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 .
This action is in response to the amendment, filed 10/31/2025, in which claims 208, 215, 219-220, 222-226 and 228 were amended.
Applicant’s arguments have been thoroughly reviewed, but are not persuasive for the reasons that follow. Any rejections and objections not reiterated in this action have been withdrawn. This action is FINAL.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 119(e) as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, Application No. 62475830, fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application.
The application fails to provide support for the claims under examination, since there is no disclosure therein of SEQ ID NOS: 741, 34, 38, 49-84, 605. Therefore, the filing date of claims 215, 222, 224, 226 are deemed to have a priority date of March 23, 2018, which is the filing date of application No. 15934945, because this application includes the first disclosure of SEQ ID NOS: 741, 34, 38 49-84, 605.
Rejection withdrawn
The objection of claim 15 has been withdrawn in view of Applicant’s amendments to the claim in the reply filed 10/31/2025.
The rejection of claims 208-228, under 35 U.S 103, has been withdrawn in view of Applicant’s amendments to the claims in the reply in the reply filed 10/31/2025.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 208-228 are rejected on the ground of nonstatutory double patenting as being unpatentable over U.S. Patent No. US 11,268,082 B2 (“082”, cited on IDS filed 07/24/2023) in view of Komor et al. (“Komor”, Nature, 2016, cited on IDS filed 07/24/2023), Liu et al. (“Liu”, US 2015/0071903 A1, March 2015, cited on IDS filed 07/24/2023), and Zhang et al. (“Zhang”, WO 2017/106657 A1, cited on IDS filed 07/24/2023).
This rejection is maintained and address the amendment to the claims in the reply filed 10/31/2025. It is noted that Applicant did not set forth any arguments addressing the double patenting rejection set forth in the previous office action.
The following rejection is in view of the decision of the Court of Appeals for the Federal Circuit in Pfizer Inc, v Teva pharmaceuticals USA Inc., 86 USPQ2d 1001, at page 1008 (March 2008), which indicates that there is no patentable distinction between claims to a product and a method of using that product disclosed in the specification of the application and that the preclusion of such a double patenting rejection under 35 USC 121 does not apply where the present application is other than a divisional application of the patent application containing such patentably indistinct claims. The instant claims are to a method of using the product claimed in the issued patent and the instant application is NOT a DIV of the instant patent.
Although the claims at issue are not identical, they are not patentably distinct from each other because both claim sets are drawn to the same ribonucleoprotein complex. The difference is that “082” claims are directed to a complex comprising the fusion protein and to a method for editing a target, whereas the instant claims are directed to a method of producing the ribonucleoprotein complex. However, one of the ordinary skill in the art would recognize that if he/she knew how to make the instantly claimed method of producing (complex of “082”), then it is obvious that the instant method of producing the complex was known at the time of the filing.
Regarding claims 208, 211, 219, “082” teaches a fusion protein comprising: (i) a nucleic acid programmable DNA binding protein (napDNAbp); (ii) a cytidine deaminase domain; and (iii) two uracil glycosylase inhibitor (UGI) domains, wherein the napDNAbp is a CasX, CasY, Cpfl, C2cl, C2c2, C2c3, or Argonaute protein (claim 1). A complex comprising the fusion protein of claim 1, and a guide RNA bound to the napDNAbp of the fusion protein (claim 2).
Regarding claims 212-214, “082” teaches a method for editing a target nucleic acid molecule, the method comprising contacting the target nucleic acid molecule with the complex of claim 2, wherein the guide RNA
comprises at least 10 contiguous nucleotides complementary to the target nucleic acid molecule, thereby editing the target nucleic acid molecule (claim 3). A method comprising contacting a nucleic acid molecule with the complex of claim 2 (claim 4).
Regarding claim 220, “082” teaches the fusion protein of claim 18, wherein the nucleic acid programmable DNA binding protein (napDNAbp) is a CasX, CasY, Cpfl, Cpfl nickase, dCpfl, C2cl, C2c2, C2c3, Cas9, dCas9, Cas9 nickase or Argonaute protein (claim 19).
Regarding claim 221, “082” teaches the fusion protein of claim 19, wherein the napDNAbp is a dCas9 or Cas9 nickase (claim 20).
Regarding claim 222, “082” teaches the fusion protein of claim 19, wherein the napDNAbp comprises an amino acid sequence that is at least 85% identical to SEQ ID NO: 34 or 38 (claim 21).
Regarding claim 223, “082” the fusion protein of claim 1, wherein the cytidine deaminase domain is a deaminase from the apolipoprotein B mRNA-editing complex (APOBEC) family (claim 11).
Regarding claim 224, “082” teaches the fusion protein of claim 1, wherein the cytidine deaminase domain comprises an amino acid sequence that is at least 85% identical to an amino acid sequence of SEQ IDNO: 49-84, wherein said at least 85% amino acid sequence identity is based on an alignment against any one of SEQ ID NOs: 49-84 by NCBI Constraint-based Multiple Alignment Tool (COBALT) (claim 12).
Regarding claim 225, the fusion protein of claim 18, wherein the fusion protein comprises the structure: NH2 -[ cytidine deaminase domain]-[napDNAbp ]-[first UGI domain]-[second UGI domain]-COOH; NH2 -[first UGI domain]-[second UGI domain]-[cytidine deaminase domain]-[napDNAbp]-COOH; NH2 -[napDNAbp]-[cytidine deaminase domain]-[first UGI domain]-[second UGI domain]-COOH; or NH2 -[first UGI domain]-[second UGI domain]-[napDNAbp]-[cytidine deaminase domain]-COOH; wherein each instance of "]-[" comprises an optional linker (claim 23).
Regarding claim 226, “082” teaches the fusion protein of claim 18, wherein the cytidine deaminase domain and the napDNAbp are linked via a
linker comprising the amino acid sequence: SGGSSGGSSGSETPGTSESATPESSGGSSGGS (SEQ ID NO: 605). (claim 24).
“082” does not teach the instant claims 209-214, 215-218, 227-228. However, these deficiencies are cured by Komor, Liu, Zhang.
Regarding claim 208, 209, Komor teaches a fusion protein comprising the nucleic acid programmable DNA binding protein domain of a dCas9 domain, an APOBEC family cytidine deaminase domain, and an uracil glycosylase inhibitor (UGI) domain (e.g., pages 420/421; Fig. 3b-c; Fig. 4). Komor teaches expression and purification of His6–rAPOBEC1-linker–dCas9 fusions, protein eluted with 5 ml of activity buffer containing 50 mM tris(hydroxymethyl)-aminomethane (Tris)-HCl (pH 7.0), 0.5 M NaCl, 20% glycerol, 10 mM TCEP. Purified fusion protein (20 μl of 1.9 μM in activity buffer) was combined with 1 equivalent of appropriate sgRNA and incubated at ambient temperature for 5 min (it reads on aqueous solution at 1:1 molar ratio) (e.g., page 425, Methods).
Regarding claims 211-212, Komor teaches in vitro transcription of sgRNAs. Linear DNA fragments containing the T7 promoter followed by the 20-bp sgRNA target sequence (e.g., page 425, Methods). Komor teaches complexes of sgRNA binding to Cas9-comprising fusion proteins. Komor teaches sequence-specific, sgRNA-dependent C to U conversion in vitro (e.g., page 420; Figure 1). Komor teaches sgRNA TC1GC3AC5CC7GTGGATTTATTTATGG (it reads on sgRNA from 10-100 nucleotides and with 10 contiguous nucleotides) (e.g., page 42; Fig. 2b).
Liu teaches compositions, preparations, kits, and related methods for delivering functional effector proteins, such as, for example, site-specific proteins that bind nucleic acids, into cells using a supercharged protein (e.g., a positively charged supercharged protein), a cationic polymer, or a cationic lipid (e.g., paragraph 0004).
Regarding claims 210, 216, Liu teaches the in vivo delivery of Cre recombinase and Cas9:sgRNA complexes to hair cells in the mouse
inner ear is shown. Additionally, Liu teaches the results when the scala media (cochlear duct) of P2 AtohlGFP mice (n=3) were injected with 0.3 μL of33 μM Cas9, 33μM sgRNA in 50% RNAiMAX or Lipofectamine 2000 (e.g., paragraph 0084; Fig. 32D). Liu teaches for delivery of Cas9:sgRNA complexes, 1 μL of 200 μM Cas9 protein was mixed with 2 μL of 100 μM
sgRNA and incubated for 5 minutes at room temperature before mixing with 3 μL of either RNAiMAX or Lipofectamine 2000 and incubating for an additional 30 minutes prior to injection (e.g., paragraph 0240).
Regarding claims 217-218, Liu teaches cationic lipids including polyethylenimine, polyamidoamin (PAMAM) starburst dendrimers, Lipofectin (a combination of DOTMA and DOPE), Lipofectase, LIPOFECTAMINE® (e.g., LIPOFECTAMINE® 2000, LIPOFECTAMINE®
3000, LIPOFECTAMINE® RNAiMAX, LIPOFECTAMINE ® LTX), SAINT-RED (e.g., paragraph 0021). Liu teaches complexes, compositions,
preparations, kits, systems, and related methods for the delivery of functional effector proteins, e.g., nucleases, recombinases, and Cas9 proteins (including variants and fusions thereof, e.g., Cas9 nickases and Cas9 fusions to deaminases, gene editing enzymes, transcriptional repressors and activators, epigenetic modifiers, etc.) (e.g., paragraph 0096).
Regarding claim 227, Liu teaches pharmaceutical composition, as a composition that can be administrated to a subject, for example, in the context of treatment of a disease or disorder. A pharmaceutical composition comprises an active ingredient, e.g., a supercharged protein associated with a functional effector protein, such as a nuclease, or a nucleic acid encoding a supercharged protein and a functional effector protein, e.g., in the form of a fusion protein, and a pharmaceutically acceptable excipient (e.g., paragraph 0035).
Regarding claim 228, Liu teaches methods for administering a composition provided herein to a subject (e.g., paragraph 0013).
Regarding claim 215, Zhang teaches engineered DNA or RNA-targeting systems comprising a novel DNA or RNA-targeting CRISPR effector protein and at least one targeting nucleic acid component like a guide RNA (e.g., abstract). Zhang teaches SEQ ID NO 247 with 100% homology with SEQ ID NO 741 of the instant claim 215.
It would have been obvious to one of ordinary skill in the art before the filling day of the claimed invention to combine the teachings of “082” – a fusion protein comprising: (i) a nucleic acid programmable DNA binding protein (napDNAbp); (ii) a cytidine deaminase domain; and (iii) two uracil glycosylase inhibitor (UGI) domains, wherein the napDNAbp is a CasX,
CasY, Cpfl, C2cl, C2c2, C2c3, or Argonaute protein with the teachings of Komor -complex dCas9 domain, an cytidine deaminase domain, an uracil glycosylase inhibitor (UGI) domain in an aqueous solution combined with 1 equivalent of sgRNA; with the teaching of Zhang a SEQ ID NO 247 (sgRNA), and with the teaching of Liu –a nuclease protein mixed with cationic lipid LIPOFECTAMINE at different ratios- to develop a method of producing a pharmaceutical composition of complex dCas9 domain, cytidine deaminase domain, and two uracil glycosylase inhibitor (UGI) domain with sgRNA using cationic lipids for delivery to host cells.
One of ordinary skill would have been motivated to develop a method for targeted manipulation of a gene associated with disease, the modulation of the expression level of a gene associated with disease by producing a pharmaceutical composition comprising the complex dCas9, a cytidine deaminase domain, and two uracil glycosylase inhibitor (UGI) domain/sgRNA for the delivery into cells for therapeutic and research purposes.
Conclusion
THIS ACTION IS MADE FINAL. 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 JULIO GOMEZ RODRIGUEZ whose telephone number is (571)270-0991. The examiner can normally be reached Monday - Friday 8:00 am - 5:00 pm.
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/JULIO WASHINGTON GOMEZ RODRIGUEZ/Examiner, Art Unit 1637
/J. E. ANGELL/Primary Examiner, Art Unit 1637