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 .
Continued Examination 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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 2/06/2026 has been entered.
Response to Amendment
The amendment filed 02/06/2026 cancelling claim(s) 45 is acknowledged.
Claims 1, 2, 5, 7, 9, 11, 12, 14, 19, 21, 24, 25, 28, 30, 32, 34, and 53 are pending.
Claims 21, 24, 25, 28, 30, 32, and 53 are withdrawn.
Claims 1, 2, 5, 7, 9, 11, 12, 14, 19, 34 are pending and under examination.
Priority
Applicant’s claim for the benefit of a prior-filed application provisional application 62/775,637 filed on 12/05/2018 and PCT/US2019/064718 filed 12/05/2019 under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged.
Information Disclosure Statement
The information disclosure statement filed 2/06/2026 fails to comply with the provisions of 37 CFR 1.98(a)(4) because it lacks the appropriate size fee assertion. It has been placed in the application file, but the information referred to therein has not been considered as to the merits.
Response to Arguments
Applicant’s arguments, see pgs. 9-11 of Remarks, filed 02/06/2026, with respect to claims 1, 2, 5, 7, 9, 11, 12, 14, 19, 34 have been fully considered and are persuasive. The 103 rejections of claims 1, 2, 5, 7, 9, 11, 12, 14, 19, 34 in view of Editas, Bednarski, Schwank, and Galetto have been withdrawn.
Claim Rejections - 35 USC § 112(a) – Written Description
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 1, 2, 5, 7, 9, 11, 12, 14, 19, 34 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 1 recites a gene editing system comprising a first polynucleotide, comprising a nucleotide sequence encoding exons 11 to 27 of the CFTR gene and a pair of 5’ and 3’ homologous arm sequences (e.g., SEQ ID NO: 23 and SEQ ID NO: 24),
a second polynucleotide comprising a second nucleotide sequence encoding an RNA-guided DNA endonuclease, and
a third polynucleotide comprising a third nucleotide sequence encoding a guide RNA (gRNA) that directs cleavage at a target site (e.g., position 4262) of intron 10 of the CFTR gene.
Claim 11 further limits the gRNA sequence (e.g., SEQ ID NO: 96).
In analyzing whether the written description requirement is met for genus claims, it is first determined whether a representative number of species have been described by their complete structure. To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof. The disclosure of a single species is rarely, if ever, sufficient to describe a broad genus, particularly when the specification fails to describe the features of that genus, even in passing. (see In re Shokal 113USPQ283(CCPA1957); Purdue Pharma L.P. vs Faulding Inc. 56 USPQ2nd 1481 (CAFC 2000).
The court explained that “reading a claim in light of the specification, to thereby interpret limitations explicitly recited in the claim, is a quite different thing from ‘reading limitations of the specification into a claim,' to thereby narrow the scope of the claim by implicitly adding disclosed limitations which have no express basis in the claim.” The court found that applicant was advocating the latter, i.e., the impermissible importation of subject matter from the specification into the claim.). See also In re Morris, 127 F.3d 1048, 1054-55, 44 USPQ2d 1023, 1027-28 (Fed. Cir. 1997).
The claims are broad for reciting specific 5’ and 3’ homology arms (e.g., SEQ ID NO: 23 and 24) with a gRNA sequence that directs cleavage at position 4262 of intron 10 of a CFTR gene. As written, the claims are generic to the target site of the gRNA (e.g., position 4262 of intron 10 of CFTR), with only claim 11 further limiting the gRNA to a specific sequence (e.g., SEQ ID NO: 96).
The specification provides limited guidance on pairings of homology arm sequences and a gRNA sequence(s). While the working examples provide one specific pairing of homology arm sequences and gRNA sequences to target a specific position of intron 10, the specification does not provide further guidance on how to determine what homology arms and gRNA sequences can be used together, and what gRNA sequences, other than SEQ ID NO: 96, would be appropriate to use to target position 4262 of intron 10 of CFTR. For example, do the homology arms represented by SEQ ID NOs: 23 and 24 only work in combination with a gRNA comprising SEQ ID NO: 96? Can other gRNA sequences be used with SEQ ID NOs: 23 and 24 to target position 4262 successfully?
Page 48 of the specification teaches a sgRNA represented by SEQ ID NO: 29 (which comprises SEQ ID NO: 96) paired with 5’ and 3’ homology arms represented by SEQ ID NOs: 23 and 24 to insert a nucleotide sequence comprising exons 11-27 of CFTR at position 4262 of intron 10 of CFTR. Figs. 7 and 8 show increased HDR rates and CFTR function when position 4262 was targeted with this gene editing system.
No other gRNAs or homology arms were used to target position 4262 in the working examples. Additionally, Table 1 of the specification only teaches SEQ ID NO: 96 being used to target position 4262 during indel screenings of gRNAs.
The art recognizes the importance of the specificity of gRNA and homology arm sequences in gene-editing.
info.abmgood.com/crispr-cas9-introduction is considered relevant art for providing an overview of CRISPR Cas9 technology. In homology directed repair (HDR), a DNA repair template that has a high degree of homology to the sequence immediately upstream and downstream (i.e., homology arms) of the intended editing site is introduced into the cell along with the appropriate gRNA and Cas9 nuclease. In the presence of this suitable template, the less error-prone HDR mechanism can faithfully make the desired changes to the Cas9 induced DSB site through recombination, allowing for more precise repair mechanisms in cells compared to NHEJ (“The homology Directed Repair (HDR) with Cas9 Nuclease”; Figure 4).
Bak R.O., Dever D.P., Porteus M.H. CRISPR/Cas9 genome editing in human hematopoietic stem cells. Nat. Protoc. 2018;13:358–376. is considered relevant prior art for teaching CRISPR/Cas9 editing via homologous recombination in human hematopoietic stem cells. Bak et al. outlines key steps for identifying and characterizing a highly active locus specific sgRNA for targeted gene editing, which is key to achieving optimal homologous recombination (HR) frequencies. Routinely, four to eight sgRNAs candidates are screened based on the frequency of insertions and deletions using tracking of INDELs by decomposition (TIDE) analysis. Once an sgRNA has been confirmed, a homologous donor template to introduce a desired genomic change is designed and cloned into an AAV vector plasmid. In general, the CRISPR cut site (between base pairs 17 and 18 of the 20-nt complementary sequence of the sgRNA) should ideally be located as close to the intended genomic change as possible.
Bak et al. also found that the farther the homology arms are from the break site, the lower the HR efficiencies, and that if the HR process is to integrate DNA exactly at the double-strand break, the arms should be split at the CRISPR cut site (Fig. 1a). (pg. 361-362, “Experimental design” – sgRNA design and Donor design).
Devkota, Sushil. "The road less traveled: strategies to enhance the frequency of homology-directed repair (HDR) for increased efficiency of CRISPR/Cas-mediated transgenesis." BMB reports 51.9 (2018): 437. is considered relevant prior art for teaching strategies to enhance homology-directed repair (HDR) for increased efficiency of CRISPR/Cas-mediated transgenesis. Devkota explains that at its core, the CRISPR/Cas system consists of an endonuclease whose DNA-targeting specificity is dictated by a short-guide RNA. One of the strategies discussed by Devkota to improve HDR efficiency is physically positioning donor DNA near the cleavage site. By supplying the donor DNA with homology-arms around the target site, a researcher can hope that the donor DNA externally supplied is used as a repair template (pg. 440, col 2, last para). Several recent studies have positioned donor DNA near the target site instead of randomly floating them in the nucleoplasm, and this strategy has been successful to increase the HDR efficiency.
In summary, the art teaches the necessity in a gene editing systems comprising an RNA-guided DNA endonuclease of specific gRNA sequences and homology arm sequences used together in order to successfully target a specific position for editing.
Thus, in light of the implied generic nature of the claims and the lack of further guidance in the specification and prior art of what gRNA sequence(s) would be appropriate to use with the 5’ and 3’ homology arm sequences recited (SEQ ID NO: 23 and 24) in order to target position 4262 of intron 10 of the CFTR gene, the Artisan would not have understood Applicant to have been in possession of the invention as claimed.
Thus, for the reasons outlined above, it is concluded that the claims do not meet the requirements for written description under 35 U.S.C. 112, first paragraph.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ALLISON M JOHNSON whose telephone number is (703)756-1396. The examiner can normally be reached Monday-Friday 9am-5pm.
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/ALLISON MARIE JOHNSON/Examiner, Art Unit 1638
/ROBERT M KELLY/Primary Examiner, Art Unit 1638
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