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 .
Detailed Action
Election/Restrictions
Applicant’s election without traverse of Group I in the reply filed on 06/09/2025 is acknowledged.
Election of the following species on the reply filed on 06/09/2025 is acknowledged: T cell receptor (TCR) and cancer antigen.
Priority
The present application is a 35 U.S.C. 371 national stage filing of International Application No. PCT/US2020/052295, filed 06/23/2020.
Applicant’s claim for the benefit of a prior-filed parent provisional application 62/915436, filed on 10/15/2019, 62/904299 filed 09/23/2019 under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged.
Thus, the earliest possible priority for the instant application is 09/23/2019.
Claims Status
Claims 118, 119, 124, and 125 are canceled, claims 132 and 134 are withdrawn as being drawn to a nonelected subject matter, and claims 114-117, 120-123, 126-131, and 133 have been considered on the merits. All arguments have been considered.
Withdrawn Objections & Rejections
Applicant's response filed 02/09/2026 has been considered. Rejections and/or objections not reiterated from the previous Office action mailed 08/08/2025 are hereby withdrawn.
The objections and rejections presented herein represent the full set of objections and rejections currently pending in the application.
Claim Rejections - 35 USC § 112 (new)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 120-122 are rejected 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.
Claims 120-122 are considered indefinite because they depend from cancelled claim 118. For purposes of compact prosecution claims 120 and 121 are examined as dependent on claim 114.
Claim Rejections - 35 USC § 103 (Modified)
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
Claims 114-115, 120-122, 126-128 and 130-131 are rejected under 35 U.S.C. 103 as being unpatentable over Sherwood et al (US 2019/002920 A1, as cited in the IDS filed 5/31/2022; cited previously) in view of Shum et al (Expert Opin Biol Ter. (2018) 18:6;1-25; cited previously) and Sadelain et al (US 2019/0119638, as cited in the IDS filed 5/31/2022; cited previously).
The rejection is essentially the same as the previous rejection but has been modified to address the claim amendments.
Regarding claim 114 and 120-121: Sherwood disclose methods for targeted genomic modification that can be used in place of a standard CRISPR/Cas system (abstract).
Sherwood teach an sgRNA targeting a genomic target (C-terminus of Histone H3.1) in mammalian cells (mouse embryonic stem cells; mESCs) (p11 para0145). Sherwood generate an HDR template with 80bp homology arms flanking the target sequence (GFP) (p11 para0145).
After introduction of a polynucleic acid (plasmid) encoding the targeting sgRNA, Cas9, and the HDR donor strand into mammalian cells (mESCs), Sherwood teach site-specific integration of the transgene (GFP) into the genomic DNA (p11 para0145; Fig1D).
While Sherwood discloses generating a first double stranded break in the genome at the target site, Sherwood do not disclose generating a second double stranded break in the genome at a second site. Sherwood also do not teach contacting the cells with an exogenous immunostimulatory agent comprising anti-CD3 or anti-CD28.
Sadelain disclose a T cell wherein one or more therapeutic transgenes are integrated within the genome of the cell (abstract). Sadelain teach a T cell wherein a first transgene is integrated at a first site within the genome and a second transgene is integrated at a second site within the genome (claim 2).
Sadelain teach edited cells are cultured using standard conditions and expanded in T cell growth medium (p149 para0680). Sadelain teach T cell growth medium comprises an exogenous immunostimulatory agent (Human T-Activator CD3/CD28) (p59 para0679/para0680).
Shum disclose tumor-specific CAR-T cells have success treating leukemia and lymphoma in a clinical setting, but that success has not been recapitulated in the treatment of solid tumors (abstract).
Shum also disclose adoptive cell therapies against solid tumors will likely require large numbers of tumor-specific lymphocytes, which could be achieved by increasing the numbers of infused T-cells and the frequency of dosing (p5 para1).
It would have been obvious to one of ordinary skill in the art to adapt the methods of Sherwood, drawn to site-specific integration of a transgene into genomic DNA of a cell, by modifying the method to introduce two site-specific transgenes into a first and second site of the genome of a cell as taught by Sadelain. Modifying the method taught by Sherwood to introduce a transgene at a first site into the genome of a cell and a transgene into a second site of the genome of the cell, as taught by Sadelain would comprise introducing a first and second double stranded break in the genome of the targeted cell because the method taught by Sherwood is mediated by Cas9, which generates double stranded breaks in the targeted genome.
Accordingly, one of ordinary skill in the art would have been motivated to modify the transgene integration method as taught by Sherwood to introduce two transgenes at two different sites because one of ordinary skill in the art would understand that introduction of two transgenes at two distinct genomic sites could generate a cell expressing two transgenes, which could make for a more efficient method for generating an effective therapeutic cell.
It would have also been obvious to one of ordinary skill in the art to adapt the method of Sherwood drawn to mammalian cell culture of cells with a site specific integration of a transgene, by treating the cells with an exogenous immunostimulatory agent as taught by Sadelain because Sadelain teach T cell expansion conditions that utilize the immunostimulant IL-2, and Shum teach that efficacy of T-cells for adoptive cell therapies can be improved by increasing the numbers of cells, which is accomplished using expansion conditions such as those taught by Sadelain.
Accordingly, one of ordinary skill in the art would have been motivated to treat the cell culture taught by Sherwood with the expansion culture conditions comprising IL-2, as taught by Sadelain for the purposes of expanding a population of cells for improved therapeutic purposes, or to generate the transgenic cells more efficiently.
Regarding claim 115: The teachings of Sherwood are discussed supra. Sherwood also teach expanding the cells after introduction of the transgene (p26 para00331).
Regarding claim 122: The teachings of Sherwood and Sadelain are discussed supra. Sadelain also teach cells are activated for 48 hours (contacted with an immunostimulatory agent) before introduction of the polynucleic acid (p59 para0680), which reasonably reads on “about 30 hours up to 36 hours”.
Additionally, contacting the cells with the exogenous immunostimulatory agent about 30-36 hours before introduction of the polynucleic acid would have been a matter of routine optimization since Sadelain teaches that the cells are activated for 48 hours, and since there is no evidence of record that optimizing the length of exposure outside of this parameter is critical.
Regarding claim 126: The teachings of Sherwood are discussed supra. Sherwood also teach in vitro culture of mammalian cells (mESCs) in media that is absent of antibiotics (p13 para0166; p14 para0190).
Regarding claim 127: The teachings of Sherwood are discussed supra. Sherwood also teach introduction of CBh Cas9-BlastR plasmid and purified homology fragment into a plurality of mammalian cells (mESCs) (p14 para0188).
Regarding claims 128 and 130-131: The teachings of Sherwood are discussed supra. Sherwood do not teach the insert sequence comprises a sequence encoding an exogenous receptor.
Sadelain teach the insert sequence comprises a sequence encoding an exogenous receptor (a chimeric antigen receptor) (claim 35). Sadelain disclose the CAR binds to a disease-associated antigen, a cancer antigen (p3 para0027).
It would have been obvious to one of ordinary skill in the art to adapt the methods of Sherwood drawn to introducing an exogenous transgene into a cell by doing introducing an exogenous receptor as taught by Sadelain because Sadelain disclose the exogenous receptor (chimeric antigen receptor) binds a cancer antigen, and thus the cell represents a potential treatment for cancer.
Accordingly, one of ordinary skill in the art would have been motivated to modify the method of Sherwood to introduce a transgene encoding an exogenous receptor as taught by Sadelain to for the purposes of generating a cancer therapy.
Claims 116-117 are rejected under 35 U.S.C. 103 as being unpatentable over Sherwood in view of Shum and Sadelain as applied to claims 114-115, 120-122, 126-128 and 130-131 above, and further in view of Garcia-Pineres et al (Journal Of Immuno Methods (2006)209-213, cited previously).
Regarding claims 116-117: The teachings of Sherwood are discussed supra. Sherwood do not teach treating the cells with DNase.
Garcia-Pineres teach cell clumping can be caused by DNA released from non-viable cells after thawing cryopreserved cells (p210 col1 para1). Garcia-Pineres further disclose formation of aggregates can compromise cell function (p210 col1 para1). Garcia-Pineres teach that cells treated with DNAse1 do not for aggregates compared with untreated cells (p211 col2 para1). Garcia-Pineres teach treatment of cells with DNase is of benefit when working with samples where cell clumping could decrease cell recovery and content (p213 col1 para2).
It would have been obvious to one of ordinary skill in the art to adapt the methods of Sherwood drawn to mammalian cell culture of cells with a site specific integration of a transgene by treating the cells with DNase as taught by Garcia-Pineres because Garcia-Pineres disclose the formation of aggregates in cell culture can compromise cell function and that DNase treatment prevents the formation of cell aggregates.
Accordingly, one of ordinary skill in the art would have been motivated to treat the cell culture taught by Sherwood with DNase as taught by Garcia-Pineres to prevent cell clumping during culture and to preserve cell function.
Claim 123 is rejected under 35 U.S.C. 103 as being unpatentable over Sherwood in view of Shum and Sadelain as applied to claims 114-115, 120-122, 126-128 and 130-131 above, and further in view of Nambiar et al (Nature Communications(2019)10;1-13; cited previously).
Regarding claims 123: The teachings of Sherwood are discussed supra. Sherwood do not teach contacting the cells with an exogenous agent that modulates DNA double strand break repair.
Nambiar teach precise editing of genomic DNA can be achieved upon repair of CRISPR-induced DNA double-stranded breaks by homology-directed repair (abstract). Nambiar also teach the protein RAD18 is a stimulator of CRISPR-mediates HDR (abstract). Figure 18 b and C disclose expression of exogenous RAD 18 increases HDR efficiency (p4 col1 para2).
It would have been obvious to one of ordinary skill in the art to adapt the methods of Sherwood drawn to introducing a transgene into a cell using double stranded DNA break repair technology such as CRISPR/Cas9 system by contacting the cells with an agent that increases HDR efficiency, such as RAD18, as taught by Nambiar, because the increasing HDR efficiency would increase the efficiency of insertion of the transgene via the HDR pathway.
Accordingly, one of ordinary skill in the art would have been motivated improve HDR efficiency by the introduction of RAD18 as taught by Nambiar for the purposes of improving the number of transgene positive cells with correctly inserted transgene at the completion of the protocol.
Claims 129 and 133 are rejected under 35 U.S.C. 103 as being unpatentable over Sherwood in view of Shum and Sadelain as applied to claims 114-115, 120-122, 126-128 and 130-131 above, and further in view of Gao et al (Cancer Medicine(2019)8;4254-4264; cited previously).
Regarding claims 129 and 133: The teachings of Sherwood are discussed supra. Sherwood do not teach the exogenous receptor is a TCR.
Gao teach T cells expressing exogenous T cell receptor (T Cell Receptor Engineered T cells) are a promising therapeutic with impressive clinical efficacy (abstract). Gao disclose T cells expressing exogenous T cell receptors are directed to recognize tumor-specific peptide epitopes (p4254 col1/2 para1/1).
It would have been obvious to one of ordinary skill in the art to adapt the methods of Sherwood drawn to introducing an exogenous transgene into a cell by introducing an T cell receptor as taught by Gao because Gao disclose the T cell receptor engineered T cells are a promising therapeutic with impressive clinical efficacy.
Accordingly, one of ordinary skill in the art would have been motivated to modify the method of Sherwood to introduce an exogenous TCR as taught by Gao to for the purposes of developing a cancer therapy.
Response to Arguments
The responses are directed to the Arguments filed 02/09/2026, all arguments have been considered.
Regarding objections to the drawings:
The replacement sheets for figures 1 and 6, filed 02/09/2026, are acknowledged and overcome the objections to the drawings. The rejection is withdrawn.
Regarding Arguments directed to 35 USC § 112:
The rejection is overcome by the amendments to the claims. Specifically, claims 118, and 120-124 were rejected for reciting the generic term “agent”. Claims 118 and 124 have been canceled which overcomes the rejection as written.
The rejection is withdrawn.
Regarding Arguments directed to 35 USC § 102:
Applicant argues the rejection is overcome by the amendments to the claims. The claim amendments bring limitations into claim 114 that were not addressed in the previous 102. Thus the argument is persuasive and the rejection is withdrawn.
Regarding Arguments directed to 35 USC § 103:
Applicant argues the rejection is overcome by the amendments to the claims. This is not persuasive because the claim limitations were addressed in the previous claims 119 and 125 (now cancelled). The rejection is maintained, however it has been modified to addresses the amendments
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ANDREA LYNNE MORRIS SPENCER whose telephone number is (571)272-3328. The examiner can normally be reached Monday-Friday 9:00-5:00.
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/ANDREA LYNNE MORRIS SPENCER/Examiner, Art Unit 1631
/TAEYOON KIM/Primary Examiner, Art Unit 1631
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