DETAILED ACTION
Applicant's amendment and response received on 5/21/26 has been entered. Claims 31-36, and 48 remain pending and under examination. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA . An action on the merits follows.
Those sections of Title 35 US code, not included in this action can be found in a previous office action.
Claim Interpretation
Independent claims 31 and 48 has been amended to recite the following limitation, “genomic disruption is in a sequence that comprises any one of SEQ ID NOS: 75-86”. As amended, the phrase “a sequence that comprises any one of SEQ ID NOS:75-86” has been given its broadest reasonable interpretation of encompassing a sequence of any length that comprises one of the sequences set forth in SEQ ID NOS: 75-86. In other words, as written, the claims do not require that the genomic disruption is in one of the sequences set forth in SEQ ID NOS:75-86. Instead, the disruption can occur anywhere in a CISH genomic sequence as long as the sequence comprises one of SEQ ID NOS:75-86.
Claim Rejections - 35 USC § 112
The rejection of claims 31-36 and 48 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for an in vitro genomically-modified human stem cell or human progenitor cell, wherein said genomic modification comprising a genomic disruption in an endogenous cytokine inducible SH2-containing (CISH) gene, wherein said genomic disruption is within a sequence corresponding to any one of SEQ ID NOS: 75-86, does not reasonably provide enablement for an in vitro genomically-modified human stem cell or human progenitor cell, wherein said genomic modification comprising a genomic disruption in an endogenous cytokine inducible SH2-containing (CISH) gene, wherein said genomic disruption is in a sequence having at least 80% identity to any one of SEQ ID NOS: 75-86, is withdrawn in view of applicant’s amendments to the claims which have deleted this limitation.
Applicant’s amendments to the claims has necessitated the following new grounds of rejection.
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 31-36 and 48 are newly rejected under 35 U.S.C. 103 as being unpatentable over Palmer et al. (November 6, 2014) J. Immunother. Canc., Vol. 2(Suppl. 3), P32, abstract, in view of Yang et al. (2013) Nat. Immunol., Vol. 14(7), 732-742, Vatakis et al. (2011) PNAS, Vol. 108(51), E1408-E1416, Themeli et al. (2013) Nat. Biotech., Vol. 31(10), 928-935, Mandal et al. (November 6, 2014) Cell Stem Cell, Vol. 15, 643-652, Cencic et al. (October 2, 2014) PLOS One, Vol. 9(10),e109213, page 1-13, Song et al. (2015) Stem Cells and Devel., Vol. 24(9), 1053-1065, Wang et al. (2010) Clin. Canc. Res., Vol. 16(1), 164-173, Uchida et al. (1997) Cytogenetics and Cell Genetics (1997) 78 (3-4), 209–212, NCBI Reference Sequence: NG_023194.1- human CISH, and Zhang et al. (2013) Nat. Immunol., Vol. 13(7), 667-673. Doi:10.1038/ni.2319.
Please note that the phrase “a sequence that comprises any one of SEQ ID NOS:75-86” has been given its broadest reasonable interpretation of encompassing a sequence of any length that comprises one of the sequences set forth in SEQ ID NOS: 75-86. In other words, as written, the claims do not require that the genomic disruption is in one of the sequences set forth in SEQ ID NOS:75-86. Instead, the disruption can occur anywhere in a CISH genomic sequence as long as the sequence comprises one of SEQ ID NOS:75-86.
Palmer et al. teaches that deletion of CISH in T cells results in augmented PLCg1 activation, Ca2+ flux, NFAT and NFkB activity and cytokine release, and that adoptive transfer of CISH-deficient CD8+ T cells eliminated established cancer (Palmer et al., abstract). Yang et al. also teaches T cells with a CISH deletion, and reports that CD4+ T cells with the CISH deletion exhibit enhanced proliferation following stimulation (Yang et al., page 734). As such, both Palmer et al. and Yang et al. provide specific teachings and motivation to generate genetically modified T cells with a deletion in the endogenous CISH gene, and further provide evidence that such T cells can in fact proliferate, express cytokines, and exhibit anti-tumor immunity. In addition, Yang et al. teaches knockout mice with a specific disruption of an endogenous CIS/CISH gene, where a region spanning exon 2 to the coding region of exon 3 is deleted by Cre-lox recombination, and where the deletion results in a null mutation with no detectable CISH expression in bone marrow or T cells (Yang et al., pages 733-734). Note that bone marrow comprises hematopoietic stem cells. Yang et al. teaches that mice with a global deletion of CISH in all cell types, including hematopoietic stem cells present in bone marrow, produced active T cells, thus demonstrating that CISH negative hematopoietic stem cells present in these mice were not only viable but capable of generating T cells in vivo during normal development (Yang et al., pages 733-735). Yang in fact states, “CIS mRNA was not detectable in bone marrow or Treg cells by RT-PCR.., and CIS protein was completely absent from CD4+ T cells by immunoblot analysis.., which indicated that a null mutation was generated and that CIS was not required for normal mouse development. The lymphoid populations in the thymus, spleen and lymph nodes of CIS-/- mice seemed grossly normal..” (Yang et al., page 733, column 2). Thus, Yang both demonstrates and plainly teaches that bone marrow cells with a CISH deletion develop into T cells are both viable and capable of proliferation and differentiation.
Palmer et al. and Yang et al. differ from the instant claims in that they do not teach to generate genetically modify human hematopoietic stem cells or induced human stem cells with a genomic disruption of the endogenous CISH gene. Vatakis et al. supplements Palmer et al. and Yang et al. by teaching that genetically engineered autologous human T cells, such as autologous human T cells genetically engineered to express tumor specific TCR, have been used successfully in adoptive transfer methods to treat cancer in human patients (Vatakis et al., page E1408). Vatakis et al., however, teaches that the genetic modification of human T cells has several drawbacks including loss of potency of the T cells due to ex vivo manipulations, and the short lifespan of the T cells which may not support a lasting therapeutic effect (Vatakis et al., page E1408). Vatakis et al. teaches that the use of genetically modified human hematopoietic stem cells (HSCs) can overcome these issues, and that human HSCs expressing tumor specific TCR, for example, when transplanted into a subject, differentiate into CTL expressing the tumor specific TCR, and are effective in treating human tumors in mice with humanized immune systems (Vatakis et al., pages E1408-E1409). Thus, Vatakis et al. provides substantial motivation to genetically modified human hematopoietic stem cells instead of human T cells in order to produce a therapeutic population genetically modified human T cells in vivo for cancer therapy. Themeli et al. supplements Palmer et al., Yang et al., and Vatakis et al., by teachings that induced pluripotent stem cells (iPSC) can provide an unlimited source of T lymphocytes and that iPSCs can be genetically engineered in vitro and then differentiated to generate therapeutic T cells (Themeli et al., page 928-929). Furthermore, the cDNA and genomic sequence of human CISH were known at the time of filing, see Uchida et al. See also NCBI Reference Sequence: NG_023194.1- human CISH, which is the CISH genomic sequence from human chromosome 3. Therefore, based on the teachings of Palmer et al. and Yang et al. that genomic disruption of CISH in both CD8+ and CD4+ T cells improves their proliferation and therapeutic activity, and the motivation provided by both Vatakis et al. and Themeli et al. to genetically modify human hematopoietic stem cells or human iPSCs in order to generate therapeutic T cells instead of directly genetically modifying the T cells themselves, the specific provided by Yang et al. to disrupt a region spanning exon 2 to the coding region of exon 3 in a CISH gene, and the known genomic sequence of the human CISH gene, it would have been prima facie obvious to the skilled artisan at the time of filing to modify human hematopoietic stem cells of human iPSCS to have a single genetic modification consisting of a genomic disruption of a region spanning exon 2 to the coding region of exon 3 in an endogenous CISH gene with a reasonable expectation of success. Note also that as each of SEQ ID NOS 75-86 are present within the genomic sequence spanning exon 2 to the coding region of exon 3 that deletion of this genomic region in a human hematopoietic stem cells qualifies as a deletion of a sequence comprising one of SEQ ID NOS:75-86. It is also noted that independent claim 48 only requires a single genetic modification of the CISH gene.
While Yang et al. teaches deletion of exon 2 to the coding region of exon 3 by Cre-lox recombination, where loxP sites are first inserted into the target gene followed by Cre mediated recombination, other methods of targeted deletion in endogenous genes were known at the time of filing. Mandal et al. supplements Palmer, Yang, Vatakis et al., and Themeli et al. by teaching an particularly effective and efficient method of targeted deletion of a gene in a human HSC using Crispr/Cas9, where a pair of gRNA are used to generate a specific deletion in a selected target site of a gene (Mandal et al., pages 643 and 650). Mandal et al. further teaches that Crispr modified human HSCs retain multi-lineage potential both in vitro and in vivo (Mandal et al., page 650). Cencic et al. further supplements Mandal et al. by teaching the mechanics of Crispr/Cas9 DNA cleavage. Cencic teaches that Cas9:sgRNA complex requires the presence of a PAM sequence 3’ to the target sequence, and that the sgRNA targeted sequence 5’ of the PAM must be within 20 base pairs of the PAM sequence for efficient sgRNA-target nucleation and cleavage ( Cencic, pages 1 and 11, Figure 7). Therefore, in view of the benefits and efficacy of Crispr/Cas9 mediated targeted gene deletion in human HSCs, it would have been prima facie obvious to the skilled artisan at the time of filing to utilize Crispr/Cas9 to introduce a deletion of spanning exon 2 up to the coding region of exon 3 into an endogenous CISH gene, where the gRNA sequences are selected to generate a double strand break within 20 base pairs 5’ of a PAM sequence in a human HSC as taught by Palmer et al., in view of Yang et al., Vatakis et al., Themeli et al., Uchida et al., and NG_023194.1- human CISH, with a reasonable expectation of success.
Palmer et al., Yang et al., Vatakis et al., Themeli et al., Uchida et al., NG_023194.1- human CISH , Uchida et al., and NG_023194.1- human CISH, Mandal et al., and Cencic et al. differ from instant claims 31-36 in that they do not further teach or suggest to introduce a second genetic modification to the human stem cells which is a genomic disruption of TGFBRII. At the time of filing, Wang et al. teaches autologous TGFB insensitive CD8+ T cells, where the T cells are genetically modified to express a dominant negative form of TGFBRII (Wang et al., pages 1-2). Wang et al. teaches that the dominant negative TGFBRII inhibits TGFB signaling which is immunosuppressive, and that the TGFB insensitive T cells were more effective in cancer immunotherapy that unmodified T cells (Wang et al., pages 8-9). Zhang et al. further supplements Wang et al. by teaching alternative methods to render T cells insensitive to TGFB, including cre-lox deletion of the endogenous TGFBRII gene (Zhang et al., page 3).
Thus, based on the teachings of Palmer et al. and Yang et al. that genomic disruption of CISH in both CD8+ and CD4+ T cells improves their proliferation and therapeutic activity, and the motivation provided by both Vatakis et al. and Themeli et al. that to genetically modify human hematopoietic stem cells or human iPSCs in order to generate therapeutic T cells instead of directly genetically modifying the T cells themselves, the further benefits to rendering T cells insensitive to TGFB for T cell immunotherapy taught by Wang et al., the teachings of Zhang et al. for specific methods of rendering a T cell insensitive to TGFB by the deleting an endogenous TGFBRII gene, it would have been prima facie obvious to the skilled artisan to generate an in vitro population of genetically modified human HSCs or iPSCs useful for generating therapeutic T cell in vitro or in vivo, where the human HSC or iPSC genomic modifications consist of a first genomic disruption in an endogenous CISH gene comprising a genomic disruption of a region spanning exon 2 to the coding region of exon 3, and a second genomic disruption in an endogenous TGFBRII gene with a reasonable expectation of success.
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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Dr. A.M.S. Wehbé
/ANNE MARIE S WEHBE/Primary Examiner, Art Unit 1634
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