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 and Priority
Claims 1-8 are pending and under examination.
The application claims domestic benefit to US provisional application 63/426618, filed November 18, 2022. The effective filing date of the claimed invention is November 18, 2022.
Drawings
The drawings are objected to for two reasons.
First, the figures are referred to as “Figure” in the drawings. MPEP §608.02.V states that according to 37 C.F.R. 1.84(u)(1) “View numbers must be preceded by the abbreviation "FIG.".
Second, the text in FIGs 1-3, 5 and 12 is too small to provide satisfactory reproduction characteristics. 37 CFR 1.84(l) states that “all drawings must be made by a process which will give them satisfactory reproduction characteristics. Every line, number, and letter must be durable, clean, black (except for color drawings), sufficiently dense and dark, and uniformly thick and well-defined.”
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
The disclosure is objected to because of the following informalities:
The Specification recites “CD-PEI”, “Ad-PAMAM” and “Ad-PEG”. The terms/abbreviations are not widely-known terms in the art of gene editing and require their full name the first time they are used. Wang et al., indicates that CD-PEI is an abbreviation for beta-cyclodextrin-grafted polyethylenimine, Ad-PANAM is an abbreviation for adamantane (Ad)-grafted polyamidoamine dendrimer, and Ad-PEG is an abbreviation for adamantane (Ad)-grafted polyamidoamine polyethylene glycol (Wang et al., Angew Chem Int Ed Engl (2009), 48: 4344-4348).
Appropriate correction is required.
Claim Objections
Claims 6 is objected to because of the following informalities:
First, the steps of the method are preceded with, (e), (f), (c), and (d). “e” and “f” should be changed to “a” and “b”.
Second, step “e” recites “incorporated into a nanoparticle to obtain a Cas9/sgRNA plasmid⊂ SMNPs”. SMNP is plural, which does not match the singular article “a”. Either the “a” needs to be deleted or the “s” at the end of SMNPs should be deleted.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
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 1-6 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.
Claim 1 recites “nanoparticles-mediated CRISPR-Cas9 carrying CRISPR-Cas9 components, which is obtained by a self-assembled synthetic preparation of Cas9/sgRNA using HITI technology”. Claim 1 is confusing for several reasons. First, “nanoparticles-mediated CRISPR-Cas9” does not make sense because the grammar suggests that the CRISPR-Cas9 is mediated by the nanoparticles. It is not clear how a nanoparticle can mediate itself into carrying Cas9/sgRNA components. Second, HITI technology is a method of integrating a piece of DNA into another piece of DNA. Thus, it is not clear how HITI can be used to prepare self-assembling nanoparticle. “a self-assembled synthetic preparation of Cas9/sgRNA using HIT technology” is interpreted as a product-by-process limitation. Since it is not clear how the Cas9/sgRNA preparation can be self-assembled using HITI, the final structure of the Cas9/sgRNA preparation is indefinite.
Claims 2-5 and 7-8 are rejected for depending from claim 1 and not remedying the indefiniteness.
Claim 5 recites “2-cut dDNA pUC57.RS1”. According to the specification, pUC57.RS1 appears to be a donor plasmid that comprises at least the RS1 coding sequence (FIG 2, [0019]). However, the Specification does not disclose the sequence of the plasmid. Therefore, it is not clear what the complete structure of the plasmid is.
Claim 6 recites “(f)… through stoichiometric mixing of DNA and three SMNP molecular building blocks, including CD-PEI, Ad-PAMAM, Ad-PEG”. Claim 6 is indefinite because it is not clear if the three building blocks are necessarily CD-PEI, Ad-PAMAM and Ad-PEG, or if the three recited components are three possible building blocks, but other building clocks are also possible.
If Applicant intends the three building blocks to be CD-PEI, Ad-PAMAM and Ad-PEG, the following claim language is suggested: “(b)… through stoichiometric mixing of DNA, CD-PEI, Ad-PAMAM and Ad-PEG;”
Claim 6 also recites “(c) using HITI-based knock-in of RS1 gene in Rosa26 locus of mouse genome internalized into the cells… the [Cas9/sgRNA] complex excises Rosa26 locus target to induce [double strand break] DSB and dDNA to generate a donor template;” Part (c) is confusing to two reasons. First, it is not clear how a single sgRNA creating a single DSB can “excise” the Rosa26 locus. The Specification illustrates a single DSB in the Rosa26 locus (FIG. 2). Thus, it is not clear if the Rosa26 locus is to be excised as the claim language suggests, or merely that a single DSB is produced within the Rosa26 locus. Second, the grammar of part (c) makes it seem that the mouse genome or at least the Rosa26 locus of the mouse genome is to be internalized into the cells. It is not clear how this could occur given that only a plasmid encoding Cas9/sgRNA and a donor DNA is to be delivered by the SMNPs.
Claim 7 recites “which comprises delivering to the target cells in the patient a target gene to the hereditary via the gene delivery system set forth in claim 1”. Claim 7 is indefinite for two reasons. First, “the target cells” lacks antecedent basis as neither claim 7 nor claim 1 recite “a target cell”. Second, it appears that there is a word or words omitted after “the hereditary”. As such it is not clear what “the hereditary” is referring to.
Claim 8 is rejected for depending from claim 7 and not remedying the indefiniteness.
Claim Interpretation
The claims are indefinite for the reasons recite above. For the purpose of compact prosecution and applying prior art, claims 1-5 are interpreted as a gene delivery system comprising 1) a nanoparticle, 2) either a Cas9/sgRNA complex or a nucleic acid encoding Cas9/sgRNA, and 3) a nucleic acid that is capable of being integrated into another nucleic acid like genomic DNA. Because HITI technology does not use homologous DNA, and any DNA is capable of being linearized (if not already linear) and integrated into a genome, any nucleic acid can be the third component of the system. Claims 3 and 5 require the nanoparticle to be an SMNP. Claim 5 is interpreted as the third component of gene delivery system comprises a plasmid that comprises the pUC57 backbone and at least an RS1 coding sequence.
Claims 7-8 are interpreted as using the system of claim 1, which is interpreted as recited above, to deliver a gene to a patient having a generic hereditary disease (claim 7) or XLRS, LHON, BD or Fabry disease (claim 8).
Claim 6 is interpreted as (a) preparing a Cas9/sgRNA plasmid and incorporating it into a first SMNP, (b) incorporating a plasmid or minicircle comprising the RS1-containing donor DNA (dDNA) into a second SMNP, (c) expressing Cas9/sgRNA from the Cas9/sgRNA-encoding plasmid, wherein upon expression the Cas9/sgRNA complex creates a double strand break (DSB) in the mouse Rosa26 locus and creates two DSBs in the plasmid or minicircle comprising the RS1 dDNA, thereby excising the RS1 dDNA from the rest of the plasmid or minicircle, and (d) integrating the RS1 dDNA into the ROSA26 locus by the NHEJ pathway (i.e., HITI-based mechanism).
Claim Rejections - 35 USC § 102
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 1-4 and 6-8 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Tseng (WO 2021097306 A1, published May 20, 2021).
Regarding claims 1-4, Tseng teaches Cas9/sgRNA-plasmids encapsulated in supramolecular nanoparticles (SMNPs) together with a donor RS1-GFP plasmid encapsulated in an SMNP (FIGs 1A-C). Tseng teaches the combination used for homology-independent targeted integration (FIGs. 1A-1C).
Regarding claim 6, step (e), Tseng teaches preparing the self-assembled Cas9/sgRNA plasmid-containing SMNPs to form a Cas9/sgRNA-plasmid⊂SMNP (FIG. 1B). Regarding step (f), Tseng teaches preparing a self-assembled donor-RS1-GFP-plasmid⊂SMNP, wherein the RS1 donor plasmid comprises two Cas9/sgRNA target sites (i.e., a 2-cut dDNA) (FIG. 1C). Tseng teaches preparing it by mixing the dDNA plasmid with CD-PEI, Ad-PEG and Ad-PAMAM (FIG. 1C). Tseng teaches to make the donor-RS1-GFP-plasmid⊂SMNP, the plasmids are mixed stoichiometric with the SMNP building blocks ([0063], [0068]). Regarding step (c), Tseng teaches once the plasmids are delivered to the mouse cells, the Cas9 and sgRNA are expressed and the Cas9/sgRNA complex forms, which then creates a DSB in the mouse Rosa26 locus and excises the RS1-GFP dDNA from the plasmid (FIG 1A; [0062]-[0063]). Regarding step (d), Tseng teaches integrating the RS1-GFP donor into the Rosa26 locus via NHEJ (FIG. 1A).
Regarding claims 7-8, Tseng teaches using Cas9/sgRNA-plasmid⊂SMNP and donor-RS1-plasmid⊂SMNP system for non-viral therapeutic solutions for gene delivery to the retina in XLRS patients ([0062]).
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.
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.
Claim 5 is rejected under 35 U.S.C. 103 as being unpatentable over Tseng (WO 2021097306 A1, published May 20, 2021) as applied to claims 1-4 and 6-8 above, and further in view of Zeng (Zeng et al., Molecular Therapy: Methods & Clinical Development (2020), 18: 422-427).
The teachings of Tseng are recited above as for claims 1-4 and 6-8 and are incorporated here. Briefly, Tseng teaches a method for gene therapy using SMNPs to deliver a Cas9/sgRNA plasmid and a plasmid encoding a dDNA that encodes the RS1 protein. Tseng also teaches in the SMNP-delivery HITI-mediated integration method that the dDNA need only have two Cas9/sgRNA sites on either side for use in the method since the gene of interest is integrated via NHEJ ([0025]-[0026]). Tseng teaches that the remainder of the donor plasmid is not used in the method (see e.g., FIG. 1). Tseng teaches the donor-RS1/GFP plasmid was purchased from a company ([0086]).
Tseng does not teach the dDNA plasmid has a pUC57 backbone.
Zeng teaches a plasmid comprising the pUC57 backbone and the RS1 cDNA (page 425, ¶5).
It would have been obvious to one skilled in the art before the effective filing date of the claimed invention to have used the pUC57 plasmid backbone as the donor plasmid in Tseng’s method. It would have amounted to the substitution of one plasmid backbone for another by known means to yield predictable results. The skilled artisan would have predicted that the pUC57-based plasmid could be used in Tseng’s method because it is clearly evident that the plasmid backbone is of little of no consequence in the HITI-based method. As such, the skilled artisan would have predicted that nearly any cloning plasmid having the RS1 coding sequence could have been used and then modified to include two sgRNA-targeted sites as taught in Tseng.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially create-d 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 1-2, 4, and 7-8 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-10 of U.S. Patent No. 12,091,677. Although the claims at issue are not identical, they are not patentably distinct from each other because:
Patented claim 1 recites A delivery system for gene editing comprising nanodiamond (ND) particles as carriers of CRISPR-Cas9 components including a Cas9 protein, a guide RNA (gRNA), a template DNA designed to introduce a mutation in a given gene… wherein the ND particles are a mixture of: (i) a first ND particle linked, through the polyhistidine tag by phosphoryl imidazole, with a first linear DNA construct for expression of the Cas9 protein, and (ii) a second ND particle linked, through the polyhistidine tag by phosphoryl imidazole, with a second linear DNA construct for expression of the gRNA/template DNA (i.e. a nucleic acid that is capable of HITI). Patented claim 8 recites A method for treating a disease or repairing a tissue damage in a subject, comprising delivering and internalizing the mutation in a given gene into said subject through the delivery system of claim 1. Patented claim 9 recites wherein the disease is X-linked retinoschisis (XLRS). Therefore, the patented claims anticipate examined claims 1-2, 4 and 7-8.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CATHERINE KONOPKA whose telephone number is (571)272-0330. The examiner can normally be reached Mon - Fri 7- 4.
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/CATHERINE KONOPKA/Primary Examiner, Art Unit 1635
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