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 .
Application Status
The Amendments and Remarks filed 28 January 2026 are acknowledged and have been entered. Claims 31, 32, 35, 41, 42, 45, and 47 are amended. Claims 1-30 are cancelled. Claims 51 is newly added. Claims 31-51 are pending and being examined on the merits.
Any rejection or objection not reiterated herein has been overcome by applicants claim amendments.
Priority
This application claims priority to application 61/826,338 filed 05/22/2013.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 31-32, 34-42, and 44-51 are rejected under 35 U.S.C. 103 as being unpatentable over Doudna (US 20140068797A1. Filed 3/15/2013). This rejection is modified to clarify the motivation and reasonable expectation of success in view of Applicant’s arguments, does not constitute a new ground of rejection for claim 31, and continues to rely on the same references, findings, and combination set forth in the prior Office Action. It provides the basis for the previously applied rejection This rejection also addresses the newly added claim 51.
Regarding claims 31-32, 41-42, and 47, Doudna teaches kits and compositions for methods of site-specific modification of a target DNA involving contacting the DNA with a Cas9 polypeptide and a DNA-targeting RNA (gRNA) [abstract, 0347, 0387]. Doudna teaches a Cas9-tracrRNA:crRNA complex/composition [0045; Fig. 13; 0127] and teaches a target DNA sequence [0266, 0296, 0347, 0387]. Doudna teaches the use of a N. meningitidis Cas9 protein, a type II Cas protein [0596; Fig. 4]. Doudna teaches that the site-directed modifying polypeptide of N. meningitidis Cas9 can comprise SEQ ID NO: 1094 which is 100% identical to SEQ ID NO: 1 of the instant application [0013; claim 73]. Doudna further teaches that guide RNA target-complementary regions may vary in length and that optimal guide lengths are between 20 and 40 nucleotides, encompassing the claimed 24 nucleotide target-binding sequence [fig. 43, 0094, 0166].
Regarding the tracrRNA limitation, Doudna teaches that tracrRNAs are initially transcribed as longer precursor transcripts and subsequently processed into shorter mature tracrRNA species. Specifically, Doudna teaches that tracrRNA is transcribed as primary transcripts of 171 nucleotides and 89 nucleotides in length, which hybridize with pre-crRNA and are recognized by RNase III in the presence of Cas9. Doudna further teaches that RNase III processing generates a shorter processed tracrRNA species of approximately 75 nucleotides together with processed crRNA intermediates [0612]. Thus, Doudna teaches that functional tracrRNAs exist in both precursor and processed forms and that Cas9-mediated cleavage activity is associated with processed tracrRNA species rather than being limited to a single precursor transcript length.
Doudna does not expressly disclose a tracrRNA portion comprising a nucleotide sequence at least about 85% identical to SEQ ID NO:46 and having a length of about 91 nucleotides.
Doudna does teach that Cas9 proteins from N. meningitidis cleaves efficiency when guided by their cognate tracrRNA:crRNA species and optimally designed tracrRNA sequences [0628, Fig. 24]. Doudna teaches exemplary activator-RNA (i.e., tracrRNA) sequences, see SEQ ID NOs:431-562 [0038]. SEQ ID NO: 438 is a 112 (i.e., about 91 nucleotides in length) RNA molecule that comprises a 91 nt RNA sequence that reverse translates to a DNA sequence that is 100% identical to SEQ ID NO: 46.
Regarding claims 34-36, 44-46, and 50, Doudna teaches a variant Cas9 protein having nuclease activity and cleaving both strands of a target DNA sequence or nicking a single strand of a target DNA sequence [0451-0453], and comprises contacting the target DNA sequence with a homologous DNA fragment [0425; 299-302].
Regarding claims 37-40, Doudna teaches that pluripotent stem cells encompass embryonic stem cells and induced pluripotent stem cells which can be target cells of the methods of genome modification [0142].
Regarding claim 48, Doudna teaches the naturally occurring duplex-forming segments of crRNA ("targeter-RNA") sequence from N. meningitides of SEQ ID NO: 646 [0039]. SEQ ID NO: 646 is an RNA molecule that comprises a RNA sequence that reverse translates to a DNA sequence that is 100% identical to SEQ ID NO: 48.
Regarding claim 49 and 51, the teachings of claim 32 and 48 are discussed above.
It would have been obvious to one ordinary skilled in the art before the effective filing date of the claimed invention to assemble a composition, complex, or kit comprising the Cas protein of NmCas9 of SEQ ID NO: 1094, a gRNA comprising a targeting binding sequence that is 24 nucleotides in length, a crRNA sequence of SEQ ID NO: 646, a functional processed tracrRNA (or unprocessed) form within the disclosed NmCas9 system of SEQ ID NO: 438, and a target DNA for the advantage of genome modifying the target DNA. One of ordinary skill would be motivated to make the modification since Doudna expressly teaches that tracrRNAs undergo RNase III-mediated maturation from longer precursor transcripts into shorter functional tracrRNA species. In view of this teaching, one of ordinary skill in the art would have understood that tracrRNA length is not limited to a single precursor transcript and that functional processed tracrRNA species may vary in length while retaining their ability to direct Cas9 activity. Accordingly, selection of a processed NmCas9 tracrRNA approximately 91 nucleotides in length would have represented no more than the use of a known functional tracrRNA species within the predictable framework taught by Doudna. Furthermore, Doudna teaches a NmCas9 protein of SEQ ID NO: 1 that can be used for site-directed modification of a target DNA, teaches that gRNA base pairing length are optimal between 20 and 40 base pairs, teaches the exemplary duplex-forming segment of targeter-RNA sequence of SEQ ID NO: 646, and teaches that N. meningitidis Cas9 cleaves efficiency when guided by their cognate and optimally designed tracrRNA:crRNA sequences. One of ordinary skill in the art would have had a reasonable expectation that a processed tracrRNA species retaining the structural elements necessary for interaction with NmCas9 and crRNA would remain functional for directing target DNA cleavage. One of ordinary skill in the art would also have a reasonable expectation of success since Doudna teach all components of the claimed invention for use in a CRISPR-associated (Cas) system that is used for genome modification.
Response to Arguments
Applicant's arguments filed 02/08/2026 have been fully considered but they are not persuasive.
Applicant argues that Doudna fails to teach the claimed tracrRNA portion because the Office relied upon Doudna SEQ ID NO:438, which Applicant states is 112 nucleotides in length and therefore does not satisfy the claimed limitation requiring a tracrRNA portion that is about 91 nucleotides in length. This argument has been fully considered but is not persuasive.
Applicant’s argument assumes that Doudna is relied upon as expressly disclosing a tracrRNA having a length of exactly 91 nucleotides. The rejection does not rely on such a finding. Rather, Doudna teaches that tracrRNAs are initially transcribed as longer precursor transcripts and subsequently processed by RNase III into shorter mature tracrRNA species. Doudna teaches that tracrRNA is transcribed as primary transcripts of 171 nucleotides and 89 nucleotides in length and that RNase III-mediated processing generates a shorter processed tracrRNA species of approximately 75 nucleotides [0612]. Thus, Doudna expressly teaches that functional tracrRNAs exist in multiple forms and lengths and that maturation of tracrRNA through processing is a normal feature of Cas9 systems. Accordingly, the relevant inquiry is not whether Doudna expressly discloses a 91 nucleotide tracrRNA sequence, but whether Doudna would have suggested the use of a functional processed tracrRNA species within the NmCas9 system. The Examiner finds that it would have. Because Doudna teaches that tracrRNAs are naturally processed into shorter functional forms and that Cas9 activity is maintained following such processing, one of ordinary skill in the art would have reasonably expected that a processed tracrRNA species having a length different from the precursor transcript, including a length of approximately 91 nucleotides, would remain functional provided the RNA retained the structural features necessary for interaction with Cas9 and crRNA.
Applicant further argues that Doudna provides no teaching or motivation to modify its disclosed tracrRNA sequences to arrive at the claimed tracrRNA. This argument has been fully considered but is not persuasive.
Doudna expressly teaches the maturation of tracrRNA molecules through RNase III-mediated processing and therefore teaches that functional tracrRNA species are not limited to a single transcript length. This teaching would have provided sufficient motivation for one of ordinary skill in the art to employ an alternative processed tracrRNA species within the disclosed NmCas9 system while maintaining expected Cas9 function.
Applicant has not provided evidence demonstrating that the claimed approximately 91 nucleotide tracrRNA exhibits unexpected results, criticality, or properties that distinguish it from other functional processed tracrRNA species known in the art.
Accordingly, the rejection under 35 U.S.C. 103 is maintained.
Allowable Subject Matter
The following is a statement of reasons for the indication of allowable subject matter: Claims 33 and 43 require that the composition further comprises a DNA sequences comprising the target DNA sequence that is flanked on its 5' end by a sequence complementary to NNNNGATT or NNNNGCTT. Mali, Doudna, nor the prior art teach or reasonably suggest that the target DNA sequence for the composition bust me flanked on its 5' end by a sequence complementary to NNNNGATT or NNNNGCTT.
Claims 33 and 43 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Conclusion
No claims allowed.
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 TIFFANY N GROOMS whose telephone number is (571)272-3771. The examiner can normally be reached M-F 830-530.
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/TIFFANY NICOLE GROOMS/Examiner, Art Unit 1637
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