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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 4/7/2026 has been entered.
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 1, 2, 4-8, 10-12, 31, 37, 38, 43, 47, 70, 109, 140, 146 and 153 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.
The written description requirement is set forth by 35 U.S.C. 112, first paragraph which states that the: “specification shall contain a written description of the invention. . .[emphasis added].” The written description requirement has been well established and characterized in the case law. A specification must convey to one of skill in the art that “as of the filing date sought, [the inventor] was in possession of the invention.” See Vas Cath v. Mahurkar 935 F.2d 1555, 1560 19 USPQ2d 1111, 1117 (Fed. Cir. 1991). Applicant may show that he is in “possession” of the invention claimed by describing the invention with all of its claimed limitations “by such descriptive means as words, structures, figures, diagrams, formulas, etc., that fully set forth the claimed invention.” See Lockwood v. American Airlines Inc. 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (Fed. Cir. 1997).
In analyzing whether the written description requirement is met, it is first determined whether a representative number of species have been described by their complete structure. Next, it is determined whether a representative number of species have been sufficiently described by other relevant identifying characteristics. The amended claim 1 recites “wherein the Cas9 domain comprises a R461I substitution in the amino acid sequence of SEQ ID NO: 9, or a corresponding substitution in any of the amino acid sequences provided in SEQ ID NO: 10-262” and has the function of recognize a non-canonical PAM sequence.” The claimed Cas9 domain in claim 1 thus encompasses a large genus of polypeptides that have mutation(s) at R461I, and other variant sequences at other position(s) (90% sequence homology to SEQ ID NO: 9 means up to 137 amino acid difference). Example 1 describes beneficial mutations conferring Cas9 activity on noncanonical PAM mapped to a S. pyogenes wild type sequence including 122, 137, 182, 62, 294, 409, 480, 543, 660, 694, 1219, 1329 (paragraph [00349]), and mapping of said mutations to Cas9 protein from other species, SEQ ID NO: 10-12. The specification teaches alignment of a total of 250 Cas9 sequences may be obtained following alignment parameters as given in the above example and disclosed in WO2017/070633. The specification states “additional suitable Cas9 sequences in which amino acid residues homologous to residues 51, 86, 261, 274, 331, 341, 388, 40, 435, 461, 510, 522, 548, 593, 653, 712, 715, 72, 77, 798, 811, 839, 847, 955, 967, 991, 1139, 1199, 1227, 1229, 1296, 1318 can be identified by known methods,” citing Supplementary Table S2 and Supplementary Figure S2 of Fonfara et al. In example 4, the specification describes identification of point mutations A262T, K294R, S409I and M694I, E480K, E543D and E1219V (paragraphs [0420]-[0421]) that results in expanded PAM recognition, and confirmed by PAM depletion assay, transcriptional activation, and base editing in mammalian cells. The function of expanded PAM recognition compared to wild type Cas9 appears to be related to specific mutations at position A262T, K294R, S409I and M694I, E480K, E543D and E1219V. There is no teaching from the specification that relates to noncanonical PAM recognition to Cas9 variants at position R461I of SEQ ID NO: 9, or corresponding amino acid residues in other amino acid sequences sharing 90% sequence identity to SEQ ID NO:9. The specification thus fails to describe a Cas9 domain has the recited mutation(s) that has the function of recognizing noncanonical PAM, or other identifying characteristics for the claimed Cas9 domain having the recited mutation. The structure and functional relationship is missing.
The knowledge from prior art does not remedy the deficiency from the specification. Neither disclosure from WO2017/070633 and Fonfara teaches mutation(s) at claimed sites R461I alone or in combination with other mutation (as recited in claims 2, 4-8, 10-12, 31 and 153) of SEQ ID NO: 9, or corresponding positions to sequences having 90% homology to SEQ ID NO: 9. Carsten teaches some of the mutations at specific sites such as 461, 777 in Cas9 domain. However, there is no teaching from Carsten indicates such mutation(s) is related to noncanonical PAM recognition. The function of Cas9 having mutation(s) R461I alone or in combination with position 51, 86, 261, 274, 331, 341, 388, 40, 435, 461, 510, 522, 548, 593, 653, 712, 715, 72, 77, 798, 811, 839, 847, 955, 967, 991, 1139, 1199, 1227, 1229, 1296, 1318 of SEQ ID NO: 9 as recited in claims as 2, 4-8, 10-12, 31 and 153, or corresponding positions to sequences having 90% homology to SEQ ID NO: 9 is thus unpredictable. A skilled artisan cannot immediately envision the structure of the claimed genus of Cas9 domain that can recognize noncanonical PAM sequence. Therefore, the specification lack sufficient description for the claimed genus of Cas9 domain to demonstrate that Applicant has possession of claimed invention at the time the application was filed.
Dependent claims requires all limitation of claim 1, which are not sufficiently described by the present specification for same reason discussed above.
Response to Arguments
Applicant argues that the R461I substitution at position 461 in SEQ ID NO: 9 is disclosed in Figure 16, in the row for clone 76, also referred to as xCas9 3.11. Applicant argues that the function of xCas9 3.11 is disclosed in the application in Figure 6A-C. Applicant states that since all of the pending claims require substitution at R461I, the application teaches a R461I substitution is capable of recognizing a target sequence that does not comprise the canonical 5’-NGG-3’ PAM at its 3’ end.
The above argument has been fully considered but deemed unpersuasive. It is noted that xCas9 3.11 (clone 76) in Figure 16 comprises multiple substitution including 108G, 262T, 409I, 461I, 543D, 673E, 694I and 1219I. The recognition noncanonical PAM sequence includes CAG, GGA,CAT, which has activities comparable to GGG, the canonical PAM sequence according to the PAM depletion score in Figure 6B-6C. Based on the data, it is unclear whether the PAM depletion is resulting from this single substitution at R461I, or the overall combination of mutation at 108G, 262T, 409I, 461I, 543D, 673E, 694I and 1219I. It is noted that the R461I substitution is not present in other clones of Cas9 domain variants. As such, the structural and functional relationship between this R461I and recognition of a noncanonical PAM sequence cannot be established. Further whether this substitution would cause the other variants having SEQ ID NO: 10-262 to recognize noncanonical PAM sequence is unpredictable. Therefore, for reasons discussed in previous office action and set forth above, this rejection is still considered proper and thus maintained.
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.
Claims 1, 2, 4-8, 10-12, 31, 37, 38, 43, 47, 70, 109, 140, 146 and 153 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim 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.
Regarding claim 1, the recitation of “in a corresponding amino acid residue in any of the amino acid sequences provided in SEQ ID NO: 10-262” renders the claim indefinite many of the sequences does not comprise R at position 461. Moreover, SEQ ID NO: 39 only has 306 amino acids, it is unclear how to find the corresponding position of the R at position 461.
Dependent claims 2, 4-8, 10-12, 31, 37, 38, 43, 47, 70, 109, 140, 146 and 153 are rejected for same reason because they depend on claim 1 but fails to clarify the indefiniteness.
With regard to claims 6, 7 and 12, the claims recites specific substitutions at position 51, 86, 261, 274, 331, 341, 388, 40, 435, 461, 510, 522, 548, 593, 653, 712, 715, 72, 77, 798, 811, 839, 847, 955, 967, 991, 1139, 1199, 1227, 1229, 1296, 1318, including L51I…L1318S. However, based on the disclosure in the sequence listing SEQ ID NO: 10-262, not all sequences has L, F, R…L at the recited position. Even the corresponding amino acid may be found in said sequences, the substitution would not be L51I if the naturally occurring amino acid is not L.
Regarding claims 2, 4, 5-8, 10, 11, 12, 153, SEQ ID NO: 13, 14, 33, 37-39, 115-118, 190, 198, 251 and 261 has various lengths shorter than SEQ ID NO: 9. It is unclear how to determine corresponding mutations at position that exceeds its lengths. For example, SEQ ID NO: 39 comprises only 306 amino acids, it is unclear how to determine where the corresponding substitution of 331…1318 occurs.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CELINE X QIAN whose telephone number is (571)272-0777. The examiner can normally be reached M-F (8-4:00).
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, Jennifer Dunston can be reached at 571-272-2916. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/CELINE X QIAN/Primary Examiner, Art Unit 1637
