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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 October 28, 2025 has been entered.
Applicants previously canceled claims 1, 5-6, 8-13, 15-34, 36, 40-42, 44, 49, 51, 53-73, 76-130, 132-134 and 141. Claims 74-75, 131, 140, and 143 remain withdrawn from consideration, being directed to a non-elected invention. Applicants amend claim 48. Claims 2-4, 7, 14, 35, 37-39, 45-48, 50, 52, and 142 are under examination.
Any objection or rejection of record in the previous Office Action, mailed August 8, 2025, which is not addressed in this action has been withdrawn in light of Applicants’ amendments and/or arguments.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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 2-4, 7, 35, 37-39, 46, and 52 are rejected under 35 U.S.C. 103 as being unpatentable over Morrissey et al. (PCT Patent Application Publication No. WO 2017/173054, published October 5, 2017 and cited in the Information Disclosure Statement filed September 27, 2024) and Kanjolia et al. (Kanjolia I, U.S. Patent No. 11,795,460, issued October 24, 2023, filed December 9, 2022, and claiming priority to U.S. Patent Application No. 16/828,573, PCT Patent Application No. PCT/US2018/053382, and U.S. Provisional Patent Application Nos. 62/671,902 and 62/566,236, filed March 24, 2020; September 28, 2018; May 15, 2018; and September 29, 2017, respectively) in view of Donohoue et al. (81 Molecular Cell 3637-3649 (2021)).
Regarding claim 2, Morrissey discloses guide RNA molecules that can be used to guide a CRISPR nuclease to a transthyretin gene (paragraphs [7] and [174]). Morrissey discloses that the guide RNA can have the sequence that is identical to instant SEQ ID NO: 275 (SEQ ID NO: 111, see Appendix I).
Regarding claim 3, Morrissey discloses expression cassettes with the nucleotide sequence encoding the guide under the control of a promoter (i.e., vectors) that comprise the guide RNA, which has the sequence that is identical to instant SEQ ID NO: 275 (paragraphs [81]-[83] and SEQ ID NO: 111, see Appendix I).
Regarding claim 4, Morrissey discloses compositions that comprise the guide RNA, which has the sequence that is identical to instant SEQ ID NO: 275 and an RNA-guided DNA binding agent, such as a CRISPR nuclease (paragraphs [65], [81]-[83] and SEQ ID NO: 111, see Appendix I).
Regarding claim 7, Morrissey discloses that the RNA-guided DNA binding agent is a Cas nuclease or nickase (paragraph [65]).
Regarding claim 35, Morrissey discloses that the guide RNA can be a dual guide RNA or a single guide RNA (paragraphs [79]-[81]).
Regarding claim 37, Morrissey discloses that the guide RNA can be modified (paragraphs [259] and [268]).
Regarding claim 38, Morrissey discloses that the modification can be a 2’-O-methyl modification (paragraphs [259] and [268])
Regarding claim 39, Morrissey discloses that the modification can be at the 5’ end of the guide RNA or the 3’ end of the guide RNA (paragraphs [259]-[260] and [268]).
Regarding claim 46, Morrissey discloses that the nucleic acids encoding the guide RNA and the mRNA encoding the RNA-guided DNA binding agent are associated in lipid nanoparticle (LNP) (paragraphs [7]-[11]).
Regarding claim 52, Morrissey discloses that the LNP can be in a pharmaceutical composition with a pharmaceutically acceptable carrier (paragraph [154]).
Regarding claims 2-4, Kanjolia I discloses methods and compositions for editing withing the TTR gene for treating subjects having amyloidosis associated with transthyretin (ATTR) (abstract). Kanjolia I discloses compositions comprising a guide sequence having a sequence of SEQ ID NO: 9, which is identical to instant SEQ ID NOS: 302 and 303, at least 17, 18, 19, or 20 contiguous nucleotides of SEQ ID NO: 9, or a guide sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%,98% or 99% identical to SEQ ID NO: 9, or a vector encoding the guide sequence, or a composition comprising the guide sequence (column 3, lines 27-50) (Appendices III and IV, SEQ ID NO: 9).
Morrissey and Kanjolia I fail to disclose that the guide RNA is a hybrid DNA-RNA guide.
Donohoue discloses that CRISPR genome editing can be improved by use of a DNA:RNA hybrid guide RNA (abstract). Donohoue discloses that such hybrid guide RNAs improves genome editing efficiency and target specificity (abstract). Donohoue further discloses that such hybrids are useful for increase Cas9 specificity, while substantially reducing off-target effects (abstract and Figures 1-3).
It would have been obvious to one with ordinary skill in the art before the effective filing date of the claimed invention to produce Morrissey’s or Kanjolia I’s guide RNAs to be DNA:RNA hybrid guide RNAs, as disclosed by Donohoue, in order to provide for a more specific, efficient, and safe gene editing. One of ordinary skill in the art would have been motivated to do so in order to provide such specific, efficient, and safe gene editing methods, that show higher on-target editing with reduced off-target effects, especially those used in the treatment of diseases, such as amyloidosis associated with transthyretin.
Claim 14 is rejected under 35 U.S.C. 103 as being unpatentable over Morrissey and Kanjolia I in view of Donohoue, as applied to claims 2-4, 7, 35, 37-39, 46, and 52 above, and in view of Yin et al. (13 Nature Communications 1204, 1-14, and cited in the Information Disclosure Statement filed September 27, 2024).
Morrissey, Kanjolia I, and Donohoue disclose and suggest a composition comprising a guide RNA having the sequence identical to instant SEQ ID NO: 302 and lipid nanoparticle compositions thereof.
Morrissey, Kanjolia I, and Donohoue fail to disclose or suggest that the Cas nuclease is fused to an exonuclease.
Regarding claim 14, Yin discloses fusions of Cas nucleases and an exonuclease (abstract). Yin discloses that fusing an exonuclease to a Cas nuclease prevents perfect DNA repair and avoids repeated cleavage (abstract). Yin discloses that the exonuclease is an optimized TREX2 (abstract).
It would have been obvious to one with ordinary skill in the art before the effective filing date of the claimed invention to fuse Morrissey’s and Kanjolia I’s CRISPR nuclease to Yin’s TREX2 exonuclease because this will prevent repair of the target site. One of ordinary skill in the art would have been motivated to make the Cas-TREX2 fusion in order to modify the transthyretin gene without additional cleavage of the target site and without repairing the target site to its original state. Thus, the fusion protein enables the composition to treat amyloidosis associated with transthyretin.
Claims 43 and 45 are rejected under 35 U.S.C. 103 as being unpatentable over Morrissey and Kanjolia I in view of Donohoue, as applied to claims 2-4, 7, 35, 37-39, 46, and 52 above, and in view of Kanjolia et al. (Kanjolia II, U.S. Patent Application Publication No. 2020/0248180, published August 6, 2020).
Morrissey, Kanjolia I, and Donohoue disclose and suggest a composition comprising a guide RNA having the sequence identical to instant SEQ ID NO: 302 and lipid nanoparticle compositions thereof.
Morrissey, Kanjolia I, and Donohoue fail to disclose or suggest that the guide RNA is a single guide RNA having a sequence identical to instant SEQ ID NO: 368.
Kanjolia II discloses compositions and methods for editing the transthyretin gene using CRISPR-Cas systems and for treating transthyretin amyloidosis (abstract). Kanjolia II discloses a single guide RNA that can be formulated as a lipid nanoparticle (paragraph [0522]). Kanjolia II discloses a single guide RNA that has a sequence that is identical to instant SEQ ID NO: 368 (see Appendix II, SEQ ID NO: 93).
It would have been obvious to one with ordinary skill in the art before the effective filing date of the claimed invention to formulate the guide RNA disclosed and suggested by Morrissey, Kanjolia I, and Donohoue into a single guide RNA having the sequence of SEQ ID NO: 368 according to Kanjolia II because this guide RNA will provide for forming a complex with an RNA-guided DNA binding agent, such as a CRISPR nuclease, because this will provide for targeting the complex directly to the transthyretin gene. One of ordinary skill in the art would have been motivated to do so because editing the transthyretin gene will provide for treating amyloidosis associated cause by expression of a dysfunctional transthyretin gene.
Claims 48, 50, and 142 are rejected under 35 U.S.C. 103 as being unpatentable over Morrissey and Kanjolia I in view of Donohoue, as applied to claims 2-4, 7, 35, 37-39, 46, and 52 above, and in view of Carter et al. (BioRxiv 1-5, Supplementary Information 1-4 (2021). This rejection is modified as necessitated by Applicants’ amendments.
Morrissey, Kanjolia I, and Donohoue disclose and suggest a composition comprising a guide RNA having the sequence identical to instant SEQ ID NO: 302 and lipid nanoparticle compositions thereof.
Morrissey, Kanjolia I, and Donohoue fail to disclose or suggest that the LNP also contains ALC0315. Morrissey fails to disclose the ratio of the lipids in the LNP.
Regarding claims 48, 50, and 142, Morrissey discloses that the LNP can include a variety of lipids, including DSPC, cholesterol, and DMG-PEG2000 (paragraphs and [0139]-[142]).
Regarding claim 48, Carter discloses RNA vaccines for Covid-19 that comprise mRNA in a lipid nanoparticle formation (abstract). Carter discloses that the LNP comprises cholesterol, DSPC, DMG-PEG2000, and ALC-0315 (page 2, Section 2.3).
Regarding claims 50 and 142, Carter discloses that the ratio of the lipids in the LNP are 16;7.44:3.35:1.86
It would have been obvious to one with ordinary skill in the art before the effective filing date of the claimed invention to incorporate Carter’s additional ALC0315 lipid in the LNP of Morrissey because this will increase the stability of the LNP particle comprising the guide RNA and the CRISPR mRNA. The increase in stability provides the motivation to modify Morrissey’s LNP in order to have a more stable pharmaceutical composition for the treatment of amyloidosis associated with transthyretin, as disclosed and suggested by Morrissey, Kanjolia I, and Donohoue.
It would also have been obvious to one with ordinary skill in the art before the effective filing date of the claimed invention to determine the optimal ratio of the lipids in the LNP disclosed and suggested by Morrissey, Kanjolia I, Donohoue, and Carter because determination of the optimal ratio of lipid components would provide an LNP that has the desired stability and bioavailability for the administration of a guide RNA and RNA-guided DNA binding agent targeted to the transthyretin gene in order to treat amyloidosis associated with the transthyretin.
Response to Amendments and Arguments
Regarding the rejections under 35 U.S.C. § 103, Applicant’s arguments have been considered but are moot because the new ground of rejection does not rely on the combination of references applied in the prior rejection of record.
Insofar as Applicants’ arguments are applicable to the rejections set forth above, Applicants
Arguments have been fully considered but are not deemed to be persuasive.
Regarding Moon, it is noted that this reference is no longer applied. And newly cited Donohoue provides the motivation to use hybrid DNA-RNA guides, which clearly show significant on target editing efficiency with significantly reduced off target effects.
However, while Applicants are correct that Morrissey discloses a guide RNA having SEQ ID NO: 275, Kanjolia I discloses SEQ ID NO: 9, which is the same as both instant SEQ ID NOS: 302 and 303. And while both SEQ ID NOS: 302 and 303 consist of 20 nucleotides, only two uracil bases can be modified to thymine to create the DNA-RNA hybrid molecule. And Donohoue discloses that CRISPR genome editing can be improved by use of a DNA:RNA hybrid guide RNA because such hybrid guide RNAs improves genome editing efficiency and target specificity, as well as reduction of off target effects. Because Donohoue provides detailed motivation to take an RNA guide molecule and create a DNA-RNA hybrid guide molecule, and because there are only two possible bases that can be modified to create that DNA-RNA hybrid guide, one of ordinary skill in the art would have known that such a guide molecule would be an improvement over an RNA guide molecule. Indeed, at the very least, given that only two of 20 bases (a finite number) could be modified to create the DNA-RNA guide molecule, it would have been obvious to try to modify those two bases and would have had a predictable and reasonable expectation of success in doing so (See KSR International Co. v. Teleflex Inc., (550 U.S. 398; 127 S.Ct. 1727; 82 USPQ2d 1385). And Donohoue shows both a significant increase in editing efficiency and specificity and a significant reduction in off target effects.
Applicants also provided information (see Appendix V) relating to the difference between Morrissey’s SEQ ID NO: 111, which Applicants assert is the same as instant SEQ ID NO: 275, and instant SEQ ID NOS: 302 and 303, and pointed to specific Tables and Figures of the instant application. While Applicants are correct that instantly claimed SEQ ID NOS: 302 and 303 (hybrid guide RNAs) show improvement in editing efficiency and a reduction in off target effects, newly cited Kanjolia I discloses SEQ ID NO: 9, which has the same sequence as instant SEQ ID NOS: 302 and 303. Thus, Morrissey and Kanjolia I, in combination with Donohoue would lead one of ordinary skill in the art directly to the claimed invention. Contrary to applicants assertions, the combination of Morrissey, Kanjolia I, and Donohoue show that the significant improvement in editing efficiency and reduction in off target effects would actually be expected, rather than the assertion of surprising results.
In addition, it is noted that instant claims 2-4 each recited, not only SEQ ID NO: 275 in addition to SEQ ID NOS: 302 and 303, but also include SEQ ID NOS: 48-81, 300-301, and 304-307. Applicants’ assertions in Appendix V relate only to SEQ ID NOS: 302 and 303. Because the combination of Morrissey, Kanjolia I, and Donohoue disclose and suggest the same results as obtained by Applicants and use the same guide sequences, the claims are deemed to be obvious over the combination of Morrissey, Kanjolia I, and Donohoue.
Applicants further assert that none of Yin, Kanjolia II, or Carter remedy the alleged deficiencies of Morrissey. However, as discussed above, newly cited Kanjolia I and Donohoue provide the motivation to create a DNA-RNA hybrid guide molecule, which has improved characteristics of regulation of biological toxicity, improving imaging, multiplexing, and editing flexibility. Yin, Kanjolia II, and Carter are cited for different providing disclosure and motivation to create the claimed guide RNA molecule.
For all these reasons, and those listed above, Morrissey, Kanjolia I, and Donohoue, taken together (with or without Yin, Kanjolia II, and/or Carter) are deemed to render the instant claims obvious.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to NANCY J LEITH whose telephone number is (313)446-4874. The examiner can normally be reached Monday - Thursday 8:00 AM - 6:30 PM.
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NANCY J. LEITH
Primary Examiner
Art Unit 1636
/NANCY J LEITH/Primary Examiner, Art Unit 1636