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 .
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.
Priority
The instant application, filed 11/04/2020, claims domestic benefit to US Provisional application 62/930,617, filed 11/05/2019.
Status of Application, Amendments, and/or Claims
Applicant’s response of 03/10/2026 is acknowledged. Claim 24 is amended and claims 1-12, 16, 18, 20, 22, 25, 28, 30, 32, 34, and 37-48 are cancelled. Claims 13-15, 17, 19, 21, 23-24, 26-27, 29, 31, 33, 35-36, and 49-52 are currently pending.
Claims 15 and 27 are withdrawn as being drawn to a non-elected species as outlined in the species election of 12/08/2022 in which a derepressible promoter including one or more tetracycline operator sequences (TetO) was elected.
Claims 13-14, 17, 19, 21, 23-24, 26, 29, 31, 33, 35-36, and 49-52 are examined on the merits herein.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 03/10/2026 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement has been considered by the examiner.
Withdrawn Objections and Rejections
In the office action of 12/10/2025, claim 24 was rejected under 35 USC 112(b). Applicant’s amendment to the claim to remove the “and” has overcome the rejection and the rejection is withdrawn.
The following grounds of rejections are maintained.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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 13-14, 17, 19, 21, 23-24, 26, 29, 31, 33, 35-36, and 49-52 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2016/196388 A1 (Odegard, V.) 08 Dec 2016 in view of Eyquem, J., et al (2017) Targeting a CAR to the TRAC locus with CRISPR/Cas9 enhances tumor rejection Nature 543(7643); 113-117.
WO’388 teaches engineered cells for adoptive therapy, including T cells, compositions for engineering and producing the cells, compositions containing the cells, and methods for their administration to subjects. The T cells contain genetically engineered antigen receptors that specifically bind to antigens, such as chimeric antigen receptors (CARs). The cells also contain an agent that is capable of reducing an inhibitory effect by repressing and/or disrupting a gene in an engineered cell, such as a gene involved in inhibiting the immune response (page 1, [0003]).
WO’388 teaches a genetically engineered T cell containing a genetically engineered antigen receptor that specifically binds to an antigen; and a polynucleotide encoding a molecule that reduces or disrupts expression of PD-1 or PD-L1 in the cell, wherein the expression or activity of the polynucleotide is conditional. WO’388 teaches that the expression is under the control of a conditional promoter or enhancer or transactivator and is an inducible promoter. WO’388 also teaches that the molecule that reduces or disrupts expression of PD-1 or PD-L1 is or includes one or more components of a CRISPR-Cas9 combination that specifically binds to, recognizes, or hybridizes to the gene (page 4, [0011]).
WO’388 further teaches that the promoter can be a tetracycline operator sequence (page 4, [0012]) and can include a repressible promoter, including a tetracycline repressible protein (page 4, [0013]; page 6, [0237]; page 85, [0302]). WO’388 teaches examples of transcription modulator domains that induce expression in the presence of a modulating factor include the transcription modulator domains found in the Tet-On transcription modulator, the Tet-On advanced transcription modulator, and the Tet-On 3G transcription modulator (page 85, [0299]). WO’388 also teaches that the inducible promoter may be several tet-operator sequences, for example, 3, 4, 5, 6, 7, 8, 9, or 10 tet-operator sequences (page 85, [0298]). WO’388 further teaches that the expression of the peptide or nucleic acids is externally controlled by treating the cell with a modulating factor, such as doxycycline, or tetracycline or analogs thereof (page 84, [0296]).
WO’388 further teaches that, in some embodiments, the step of reducing, suppressing, or disrupting the expression of one or more inhibitory molecules, such as PD-1 and/or PD-L1 is performed ex vivo (page 23, [0084]; page 113 claim 54 – page 114, claim 62).
WO’388 further teaches that the nucleic acid is provided in a vector including a plasmid, lentiviral vector, retroviral vector, adenoviral vector, or adeno-associated viral vector (page 6, [0021]). In some embodiments, delivery is via the use of RNA or DNA viral based systems for the delivery of nucleic acids. Viral vector delivery systems include DNA and RNA viruses which have either episomal or integrated genomes after delivery to the cell (page 90, [0317]). The term ‘vector’ refers to a nucleic acid molecule capable of propagating another nucleic acid to which it is linked. The term includes the vector as a self-replicating nucleic acid structure as well as the vector incorporated into the genome of a host cell into which it has been introduced (page 108, [0399]). WO’388 further teaches that an introduced nucleic acid that is or encodes an inhibitory agent can be removed at any time subsequent to its integration into a host genome, such as by using site-specific recombination methods (page 87, [0309]), further establishing that the nucleic acid is integrated into the genome. WO’388 also teaches that the transactivator may be provided in any vehicle for delivery of a nucleic acid sequence, for example, a virus, plasmid, cosmid, or transposon (page 85, [0301]).
WO’388 further teaches that various methods for the introduction of genetically engineered components, e.g., antigen receptors e.g., CARs, are well known and may be used with the provided methods and compositions. Exemplary methods include those for transfer of nucleic acids encoding the receptors, including via viral, e.g., retroviral or lentiviral, transduction, transposons, and electroporation (page 44, [0156]).
WO’388 further teaches that the introduction of the agent that reduces or is capable of reducing expression of the immune inhibitory molecule can occur simultaneously or sequentially with the introduction of a nucleic acid encoding the transgenic receptor, such as the CAR (page 56, [0207]).
WO’388 teaches that the preparation of the engineered cells may include one or more culture and/or preparation steps (page 46, [0164]). The cells can be processed such as through separation, centrifugation, genetic engineering, e.g. transduction with a viral vector, washing, and/or incubation (page 46, [0165]). The method provided includes cultivation, incubation, culture, and/or genetic engineering steps. The cells can be incubated and/or cultured prior to or in connection with genetic engineering (page 55, [0201]). WO’388 teaches that, in some embodiments, gene transfer is accomplished by first stimulating cell growth, e.g., T cell growth, proliferation, and/or activation, followed by transduction of the activated cells, and expansion in culture to numbers sufficient for clinical applications (page 44, [0154]). WO’388 teaches that the cells are to be administered in the range of about one million to about 100 billion cells (page 100, [0358]), including between 108 and 1012 or between 1010 and 1011 T cells (pages 100-101, [0361]), suggesting expansion to these numbers.
WO’388 teaches that the preparation methods also include steps for freezing, e.g., cryopreserving, the cells, either before or after isolation incubation and/or engineering (page 54, [0200]).
WO’388 further teaches methods of using the cells, such as in adoptive cell therapy in the treatment of cancers (page 32, [0108]).
The teachings of WO’388 differ from the instantly claimed invention in that WO’388 does not disclose introducing a guide RNA with the nucleic acid encoding the CAR, that the nucleic acid encoding the CAR is introduced into the genome of the T cell, or knocking out expression of the T cell receptor.
Eyquem teaches that CARs are synthetic receptors that redirect and reprogram T cells to mediate tumor rejection. CARs are typically transduced into the T cells of a patient using gamma retroviral vectors or other randomly integrating vectors, which may result in clonal expansion, oncogenic transformation, variegated transgene expression and transcriptional silencing. Recent advances in genome editing enable efficient sequence-specific interventions in human cells, including targeted delivery to the CCR5 and AAVS1 loci. Eyquem shows that directing a CD19 specific CAR to the T-cell receptor alpha constant (TRAC) locus not only results in uniform CAR expression in human peripheral blood T cells, but also enhances T cell potency with edited cells vastly outperforming conventionally generated CAR T cells in a mouse model of acute lymphoblastic leukemia. It is further demonstrated that targeting the CAR to the TRAC locus averts tonic CAR signaling and establishes effective internalization and re-expression of the CAR following single or repeated exposure to the antigen, delaying effector T cell differentiation and exhaustion. Eyquem teaches that the findings disclosed uncover facets of CAR immunobiology and underscores the potential of CRISPR/Cas9 genome editing to advance immunotherapeutics (abstract).
Eyquem teaches that to disrupt the TRAC locus and place the CD19 specific CAR under its transcriptional control, a guide RNA (gRNA) was designed targeting the 5’end of the first exon of the TRAC and an adeno-associated virus AAV vector repair matrix encoding a self-cleaving P2A peptide followed by the CAR cDNA. T cell electroporation of Cas9 mRNA and gRNA yielded a high knockout frequency with limited cell death. Approximately 95% of the CAR+ T cells were TCR negative validating the 2-in-1 TCR knockout and CAR knock-in strategy (page 2, paragraph 1).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method of WO’388 by introducing the CAR using a g-RNA targeting TRAC resulting in TCR knockout and CAR knock-in as taught by Eyquem. An ordinarily skilled artisan would have been motivated to use a g-RNA targeting TRAC for knockout of the TCR and knock-in of the CAR as Eyquem demonstrates that directing the CAR to the TRAC locus not only results in uniform CAR expression in human peripheral blood T cells, but also enhances T-cell potency, with edited cells vastly outperforming conventionally generated CAR T cells in mouse models. Additionally, targeting the CAR to the TRAC locus averts tonic CAR signaling and establishes effective internalization and re-expression of the CAR following single or repeated antigen exposure, and delays effector T cell differentiation and exhaustion. An ordinarily skilled artisan would have had a reasonable expectation of success as Eyquem teaches methods of introducing CARs into T cells for use in adoptive cell transfer for the treatment of cancer and WO’388 is also teaching T cells that have been engineered to express CARs for the treatment of cancer.
Response to Arguments
Applicant’s arguments in the response filed 03/10/2026 have been fully considered, but are not persuasive.
With regards to the rejection of the claims under 35 USC 103, applicant argues that independent claims 13 and 26 require the integration of a nucleic acid molecule encoding a CRISPR-associated or Cas9/Cas12 nuclease into the genome of the T cell line to generate an inducible nuclease T cell line; expanding the T cell line, and inducing the expression of the nuclease by activating the controllable promoter. Applicant argues that, as disclosed in paragraphs [0079]-[0083], the activation of the expression of the integrated nuclease is required to knock out the expression of a T cell receptor and to introduce the gene of interest into the genome of the expanded cell line. Applicant argues that; therefore, the integrated nuclease must be active when expressed.
This argument is not persuasive.
The instant specification [0079]-[0083] may disclose an embodiment in which the activation of the integrated nuclease is required to knockout expression of a T cell receptor; however, this feature is not recited in the rejected claims. Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
The instant claims do not require any specific nucleic acid molecule or CRISPR-associated nuclease. Rather, in the broadest reasonable interpretation of the claims, the integrated CRISPR-associated nuclease could be anything and target anything, for instance, PD-1 or PD-L1 as disclosed by WO’388 (referenced by applicant as “Odegard”). Similarly, the claim does not require that the step of knocking out expression of the T cell receptor for introduction of the CAR into the genome occur through the use of the previously recited, or any other, CRISPR-associated nuclease that has been integrated into the T cell genome. Rather, in the broadest reasonable interpretation of the claim, knockout of expression of a T cell receptor and introduction of the gene of interest into the genome of the expanded T cell line could be achieved, for instance, with the methods disclosed by Eyquem in which Cas9 mRNA and gRNA are used to disrupt the TRAC locus and place the CAR under its transcriptional control.
Applicant further argues that WO’388 discloses throughout that the agents or molecules that are capable of reducing or disrupting the expression of PD-1/PD-L-1, which can include one or more components of CRISPR-Cas9, including those that are enzymatically inactive, citing WO’388, [0241]. Applicant argues that WO’388 discloses that the genetically engineered antigen coreceptor is introduced using various methods, such as viral vectors, that do not require the presence of CRISPR-associated nuclease as recited in the instant claims. Applicant argues that this corresponds with differences between WO’388 and the instant application, where WO’388 does not use a guide RNA with the nucleic acid encoding the CAR or that the CAR is introduced into the genome of the T cell and knocking out of the TCR.
As discussed in the rejection of record, WO’388 teaches that the molecule that reduces or disrupts expression of PD-1 or PD-L1 is or includes one or more components of a CRISPR-Cas9 combination that specifically binds to, recognizes, or hybridizes to the gene (page 4, [0011]). Even if WO’388 teaches embodiments in which alternatives are used, such as gRNA and eiCas9, the teachings of alternatives does not criticize, discredit, or otherwise discourage the use of CRISPR-Cas9 as a means to disrupt the expression of PD-1 or PD-L1 as disclosed in WO’388. See MPEP 2123 (II). With regards to applicants arguments that the CAR in WO’388 is not introduced into the genome of the T cell using a gRNA with knockout of the TCR, WO’388 is not required to teach these limitations as the rejection of record depends on the combination of applied references and what the combination would have suggested to one of ordinary skill in the art. See MPEP 2145 (IV). In the rejections, Eyquem is introduced to demonstrate that knockout of the TCR and the use of gRNA targeting the CAR to TRAC was known and motivated by the teachings of the prior art.
With regards to Eyquem, applicant argues that, although Eyquem disclosed using CRISPR/Cas9 in to place the CD19 specific CAR under the transcriptional control of the TRAC locus, the CRISPR/Cas9 used in Eyquem was not integrated into the genome of the T-cell. Applicant argues that Eyquem teaches T-cell electroporation of Cas9 mRNA and gRNA yielded a high knockout frequency indicating that the CRISPR/Cas9 was introduced into the cell using a non-viral method for transient expression of the nuclease. Applicant argues that the rejection has not established a prima facie case of obviousness because neither reference, alone or in combination, disclosed integrating a nucleic acid molecule [encoding a CRISPR-associated or Cas9/Cas12 nuclease] into the genome of the T cell line to generate an inducible nuclease T cell line.
This argument is not persuasive. As discussed in detail in the rejection, WO’388 teaches the integration of a molecule that reduces or disrupts expression of PD-1 or PD-L1 into the genome of a T cell and teaches that the expression of the polynucleotide encoding the molecule is conditional and is under the control of an inducible promoter. WO’388 also teaches that that molecule can be a CRISPR-Cas9 combination (page 4, [0011]). As such, and contrary to applicant’s arguments, the applied prior art does teach integrating a nucleic acid molecule encoding a CRISPR-associated or Cas9/Cas12 nuclease into the genome of a T cell line to generate an inducible nuclease T cell line.
As discussed in detail above, the instant claims do not require that the integrated CRISPR/Cas9/Cas12 nuclease be anything specific or target anything specific and the claims also do not require that the knockout of a TCR be performed with a CRISPR-associated nuclease that is integrated into the genome of the T cell. As such, Eyquem is not required to teach that the CRISPR/Cas9 nuclease be integrated into the genome and even the addition of the methods of Eyquem to the methods of WO’388 would still meet the instant claim limitations.
For these reasons, applicant’s arguments are not persuasive.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any 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 AUDREY L BUTTICE whose telephone number is (571)270-5049. The examiner can normally be reached M-Th 8:00-4:00.
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/AUDREY L BUTTICE/Examiner, Art Unit 1647
/SCARLETT Y GOON/Supervisory Patent Examiner
Art Unit 1693
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