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 .
Priority
The instant application, filed on 31 August 2023, claims domestic benefit to US provisional application no. 63/155,295, filed on 03/01/2021 and PCT/US2022/018389, filed on 03/01/2022.
Status of Application, Amendments, and/or Claims
The response filed on 02, April 2024 has been entered in full. The response is an amendment to a Non-Final Rejection to the claim set filed on 02 April, 2024 In the amendment claims 1, 2, 4, 6, 7, 14, and 70 are amended, claims 3, 5, 9, 10, 13 and 18-21 are previously presented, claims 8, 11, 12, 15-17, 22-69, and 71-81, and claims 82-85 are new. Therefore, claims 1-7, 9, 10, 13, 14, 18-21, 70, and 82-85 are pending and are the subject of this Office Action.
Status of Objections and Rejections
In the office action of 03/30/2026
Claims 24 and 25 were rejected under 35 U.S.C. 103 and Non-Statutory Double Patenting over Shifrut et al. in view of Siddiqui et al. The cancellation of the claims renders the rejections moot and the rejections are withdrawn.
Claims 53 and 58 were rejected under 35 U.S.C. 103 over Shifrut et al. in view of Wang et al. and Shinohara et al. The cancellation of the claims renders the rejections moot and the rejections are withdrawn.
Claim 58 was rejected under 35 U.S.C. 112(b) for indefiniteness. The cancellation of the claim renders the rejection moot and the rejection is withdrawn.
Claim 6 was rejected under 35 U.S.C. 112(b) for indefiniteness. The amendment of the claim has overcome this rejection.
Claims 1, 2, 3, 10, 13, 14, 18, 19, and 70 were rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) over Rosen et al. The Rejection of the claims still stands with expanded reference to the section of the same example originally relied upon in response to the amendment to update all T cells to naïve T cells for further elucidation.
Claims 1, 9, 20, and 21 were rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) over Rosen et al. The Rejection of the claims still stands.
Claims 4 and 6 were rejected under 35 U.S.C. 103 over Rosen et al. in view of Kurreck et al. The rejection of the claims still stands.
Claims 5 and 7 were rejected under 35 U.S.C. 103 over Rosen et al. in view of Seki and Rutz. The rejection of the claims still stands.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1, 2, 3, 10, 13, 14, 18, 19, and 70 are rejected under 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2) as being anticipated by Rosen et al. (WO2019/018603).
In regards to claims 1 and 14 Rosen anticipates a method of T cell populations modified towards a central memory T cell phenotype (pg.72, lines 31-33) in which the T cells are isolated from fresh leukopaks and cultured with IL-2 and anti-CD3/anti-CD28 beads (agents that stimulate expansion) (pg.70, lines 3-13) and then further incubating the cells with a list of inhibitors including a JAK inhibitor (an inhibitor of a negative modulator gene of TCF7) (pg.73, lines 14-16/ Figure 1A) before being modified further by a CAR. Rosen also anticipates a sufficient length of time for modulating immune cells to be no less than 30, 42, 54, 66, 78, or 90 hours (pg.14, lines 20-22). Further Rosen anticipates the method used on distinct T cell phenotypes including Naïve T cells (pg.69, lines 25-26 / pg.70, lines 20-22).
In regards to claim 2 Rosen anticipates a sufficient length of time for modulating immune cells to be no less than 30, 42, 54, 66, 78, or 90 hours (pg.14, lines 20-22).
In regards to claim 3 Rosen anticipates the inhibitor being a small molecule inhibitor (pg.31 line 29- pg.32 line 1/ Table 1, compounds 16-19).
In regards to claims 10, 18, and 19 Rosen anticipates the use of a JAK inhibitor (negative modulator gene JAK2) and further anticipates the use of specific JAK inhibitors ruxolitinib and pacritinib (Table 1).
In regards to claim 13 Rosen anticipates the T cells are isolated from fresh leukopaks (ex-vivo) (pg.70, lines 3-5).
In regards to claim 70 Rosen anticipates in vivo functionality in a CD19+ xenograft mice model in which the modified CAR-T cells are delivered to NSG mice bearing Nalm-6-luc CD19+ disseminated tumors (pg.79, lines 17-21).
Claims 1, 9, 20 and 21 are rejected under 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2) as being anticipated by Rosen et al. (US2019/0125795, of record, IDS 04/02/2024, hereafter Rosen (US)) as evidenced by Kim and Lee (2007) STAT1 as a key modulator of cell death Cellular Signaling (19) 454-465 (hereafter Kim and Lee).
In regards to claim 1 Rosen(US) anticipates a method of modifying T cell populations towards a central memory T cell phenotype (pg.29, col 1, lines 5-9) in which the T cells are isolated from fresh leukopaks and cultured with IL-2 and anti-CD3/anti-CD28 beads (agents that stimulate expansion) (pg.27, col 2, 49-60) and then further incubating the cells with a list of inhibitors including a STAT1 inhibitor (an inhibitor of a negative modulator gene of TCF7) (pg.29, col 1, lines 16-21). Rosen also anticipates a sufficient length of time for modulating immune cells to be no less than 30, 42, 54, 66, 78, or 90 hours (pg.14, col 2, lines 12-14). Further Rosen anticipates the method used on distinct T cell phenotypes including Naïve T cells (pg.69, lines 25-26).
In regards to claims 20 and 21 Rosen teaches the use of a STAT1 inhibitor and further where the STAT1 inhibitor is Fludarabine (pg.29, col 1, lines 16-21/ Table 1).
In regards to claim 9 Rosen teaches the use of a STAT1 inhibitor. The STAT1 gene encodes the STAT1 protein which is a transcription factor as evidenced by Kim and Lee which states STAT factors were originally discovered as latent transcriptional factors in the cytoplasm (pg.455, col 1, lines 1-3). Thus, Rosen’s use of a STAT1 inhibitor is the inhibition of a gene which encodes a transcription factor.
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.
Claims 4 and 6 are rejected under 35 U.S.C. 103 as being unpatentable over Rosen as applied to claim 1 above, and further in view of Kurreck (2006) siRNA Efficiency: Structure or Sequence- That is the Question Journal of Biomedicine and Biotechnology (83757) 1-7 (hereafter Kurreck).
Rosen teaches a method of modifying T cell populations towards a central memory T cell phenotype (pg.72, lines 31-33) in which the T cells are isolated, cultured with a stimulating agent, and incubated with a JAK inhibitor (negative modulator gene of TCF7) as outlined above. Further Rosen teaches the JAK inhibitor can be an siRNA (short interfering RNA) (pg.40, lines 7-8).
Rosen fails to teach a siRNA sequence comprising at least 10 contiguous nucleotides that is complementary to a genomic sequence of claim 4. Kurreck, however, teaches that siRNAs can be between 19-27 nucleotides and that length has a significant impact on siRNA efficiency (pg.5 col 2 line 16- pg.6 col 1, line 3) and further teaches that siRNA works by binding to the complementary of the target gene RNA in order to disrupt translation of the protein (pg.1 col 1, lines 10-16).
Thus, Rosen discloses a method of developing modified T cells wherein T cells are isolated stimulated and contacted with an inhibitor of a negative modulator gene of TCF7 and further teaches this inhibitor can be an siRNA. Kurreck teaches that siRNAs have been studied between 19-27 nucleotides long and that the length of the siRNA impacts its efficiency, further Kurreck teaches the siRNA much be complementary to a target gene in order to interrupt translation of the target protein. Therefore, a person of ordinary skill in the art before the effective filing date of the claimed invention would have found it obvious to combine the teachings of Rosen with the teachings of Kurreck to use an siRNA inhibitor informed by the teachings of Kurreck to be longer than 10 nucleotides and complementary to the target gene with a reasonable expectation of success to develop an expanded modified T cell population with increased TCF7 expression.
Claims 5 and 7 are rejected under 35 U.S.C. 103 as being unpatentable over Rosen as applied to claim 1 above, and further in view of Seki and Rutz (2018) Optimized RNP transfection for highly efficient CRISPR/Cas9 – mediated gene knockout in primary T cells J. Exp. Med. (215)3 985-997 (hereafter Seki and Rutz).
Rosen teaches a method of modifying T cell populations towards a central memory T cell phenotype (pg.72, lines 31-33) in which the T cells are isolated, cultured with a stimulating agent, and incubated with a JAK inhibitor (negative modulator gene of TCF7) as outlined above.
Rosen fails to teach the inhibitor as a complex comprising a CRISPR-associated protein and a guide RNA of at least 10 contiguous and complementary nucleotides of claim 5. Rosen further fails to teach the use of a polynucleotide encoding the complex of claim 7.
Seki and Rutz however teach an optimized method of inducing gene knockout using a polynucleotide encoding Cas9 and guide RNA (pg.995, col 2, lines 22-36) with electroporation for higher transfection rates (pg.986, col 2, lines 29-54). Seki and Rutz further teach guide RNAs which are more than ten nucleotide long that encode compliments to target genes (Table S1).
Thus, Rosen discloses a method of developing modified T cell populations towards a central memory T cell phenotype in which the T cells are isolated, cultured with IL-2 and anti-CD3/anti-CD28 beads and then incubating the cells with an inhibitor of a negative modulator gene of TCF7. Rosen also teaches a sufficient length of time for modulating immune cells to be no less than 30, 42, 54, 66, 78, or 90 hours. Seki and Rutz teach an optimized method of transfection using Cas9 and guide RNA. Therefore, a person of ordinary skill in the art before the effective filing date of the claimed invention would have found it obvious to combine the teachings of Rosen with the teachings of Seki and Rutz with a reasonable expectation of success to develop a method of expanding and modifying naïve T cells using a Cas9 and guide RNA complex to knock out gene expression of a target gene for higher transfection rate and a larger yield of modified T cells.
Claims 82-85 are rejected under 35 U.S.C. 103 as being unpatentable over Rosen as applied to claim 1 above, and further in view of Chen et al. (2012) Modulation of IFN- Receptor 1 Expression by AP-2 Influences IFN- Sensitivity of Cancer Cells American Journal of Pathology 180(2); 661-671.
Rosen teaches a method of modifying T cell populations towards a central memory T cell phenotype (pg.72, lines 31-33) in which the T cells are isolated, cultured with a stimulating agent, and incubated with a JAK2 inhibitor as outlined above.
Rosen fails to teach the negative modulator gene being one of the options of claims 82-85, however, Chen teaches IFNGR1 is a prerequisite to the initiation of IFNG signaling which plays a crucial role in regulating innate and adaptive immunity (Abstract). Further IFNGR1 binding initiates autophosphorylation and trans-phosphorylation which activates janus-activated kinases and lead to recruitment of stat1 proteins, and how the loss of IFNGR1 expression is associated with the underexpression of JAK1 and Stat1, and the production of abnormal JAK2 (pg.661, col 2, line 22 – pg.662, col 1, line 15).
Thus, Rosen discloses a method of developing modified T cell populations towards a central memory T cell phenotype in which the T cells are isolated, cultured with IL-2 and anti-CD3/anti-CD28 beads and then incubating the cells with an inhibitor of a negative modulator gene of TCF7. Rosen also teaches a sufficient length of time for modulating immune cells to be no less than 30, 42, 54, 66, 78, or 90 hours. Chen teaches disrupting IFNGR1 interaction with IFNG further disrupts the normal expression of JAK1, JAK2, and STAT1. Therefore, a person of ordinary skill in the art before the effective filing date of the claimed invention would have found it obvious to combine the teachings of Rosen with the teachings of Chen to simply substitute the JAK2 inhibitor with an IFNGR1 inhibitor with a reasonable expectation of success to affect more downstream genes while also subsequently increasing TCF7 expression.
Response to Arguments
Applicant's arguments filed 30 June, 2026 have been fully considered but they are not persuasive.
In response to applicant's argument that “the examiner’s position appears to rely implicitly on an inherency theory because JAK2 happens to be a negative modulator of TCF7 in naïve T cells” (Applicant Remarks 06/30/2026 pg.8, lines 1-2), a recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim. Further as highlighted above in the 102 rejection Rosen uses the methods on naïve T cell populations exclusively and still see beneficial effects (Rosen pg. 69, line 25 - pg.70, line 2).
Conclusion
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 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 DASIA A ALDARONDO whose telephone number is (571)272-1977. The examiner can normally be reached on Monday - Thursday from 7am to 4pm and Friday 7am to 11am.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Joanne Hama, can be reached at telephone number ((571)272-1977. The fax phone number for the organization where this application or proceeding is assigned is (571)273-8300.
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/D.A.A/Examiner, Art Unit 1647
/JOANNE HAMA/Supervisory Patent Examiner, Art Unit 1647
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