guide with the DNA target, and that the degree of complementarity between the guide and the target is greater than 94.5% (paragraphs [0076] and [0298]). Zhang I discloses that the cells can be human cells, including lymphocytes, which encompasses T cells (paragraphs [0089] and [0988]).
Regarding claims 159-160, Zhang I discloses that the cells can be human cells, including lymphocytes (paragraphs [0089] and [0988]).
Regarding claims 161-164 and 170, Zhang I discloses that the CRISPR-Cas9 system can provide for modified cells where the cells are associated with a genetic disease or disorder, including sickle-cell anemia (a blood disorder) and cancer, where the cells can be prepared ex vivo and reinfused into a patient, which is interpreted as being a pharmaceutical composition (paragraphs [0365] and [0414]). Zhang I discloses that the modified cells can be administered to a patient, which is also interpreted as being a pharmaceutical composition of the modified cells (paragraph [1691]).
Regarding claims 166-167, Zhang I discloses that the Cas9 can be from either Streptococcus pyogenes or Staphylococcus aureus (paragraphs [0303] and [0386]). Zhang I discloses that the PAM sequence for S. pyogenes is NGG (paragraph [0579]).
Regarding claim 168, Zhang I discloses that the guide RNA can be a chimeric sgRNA, which comprises the crRNA (guide) and the tracr linked together (paragraphs [0106]-[0108] and [0116]).
Regarding claim 169, Zhang I discloses that CRISPR-Cas9 systems can be applied to stem cells (paragraph [0166]).
Mandal discloses CRISPR/Cas9 targeting of the B2M gene in human primary T cells (abstract). Mandal discloses that CRISPR/Cas9 can efficiently ablate genes with minimal off-target mutagenesis abstract). Mandal discloses that the B2M (beta-2 microglobulin) encodes the accessory chain of the major histocompatibility complex (MHC) Class I molecules and that deletion or alteration of B2M is well-known to ablate MCH class ( surface expression (paragraph bridging pages 643 and 644). Mandal discloses that ablation of the B2M gene is useful in transplantation and adoptive immunotherapy (paragraph bridging pages 643 and 544).
Chen discloses using CRISPR-Cas9 to delete a variety of genes, including CTLA-4 (page 669, paragraph bridging columns 1 and 2). Chen discloses T-cell therapy can be used for cancer, viral infections, and autoimmune diseases (abstract). Chen also discloses that blocking CTLA-4 and PD-1 signaling have shown marked efficacy in treating melanoma (paragraph bridging pages 667 and 668).
Knipping discloses that adoptive transfer of T cells with transgenic high avidity T cell receptors (TCR) is a promising therapeutic approach (abstract). Knipping discloses that CRISPR/Ca9 can be used with guide RNAs targeting the constant region of the TCR α-chain (TRAC) (abstract). Knipping discloses that this leads to successful elimination of surface TCR expression, which can be used for T cell engineering (abstract).
It would have been obvious to one with ordinary skill in the art before the effective filing date of the claimed invention to modify the claims of the ‘100 patent by employing the candidate genes of Zhang and/or to alter the expression of CD52, PDCD1, B2M, CTLA-4, and/or TRAC as disclosed by Mandal, Chen, and Knipping for the eukaryotic cells of Zhang I because this provides a mechanism to create eukaryotic cells with altered CD52, PDCD1, B2M and CTLA-4 expression, which cells can then be used in cancer therapy and immunotherapy without the potential issue of off-target effects and increased potential for unwanted surface molecules to be expressed. One of ordinary skill in the art would have had a predictable and reasonable expectation of success modifying the ‘100 patent claims with Zhang’s CRISPR-Cas9 to alter the expression of CD52, PDCD1, B2M, CTLA-4, and/or TRAC as disclosed by Mandal, Chen, and Knipping, in order to produce eukaryotic cells for use in cancer therapy and immunotherapy.
Claims 156-157, 159-164, 166-170, and 175 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of U.S. Patent No. 11,149,267 in view of Zhang et al. (Zhang I, U.S. Patent Application Publication No. 2019/0010471, published January 10, 2019, and claiming priority to PCT Patent Application No. PCT/US2016/038034, filed June 17, 2016, and U.S. Provisional Patent Application Nos. 61/181,453; 62/207,312; 62/237,360; 62/255,256; and 62/269,876, filed June 18, 2015; August 19, 2015; October 5, 2015; November 13, 2015; and December 18, 2015, respectively), Mandal et al. (15 Cell Stem Cell 643-652 (2014), and cited in the Information Disclosure Statement filed January 14, 2021), Chen (36(11) Trends in Immunology 667-669 (2015)), and Knipping et al. (24(Supplement 1) Molecular Therapy S50 (2016)). This rejection is modified as necessitated by Applicants’ amendments, and is maintained.
It is noted that claims 156-157, 159-164, 166-170, and 175 are product-by-process claims. Therefore, the claims are being interpreted as encompassing a modified eukaryotic cell prepared by any method that reduces off-target effects of a CRISPR-Cas9 system.
Although the claims at issue are not identical, they are not patentably distinct from each other because the ‘267 patent claims a method of developing or designing a CRISPR-Cas system-based therapy/therapeutic by selecting target sequences that are not off-target sites. While the ‘267 patent does not specifically claim a cell made by a method of reducing off-target effects, it discloses such cells. However, it would have been obvious to one with ordinary skill in the art before the effective filing date of the claimed invention that the method claimed by the ‘267 patent would result in modified eukaryotic cells with reduced off-target effects. Furthermore, the ‘267 patent disclosed, but did not claim the modified eukaryotic cells made by a method where off-target effects were reduced. The instant case is analogous to Sun Pharmaceutical Industries, Ltd. v. Eli Lilly and Company (Fed. Cir. July 28, 2010), where the courts ruled that obviousness-type double patenting exist between previously-disclosed, but newly-claimed utility.
The ‘267 patent fails to claim specific candidate target sequences or altered expression of the B2M gene.
Regarding claims 156-157, Zhang I discloses a CRISPR-Cas9 system where the Cas9 can be guided to specific locations within genomes (abstract and paragraph [0076]). Zhang I discloses that off-target effects can be seen where the Cas9 can bind to off-target loci (abstract and paragraph [0076]). Zhang I discloses that these off-target effects can be computationally determined (paragraph [0632]). Zhang I discloses modified cells where off-target effects are reduced (paragraph [1180]). Zhang I discloses that the modified cells can have altered expression of PDCD1, CTLA4, and TRAC (i.e., TCRA) (paragraph [1566]). Zhang I also discloses that CD52 can be targeted (paragraph [1567]). Zhang I further discloses that the off-target candidates include HBB (Table B). Zhang I discloses that additional off-target candidates include LC2A2, GLUT2, G6PC, G6PT, G6PT1, GAA, LAMP2, LAMPB, AGL, GDE, GBE1, GYS2, PYGL, PFKM (Table B). Zhang I discloses that Cas9 target recognition is dictated by base-pairing interactions of the guide with the DNA target, and that the degree of complementarity between the guide and the target is greater than 94.5% (paragraphs [0076] and [0298]). Zhang I discloses that the cells can be human cells, including lymphocytes, which encompasses T cells (paragraphs [0089] and [0988]).
Regarding claims 159-160, Zhang I discloses that the cells can be human cells, including lymphocytes (paragraphs [0089] and [0988]).
Regarding claims 161-164 and 170, Zhang I discloses that the CRISPR-Cas9 system can provide for modified cells where the cells are associated with a genetic disease or disorder, including sickle-cell anemia (a blood disorder) and cancer, where the cells can be prepared ex vivo and reinfused into a patient, which is interpreted as being a pharmaceutical composition (paragraphs [0365] and [0414]). Zhang I discloses that the modified cells can be administered to a patient, which is also interpreted as being a pharmaceutical composition of the modified cells (paragraph [1691]).
Regarding claims 166-167, Zhang I discloses that the Cas9 can be from either Streptococcus pyogenes or Staphylococcus aureus (paragraphs [0303] and [0386]). Zhang I discloses that the PAM sequence for S. pyogenes is NGG (paragraph [0579]).
Regarding claim 168, Zhang I discloses that the guide RNA can be a chimeric sgRNA, which comprises the crRNA (guide) and the tracr linked together (paragraphs [0106]-[0108] and [0116]).
Regarding claim 169, Zhang I discloses that CRISPR-Cas9 systems can be applied to stem cells (paragraph [0166]).
Mandal discloses CRISPR/Cas9 targeting of the B2M gene in human primary T cells (abstract). Mandal discloses that CRISPR/Cas9 can efficiently ablate genes with minimal off-target mutagenesis abstract). Mandal discloses that the B2M (beta-2 microglobulin) encodes the accessory chain of the major histocompatibility complex (MHC) Class I molecules and that deletion or alteration of B2M is well-known to ablate MCH class ( surface expression (paragraph bridging pages 643 and 644). Mandal discloses that ablation of the B2M gene is useful in transplantation and adoptive immunotherapy (paragraph bridging pages 643 and 544).
Chen discloses using CRISPR-Cas9 to delete a variety of genes, including CTLA-4 (page 669, paragraph bridging columns 1 and 2). Chen discloses T-cell therapy can be used for cancer, viral infections, and autoimmune diseases (abstract). Chen also discloses that blocking CTLA-4 and PD-1 signaling have shown marked efficacy in treating melanoma (paragraph bridging pages 667 and 668).
Knipping discloses that adoptive transfer of T cells with transgenic high avidity T cell receptors (TCR) is a promising therapeutic approach (abstract). Knipping discloses that CRISPR/Ca9 can be used with guide RNAs targeting the constant region of the TCR α-chain (TRAC) (abstract). Knipping discloses that this leads to successful elimination of surface TCR expression, which can be used for T cell engineering (abstract).
It would have been obvious to one with ordinary skill in the art before the effective filing date of the claimed invention to modify the claims of the ‘267 patent by employing the candidate genes of Zhang and/or to alter the expression of B2M, PDCD1, CTLA-4, and/or TRAC as disclosed by Mandal, Chen, and Knipping for the eukaryotic cells of Zhang I because this provides a mechanism to create eukaryotic cells with altered B2M and CTLA-4 expression, which cells can then be used in cancer therapy and immunotherapy without the potential issue of off-target effects and increased potential for unwanted surface molecules to be expressed. One of ordinary skill in the art would have had a predictable and reasonable expectation of success modifying the ‘267 patent claims with Zhang’s CRISPR-Cas9 to alter the expression of CD52, CTLA-4, B2M, and/or TRAC, as disclosed by Mandal, Chen, and Knipping in order to produce eukaryotic cells for use in cancer therapy and immunotherapy.
It would have been obvious to one with ordinary skill in the art before the effective filing date of the claimed invention to modify the claims of the ‘267 patent by employing the candidate genes of Zhang and/or to alter the expression of CD52, B2M, PDCD1 and CTLA-4, as disclosed by Mandal and Chen for the eukaryotic cells of Zhang I because this provides a mechanism to create eukaryotic cells with altered B2M and CTLA-4 expression, which cells can then be used in cancer therapy and immunotherapy without the potential issue of off-target effects and increased potential for unwanted surface molecules to be expressed. One of ordinary skill in the art would have had a predictable and reasonable expectation of success modifying the ‘267 patent claims with Zhang’s CRISPR-Cas9 to alter the expression of both CTLA-4 and B2M, as disclosed by Mandal and Chen, in order to produce eukaryotic cells for use in cancer therapy and immunotherapy.
Claims 156-157, 159-164, 166-170, and 175 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11 of U.S. Patent No. 12,305,204 in view of Zhang et al. (Zhang I, U.S. Patent Application Publication No. 2019/0010471, published January 10, 2019, and claiming priority to PCT Patent Application No. PCT/US2016/038034, filed June 17, 2016, and U.S. Provisional Patent Application Nos. 61/181,453; 62/207,312; 62/237,360; 62/255,256; and 62/269,876, filed June 18, 2015; August 19, 2015; October 5, 2015; November 13, 2015; and December 18, 2015, respectively), Mandal et al. (15 Cell Stem Cell 643-652 (2014), and cited in the Information Disclosure Statement filed January 14, 2021), Chen (36(11) Trends in Immunology 667-669 (2015)), and Knipping et al. (24(Supplement 1) Molecular Therapy S50 (2016)). This rejection is modified as necessitated by Applicants’ amendments, and is maintained.
It is noted that claims 156-157, 159-164, 166-170, and 175 are product-by-process claims. Therefore, the claims are being interpreted as encompassing a modified eukaryotic cell prepared by any method that reduces off-target effects of a CRISPR-Cas9 system.
Although the claims at issue are not identical, they are not patentably distinct from each other because the ‘261 application claims a method of developing or designing a CRISPR-Cas system-based therapy/therapeutic by selecting target sequences that are not off-target sites, as well as a cell made by the processes. The ‘261 application claims removal of candidate therapeutic target sequences having off-target effects that occur in at least 0.1% of the target population, to define a final target sequence set.
The ‘261 application fails to claim specific candidate target sequences or altered expression of the B2M gene.
Regarding claims 156-157, Zhang I discloses a CRISPR-Cas9 system where the Cas9 can be guided to specific locations within genomes (abstract and paragraph [0076]). Zhang I discloses that off-target effects can be seen where the Cas9 can bind to off-target loci (abstract and paragraph [0076]). Zhang I discloses that these off-target effects can be computationally determined (paragraph [0632]). Zhang I discloses modified cells where off-target effects are reduced (paragraph [1180]). Zhang I discloses that the modified cells can have altered expression of PDCD1, CTLA4, and TRAC (i.e., TCRA) (paragraph [1566]). Zhang I also discloses that CD52 can be targeted (paragraph [1567]). Zhang I further discloses that the off-target candidates include HBB (Table B). Zhang I discloses that additional off-target candidates include LC2A2, GLUT2, G6PC, G6PT, G6PT1, GAA, LAMP2, LAMPB, AGL, GDE, GBE1, GYS2, PYGL, PFKM (Table B). Zhang I discloses that Cas9 target recognition is dictated by base-pairing interactions of the guide with the DNA target, and that the degree of complementarity between the guide and the target is greater than 94.5% (paragraphs [0076] and [0298]). Zhang I discloses that the cells can be human cells, including lymphocytes, which encompasses T cells (paragraphs [0089] and [0988]).
Regarding claims 159-160, Zhang I discloses that the cells can be human cells, including lymphocytes (paragraphs [0089] and [0988]).
Regarding claims 161-164 and 170, Zhang I discloses that the CRISPR-Cas9 system can provide for modified cells where the cells are associated with a genetic disease or disorder, including sickle-cell anemia (a blood disorder) and cancer, where the cells can be prepared ex vivo and reinfused into a patient, which is interpreted as being a pharmaceutical composition (paragraphs [0365] and [0414]). Zhang I discloses that the modified cells can be administered to a patient, which is also interpreted as being a pharmaceutical composition of the modified cells (paragraph [1691]).
Regarding claims 166-167, Zhang I discloses that the Cas9 can be from either Streptococcus pyogenes or Staphylococcus aureus (paragraphs [0303] and [0386]). Zhang I discloses that the PAM sequence for S. pyogenes is NGG (paragraph [0579]).
Regarding claim 168, Zhang I discloses that the guide RNA can be a chimeric sgRNA, which comprises the crRNA (guide) and the tracr linked together (paragraphs [0106]-[0108] and [0116]).
Regarding claim 169, Zhang I discloses that CRISPR-Cas9 systems can be applied to stem cells (paragraph [0166]).
Mandal discloses CRISPR/Cas9 targeting of the B2M gene in human primary T cells (abstract). Mandal discloses that CRISPR/Cas9 can efficiently ablate genes with minimal off-target mutagenesis abstract). Mandal discloses that the B2M (beta-2 microglobulin) encodes the accessory chain of the major histocompatibility complex (MHC) Class I molecules and that deletion or alteration of B2M is well-known to ablate MCH class ( surface expression (paragraph bridging pages 643 and 644). Mandal discloses that ablation of the B2M gene is useful in transplantation and adoptive immunotherapy (paragraph bridging pages 643 and 544).
Chen discloses using CRISPR-Cas9 to delete a variety of genes, including CTLA-4 (page 669, paragraph bridging columns 1 and 2). Chen discloses T-cell therapy can be used for cancer, viral infections, and autoimmune diseases (abstract). Chen also discloses that blocking CTLA-4 and PD-1 signaling have shown marked efficacy in treating melanoma (paragraph bridging pages 667 and 668).
Knipping discloses that adoptive transfer of T cells with transgenic high avidity T cell receptors (TCR) is a promising therapeutic approach (abstract). Knipping discloses that CRISPR/Ca9 can be used with guide RNAs targeting the constant region of the TCR α-chain (TRAC) (abstract). Knipping discloses that this leads to successful elimination of surface TCR expression, which can be used for T cell engineering (abstract).
It would have been obvious to one with ordinary skill in the art before the effective filing date of the claimed invention to modify the claims of the ‘261 application by employing the candidate genes of Zhang and/or to alter the expression of CD52, PDCD1, B2M, CTLA-4, and/or TRAC as disclosed by Mandal, Chen, and Knipping for the eukaryotic cells of Zhang I because this provides a mechanism to create eukaryotic cells with altered B2M and CTLA-4 expression, which cells can then be used in cancer therapy and immunotherapy without the potential issue of off-target effects and increased potential for unwanted surface molecules to be expressed. One of ordinary skill in the art would have had a predictable and reasonable expectation of success modifying the ‘261 application claims with Zhang’s CRISPR-Cas9 to alter the expression of PDCD1, CD52, CTLA-4, B2M, and/or TRAC as disclosed by Mandal, Chen, and Knipping in order to produce eukaryotic cells for use in cancer therapy and immunotherapy.
Claims 156-157, 159-164, 166-170, and 175 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 11-15, 35-36, 38-41, 43, 45, 67, 70, 76, 82-84, 95, 97, 102, 105, 108, and 110 of copending Application No. 17/742,127 (reference application) in view of Zhang et al. (Zhang I, U.S. Patent Application Publication No. 2019/0010471, published January 10, 2019, and claiming priority to PCT Patent Application No. PCT/US2016/038034, filed June 17, 2016, and U.S. Provisional Patent Application Nos. 61/181,453; 62/207,312; 62/237,360; 62/255,256; and 62/269,876, filed June 18, 2015; August 19, 2015; October 5, 2015; November 13, 2015; and December 18, 2015, respectively), Mandal et al. (15 Cell Stem Cell 643-652 (2014), and cited in the Information Disclosure Statement filed January 14, 2021, Chen (36(11) Trends in Immunology 667-669 (2015)), and Knipping et al. (24(Supplement 1) Molecular Therapy S50 (2016)). This rejection is modified as necessitated by Applicants’ amendments, and is maintained.
It is noted that claims 156-157, 159-164, 166-170, and 175 are product-by-process claims. Therefore, the claims are being interpreted as encompassing a modified eukaryotic cell prepared by any method that reduces off-target effects of a CRISPR-Cas9 system.
Although the claims at issue are not identical, they are not patentably distinct from each other because the ‘127 application claims a method of developing or designing a CRISPR-Cas system-based therapy/therapeutic by selecting target sequences that are not off-target sites, as well as a cell made by the processes.
The ‘127 application fails to claim specific candidate target sequences or altered expression of the B2M gene.
Regarding claims 156-157, Zhang I discloses a CRISPR-Cas9 system where the Cas9 can be guided to specific locations within genomes (abstract and paragraph [0076]). Zhang I discloses that off-target effects can be seen where the Cas9 can bind to off-target loci (abstract and paragraph [0076]). Zhang I discloses that these off-target effects can be computationally determined (paragraph [0632]). Zhang I discloses modified cells where off-target effects are reduced (paragraph [1180]). Zhang I discloses that the modified cells can have altered expression of PDCD1, CTLA4, and TRAC (i.e., TCRA) (paragraph [1566]). Zhang I also discloses that CD52 can be targeted (paragraph [1567]). Zhang I further discloses that the off-target candidates include HBB (Table B). Zhang I discloses that additional off-target candidates include LC2A2, GLUT2, G6PC, G6PT, G6PT1, GAA, LAMP2, LAMPB, AGL, GDE, GBE1, GYS2, PYGL, PFKM (Table B). Zhang I discloses that Cas9 target recognition is dictated by base-pairing interactions of the guide with the DNA target, and that the degree of complementarity between the guide and the target is greater than 94.5% (paragraphs [0076] and [0298]). Zhang I discloses that the cells can be human cells, including lymphocytes, which encompasses T cells (paragraphs [0089] and [0988]).
Regarding claims 159-160, Zhang I discloses that the cells can be human cells, including lymphocytes (paragraphs [0089] and [0988]).
Regarding claims 161-164 and 170, Zhang I discloses that the CRISPR-Cas9 system can provide for modified cells where the cells are associated with a genetic disease or disorder, including sickle-cell anemia (a blood disorder) and cancer, where the cells can be prepared ex vivo and reinfused into a patient, which is interpreted as being a pharmaceutical composition (paragraphs [0365] and [0414]). Zhang I discloses that the modified cells can be administered to a patient, which is also interpreted as being a pharmaceutical composition of the modified cells (paragraph [1691]).
Regarding claims 166-167, Zhang I discloses that the Cas9 can be from either Streptococcus pyogenes or Staphylococcus aureus (paragraphs [0303] and [0386]). Zhang I discloses that the PAM sequence for S. pyogenes is NGG (paragraph [0579]).
Regarding claim 168, Zhang I discloses that the guide RNA can be a chimeric sgRNA, which comprises the crRNA (guide) and the tracr linked together (paragraphs [0106]-[0108] and [0116]).
Regarding claim 169, Zhang I discloses that CRISPR-Cas9 systems can be applied to stem cells (paragraph [0166]).
Mandal discloses CRISPR/Cas9 targeting of the B2M gene in human primary T cells (abstract). Mandal discloses that CRISPR/Cas9 can efficiently ablate genes with minimal off-target mutagenesis abstract). Mandal discloses that the B2M (beta-2 microglobulin) encodes the accessory chain of the major histocompatibility complex (MHC) Class I molecules and that deletion or alteration of B2M is well-known to ablate MCH class ( surface expression (paragraph bridging pages 643 and 644). Mandal discloses that ablation of the B2M gene is useful in transplantation and adoptive immunotherapy (paragraph bridging pages 643 and 544).
Chen discloses using CRISPR-Cas9 to delete a variety of genes, including CTLA-4 (page 669, paragraph bridging columns 1 and 2). Chen discloses T-cell therapy can be used for cancer, viral infections, and autoimmune diseases (abstract). Chen also discloses that blocking CTLA-4 and PD-1 signaling have shown marked efficacy in treating melanoma (paragraph bridging pages 667 and 668).
Knipping discloses that adoptive transfer of T cells with transgenic high avidity T cell receptors (TCR) is a promising therapeutic approach (abstract). Knipping discloses that CRISPR/Ca9 can be used with guide RNAs targeting the constant region of the TCR α-chain (TRAC) (abstract). Knipping discloses that this leads to successful elimination of surface TCR expression, which can be used for T cell engineering (abstract).
It would have been obvious to one with ordinary skill in the art before the effective filing date of the claimed invention to modify the claims of the ‘127 application by employing the candidate genes of Zhang and/or to alter the expression of PDCD1, CD52, B2M, CTLA-4, and/or TRAC as disclosed by Mandal, Chen, and Knipping for the eukaryotic cells of Zhang I because this provides a mechanism to create eukaryotic cells with altered B2M and CTLA-4 expression, which cells can then be used in cancer therapy and immunotherapy without the potential issue of off-target effects and increased potential for unwanted surface molecules to be expressed. One of ordinary skill in the art would have had a predictable and reasonable expectation of success modifying the ‘127 application claims with Zhang’s CRISPR-Cas9 to alter the expression of PDCD1, CD52, CTLA-4, B2M, and/or TRAC as disclosed by Mandal, Chen, and Knipping in order to produce eukaryotic cells for use in cancer therapy and immunotherapy.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 156-157, 159-164, 166-170, and 175 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-7 and 11-12 of copending Application No. 18/345,935 (reference application) in view of Zhang et al. (Zhang I, U.S. Patent Application Publication No. 2019/0010471, published January 10, 2019, and claiming priority to PCT Patent Application No. PCT/US2016/038034, filed June 17, 2016, and U.S. Provisional Patent Application Nos. 61/181,453; 62/207,312; 62/237,360; 62/255,256; and 62/269,876, filed June 18, 2015; August 19, 2015; October 5, 2015; November 13, 2015; and December 18, 2015, respectively), Mandal et al. (15 Cell Stem Cell 643-652 (2014), and cited in the Information Disclosure Statement filed January 14, 2021), Chen (36(11) Trends in Immunology 667-669 (2015)), and Knipping et al. (24(Supplement 1) Molecular Therapy S50 (2016)). This rejection is modified as necessitated by Applicants’ amendments, and is maintained.
It is noted that claims 156-157, 159-164, 166-170, and 175 are product-by-process claims. Therefore, the claims are being interpreted as encompassing a modified eukaryotic cell prepared by any method that reduces off-target effects of a CRISPR-Cas9 system.
Although the claims at issue are not identical, they are not patentably distinct from each other because the ‘935 application claims a method of developing or designing CRISPR-Cas system-based guide molecules by selecting target sequences that are not off-target sites, as well as a cell made by the processes. The ‘935 application claims removal of candidate therapeutic target sequences having off-target effects that occur in at least 0.1% of the target population, to define a final target sequence set. The ‘935 application claims that the candidate target sequence can be BCL11A. The ‘935 application claims that the loci can be related to a blood disorder.
The ‘935 application fails to claim several specific candidate target sequences or altered expression of the B2M gene.
Regarding claims 156-157, Zhang I discloses a CRISPR-Cas9 system where the Cas9 can be guided to specific locations within genomes (abstract and paragraph [0076]). Zhang I discloses that off-target effects can be seen where the Cas9 can bind to off-target loci (abstract and paragraph [0076]). Zhang I discloses that these off-target effects can be computationally determined (paragraph [0632]). Zhang I discloses modified cells where off-target effects are reduced (paragraph [1180]). Zhang I discloses that the modified cells can have altered expression of PDCD1, CTLA4, and TRAC (i.e., TCRA) (paragraph [1566]). Zhang I also discloses that CD52 can be targeted (paragraph [1567]). Zhang I further discloses that the off-target candidates include HBB (Table B). Zhang I discloses that additional off-target candidates include LC2A2, GLUT2, G6PC, G6PT, G6PT1, GAA, LAMP2, LAMPB, AGL, GDE, GBE1, GYS2, PYGL, PFKM (Table B). Zhang I discloses that Cas9 target recognition is dictated by base-pairing interactions of the guide with the DNA target, and that the degree of complementarity between the guide and the target is greater than 94.5% (paragraphs [0076] and [0298]). Zhang I discloses that the cells can be human cells, including lymphocytes, which encompasses T cells (paragraphs [0089] and [0988]).
Regarding claims 159-160, Zhang I discloses that the cells can be human cells, including lymphocytes (paragraphs [0089] and [0988]).
Regarding claims 161-164 and 170, Zhang I discloses that the CRISPR-Cas9 system can provide for modified cells where the cells are associated with a genetic disease or disorder, including sickle-cell anemia (a blood disorder) and cancer, where the cells can be prepared ex vivo and reinfused into a patient, which is interpreted as being a pharmaceutical composition (paragraphs [0365] and [0414]). Zhang I discloses that the modified cells can be administered to a patient, which is also interpreted as being a pharmaceutical composition of the modified cells (paragraph [1691]).
Regarding claims 166-167, Zhang I discloses that the Cas9 can be from either Streptococcus pyogenes or Staphylococcus aureus (paragraphs [0303] and [0386]). Zhang I discloses that the PAM sequence for S. pyogenes is NGG (paragraph [0579]).
Regarding claim 168, Zhang I discloses that the guide RNA can be a chimeric sgRNA, which comprises the crRNA (guide) and the tracr linked together (paragraphs [0106]-[0108] and [0116]).
Regarding claim 169, Zhang I discloses that CRISPR-Cas9 systems can be applied to stem cells (paragraph [0166]).
Mandal discloses CRISPR/Cas9 targeting of the B2M gene in human primary T cells (abstract). Mandal discloses that CRISPR/Cas9 can efficiently ablate genes with minimal off-target mutagenesis abstract). Mandal discloses that the B2M (beta-2 microglobulin) encodes the accessory chain of the major histocompatibility complex (MHC) Class I molecules and that deletion or alteration of B2M is well-known to ablate MCH class ( surface expression (paragraph bridging pages 643 and 644). Mandal discloses that ablation of the B2M gene is useful in transplantation and adoptive immunotherapy (paragraph bridging pages 643 and 544).
Chen discloses using CRISPR-Cas9 to delete a variety of genes, including CTLA-4 (page 669, paragraph bridging columns 1 and 2). Chen discloses T-cell therapy can be used for cancer, viral infections, and autoimmune diseases (abstract). Chen also discloses that blocking CTLA-4 and PD-1 signaling have shown marked efficacy in treating melanoma (paragraph bridging pages 667 and 668).
Knipping discloses that adoptive transfer of T cells with transgenic high avidity T cell receptors (TCR) is a promising therapeutic approach (abstract). Knipping discloses that CRISPR/Ca9 can be used with guide RNAs targeting the constant region of the TCR α-chain (TRAC) (abstract). Knipping discloses that this leads to successful elimination of surface TCR expression, which can be used for T cell engineering (abstract).
It would have been obvious to one with ordinary skill in the art before the effective filing date of the claimed invention to modify the claims of the ‘935 application by employing the candidate genes of Zhang and/or to alter the expression of PDCD1, CD52, B2M, CTLA-4, and/or TRAC as disclosed by Mandal, Chen, and Knipping for the eukaryotic cells of Zhang I because this provides a mechanism to create eukaryotic cells with altered B2M and CTLA-4 expression, which cells can then be used in cancer therapy and immunotherapy without the potential issue of off-target effects and increased potential for unwanted surface molecules to be expressed. One of ordinary skill in the art would have had a predictable and reasonable expectation of success modifying the ’935 application claims with Zhang’s CRISPR-Cas9 to alter the expression of PDCD1, CD52, CTLA-4, B2M, and/or TRAC as disclosed by Mandal, Chen, and Knipping in order to produce eukaryotic cells for use in cancer therapy and immunotherapy.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 156-157, 159-164, 166-170, and 175 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-30 of copending Application No. 18/454,343 (reference application) in view of Zhang et al. (Zhang I, U.S. Patent Application Publication No. 2019/0010471, published January 10, 2019, and claiming priority to PCT Patent Application No. PCT/US2016/038034, filed June 17, 2016, and U.S. Provisional Patent Application Nos. 61/181,453; 62/207,312; 62/237,360; 62/255,256; and 62/269,876, filed June 18, 2015; August 19, 2015; October 5, 2015; November 13, 2015; and December 18, 2015, respectively), Mandal et al. (15 Cell Stem Cell 643-652 (2014), and cited in the Information Disclosure Statement filed January 14, 2021), Chen (36(11) Trends in Immunology 667-669 (2015)), and Knipping et al. (24(Supplement 1) Molecular Therapy S50 (2016)). This rejection is modified as necessitated by Applicants’ amendments and is maintained.
It is noted that claims 156-157, 159-164, 166-170, and 175 are product-by-process claims. Therefore, the claims are being interpreted as encompassing a modified eukaryotic cell prepared by any method that reduces off-target effects of a CRISPR-Cas9 system.
Although the claims at issue are not identical, they are not patentably distinct from each other because the ‘343 application claims a cell made by the processes of reducing off-target effects. The ‘343 application claims that the candidate target sequence can be B2M.
The ‘343 application fails to claim several specific candidate target sequences.
Regarding claims 156-157, Zhang I discloses a CRISPR-Cas9 system where the Cas9 can be guided to specific locations within genomes (abstract and paragraph [0076]). Zhang I discloses that off-target effects can be seen where the Cas9 can bind to off-target loci (abstract and paragraph [0076]). Zhang I discloses that these off-target effects can be computationally determined (paragraph [0632]). Zhang I discloses modified cells where off-target effects are reduced (paragraph [1180]). Zhang I discloses that the modified cells can have altered expression of PDCD1, CTLA4, and TRAC (i.e., TCRA) (paragraph [1566]). Zhang I also discloses that CD52 can be targeted (paragraph [1567]). Zhang I further discloses that the off-target candidates include HBB (Table B). Zhang I discloses that additional off-target candidates include LC2A2, GLUT2, G6PC, G6PT, G6PT1, GAA, LAMP2, LAMPB, AGL, GDE, GBE1, GYS2, PYGL, PFKM (Table B). Zhang I discloses that Cas9 target recognition is dictated by base-pairing interactions of the guide with the DNA target, and that the degree of complementarity between the guide and the target is greater than 94.5% (paragraphs [0076] and [0298]). Zhang I discloses that the cells can be human cells, including lymphocytes, which encompasses T cells (paragraphs [0089] and [0988]).
Regarding claims 159-160, Zhang I discloses that the cells can be human cells, including lymphocytes (paragraphs [0089] and [0988]).
Regarding claims 161-164 and 170, Zhang I discloses that the CRISPR-Cas9 system can provide for modified cells where the cells are associated with a genetic disease or disorder, including sickle-cell anemia (a blood disorder) and cancer, where the cells can be prepared ex vivo and reinfused into a patient, which is interpreted as being a pharmaceutical composition (paragraphs [0365] and [0414]). Zhang I discloses that the modified cells can be administered to a patient, which is also interpreted as being a pharmaceutical composition of the modified cells (paragraph [1691]).
Regarding claims 166-167, Zhang I discloses that the Cas9 can be from either Streptococcus pyogenes or Staphylococcus aureus (paragraphs [0303] and [0386]). Zhang I discloses that the PAM sequence for S. pyogenes is NGG (paragraph [0579]).
Regarding claim 168, Zhang I discloses that the guide RNA can be a chimeric sgRNA, which comprises the crRNA (guide) and the tracr linked together (paragraphs [0106]-[0108] and [0116]).
Regarding claim 169, Zhang I discloses that CRISPR-Cas9 systems can be applied to stem cells (paragraph [0166]).
Mandal discloses CRISPR/Cas9 targeting of the B2M gene in human primary T cells (abstract). Mandal discloses that CRISPR/Cas9 can efficiently ablate genes with minimal off-target mutagenesis abstract). Mandal discloses that the B2M (beta-2 microglobulin) encodes the accessory chain of the major histocompatibility complex (MHC) Class I molecules and that deletion or alteration of B2M is well-known to ablate MCH class ( surface expression (paragraph bridging pages 643 and 644). Mandal discloses that ablation of the B2M gene is useful in transplantation and adoptive immunotherapy (paragraph bridging pages 643 and 544).
Chen discloses using CRISPR-Cas9 to delete a variety of genes, including CTLA-4 (page 669, paragraph bridging columns 1 and 2). Chen discloses T-cell therapy can be used for cancer, viral infections, and autoimmune diseases (abstract). Chen also discloses that blocking CTLA-4 and PD-1 signaling have shown marked efficacy in treating melanoma (paragraph bridging pages 667 and 668).
Knipping discloses that adoptive transfer of T cells with transgenic high avidity T cell receptors (TCR) is a promising therapeutic approach (abstract). Knipping discloses that CRISPR/Ca9 can be used with guide RNAs targeting the constant region of the TCR α-chain (TRAC) (abstract). Knipping discloses that this leads to successful elimination of surface TCR expression, which can be used for T cell engineering (abstract).
It would have been obvious to one with ordinary skill in the art before the effective filing date of the claimed invention to modify the claims of the ‘343 application by employing the candidate genes of Zhang and/or to alter the expression of PDCD1, CD52, B2M, CTLA-4, and/or TRAC as disclosed by Mandal, Chen, and Knipping for the eukaryotic cells of Zhang I because this provides a mechanism to create eukaryotic cells with altered B2M and CTLA-4 expression, which cells can then be used in cancer therapy and immunotherapy without the potential issue of off-target effects and increased potential for unwanted surface molecules to be expressed. One of ordinary skill in the art would have had a predictable and reasonable expectation of success modifying the ’343 application claims with Zhang’s CRISPR-Cas9 to alter the expression of PDCD1, CTLA-4, B2M, CD52, and/or TRAC as disclosed by Mandal, Chen, and Knipping in order to produce eukaryotic cells for use in cancer therapy and immunotherapy.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Amendments and Arguments
Regarding the rejection under 35 U.S.C. § 103 based upon Zhang I in view of Mandal and Knipping; Hsu/Zhang II/Wang in view of Zhang I, Mandal, Chen, and Knipping, Applicants’ amendments and arguments have been fully considered, and are not deemed to be persuasive.
Applicants again assert that none of the cited prior art references disclose or suggest isolated T cells prepared by optimization of target sequence location by selecting target loci across a target population.
However, as stated above and previously, claims 156-157, 159-164, 166-170, and 175 are product-by-process claims, as acknowledged by Applicants. Therefore, because the claims are still being interpreted as encompassing any modified eukaryotic cell prepared by any method that reduces off-target effects of a CRISPR-Cas9 system, the modified eukaryotic cells disclosed by the cited prior art references are deemed to be the same as, or obvious variants thereof, the modified eukaryotic cells of the instant invention. The cited prior art references disclose eukaryotic cells having the same or similar characteristics as the claimed eukaryotic cells. The cited prior art, taken together, discloses eukaryotic cells that have reduced off-target effects, where PDCD1, CD52, B2M, CTLA-4, and/or TRAC gene expression is altered by CRISPR-Cas9. Applicants have still not presented any evidence that the instantly claimed modified isolated eukaryotic cells are different than any other eukaryotic cells that have been prepared by methods that reduce off target effects. Applicants merely assert that there is no motivation to combine the references without pointing to specific reasons or data that show that the claimed T cells are different from any other T cells having the claimed modifications. And such modifications are disclosed by the combination of prior art references, as discussed above.
In addition, Applicants still appear to be attacking the cited prior art references individually. However, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., Inc., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Here, Zhang I discloses cells that can altered expression of PDCD1, CD52, CTLA-4 and TRAC. Mandal discloses alteration of B2M expression. Chen disclose altered expression of CTLA-4. Thus, it is the combination of the cited prior art references taken as a whole that renders the claims obvious because each of the required modified gene expression is set forth. As noted previously and above, the combination of references, taken together and as a whole would lead one of ordinary skill in the art directly to the claimed invention. Because the claims are all directed to modified, isolated eukaryotic cells having reduced off-target effects, each of these references taken together and as a whole provide both disclosure and motivation to prepare eukaryotic cells having the required expression characteristics.
Further, Applicants have still not provided any evidence that the eukaryotic cells of the instant application are different than those disclosed by the cited art. Whether made by similar or even different processes, the eukaryotic cells of both the instant invention and the cited prior art are still deemed to be the same or insignificantly different, especially since the cited prior art discloses that CTLA4 and TRAC, as well as B2M, PDCD1, and/or CD52 and B2M, expression can be modified. Absent objective and factually supported evidence that the instantly claimed cells are different from any other modified eukaryotic cells where off-target effects are reduced, the cited prior art references are deemed to render obvious the instantly claimed modified isolated eukaryotic cells that have a reduced frequency of off-target effects and where B2M and CTLA-4 have altered gene expression. Applicants have still not provided any evidence that the claimed cells are different from those disclosed and suggested by the prior art. Applicants have again provided only the same arguments of counsel, and still do not point to how any of the amendments or to any data that would allegedly obviate these rejections. As noted previously, arguments of counsel cannot take the place of factually supported objective evidence. See, e.g., In re Huang, 100 F.3d 135,139-40, 40 USPQ2d 1685, 1689 (Fed. Cir. 1996); In re De Blauwe, 736 F.2d 699, 705, 222 USPQ 191, 196 (Fed. Cir. 1984). Applicants have not yet shown that modified isolated T cells made by the method of the instant applications are different in any amount, structure, or function than any other modified isolated T cells. Should Applicants have any data to present that shows that the instantly claimed modified isolated eukaryotic cells are any different from eukaryotic cells having reduced off target effects, such data should be presented.
For all these reasons, and those listed above, claims 156-157, 159-164, 166-170, and 175 are still deemed to be rendered obvious over, the cited prior art references, as set forth above.
Regarding the non-statutory double patenting rejections over U.S. Patent Nos. 10,494, 621; 10,876,100; 11,149,267; and 12,305,204; these rejections are maintained. As stated above, the claims are interpreted as encompassing a modified T cell prepared by any method that reduces off-target effects of a CRISPR-Cas9 system. Therefore, for the same reasons as discussed above with regard to the prior art rejections, the non-statutory double patenting rejections are maintained because the claims of these patents are deemed to encompass the instant isolated T cells having a reduced frequency of off-target effects, having candidate target sequences, as disclosed by Zhang I, which include of PDCD1, CD52, CTLA-4, and/or TRAC, and which have altered expression of B2M, as disclosed by Mandal, and CTLA-4, as disclosed by Chen. Therefore, these rejections are maintained.
Regarding the non-statutory double patenting rejection over U.S. Patent Application Nos. 17/742,127 and 18/345,935, Applicants assert the same reasons as those above to traverse these rejections. However, as discussed above, the non-statutory double patenting rejections are maintained because the claims of these patents are deemed to encompass the instant isolated T cells having a reduced frequency of off-target effects, having candidate target sequences, as disclosed by Zhang I, which include of PDCD1, CD52, CTLA-4, and/or TRAC, and which have altered expression of B2M, as disclosed by Mandal, and CTLA-4, as disclosed by Chen. Applicants do note that should these rejections remain when allowable subject matter is indicated, filing a Terminal Disclaimer will be considered. Applicants request that these rejections be held in abeyance. Therefore, these rejections are maintained.
Regarding the non-statutory double patenting rejection over U.S. Patent Application No. 18/454,343, Applicants do not address this rejection. Therefore, this rejection is maintained.
It is noted that U.S. Patent Application Nos. 18/905,630 and 19/342,889 claim a modified CRISPR-Cas9 protein and a cell comprising the Cas9 protein. However, the modifications claimed by the ‘630 and ‘889 applications are modifications in the Cas9 protein itself, rather than modifications of B2M, CTLA-4, and/or TRAC genes in the cells. Therefore, no non-statutory double patenting rejection is set forth because the claims are deemed to be patentably distinct.
Conclusion
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.
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NANCY J. LEITH
Primary Examiner
Art Unit 1636
/NANCY J LEITH/Primary Examiner, Art Unit 1636