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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 08/14/2026 has been entered.
Status of claims
Claims 1-2, 6-7, 10, 14, 16, 18, 22, 23, 26, 28, 32-37, 76, 114, and 121-135 are pending and under examination.
Need to note if previous rejections of record have been withdrawn
Claim Rejections - 35 USC § 112
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 7, 18, 26, 114, 131, 135 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 131 requires a gRNA sequence differing by 1-6 ntd from any one of SEQ ID NOs 36, 46, 47, 50, 53, 56, 57, 198, 209-213, 215-232, and 329 a second nucleic acid sequence that differs by 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleotides from the nucleotide sequence of SEQ ID NO: 170. Thus, the claim encompasses a large number of nucleotide differences from the identified sequences.
The specification does not adequately describe this claimed genus of gRNA variants. In particular, the specification does not provide representative examples demonstrating gRNAs having the claimed 1-6 nucleotide difference from the claimed sequences. The specification does not identify common structural features or functional characteristics that would reasonably allow one of ordinary skill in the art to recognize that the applicant was in possession of the full scope of the claimed gRNAs encompasses by these numerical ranges.
This deficiency is particularly significant because the claimed nucleotide substitutions are made within the guide targeting sequence, where a nucleotide identity can affect hybridization to the intended target nucleotide relative to editor’s activity window. The specification therefore cannot rely merely on the general concept that gRNA sequences may be varied. Rather the disclosure must reasonably convey possession that the claimed gRNA can perform the claimed base-editing method.
Accordingly, disclosure of the specifically identified reference gRNA sequences without sufficient disclosure of representative sequence variants differing from those sequences by the claimed numbers of nucleotides or a reasonable structure-function correlation supporting the claimed variants, does not provide written description commensurate with the scope of claim 131.
Claim 26 and 18: Regarding claim 1: Applicant’s claims do not provide support for all nucleotides comprising 85% identity to SEQ ID NO: 170. The specification as filed does not provide sufficient evidence that Applicants were in possession of the full scope of the claimed invention at the time of filing of the instant invention. As such, >85% identity to a 76 base pair polynucleotide, polynucleotide encompasses
76
C
15
×
3
15
= more than
4
×
10
22
nucleotide molecules. This amounts to enormous number of polynucleotides which do not have support in the specification. The specification also does not provide any guidance on how or where the nucleotides need to be changed. Thus, Applicants were not in possession of the full scope of the claimed invention at the time of filing of the instant invention. It is clear that the vector of the invention was restricted to SEQ ID NOs: 170.
Similar rejection applies to claim 18.
Regarding claim 7 and 114: The claim recites a base editor comprising an amino acid sequence having at least 99% identity to SEQ ID NOS: 373-388. As an example, SEQ ID NO: 373 is 1561 amino acid long. Accordingly, the claimed 99% sequence-identity limitation encompasses numerous variant polypeptides having amino acid substitutions relative to each of the sixteen specifically identified reference sequences. For a 1561 amino acid sequence, a 99% identity threshold permits substantial sequence variation, including approximately 15 amino acid difference while remaining at least 99% identical subject to particular sequence identity calculation.
The specification however, does not adequately describe a representative number of such variant base editors. In particular, the specification does not disclose representative base-editor species having the claimed amino acid mutations while retaining the base editing activity. Further the specification does not establish a structure-function correlation demonstrating that base editing activity is maintained throughout the full scope of the claimed 99% sequence identity variants. IT is noted that the claimed subject matter is defined not merely by sequence identity, but by a functional base editor. Amino acid substitutions, deletions etc can affect protein folding , catalytic activity target recognition among others. Thus the disclosure of the reference sequences themselves do not convey possession of substantially broader genus of variant base editors encompassed by the 99% sequence identity limitation.
Similar rejection applies to claim 7.
Claim 135 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, does not reasonably provide enablement for partially or completely restores auditory or visual function.
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
Analysis of whether a particular claim is supported by the disclosure in an application requires a determination of whether that disclosure, when filed, contained sufficient information regarding the subject matter of the claims as to enable one skilled in the pertinent art to make and use the claimed invention without undue or unreasonable experimentation. See Mineral Separation v. Hyde, 242 U.S. 261, 270 (1916). The key word is 'undue,' not experimentation.' " (Wands, 8 USPQ2d 1404). The factors to be considered in determining whether undue experimentation is required are summarized In re Wands 858 F.2d 731, 8 USPQ2nd 1400 (Fed. Cir, 1988). The factors to be considered in determining whether undue experimentation is required include: (1) the quantity of experimentation necessary, (2) the amount or direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims. While all these factors are considered, a sufficient number are discussed below so as to create a prima facie case.
Applicants' claims are directed to a method of complete or partial restoration of Usherin protein stability or function or a method of completely or partially treating visual or hearing loss, or partial or complete restoration of auditory or visual function using their adenosine-Cas9 editing method.
The specification did not provide evidence for partial or complete restoration of protein stability or function or partial or complete reversal of hearing or visual loss using their claimed method.
At the time the invention was made it was known that therapeutic rescue of Usher-syndrome phenotypes was highly uncertain, even when gene expression could be restored. In Isgrig et al. (previously cited), the authors reported partial hearing rescue in a different Usher subtype (USH1G) following AAV-mediated gene supplementation (Isgrig, Nat. Biotechnol. 2017/2018). Isgrig emphasized the incomplete and variable restoration of hearing (See Isgrig et al p. 784, col. 1, last para). Further as evidenced by Mauriac, “Cochlear implants or hearing aids are the standard of care for USH2A hearing impairment, but no biological treatments are available that alter the progression of the disease, which leads to vision loss in USH2A patients. “ (See Mauriac, p. 2391, col. 2, last para). Mauriac further taught that role of USH2A in retina is poorly understood. (See Mauriac, p. 2391, col. 2, first para). As such the prior art did not teach partial or complete restoration of hearing loss or vision loss was possible by editing G to A mutations.
Therefore, there was a recognized level of unpredictability with regards to underlying molecular mechanisms involved in treatment of usher syndrome. Due to the lack of teachings in the art regarding treatment of usher syndrome, and the recognized unpredictability in ameliorating the symptoms, a large amount of guidance and teachings would be necessary in order to be enabling for methods of such.
Guidance and teachings provided by Applicants in the instant specification is limited to disclosure about plausibility of base editing of USH2A in vitro. For example, [0543] taught that it was possible to introduce skipping of exons by mutating splice sites of the Ush2a gene in mouse organ of Corti (OC-k1) cells and mouse retina. (See Figure 10). Further the specification provided guidance about in vitro editing of human cells and rhesus monkey cells. It is acknowledged that the Office does not require the presence of working examples to be present in the disclosure of the invention (see MPEP §2164.02). However, in light of the state of the art, discussed above, which recognizes a high level of unpredictability in the field of treatments for Usher syndrome, and teachings of uncertainty regarding genetic correlation causing symptoms of Usher syndrome, with no consensus being reached using any single protein for treatment of Usher syndrome, the Office would require appropriate disclosure to support the contention that method of claim 1 may be successfully employed in fully or partially resolving hearing or vision loss in usher syndrome. The amount of guidance or direction needed to enable the invention is inversely related to the amount of knowledge in the state of the art as well as the predictability in the art. In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). Thus, due to the high level of unpredictability in the art, the current specification would have to provide greater amounts of teachings and guidance directed to methods of carrying out the claimed invention.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 130 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as failing to set forth the subject matter which the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the applicant regards as the invention.
Claim 130 requires an increase in full length Usherin protein. It is however, not clear to what quantity the “increase” in protein level is being measured. Appropriate clarification is required.
Conclusion
Pending claims are free of art.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JAGAMYA VIJAYARAGHAVAN whose telephone number is (703)756-5934. The examiner can normally be reached 9:00a-5:00p.
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/JAGAMYA NMN VIJAYARAGHAVAN/ Examiner, Art Unit 1633
/EVELYN Y PYLA/ Primary Examiner, Art Unit 1633
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