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 .
Claim Status
Claims 1,5,11,13, and 26 are amended
Claims 2, 4, 32-34, 39, 40, 44, 52, and 68 are cancelled.
Claims 1,5-6,11,13,19,26,and 41-43 are pending.
Withdrawn Objections
The objection raised against claims 39 is withdrawn in light of claim cancelation.
The objection raised against claims 26 is withdrawn in light of Applicant amendment.
Withdrawn Rejections
Claim Rejections - 35 USC § 102
The rejection of claims 1-2,4,11,13,19,26,33-34, and 39-44 under 35 U.S.C. 102(a)(1) as being anticipated by Wilson et al (WO 2018/204626 A1) is withdrawn in light of Applicant amendments to specify the product of the first transgene being an inhibitory RNA; as well as the specific arrangement of the elements within the regulatable gene editing system.
The rejection of claims 1,4-6, 26, and 32 under 35 U.S.C. 102(a)(1) as being anticipated by Wilson et al (WO 2013/049493 A1) is withdrawn in light of the aforementioned Applicant amendments.
New Rejection Necessitated By Claim Amendments
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 text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
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.
Claims 1,5-6,11,13,19,26, and 41-44 is/are rejected under 35 U.S.C. 103 as being unpatentable over Wilson et al (WO 2018/204626 A1) hereafter “Wilson (2018)”, in view of Wilson et al (WO 2013/049493 A1), hereafter “Wilson (2013)”, and Roeth et al ( AU 2016202426 A1).
Regarding claims 1, and 5-6, Wilson (2018) teach a regulatable gene editing system. The gene editing system of Wilson comprises of two expression cassettes flanked by a 5’ and 3’ inverted terminal repeat (ITR), flanking in the following order:
A first cassette comprising of a promoter that controls the expression of a transgene encoding switch proteins comprising of: an FKBP-rapamycin binding protein (FRB), a transcription activator domain (i.e. P65), a rapamycin-binding protein (FKBP), and a zinc finger protein (ZFHD1) that is capable of binding to the regulatable promoter of a second expression cassette (i.e. the regulatable IL-2 promoter). It should be noted that the ZFHD1 (i.e. DNA binding domain) is fused to FKBP domain, whereas the P65 is fused to the FRB domain. ( See Fig.2 below, example 2-page 29, and claims 1-5).
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A second expression cassette comprises of regulatable promoter which controls the expression of a second transgene, wherein the second transgene encodes a gene editing nuclease and the regulatable promoter is the minimal IL2 promoter.
It is noted that Wilson (2018) teaches a gene editing system comprising of switch proteins regulating the expression of meganuclease ( See Fig.2 above). This differs from the gene editing system recited in the instant claims, which includes switch proteins regulating the expression of an inhibitory RNA.
Wilson (2013) teaches a gene editing system comprising of two expression cassettes: a dimerizable transcription factor cassette (i.e. a first expression cassette/ encoding switch proteins) and an ablation unit (i.e. second expression cassette), arranged in the following order;
A dimerizable transcription factor unit comprises of a first expression cassette containing a CMV promoter that drives the expression of a FRB-p65 fusion protein (referred to it FRB-TA), and a ZFHD-FKBP fusion protein (referred to it Z-3XFKBP). (See Figs.3B (below), Fig.4, and Example 3-pages 104-107). Wilson (2013) further discloses an rAAV vector comprising said gene editing system for use in the treatment of various disorders (Examples 6-10).
The ablation unit comprises of a second expression cassette containing a regulatable promoter, such as the minimal IL-2 promoter (labeled Z8I-see Fig.3B below), which controls the expression of a second transgene encoding Cre or I-SecI.
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Wilson (2013) also teaches that the gene editing system can be employed to deliver shRNA targeting the mutant Huntington gene (HTT), this reads on a transgene encoding an inhibitory RNA . (See Table 2, page 86).
It is also noted that the arrangement of the first and second cassettes inside the gene editing systems of Wilson’s (2013) and (2018) differs from the layout of the two cassettes recited in the instant claim1. For example, the instant claim is directed to a gene editing system, that from the 5’ to 3’ end comprises of a first cassette encoding an inhibitory RNA followed by a cassette encoding the switch proteins (i.e. the FRB-P65, and the ZNHD-FKBP), whereas the arrangement of the same elements inside the gene editing system of Wilson 2018 and 2013 are flipped (i.e. from the 5’ to the 3’ end comprises of a cassette encoding the switch proteins followed by a cassette encoding a transgene).
It is submitted that the choice of arranging elements inside the first and second cassettes relative to the 5’ end of the claimed gene editing system would have been routine and can easily be done by a person of ordinary skill in the art. Furthermore, nothing in Applicants disclosure suggests that the claimed specific arrangement would be preferable to the arrangement disclosed in the cited prior art. Even if Applicants argue that selecting or arranging items within the editing systems is not a common practice and is beyond the scope of ordinary skill in the art, such arrangement has already been disclosed by prior art. For example, Roeth et al disclose a gene editing system comprising of two expression cassettes, wherein the cassettes are arranged form the 5’ to the 3’ end in the following order;
A first cassette comprising a regular promoter which controls the expression of a first transgene, wherein the first transgene encodes IL12. ( See Fig.9 below). Roeth et al also teach that the gene editing system can be employed to deliver inhibitory RNA targeting PD-L1 gene (i.e. PD-L1 RNAi). ( See [00477]).
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A second expression cassette comprising a second promoter that controls the expression of gene switch encoding VP16-RXR and Gal4-EcR ( See Fig.9), wherein the Vp16-RXR is a fusion protein that combines the VP16 transcription activation domain with the retinoid X receptor to enhance transcriptional activity, and the Gal4-ECR is a modified ecdysone receptor that binds to the Gal4 DNA-binding domain, forming a heterodimer that can induce gene expression when activated. (See [00615]). In another embodiment, Roeth et al also teach that the gene switch could be based on Rapamycin gene switch (i.e. FRB-P65, and ZFHD1-FKBP). (See [00336]).
Therefore, claims 1and 5-6 are combining prior art elements according to known methods to yield predictable results, namely the predictable result being the use of the gene editing system of claim 1. Wilson (2018) teaches a regulatable gene editing system comprising of a first expression cassette encoding a transgene and a second cassette encoding a rapamycin gene switch, but fails to teach a gene editing system comprising a transgene encoding an inhibitory RNA. Wilson (2013) teaches a regulatable gene editing system comprising of a first expression cassette encoding a transgene and a second cassette encoding a rapamycin gene switch, and clearly suggest that the gene editing system can be employed to deliver shRNA targeting the mutant Huntington gene (HTT). Neither Wilson 2018 nor 2013 teach the specific arrangement of elements inside the gene editing system as required by the instant claims. Roeth et al supplement such deficiency by teaching a regulatable gene editing system comprising of a first expression cassette encoding a transgene and a second cassette encoding a gene switch, and also suggest that the editing system can be employed to deliver inhibitory RNA to target PD-L1 gene, as well as provide a platform comprising the specific arrangement of elements as required by the instant claims, an ordinary skill in the art can employ when constructing a regulatable gene editing system. Therefore, an ordinary skill in the art who had viewed Wilson 2018 could have come across Wilson 2013 and Roeth et al and immediately noticed the strong possibility of employing the regulatable gene editing system of Wilson 2018 to deliver an RNA inhibitory, as taught by Wilson 2013 and Roeth, as well as the arrangement of elements inside the gene editing system, as taught by Roeth, would have the predictable results of generating an effective regulatable gene editing system that can be employed to deliver an inhibitory RNA.
Regarding claim 11, the expression cassette encoding the switch gene in Wilson’s gene editing system contains a tissue specific promoter (e.g. a liver specific promoter). (See Example 2-page 29, and Fig.2).
Regarding claim 13, Wilson et al teach that the FKBP could be an FKBP12 ( referred to it as FK506-binding protein with 12 kDa). (See page 30 line 29-31 ).
Regarding claim 19, Wilson et al teach that the transcription activator domain is the P65 activation domain. (See claim 4).
Regarding claim 26, Wilson et al’s gene editing system contains a 3’ untranslated region of the human growth hormone (e.g. hGH 3’ UTR). (See Figs.1-2).
Regarding claims 41- 43, Wilson et al teach that the gene editing system can be packaged for delivery using a recombinant adeno-associated virus (rAAV), where the rAAV contains a protein capsid of a serotype 8 (e.g. AAV8). Wilson et al also teach that the rAAV is a single-stranded viral vector. (See page 18-line 20).
Response to Arguments
Applicant's arguments filed 01/08/2026 have been fully considered but they are not
persuasive.
Applicants argue that Wilson 2013 and 2018 fail to anticipate amended claim 1, because they do not each and every element as arranged in the amended claims. For example, neither Wilson 2018 nor Wilson 2013 disclose an IL-2 promoter operably linked to a nucleotide sequence encoding an inhibitory RNA positioned upstream of an activator domain, as recited in amended claim 1. Rather, Wilson 2018 and 2013 disclose a mini-IL-2 promoter linked to a
a transgene, positioned downstream of an activator domain.
Examiner’s Response to Traversal: Applicant’s arguments have been carefully considered but are not found persuasive. This is because Applicants amended claim 1 to include specific arrangements for the elements within the regulatable gene editing system, while neither Wilson 2018 nor Wilson 2013 teach the specific arrangement of elements as required by instant claim 1; however, a new ground of rejection is made over Wilson 2018 in view of Wilson 2013 and Roeth, that covers all of the added claim limitations ( as discussed above).
Conclusion
No claim is 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 FATIMAH KHALAF MATALKAH whose telephone number is (703)756-5652. The examiner can normally be reached Monday-Friday,7:30 am-4:30 pm EST.
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/FATIMAH KHALAF MATALKAH/Examiner, Art Unit 1638
/Tracy Vivlemore/Supervisory Primary Examiner, Art Unit 1638