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 .
Status of Claims
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
This action is in response to the papers filed on January 16, 2026. Claims 267, 268, 272, and 296 - 312 are currently pending. Claims 267, 268, 272, 298, 301 – 303, and 308 have been amended in the Applicant’s amendment filed January 16, 2026. No claims have been added or canceled in the Applicant’s amendment filed January 16, 2026.
Applicant elected group IV, (claims 267, 268, and 272) drawn to a method of producing a modified immune effector cell, in the response filed 29 July, 2025. In the response filed on 12 September, 2025, Applicant added new claims 296 – 312, and canceled claims 1, 20-21, 50-52, 98, 108, 160, 166, 252, 281, and 289 – 293.
Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election of invention has been treated as an election without traverse (MPEP § 818.03(a)). The restriction requirement is still deemed proper and is therefore made FINAL.
Therefore, claims 267, 268, 272, and 296 - 312 are under consideration to which the following grounds of rejection are applicable. Claims 267, 268, and 272 are independent claims.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on January 16, 2026 has been considered. An initialed copy of the IDS accompanies this Office Action.
Priority
The present application filed August 25, 2022 is a CON of Application 16/354,098 03/14/2019 (now abandoned). Applicant’s claim for the benefit of a prior-filed parent provisional applications 62/692,010 field 06/29/2018, 62/768,428 filed 11/16/2018, 62/643,582 filed 03/15/2018, 62/692,014 filed 06/29/2018, 62/768,430 filed 11/16/2018, 62/804,259 filed 02/12/2019, 62/714,333 filed 08/03/2018,
62/768,459 filed 11/16/2018, 62/714,337 filed 08/03/2018 and 62/768,462 filed 11/16/2018 under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged.
Therefore, the earliest priority date is March 15, 2018.
Withdrawn Objections/Rejections
Claim Rejection - 35 USC § 112(d)
The rejection of claim 309 under 35 U.S.C. 112(d) as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends is withdrawn.
Applicant has amended claim 309, and is now further limiting of claim 267.
In view of the withdrawn rejection, Applicant’s argument is moot.
Maintained Objections/Rejections
Claim Rejection - 35 USC § 112(b)
The rejection of claims 298 - 306 is maintained under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 298 and by dependency claims 299-306 are indefinite because of the recitation in claim 298 of “an enzymatic protein”. Claim 298 depends on claim 296 which recites “ (ii) one or more enzymatic proteins of (i)”. However, “(i) of claim 296 recites one or more nucleic acid molecules,” and does not teach enzymatic proteins. Thus, the antecedent bases of “an enzymatic protein” in claim 298 is unclear.
Claim 301 is indefinite for reciting improper alternative expression (i.e. "Markush") format. Per MPEP § 2 l 73.05(h), alternative expressions are permitted if they present no uncertainty or ambiguity with respect to the question of scope or clarity of the claims. A "Markush" claim recites a list of alternatively useable species. In re Harnisch, 631 F.2d 716, 719-20,206 USPQ 300, 303-04 (CCPA 1980); Ex parte Markush, 1925 Dec. Comm'r Pat. 126, 127 (1924). A Markush claim is commonly formatted as: "selected from the group consisting of A, B, and C." Alternative expressions using "or" are acceptable, such as "wherein R is A, B, C, or D." However, the phrase "Markush claim" means any claim that recites a list of alternatively useable species regardless of format. For example, claim 301 lists the genome coordinates, without the use of a Markush group.
Claims 302 and 303 are indefinite for the recitation of “Seq ID Nos: 708 – 772.” The as-Filed Specification teaches that Seq ID Nos 708 – 764 are directed to 57 BCOR gRNAs. It is unclear what sequences 765 – 772 are directed to. Thus, the metes and bounds of the claim cannot be determined.
Claim Rejection - 35 USC § 103
The rejection of claims 267, 268, 272, and 296 – 312 is maintained under 35 U.S.C. 103 as being unpatentable over Chapman et al. (hereinafter referred to as “Chapman”) (US 20170224734 A1, published 10 August, 2017), and further in view of Sharp et al. (hereinafter referred to as “Sharp”) (US 20180010134 A1, published 11 January, 2018), as evidenced by Hatchwell et al. (US20140155271 A1, published June 5, 2014). This rejection has been modified as necessitated by the response filed January 16, 2026.
Regarding claims 267, 268, and 272, Chapman teaches methods of preparing tumor infiltrating cells engineered to express a pro-inflammatory polypeptide (Abstract). Chapman teaches the method of treating melanoma with the genetically engineered T cells, wherein the tumor biopsies are obtained from which the TILs are isolated, the TILs are then transfected with the IL-2 encoding CRISPR construct, the cells are expanded, and re-introduced into the patient (Paragraph [0352] – [0375]) (interpreted as a method of producing a modified immune effector cell, instant claims 267, 268, and 272 (all in part)). Chapman teaches that the genetically engineered cells can have enhanced activity, such as enhanced tumor targeting and/or enhanced effector function(s) (Paragraph [0071]) (interpreted as an effector function is enhanced in the modified immune effector cell relative to an unmodified immune effector cell, instant claims 267, 267, and 272 (all in part)).
Chapman does not specifically exemplify that the gene regulating system is capable of reducing expression and/or function of an endogenous BCOR (claims 267, 268, and 272, (all in part)).
Sharp teaches that a vector containing nucleic acid molecules that is able to express Cas9, and the vector expresses and provides a plurality of RNAs to guide the Cas9, and a plurality of specific mutations in a plurality of target loci are introduced (Claim 1) (interpreted as introducing the gene regulating system into the immune effector cell, instant claim 267, 268, and 272 (all in part)). Sharp teaches that this invention is pharmaceutically relevant for treatment of cancer (Abstract). Sharp teaches that this invention teaches ex vivo and in vivo modeling of multiple genetic, e.g., cancer or tissue-specific mutations (Paragraph [0009]).
Sharp teaches that the RNAs to guide Cas9 comprise CRISPR RNA and chimeric single guide RNA (sgRNA), wherein the sgRNA target BCOR (claim 4 and 16) Sharp teaches that the invention teaches that the expression of the gene product being decreased Paragraph [0117]) (interpreted as the gene regulating system capable or reducing expression of endogenous BCOR, instant claim 267, 268, and 272).
Therefore, in view of the benefits of developing treatments for cancer through ex vivo and in vivo models of multiple cancer specific mutations as evidenced by Sharp, it would have been prima facia obvious to modify the method of treating cancer, wherein the genetically engineered TILs cells are transfected with a CRISPR construct, as taught by Chapman, to include the CRISPR construct that comprises sgRNA which target BCOR, as taught by Sharp, with a reasonable expectation of success in generating a BCOR specific inactivating mutation in the TILs. It would have been prima facia obvious to combine the cited art because Chapman teaches the genetic method of preparing TILs engineered to express a pro-inflammatory polypeptide, comprising the use of a CRISPR Cas9 system, and Sharp teaches the advantage of targeting BCOR gene expression to reduce expression of an endogenous BCOR gene or product using the CRISPR Cas9 system.
Regarding claim 304, Sharp teaches that the Cas9 enzyme can be combined with multiple sgRNAs to achieve efficient multiplex genome editing at multiple loci simultaneously (Paragraph [0165]).
Regarding claim 305, Sharp teaches that a double stranded break is introduced into the genome sequence by the CRISPR complex (Paragraph [0119]).
Regarding claim 306, Sharp teaches RNAs to guide Cas9 comprise CRISPR RNA and chimeric single guide RNA (sgRNA) (claim 4).
Regarding claim 307 and 308, Sharp teaches that the CRISPR complex of the invention has a wide variety of utilities including modifying (e.g., deleting, inserting, translocating, inactivating, activating) a target polynucleotide in a multiplicity of cell types (Paragraph [0009]). Therefore, it would have been obvious for one of ordinary skill in the art to use the CRISPR system to introduce an inactivating mutation in the BCOR gene by a deletion, insertion or inactivation of the endogenous BCOR gene.
Regarding claim 296, the combined teachings of Chapman and Sharp render obvious claims 267, 268, and 272. Moreover, Chapman teaches that the genetic engineering can be accomplished using, for example, zinc finger proteins, siRNAs, TALENs, and/or Cas-CRISPR, thereby inducing targeting mutagenesis (Paragraph [0224]).
Regarding claim 297, the combined teachings of Chapman and Sharp render obvious claims 267, 268, and 272. Moreover, Chapman teaches that the genetic engineering can be accomplished using siRNA (Paragraph [0224]).
Regarding claim 298 and 299, the combined teachings of Chapman and Sharp render obvious claims 267, 268, and 272. Moreover, Chapman teaches that the genetic engineering can be accomplished using TALENs (Paragraph [0224]).
Regarding claim 300, the combined teachings of Chapman and Sharp render obvious claims 267, 268, and 272. Moreover, Chapman teaches that the genetic engineering can be accomplished using Cas-CRISPR.
Regarding claim 310 and 311, the combined teachings of Chapman and Sharp render obvious claims 267, 268, and 272. Moreover, Chapman teaches methods of preparing tumor infiltrating cells engineered to express a pro-inflammatory polypeptide (Abstract).
Regarding claim 312, the combined teachings of Chapman and Sharp render obvious claims 267, 268, and 272. Moreover, Chapman teaches the method of treating melanoma with the genetically engineered T cells, wherein the tumor biopsies are obtained from which the TILs are isolated, the TILs are then transfected with the IL-2 encoding CRISPR construct, the cells are expanded, and re-introduced into the patient (Paragraph [0352] – [0375]) (interpreted as the gene-regulating system is introduced after expanded the population of immune effector cells).
Regarding claims 301 - 303, Chapman and Sharp do not specifically exemplify Seq ID No. 708 – 772 (the targeting domain of the gRNA), however, one of ordinary skill in the art would be able to use these gRNAs in a CRISPR-Cas9 system as described by Chapman and Sharp. This can be evidenced by Hatchwell et al. (US20140155271 A1, published June 5, 2014), who teaches that the nucleotide of Seq ID No. 737 and 738 have a 100% alignment score with instant Seq ID NO. 730 (which is the BCOR intronic sequence). Hatchwell teaches an isolated polypeptide encoded by an RNA sequence transcribed from the genomic sequence of Seq ID Nos 383 – 1020 (Paragraph [0024]). Thus, one of ordinary skill in the art would be able to use the desired RNA sequence in the CRISPR/Cas9 systems as taught by Chapman and Sharp. Further regarding claim 301, the as-Filed Specification teaches that instant Seq ID No. 708 – 764 are directed to BCOR gRNAs (Paragraph [0604]) Table 5A teaches that the target is BCL3. Thus, by using the Seq ID No. 737 or 738 taught by Hatchwell et al, one of ordinary skill in the art would be able to design the gRNA able to bind to a nucleic acid sequence set by the coordinates recited in claim 301.
Response to Arguments as they apply to rejection of claims 267, 268, 272, and 296 – 312 under 35 USC § 103
Applicant’s arguments filed 16 January, 2026 have been fully considered but they are not persuasive. Applicant essentially asserts (a) a person of ordinary skill in the art would not have had any reason to have specifically selected to target endogenous BCOR (pg. 10, first paragraph, and pg. 12, first paragraph), (b) Chapman does not teach the gene regulating system capable of reducing expression of endogenous BCOR, and Sharp does not teach modifying BCOR in an immune effector cell (pg. 10, last paragraph, and pg. 11, first paragraph), (c) Examiner has used hindsight and is picking and choosing the specific target gene, BCOR (pg. 11, third paragraph).
Please note: this rejection has been amended as necessitated by the response filed January 16, 2026.
Regarding (a) and (c), Applicant’s arguments are not found persuasive. The methods are directed to a method of producing a modified immune effector cell, wherein such methods of modifying immune effector cells and gene-regulating systems are very well known in the art. Thus, it is reasonable that one of ordinary skill in the art would know how to modify the immune effector cell with their gene of choice. The Examiner is not “picking and choosing” BCOR, but rather is showing that one of ordinary skill would be able to introduce any gene regulating system into a cell, including a gene regulating system for reducing expression of BCOR. Further, Sharp teaches that the sgRNAs targeting BCOR are useful in treating colorectal cancer (Paragraph [0196]) and endometrial cancer (Paragraph [0198]). Sharp teaches that these sgRNAs treat or inhibit the development of a genetic disease by providing personalized treatment comprising delivering sgRNAs that target the genetic loci associated with disease (Paragraph [0018]). Thus, one of ordinary skill in the art would have targeted downregulating BCOR for treatment of colorectal cancer and/or endometrial cancer.
Regarding (b), Applicant is reminded that none of the references has to teach each and every claim limitation. If they did, this would have been anticipation and not an obviousness-type rejection. One cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Applicant’s assertion that Chapman does not teach the gene regulating system capable of reducing expression of endogenous BCOR, and Sharp does not teach modifying BCOR in an immune effector cell is not found persuasive. Note that the instant claims merely require reducing expressing and function of an endogenous BCORl gene. The applicant is reminded that the rejection of record is based on the combination of Chapman and Sharp, wherein Chapman teaches the genetic method of preparing TILs engineered to express a pro-inflammatory polypeptide, comprising the use of a CRISPR Cas9 system, and Sharp teaches the advantage of targeting BCOR gene expression to reduce expression of an endogenous BCOR gene or product using the CRISPR Cas9 system.
Conclusion
Claims 267, 268, 272, and 296 – 312 remain rejected.
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 extension fee pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to VYOMA SHUBHAM TIWARI whose telephone number is (571)272-2954. The examiner can normally be reached M-F 8:30 - 5:30 EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Maria Leavitt can be reached on (571) 272-1085. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/VYOMA SHUBHAM TIWARI/Examiner, Art Unit 1634
/MARIA G LEAVITT/Supervisory Patent Examiner, Art Unit 1634
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