DETAILED ACTION
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 3/10/26 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.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 3/10/26 is in compliance with the provisions of 37 CFR 1.97 and 1.98. Accordingly, the information disclosure statements has been considered by the examiner and an initialed and signed copy of the 1449 is attached to this action.
Claim Rejections - 35 USC § 103
The rejection of claims 31-36 and 48 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, and Zhang et al. (2013) Nat. Immunol., Vol. 13(7), 667-673. Doi:10.1038/ni.2319, is withdrawn in view of applicant’s amendments to the claims which now recite that the cells comprise a genomic disruption in the CISH gene where the genomic disruption is in a sequence having a least 80% identity to any one of SEQ ID NOS: 75-86.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 31-36 and 48 are newly rejected 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. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make or use the invention commensurate in scope with these claims.
The claims have been amended to recite an in vitro genomically-modified human stem cell or human progenitor cell, wherein said genomic modification comprises 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. The specification does not provide an enabling disclosure for introducing a genomic disruption into any sequence within a human CISH gene which has less than 100% identity to one of SEQ ID NOS 75-86. The claims are drawn to a genomic disruption in an endogenous CISH gene in a human stem or progenitor cell, thus the CISH gene has a human CISH gene genomic sequence. The specification teaches to generate gRNA capable of targeting a 20 nucleotide target sequence with the human genomic CISH gene sequence which is near a PAM sequence. More specifically, the specification teaches that the target sequence is present in exon 2 or exon 3. The specification discloses a single genomic sequence for human CISH which is identified as SEQ ID NO:103 in the specification. This sequence corresponds to the genomic sequence of human CISH known in the prior art. The specification’s working examples designed 12 different gRNA for recognition of 12 specific genomic target sequences in exon 2 or exon 3. The gRNA are disclosed in the specification as having been designed to specifically recognize the 20 nucleotide target sequences recited as SEQ ID NOS 75-86. While the specification broadly discloses that the target sequence could have 80% identity to one of these sequences, the specification does not actually disclose any human CISH genomic sequence which has sequence within exons 2 and 3 that differs by as much as 20% from the known sequence of human CISH (SEQ ID NO:103 in the instant specification), or disclose any gRNA capable of targeting a sequence which has only 80% identity to any one of SEQ ID NOS:75-86. The specification further does not disclose any modifications to the CISH genomic sequence, and more particularly the CISH target sequences in exons 2 and 3 identified as SEQ ID NOS 75-86 which would not negatively effect the binding and activity of a gRNA which has been specifically designed to bind to one of SEQ ID NOS 75-86. It is further noted that the working examples only tested the 12 gRNA for target indel activity against a human CISH sequence which is not disclosed as having any modifications from wild type human CISH genomic sequence. While Figure 66 appears to show that the 12 disclosed gRNA which each specifically target one of SEQ ID NOS 75-86 were functional in genome modification of the human genomic CISH sequence, there is no evidence that these gRNA were active against target sequence with less than 100% identify to SEQ ID NOS 75-86. It is also noted that the specification clearly discloses that not all gRNA, even ones specifically designed according to the teachings of the specification for binding a target sequence in a gene of interest, are capable of indel formation/genomic modification- see for example Figures 50 and 52. Furthermore, at the time of filing, it was known that modification to the target sequence can substantially effect gRNA binding and functionality. Zheng et al., for examples teaches that even a single modification to a 20 nucleotide target sequence can negatively effect gRNA binding and activity for a gRNA specifically designed to bind to the 20mer target sequence, and lead to a substantial increase in unwanted off-target effects (Zheng et al. (2017) Scientific Reports, Vol. 7: 40638. Doi:10.1038/srep40638, pages 1-8).
Therefore, in view of the state of the art of gRNA design and target sequence specificity at the time of filing, the lack of specific guidance in the specification for human CISH genomic sequence other than that set forth in SEQ ID NO:103, the lack of disclosure for gRNA capable of binding to sequence with less than 100% identity to SEQ ID NOS 75-86, the limitation of the working examples to targeting SEQ ID NOS 75-86, and the breadth of the claims, it would have required undue experimentation to make and use the genome modified cells as claimed.
No claims are allowed.
Any inquiry concerning this communication from the examiner should be directed to Anne Marie S. Wehbé, Ph.D., whose telephone number is (571) 272-0737. If the examiner is not available, the examiner’s supervisor, Maria Leavitt, can be reached at (571) 272-1085. For all official communications, the technology center fax number is (571) 273-8300. Please note that all official communications and responses sent by fax must be directed to the technology center fax number. For informal, non-official communications only, the examiner’s direct fax number is (571) 273-0737. For any inquiry of a general nature, please call (571) 272-0547.
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Dr. A.M.S. Wehbé
/ANNE MARIE S WEHBE/Primary Examiner, Art Unit 1634