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 .
Status of Application/Amendments/Claims
Applicant’s response filed on 8/28/2025 has been considered. Claims 34-35 and 40-43 have been canceled. Claims 21-22, 24-25, 28-33, 38 and 39 are pending and are the subject of the present Official action. The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Priority
Applicant’s claim for the benefit of a prior-filed application, provisional application PRO 62/398,801, PCT/US17/52919 and CON of 16/334,826 filed on 9/23/2016, 9/22/2017 and 3/20/2019, respectively, under 35 U.S.C 119(e) or under 35 U.S.C 120, 121 or 365(c) is acknowledged.
Accordingly, the effective priority date of the instant application is granted as 9/23/2016
Withdrawn Rejections
The nonstatutory double patenting rejection of claims 21 and 28-30 over claims 1-13 copending Application No: 16/334,826 (US Patent Number 11,566,237) has been withdrawn in light of applicant’s terminal disclaimer submitted 8/28/2025.
Maintained Claim Rejections - 35 USC § 103
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 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 21-22, 24-25, 28, 31-33 and 39 stand rejected under 35 U.S.C. 103 as being unpatentable over McCullers et al. "CRISPR-Cas9 Utility in Genome Engineering." The Owl 6.1 (April 12, 2016) (hereinafter McCullers, reference of record) in view of Harper et al. WO 2013/016352, published 1/31/2013 (hereinafter Harper, reference of record). This rejection is maintained for the same reasons as outlined in the office action mailed on 5/29/2025. A response to applicant’s traversal is found below.
Claims 21 and 28: McCullers describes a recombinant gene editing complex comprising a catalytically inactive dCas9 protein fused to a transcriptional repressor domain Kruppel-associated box (KRAB) which can specifically target highly repetitive facioscapulohumeral muscular dystrophy (FSHD) microsatellite arrays and repress expression of DUX4 in human cells (McCullers, pg 69-70 and Fig 5). In particular, McCullers identified chromosome 4q35 as a target region which houses microsatellite D4Z4 (McCullers, Fig 1). McCullers describes engineering gRNAs that would recruit dCas9-KRAB fusion proteins to bind to the DUX4 ORF (which is inclusive of exon 1) and regulatory regions (“eg. promoters”) (McCullers, pg 69 and Fig 5). McCullers discloses a number of these gRNA oligos and vectors in Table 2. McCullers describes cloning and expression of the CRISPR-dCas9-KRAB constructs into suitable vectors (McCullers, Table 2 and Results pg 74). Although McCullers describes strategies to target the DUX4 ORF (which includes exon 1), McCullers does not expressly describe a gRNA which specifically hybridizes to a target nucleic acid sequence encoding a DUX4 promoter or exon 1 of DUX4.
Claims 22, 25 and 39: McCullers conducts these experiments in human embryonic kidney 293 cells, considers further experiments in human myoblasts and applications towards in vivo human gene therapy for treating FSHD (McCullers, pg 70 and 77).
Claims 32-33: KRAB is a transcriptional repressor domain (McCullers, pg 69-70).
Claim 21: Harper describes RNA interference-based methods for inhibiting the expression of the DUX4 gene as a treatment for muscular dystrophies including FSHD (Harper, field of invention). Harper describes a human DUX4 gene-specific miRNA antisense guide strand (SEQ ID NO: 7768), which specifically hybridizes to the DUZ4 promoter or exon 1 of DUX4.
Claims 24-25 and 31: Harper describes the use of recombinant adeno-associated virus (rAAV) vectors and lentiviral platforms which express the miRNA in a cell of interest (Harper, para 13-18). Harper describes administration via injection into muscles cells of a subject (Harper, para 32, 33, 40),
It would have been prima facie obvious to one of ordinary skill in the art to design a gRNA that specifically hybridizes to the human DUX4 gene promoter or exon 1, which is the same location as the miRNA target identified by Harper, in order to inhibit the expression of the DUX4 gene as a treatment for muscular dystrophies like FSHD in the dCas9-KRAB recombinant gene editing based methods of McCullers. It would been a matter of combining prior art elements according to known methods to yield predictable results since McCullers teaches numerous other gRNAs with similar complexity, targeting efficiency and length which are compatible with the dCas9-KRAB recombinant gene editing complex for targeting similar areas of the DUX4 ORF and promoter regulatory regions. One would have been motivated to make this combination in order to more efficiently inhibit DUX4 gene expression with dCas9 as taught by McCullers rather than the RNA interference-based methods as described by Harper since dCas9 offers an alternative and more effective approach for silencing gene expression. One would have a reasonable expectation of success given that the DUZ4 promoter and exon 1 are known gene targets and there exists predictable means for interchanging different gRNAs into the dCas9-KRAB recombinant gene editing system as described by McCullers.
Response to Traversal
Applicant traverses the instant rejection by arguing that a person of ordinary skill in the art would not have had any reason to have specifically elected a gRNA targeting a DUX4 promoter or exon 1 of the DUX4 gene based on the combination of cited references. Applicant argues that the examiner has applied hindsight reasoning given that McCullers discloses three gRNAs that target exon 3 and Harper discloses over 10,000 potential miRNA sequences without guidance to suggest that a miRNA strand would function as a gRNA. Applicant argues that there is no rationale for selecting a gRNA that would target a DUX4 promoter or exon 1 of DUX4 over other known gene targets.
These arguments have been fully considered, but are not found persuasive. Firstly, it is emphasized that McCullers expressly describes engineering gRNAs that would recruit dCas9-KRAB fusion proteins to bind to the DUX4 ORF (which is inclusive of exon 1) and regulatory regions (“eg. promoters”) (McCullers, pg 69 and Fig 5). McCullers states “directive gRNAs would recruit a dCas9 protein that binds to a regulatory region (eg. Promoter) in D4Z4…modifications to the DUX4 target sites may result in sustained heterochromatin that is maintained throughout multiple somatic cell divisions... demonstrating the utility of the CRISPR system in genome engineering and manipulation by examining its applications to FSHD” (McCullers, pg 69). It is emphasized that the claims are generic to ANY gRNA that targets the DUX4 promoter or exon 1 of DUX4. Furthermore, Harper shows that target sites located at the DUZ4 promoter or exon 1 of DUX4 are particularly good therapeutic targets for gene silencing, which provides further motivation for one of ordinary skill in the art to look at developing gRNAs that specifically hybridize to these regions. Figure 5 from McCullers is reproduced below for clarification.
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Claims 29-30 and 38 stand rejected under 35 U.S.C. 103 as being unpatentable over McCullers (supra) and Harper (supra) as applied to claims 21-22, 24-25, 28, 31-33 and 39 above in further view of Gersbach, US 2019/0127713, published 5/2/2019, provisional application filed on 4/13/2016 and 8/1/2016 (hereinafter Gersbach, reference of record). This rejection is maintained for the same reasons as outlined in the office action mailed on 5/29/2025. A response to applicant’s traversal is found below.
A description of McCullers and Harper can be found above. Neither McCullers nor Harper describe the use of CRISPR Cas proteins derived from Staphylococcus aureus (SaCas), the specific embodiment forth in elected SEQ ID No: 45 or a U6 promoter operably linked to the gRNA.
Claim 29: Gersbach describes dCas9 molecules comprising Staphylococcus aureus Cas proteins (SaCas). Gersbach describes dCas9 and dCas9-effector domain fusion proteins for the epigenetic modulation of gene transcription (Gersbach, para 3). Gersbach provides several reasons for using SaCas proteins over SpCas proteins. Gersbach states that gene delivery of Sp dCas9-KRAB constructs in vivo remains challenging because the large size of Sp-dCas9-KRAB constructs, which exceed the packaging limits of standard AAV vectors (Gersbach, para 3). SaCas proteins are significantly smaller and are therefore better suited for AAV delivery.
Claim 30: In particular, Gersbach discloses SEQ ID No: 3, which has a 100% query match to the elected Sa-dCas9 embodiment set forth in SEQ ID No: 45 (Gersbach, para 20, 27, 35, 58 and claims 24, 32, 41, 42 and 66; sequence search results shown below).
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Claim 21, 24 and 31: Gersbach describes different administration routes to achieve either systemic or local administration. Gersbach describes intravenous and intramuscular injections (Gersbach, para 323).
Claim 38: Gersbach describes the use of U6 promoters operably linked to gRNAs (Gersbach, para 509, 514, 532).
It would have been prima facie obvious to one of ordinary skill in the art to use the Sa-dCas9-KRAB recombinant gene editing complex described by Gersbach to target and repress DUX4 expression at the DUX4 promoter or exon 1as a treatment for FSHD as described by McCullers in view of Harper. It would have been a matter of combining prior art elements according to known methods to yield predictable results for one of ordinary skill to use the Sa-dCas9-KRAB recombinant gene editing complex described by Gersbach in the FSHD treatment methods of McCullers in view of Harper. One would have been motivated to use Sa-dCas9 in particular given its significantly smaller size when compared to Sp-dCas9 and higher compatibility with standard AAV vectors (Gersbach, para 3). One would have a reasonable expectation of success given that Gersbach successfully demonstrated the cloning, delivery and gene silencing capabilities of Sa-dCas9-KRAB. Furthermore, the sequence of Sa-dCas9-KRAB is disclosed by Gersbach and corresponds to elected SEQ ID NO: 45 of the instant invention. Accordingly, in the absence of evidence to the contrary, one of ordinary skill in the art would have considered the claimed invention to have been prima facie obvious to at the time the invention was made.
Response to Traversal
Applicant traverses the instant rejection by arguing that Gersbach does not disclose any methods for treating FSHD that involve targeting DUX4 or any gRNAs that target the DUX4 promoter or exon 1. Applicant argues that the collection of cited prior art does not provide a rationale for selecting any such gRNAs.
These arguments have been fully considered, but are not found persuasive. One cannot show non-obviousness by attacking references individually where the rejections are based on combinations of references, see MPEP 2145. McCullers provides the disclosure which describes a recombinant gene editing complex comprising a catalytically inactive dCas9 protein fused to a transcriptional repressor domain Kruppel-associated box (KRAB) which can specifically target highly repetitive facioscapulohumeral muscular dystrophy (FSHD) microsatellite arrays and repress expression of DUX4 in human cells (McCullers, pg 69-70 and Fig 5). Applicant can review previous arguments regarding gRNAs targeting the DUX4 promoter or exon 1.
Nonstatutory Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the "right to exclude" granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Langi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717 .02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP 706.02(1)(1) - 706.02(1)(3) for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
Claims 21-22, 25 and 28 stand provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-33 copending Application No: 17/919,198 (US Patent Application Publication Number 2023/0174958). Although the claims at issue are not identical, they are not patentably distinct from each other because the patented claims would anticipate the instant claims if they were available as prior art. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented. This rejection is applied in modified form to address applicants claim amendments on 2/25/2025. A response to applicant’s arguments is found below.
Claims 21-22 and 28: The co-pending claims are drawn to a CRISPRi platform comprising a sgRNA and a fusion polypeptide comprising a dCas9 protein fused to an epigenetic repressor. Epigenetic repressor is considered a type of transcriptional repressor domain as described in claim 32 and 33 of the instant claims (Claims 1, 3, 21). The co-pending claims describe targeting the DUX4 locus using the CRISPRi platform and a method of treating human FSHD with the gene editing complex (Claims 1, 3, 21). With respect to the amendments to claim 21, the co-pending claims describe sgRNAs which specifically target the DUX4 promoter or exon 1 of DUX4 (Claims 23-24).
Claims 25: The co-pending claims describe administering the CRISPRi platform to muscle cells of a subject (Claims 1, 4, 29). The co-pending claims describe the repression of DUX4 in skeletal muscle cells of a subject being treated using a hybridizable gRNA (Claims 1, 21, 25).
Thus, the co-pending claims would in-part anticipate the instantly claimed invention, which is drawn to a method for treating FSHD via a recombinant gene editing complex comprising a gRNA that targets the DUX4 promoter or exon 1 and a CRISPR Cas fusion protein which is catalytically inactive.
Response to Traversal
Applicant traverses the instant rejection by pointing to claim amendments and the priority date of the instant application which is earlier than the co-pending claims.
These arguments have been fully considered, but are not found persuasive since the co-pending claims would in-part anticipate the instantly claimed invention which is drawn to a method for treating FSHD via a recombinant gene editing complex comprising a gRNA that targets the DUX4 promoter or exon 1 and a CRISPR Cas fusion protein which is catalytically inactive.
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 ALEXANDER NICOL whose telephone number is (571)272-6383. The examiner can normally be reached on M-F 8-5 EST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Maria Leavitt can be reached on (571)272-1085. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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Alexander Nicol
Patent Examiner
Art Unit 1634
/ALEXANDER W NICOL/Examiner, Art Unit 1634