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/RCE under 37 CFR 1.114
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1.114 and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 6/3/2026 has been entered.
No claims have been amended. 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Withdrawn Rejections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 21-22, 25 and 28 over claims 1-33 copending Application No: 17/919,198 (US Patent Application Publication Number 2023/0174958) has been withdrawn since the copending claims have been abandoned.
New Claim Rejections - 35 USC§ 112, Scope of Enablement
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 21-22, 24-25, 28-33, 38 and 39 are 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 treating FSHD comprising administering specific gRNAs that hybridize to a DUX4 promoter or exon 1 of DUX4 and a catalytically dead Cas9 protein (dCas9) fused to a transcriptional repressor (KRAB) domain, does not reasonably provide enablement for a method for treating FSHD with any CRISPR Cas protein fused to any transcriptional regulator domain as presently claimed. This rejection is supported by the disclosure of Gersbach et al (hereinafter Gersbach, reference of record).
The factors listed below have been considered in the analysis of enablement regarding methods for wound healing comprising the administration of ANY antidepressant:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
The breadth of claims read on a method to treat FSHD comprising administering a recombinant gene editing complex comprising ANY gRNA that specifically hybridizes to a target nucleic acid sequence encoding a DUX4 promoter or exon 1 of DUX4 and ANY CRISPR Cas protein fused to ANY transcriptional regulator domain. The current claim language encompasses any CRISPR Cas protein including catalytically active variants and any transcriptional regulator domain including transcriptional enhancers.
The nature of the invention relates to the treatment of FSHD in any subject comprising administering a recombinant gene editing complex comprising ANY gRNA that specifically hybridizes to a target nucleic acid sequence encoding a DUX4 promoter or exon 1 of DUX4 and ANY CRISPR Cas protein fused to ANY transcriptional regulator domain. The state of the prior art is silent on how using a catalytically active CRISPR Cas protein or a transcriptional enhancer would achieve a down regulation of the DUX4 gene. For example, Gersbach teaches the use of transcriptional repressors like KRAB which are fused to a dCas9 variant which can target specific genes through the use of a gRNA for transcriptional repression (Gersbach, para 3-11). However, Gersbach shows that this platform is only useful for transcriptional repression through the use of specific fusion constructs (Gersbach, para 26).
The specification teaches that FSHD is caused by relaxation of chromatin which is normally repressed by mutations in proteins that maintain epigenetic silencing, both resulting in abnormally increased expression of the DUX4 gene. This abnormal expression of DUX4 thus causes the pathology of FSHD (Spec, pg 31). The specification further teaches the use of the mouse model, and while useful as a model, does not capture the full complexity of the human disease. The specification provides working examples using specific transcriptional repressors like KRAB and no examples showing how a transcriptional enhancer or a catalytically active CRISPR cas variant could predictably be used to treat FSHD. Thus, the specification as filed does not provide guidance that overcomes this unpredictability within the art.
Thus, applicant is not enabled for a method to treat FSHD comprising administering a recombinant gene editing complex comprising ANY gRNA that specifically hybridizes to a target nucleic acid sequence encoding a DUX4 promoter or exon 1 of DUX4 and ANY CRISPR Cas protein fused to ANY transcriptional regulator domain as described which would lead one of ordinary skill in the art to practice the claimed invention without undue experimentation.
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 12/10/2025. 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 McCullers does not disclose a gRNA which specifically hybridizes to a target nucleic acid sequence encoding a DUX4 promoter or exon 1 of DUX4. Applicant argues that the generic disclosure of McCullers depicted in Fig 5 generally targets the DUX4 ORF and that the examiner has suggested that this is broadly equivalent to targeting exon 1 of DUX4. Applicant argues that miRNAs and gRNAs are mechanically distinct and operate through entirely different biological pathways on different substrates and these systems are not predictive of the success of one another. Applicant also points to the 2013 publication date which is before the 2016 publication date of McCullers. 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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Although it is acknowledged that miRNAs and gRNAs are mechanistically distinct, one of ordinary skill in the art would understand that both rely on short, specific 20-nucleotide sequences to bind targets and share similar binding rules. Thus, 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.
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 12/10/2025. 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.
Conclusion
No claims allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Dr. ALEXANDER NICOL whose telephone number is (571)272-6383. The examiner can normally be reached on M-F 8-5 EST.
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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
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