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 .
Applicants’ response of 2/3/2026 has been received and entered into the application file. Claims 1, 4-6, 8, 9, 13-21, and 37 are pending. Claims 1, 4-6, 8, 9 and 13-20 have been considered on the merits. Claim 21 remains withdrawn from consideration as being directed to a non-elected invention.
Specification
The substitute specification filed 2/3/2026 has been received and entered into the application file.
Status of Prior Rejections/Response to Arguments
RE: Drawings:
It is acknowledged that Applicants filed a petition for acceptance of color drawings on 2/3/2026. The petition is awaiting review. If/when the petition is granted, then the objection will be withdrawn. As the petition has not been decided as of preparation of this office action, the objection remains in place.
RE: Nucleotide Sequence Disclosures:
The updated/amended sequence listings are sufficient to obviate the previous errors.
RE: Claim Objections: The amendments are sufficient to obviate the previous issues. The objections are withdrawn.
RE: Rejection of claim 10 under 35 USC 112(d):
The cancellation of claim 10 renders the rejection thereof moot, the rejection is withdrawn.
RE: Rejection of claims 1, 2, 8, 9, 17, 19 and 37 under 35 USC 102(a)(1) over Gersbach et al (US 2016/0201089):
Applicant has traversed the rejection on the grounds that Gersbach et al (‘089) does not teach all claim limitations.
In light of the claim amendments, the argument is found persuasive. Gersbach et al (‘089) does not teach contacting the cells with a template DNA comprising the nucleotide sequence of exons 45 to 55 of wild type DMD. The rejection is withdrawn.
RE: Rejection of claims 1, 2, 8, 9, 13, 14, 17, and 19 under 35 USC 103 over Gersbach et al (US 2016/0201089):
Applicant has traversed the rejection on the grounds that Gersbach et al (‘089) does not teach or suggest all claim limitations.
In light of the claim amendments, the argument is found persuasive. Gersbach et al (‘089) does not teach contacting the cells with a template DNA comprising the nucleotide sequence of exons 45 to 55 of wild type DMD. The rejection is withdrawn.
RE: Rejection of claims 1-6, 8, 9, and 13-20 under 35 USC 103 over Gersbach et al (US 2016/0201089), in view of Sun et al (Mol Ther, 2019) and Gersbach et al (US 2022/0195406): Applicant has traversed the rejection on the grounds that the office has failed to set forth a prima facie case of obviousness.
Applicant asserts the rejection relies on impermissible hindsight instead of articulated reasoning with some rationale underpinning needed to support the conclusion of obviousness.
This argument has been fully considered, but is not found persuasive. The rejection establishes the teachings of primary reference Gersbach et al (‘089), particularly Example 10, as being exceedingly similar to the currently claimed method, the only difference being inclusion of a template DNA comprising the nucleotide sequences of exons 45 to 55 of wild type DMD as part of the CRISPR/Cas-based system. However, Gersbach et al (‘089) teaches CRISPR/Cas-based system can further comprises (C) donor DNA, used for situations where the CRISPR/Cas-based system is intended to correct a mutant gene to treat a subject. Thus Gersbach et al (‘089) provides a clear teaching to include donor/template DNA. Gersbach et al (‘406) and Sun et al each further teach excision of mutated DMD regions, followed by replacement with corresponding DNA encoding exons of the wild-type DMD sequence. Gersbach et al (‘406) and Sun et al both show the ‘excise and replace’ technique was enabled as of the effective filing date of the instant application. This is considered sufficient to establish a prima facie case of obviousness. The rationale underpinning this conclusion is a teaching, suggestion or motivation in the art to make the modification.
Applicant further asserts that the cited prior art fails to expressly or impliedly suggest each and every claim limitation. Specifically, Applicant asserts that the cited prior art fails to teach or suggest a template DNA comprising the nucleotide sequence of exons 45 to 55 of wild-type DMD. Applicant challenges the Official Notice taken that exons 45-55 of DMD were known and requests evidence of such be made of record.
In response to Applicant’s request for evidence that exons 45 to 55 of wild-type DMD were well-known, Leiden Muscular Dystrophy pages website is made of record. Specifically the page titled “DMD (dystrophin) cDNA Reference Sequence, updated November 29, 2005 (www.dmd.nl), which lists the sequence of all 79 exons of the DMD gene. This webpage is referenced in Applicant’s specification (¶0048).
Gersbach et al (‘406) and Sun et al each support that it was within the skill set of the artisan of ordinary skill in the art to deliver known DNA sequences, in particular sequences of exons of the DMD gene, as part of a CRISPR/Cas system to integrate the donor sequences into a target cell to restore the cell’s ability to produce functional dystrophin.
Applicant further asserts that a person having ordinary skill in the art would not have had a reasonable expectation of successfully modifying the method of Gersbach et al (‘089), asserting that none of the references specifically teach such a template DNA. Applicant further asserts that Gersbach et al (‘406) cannot be relied upon because the priority document of Gersbach et al (‘406) only discloses exon 52.
The arguments have been fully considered, but are not found persuasive. The rejection of record properly addresses all limitations, articulates a rationale for performing the modification, and provides secondary references that support enablement. Applicant’s arguments are not persuasive of error.
Regarding the argument that Gersbach et al (‘406) cannot be relied upon for its priority filing date: Gersbach et al (‘406) claims benefit of US Provisional application 62/833759 (filed 4/14/2019). The provisional application discloses restoring dystrophin function by inserting wild type exons corresponding to mutated or deleted exons (See provisional app at ¶0010-0011, and 0052). While replacement of exon 52 is the focus, a reference can be relied upon for all it teaches.
Overall, the rejection has been modified to address the claims as amended.
RE: Rejection of claim 37 on grounds of NDSP over claims of US Patent 11666665:
The amendment to claim 37 to require the use of a template DNA comprising the nucleotide sequences of exons 45-55 of DMD is sufficient to differentiate from the patented claims. The patented claims do not include a template DNA. The rejection is withdrawn.
RE: Provisional rejection of claim 37 on grounds of NSDP on claims of co-pending application 18/145996 (now issued as USP 12415001):
The amendment to claim 37 to require the use of a template DNA comprising the nucleotide sequences of exons 45-55 of DMD is sufficient to differentiate from the patented claims. The patented claims do not include a template DNA. The rejection is withdrawn.
Drawings
The drawings submitted 6/16/2022 and 2/3/2026 are objected to because the contain color images. Color photographs and color drawings are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted. Any such petition must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via the USPTO patent electronic filing system or three sets of color drawings or color photographs, as appropriate, if not submitted via the via USPTO patent electronic filing system, and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification:
The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2).
Claim Interpretation
In claims 17 and 18, “the cell with a modified genome” is interpreted as referring to the cell produced by the method of claim 1.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 17 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 17 was drawn to an embodiment of the invention which is no longer covered by claim 1. Claim 1 has been amended to require replacement of the nucleic acid sequence between introns 44 and 55 of the DMD gene with nucleic acid sequence encoding exons 45-55 of wild type DMD gene. This replacement will necessarily result in restoration of the full length wild-type DMD protein in the modified cells (i.e. as claimed in claim 18). Claim 17 is drawn to an alternative embodiment wherein the nucleic acid sequence between introns 44 and 55 of the DMD gene are cut out, resulting in a truncated DMD protein in the modified cells. Claim 17 no longer properly further limits parent claim 1.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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 1, 4-6, 8, 9, 13-16, 18-20, and 37 are rejected under 35 U.S.C. 103 as being unpatentable over Gersbach et al (US 2016/0201089), in view of Sun et al (Mol Ther, 2019) and Gersbach et al (US 2022/0195406), evidenced by Leiden Muscular Dystrophy pages “DMD (dystrophin) cDNA Reference Sequence” (2005).
Gersbach et al (‘089) disclose gene editing using CRISPR/Cas-based systems. Gersbach et al (‘089) specifically teach gene editing in muscle cells (See Gersbach et al ‘089 ¶0003, 0162). The CRISPR/Cas-based system of Gersbach et al (‘089) includes (A) a fusion protein with two polypeptide domains: the first domain being a Cas protein, such as Cas9, and the second being a protein with one of the following activities: transcription activation activity, transcription repression activity, transcription release factor, histone modification activity, nuclease activity, nucleic acid association activity, methylase activity and demethylase activity, and (B) at least one gRNA that can bind to, inter alia, a dystrophin gene (See Gersbach et al ‘089 ¶0008-0010, 0162, 0192-0196). Gersbach et al (‘089) also teach embodiments wherein the CRISPR/Cas-based system further comprises (C) donor DNA, used for situations where the CRISPR/Cas-based system is intended to correct a mutant gene to treat a subject (See Gersbach et al ‘089¶0267).
In Example 10, Gersbach et al (‘089) disclose using a multiplex CRISPR/Cas9 system to rescue dystrophin in cells with common mutations by deleting the entire exon 45-55 region (Gersbach et al ‘089 ¶0365). The multiplex system comprises two separate sgRNA that target two locations on either size of the exon 45-55 region, thereby excising the exon 45-55 region. Example 10 refers to Fig. 22. From Fig. 22A it can be seen that the two sgRNA used are “CR6” and “CR36”. Table 6 of Gersbach et al (‘089) defines CR6 as targeting intron 44, and CR36 as targeting intron 55. In one embodiment, Gersbach et al (‘089) test “in DMD patient cells harboring a background deletion of exons 48-50 of unknown length”. From Fig. 22A, and the brief description of Fig. 22 (Gersbach et al ‘089 at ¶0056), it can be seen that the “DMD patient cells” are human myoblasts. Gersbach et al (‘089) report their system successfully deleted the region between the two sgRNA target sites, resulting in a fusion between exons 44 and 56.
The embodiment of Gersbach et al (‘089) in Example 10, wherein a multiplex CRISPR/Cas9 system comprising two sgRNAs: CR6 and CR36, are applied to human DMD myoblasts renders obvious the claims as follows: Regarding claims 1, 5, and 18: The method of Example 10 of Gersbach et al (‘089) successfully modifies the genome of the mammalian muscle precursor cell having a mutation associated with a disease or condition (the human DMD myoblast has a background deletion of exons 48-50 of unknown length, which causes DMD). The method involves contacting the cell with a Cas-protein (the first polypeptide of the fusion protein), and a first and second gRNA. The first gRNA hybridizes to a first target site located in intron 44 of DMD (CR6 gRNA targets intron 44). The second gRNA hybridizes to a second target site located in intron 55 of DMD (CR36 gRNA targets intron 55). Gersbach et al ‘089 teach this results in excising/deleting the region between intron 44 and intron 55 (i.e. effectively deleting any existing DNA for exons 45-55).
The exemplified method differs from claim 1 in that they do not teach further contacting the cell with a template DNA comprising the nucleotide sequence of exons 45-55 of wild-type DMD (i.e. to restore the wild-type DMD gene for production of the full dystrophin protein).
However, as discussed in the summary of teachings, Gersbach et al ‘089 teach embodiments wherein the CRISPR/Cas-based system further comprises (C) donor DNA, used for situations where the CRISPR/Cas-based system is intended to correct a mutant gene to treat a subject (See Gersbach et al ‘089, ¶0267).
Gersbach et al ‘406 expand on this, providing more detail that the donor DNA comprises a fragment of the wild-type dystrophin gene, specifically exons, and more specifically exons that have been deleted from the mutant dystrophin gene (See Gersbach et al, ‘406, ¶0005, see priority document at ¶00010-00011 & 00052). The effect is generation of a nucleic acid that will encode for full length, wild-type dystrophin.
Sun et al reduce to practice this “excise-and-replace” technique in cardiomyocytes harboring a deletion of DMD exon 51 by using CRISPR/Cas system with gRNA pairs to excise exon 50 or 52, and then replace with a donor construct containing conjugated exons 50-51 or 51-52, respectively. Sun et al teach their strategy can be utilized to correct various exon deletions (See Sun et al, abstract).
Both Gersbach et al ‘406 and Sun et al use the HITI technique to achieve insertion of the donor DNA.
Based on the suggestion of Gersbach et al ‘089 to deliver donor DNA via the CRISPR/Cas system, and the teachings in Gersbach et al ‘406 and Sun et al that both teach delivering DNA of the excised wild-type exons to restore a full-length dystrophin gene, it would have been prima facie obvious to have modified the method of Example 10 of Gersbach et al ‘089 to further include a step of contacting the myoblasts with a template DNA comprising the nucleotide sequence of exons 45-55 of wild-type DMD. It is emphasized that the method of Example 10 deletes genetic sequences between introns 44 and 45 of the DMD gene (which includes exons 45-55), thus it would have been prima facie obvious to have replaced the excised portion with the corresponding wild-type exons. This conclusion of obviousness is based off the suggestion of Gersbach et al ‘089, and the teachings of Gersbach et al ‘406 and Sun et al regarding the benefits of ‘excise-and-replace’ technique. The sequence of exons 45-55 of wild-type DMD was known (See Leiden Muscular Dystrophy pages “DMD (dystrophin” cDNA Reference Sequence). One would have had a reasonable expectation of successfully modifying the method of Example 10 to further involve use of donor DNA comprising the nucleic acid sequence of exons 45-55 because (1) the sequence of exons 45-55 was known and available, (2) Gersbach et al ‘406 teach that exons can be delivered via donor DNA (See ¶0005; see priority document at ¶00064), and (3) Sun et al reduce to practice the ‘excise-and-replace’ technique using HITI.
Regarding claim 4: Following the discussion of claim 1 above, Gersbach et al ‘406 provide the details that the donor DNA (template DNA) comprises portions of the first and second target sites flanking the nucleotide sequence of the exons to be inserted (See Gersbach et al, ¶0005).
Regarding claim 6: following the discussion of claim 5 above, HITI utilizes NHEJ.
Regarding claims 8-9: following the discussion of claim 1 above, Gersbach et al (‘089) perform the gene edit in human DMD cells.
Regarding claims 13 and 14: While Example 10 does not utilize AAVs to transduce the CRISPR/Cas9 system into the DMD patient cells, Gersbach et al (‘089) does teach that viral delivery vectors, including AAVs, can be used to deliver the CRISPR/Cas9 system components into muscle cells (See ¶0203-0204, 0371).
Therefore, it is considered to have been at least prima facie obvious to have utilized an AAV to deliver the various components of the CRISPR/Cas9 system into the DMD patient cells in the method of Example 10 of Gersbach et al (‘089). This conclusion of obviousness is based on a teaching in the reference. One would have had a reasonable expectation of success because in Example 15, Gersbach et al (‘089) teach using an AAV to deliver a multiplex CRISPR/Cas9 system to delete exon 51. This is the same technology that would be used to deliver the CR6 and CR36 sgRNAs to carry out method of Example 10 with an AAV delivery vector.
Regarding claims 15-16: following the discussion of claims 1 and 13 above, the references teach or suggest use of AAV to deliver the components. Packaging of the different nucleic acids onto separate AAV would have been a matter of experimental design that does not affect the final outcome.
Regarding claim 19: following the discussion of claim 1 above, Gersbach et al (‘089) perform their method in vitro.
Regarding claim 20: following the discussion of claims 1 and 13 above, the sequence encoding the human DMD gene, including exons 45-55, was known at the time of filing (See Leiden Muscular Dystrophy page). SEQ ID NO: 28 of the instant application is the sequence encoding the region of exons 45-55. Providing the sequence of the human DMD gene including the region of exons 45-55 (i.e. SEQ ID NO: 28) in an AAV would have been prima facie obvious for the reasons set forth above. Said AAV reads on a virus comprising … a portion of the nucleic acid of SEQ ID NO: 26 encoding for….a template DNA comprising the nucleotide sequences of exons 45-55 of a wild-type DMD.
Regarding claim 37: Claim 37 is broader than claim 1, in that it does not specify the target sites to which the first and second gRNA hybridize to, beyond that the sites must be on separate introns of DMD. Following the discussion of claim 1 above, Example 10 of Gersbach et al (‘089), modified as discussed above, in view of Sun et al and Gersbach et al (‘406) also renders obvious claim 37.
Conclusion
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 ALLISON M FOX whose telephone number is (571)272-2936. The examiner can normally be reached M-F 10-6 EST.
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/ALLISON M FOX/Primary Examiner, Art Unit 1633