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 .
Status of Application, Amendments, And/Or Claims
The Applicants amendments/remarks received 11/11/2025 are acknowledged. Claims 1 and 44 are amended; claims 2-10, 12-14, 16-23, 25-26, 28-31, 34, 36-38 and 40 are canceled; claim 45 is new; claims 1, 11, 15, 24, 27, 32-33, 35, 39 and 41-45 are pending; claims 32-33, 35, 39 and 41 are withdrawn; claims 1, 11, 15, 24, 27 and 42-45 have been examined on the merits.
Information Disclosure Statement
The information disclosure statement submitted on 11/11/2025 has been considered by the examiner.
Claim Rejections - 35 USC § 102
The rejection of claims 1, 11, 15, 24, 27, 42 and 44 under 35 U.S.C. § 102(a)(2) over Divita et al., US 2019/0211317 (cite A, PTO-892, 5/14/2025) as set forth at pp. 2-5 of the previous Office Action, is withdrawn in view of the amendment of the claims.
The rejection of claims 1, 11, 15, 24, 27 and 42 under 35 U.S.C. § 102(a)(2) over Maianti et al., US 2018/0237787 (cite B, PTO-892, 3/14/2023) as set forth at pp. 6-8 of the previous Office Action, is withdrawn in view of the amendment of the claims.
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1, 11, 15, 24, 27, 42 and 44 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Liras et al., US 2017/0137801 (cite A, attached PTO-892; herein “Liras”) in light of Longo et al., 2024 (cite U, attached PTO-892; herein “Longo”).
Liras teaches compositions and methods for editing a gene for treating a disease condition or disorder (Abst.) wherein the gene can be PCSK9 ([0118-119], [0760-766]), comprising incubating human hepatocytes with gene-editing ribonucleoprotein complexes (RNPs) [0760-766] comprising a Cas9 endonuclease and a single guide RNA (sgRNA) wherein the RNP comprising the Cas9 and sgRNA comprises a cell penetration-facilitating moiety (endosomal escape agent) ([0104], [0750-756]), wherein the Cas9 can comprise wild type Streptococcus pyogenes Cas9 (SpCas9) [0110] and the sgRNA can comprise PCSK9 single guide RNA sequence 3 (SEQ ID NO: 898) [0149]. The sgRNA of Liras SEQ ID NO: 898 comprises a spacer sequence that is an RNA sequence with 100% identity to instant SEQ ID NO: 7970. The Cas9 protein and sgRNA are pre-complexed [0104].
Longo is cited as an evidentiary reference that wild type SpCas9 edits DNA by making double-strand breaks (which are either blunt or staggered) (Abst.). Thus, the RNPs of Liras comprising wild type SpCas9 and the sgRNA directed to PCSK9 which comprises the spacer sequence of instant SEQ ID NO: 7970 would necessarily effect one or more double-strand breaks (DSBs) within or near the PCSK9 gene or PCSK9 regulatory elements that results in one or more permanent insertions, deletions or mutations of at least one nucleotide within or near thePCSK9 gene upon repair by an endogenous cellular process comprising homology-directed repair, non-homologous end joining, or microhomology-mediated end joining, wherein the cutting efficiency of the one or more sgRNAs is at least 50% anticipating claims 1, 15, 24, 42 and 44.
Liras demonstrates that their method is effective for editing the PCSK9 gene, wherein administration of genome-editing RNP complexes comprising Cas9 protein and guide RNA targeting exons 4-5 of PCSK9 edited the PCSK9 gene in hepatocytes ([0057]; Fig. 5), but Liras does not specifically disclose the cutting efficiency of the sgRNA comprising the spacer sequence identical to instant SEQ ID NO: 7970. However, the cutting efficiency of the sgRNA is an inherent property of the sgRNA which varies only in its spacer sequence (guide RNA or gRNA). The cutting efficiency is NOT dependent on what Liras does or does not state. The Liras sgRNA (SEQ ID NO: 898) comprising instant SEQ ID NO: 7970 has a cutting efficiency of 73.1% (Table 7, instant disclosure); thus, Liras’ method anticipates claim 1 regardless of whether Liras ever tested or knew the cutting efficiency of the sgRNA comprising instant SEQ ID NO: 7970.
It is noted that Longo is not prior art. In certain circumstances, references cited to show a universal fact need not be available as prior art before applicant's filing date. In re Wilson, 311 F.2d 266, 135 USPQ 442 (CCPA 1962). Such facts include the characteristics and properties of a material or a scientific truism. See M.P.E.P. § 2124. In Wilson, the examiner relied on a reference published after the filing date of the relevant application as evidence of inherent properties of polyurethane foams, and the CAFC wrote, "The board considered that the publication was properly cited to show a state of fact. After reading the entire publication, so do we. It clearly is a discussion of the properties of polyurethane foam products generally, products made by the processes of the prior art of record in this case .... As evidence of the characteristics of prior art foam products, however, we know of no reason in law why it is not acceptable." In this case, Longo is cited solely as evidence that wild type Streptococcus pyogenes Cas9 inherently possesses the capacity to cut genomic DNA templated by the sgRNA with double stranded breaks which are either blunt ended or with staggered ends.
Liras teaches that the compositions can be administered by intravenous infusion [0191], i.e., systemic infusion anticipating claim 11.
Liras teaches that the RNPs comprising wild type SpCas9 and the sgRNA directed to PCSK9 can be formulated in a liposome or lipid nanoparticle ([0056], [0079], [0179], [0193], [0195]) anticipating claim 27.
Claim Rejections - 35 USC § 103
The rejection of claims 1, 11, 15, 24, 27 and 42-44 under 35 U.S.C. § 103(a) over Divita in view of Bouchon et al., US 2018/0127786 (cite B, PTO-892, 5/14/2025) as set forth at pp. 9-11 of the previous Office Action, is withdrawn in view of the amendment of the claims.
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 1, 11, 15, 24, 27 and 42-45 are rejected under 35 U.S.C. 103 as being unpatentable over Liras in view of Bouchon et al., US 2018/0127786 (cite B, attached PTO-892; herein “Bouchon”) in light of Longo.
The discussion of Liras regarding claims 1, 11, 15, 24, 27, 42 and 44 set forth in the rejection above is incorporated herein.
Claims 1, 11, 15, 24, 27, 42 and 44 are rejected under 35 U.S.C. 103 over Liras because claims 1, 11, 15, 24, 27, 42 and 44 are prima facie obvious over the disclosure of Liras as anticipation is the epitome of obviousness.
Liras is silent on the hepatocyte being differentiated from an induced pluripotent stem cell; however, a person of ordinary skill in the art at the time of filing would have found it obvious to practice Liras’ method of editing PCSK9 in hepatocytes wherein the hepatocytes are substituted with hepatocytes which have been differentiated from an induced pluripotent stem cell in view of the disclosure of Bouchon.
Bouchon teaches genome editing of the Wiskott-Aldrich syndrome gene (WAS gene) (Abst.) wherein the genome editing can comprise inserting a functional WAS gene into a safe harbor locus wherein the safe harbor locus can be PCSK9 ([0008], [0022-23], [0057-59]) wherein the genome edited cell can be a patient specific induced pluripotent stem cell which is then differentiated into a hepatocyte before implantation in the patient ([0116], [0393]); therefore, claims 42-43 are prima facie obvious.
Liras is silent on introducing into the cell a donor template; however, a person of ordinary skill in the art at the time of filing would have found it obvious to practice Liras’ method of editing PCSK9 in hepatocytes wherein a donor template is introduced into the cell in view of the disclosure of Bouchon.
Bouchon teaches that the method of gene editing in a cell with a Cas9 endonuclease can further comprise introducing a donor template into the cell to be used for homology-directed repair (HDR) of the double-stranded breaks in the edited gene ([0009], [0066], [0103], [0105-106], [0133-135], [0138], [0141], [0155-158], [0169], [0187], [0189], [0643]). Hence, a person of ordinary skill in the art at the time of filing would have found it obvious to practice Liras’ method of editing PCSK9 in hepatocytes wherein a donor template is introduced into the cell to be used for homology-directed repair (HDR) of the double-stranded breaks in the edited PCSK9 gene; therefore, claim 45 is prima facie obvious.
Response to Arguments
Applicant's arguments filed 11/11/2025 have been fully considered but they are not persuasive. Arguments of the Applicant’s Response on pp. 5-8 regarding the rejections under 35 U.S.C. §§ 102(a)(2) and 103 are moot as the rejections have been withdrawn. The new rejections set forth above, necessitated by amendment, address all the claim limitations of all the claims under examination.
Conclusion
No claims are 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 Trent R Clarke whose telephone number is (571)272-2904. The examiner can normally be reached M-F 10-7 MST.
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/TRENT R CLARKE/ Examiner, Art Unit 1651
/DAVID W BERKE-SCHLESSEL/ Primary Examiner, Art Unit 1651