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 .
Election/Restrictions
Applicant’s election of Group 1 and the species of protein core spherical nucleic acids, claims 1-2, 30-31, 47, 49-50, 55-56, and 83-84 in the reply filed on March 17, 2026 is acknowledged. Applicant has not indicated traversal therefore the election of Group 1 and species of protein core spherical nucleic acids is being treated as without traverse.
Claims 14-16, 20, 27, 58, 60, 62, 64-65, and 85 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected groups and species, there being no allowable generic or linking claim.
Claims 3-13, 17-19, 21-26, 28-29, 32-46, 48, 51-54, 57, 59, 61, 63, and 66-82 were previously canceled.
Claims 1-2, 30-31, 47, 49-50, 55-56, and 83-84 are examined on the merits.
Priority
The present application is a 35 U.S.C. 371 national stage filing of the International Application No. PCT/US22/17984, filed on February 25, 2022. The instant application claims 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) to U.S. provisional application(s) 63/154530, filed on February 26, 2021; 63/273086, filed on October 28, 2021; and 63/290522, filed on December 16, 2021.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on February 17, 2025 and March 17, 2026 is in compliance with the provisions of 37 CFR 1.97 and is being considered by the examiner.
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Objection to the Drawings
The drawings are objected to because:
Figures 2, 4, 5, 6, and 14 and Paras. [0024], [0026], [0027], [0028], and [0036] of the specification recite portions of the figure as indicated in color while the drawings are in black and white.
The drawings are objected to as failing to comply with 37 CFR 1.84(p)(5) because they include the following reference character(s) not mentioned in the description: Figure 8d is not referenced in Para. [0179] of the specification.
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.
Color photographs and color drawings are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted. Any such petition must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via the USPTO patent electronic filing system or three sets of color drawings or color photographs, as appropriate, if not submitted via the via USPTO patent electronic filing system, and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification:
The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2).
Specification
The use of the terms EnGen (Para. [0152]) One ShotBL21 (Paras. [0167], [0182], [0183]), Bio-Scale Mini Profinity (Para. [0167]), Bio-Scale Mini Bio-Gel (Para. [0183]), OrganomationMultivap (Para. [0184]), MEGAscript (Para. [0185]), Alexa Fluor (Para. [0186]) CellLight (Para. [0207]), Lipofectamine CRISPRMAX (Para. [0209]) , which is are trade names or a marks used in commerce, has been noted in this application. The terms should be accompanied by the generic terminology; furthermore the terms should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the terms. This is not intended to be an exhaustive list; Applicant is advised to review the specification for other uses of trade names or marks.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
The disclosure is objected to because it contains embedded hyperlinks and/or other forms of browser-executable code in Para. [0070]. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Claim Interpretation
Claim 50 recites the limitation “a gene editor substrate DNA or RNA” and claim 83 recites the limitation “a DNA or RNA gene editor substrate”. Although a skilled artisan would likely interpret the gene editor substrate to be the nucleotide sequence targeted by the gene editing protein, the instant specification appears to define “a DNA or RNA gene editor substrate” as a guide RNA (Para. [0072]). The instant specification does not define “a gene editor substrate DNA or RNA” (Paras. [0008], [0078]), however, these terms appear to be used interchangeably and have been interpreted as intending to refer to a guide RNA.
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 1-2, 30-31, 47, 49-50, 55-56, and 83-84 are rejected under 35 U.S.C. 103 as being unpatentable over Mirkin and Brodin (US 2017232109, found in IDS dated 02/17/2025, PGPUB of US 12,264,344) and Lee et al. (US 20200405884, hereafter “Lee”).
With regard to claim 1, Mirkin and Brodin teach protein based materials comprising a protein core and oligonucleotide shell (Paras. [0010], [0085], which is considered to reasonably read on protein core spherical nucleic acid (See Fig 1). Additionally, Mirkin and Brodin teach that this structure is generalizable to any protein (Para. [0010]) and that the protein core can be an enzyme (Para. [0095]). Mirkin and Brodin teach that the protein core spherical nucleic acids provide reduced immunogenic response and increased cellular uptake (Para. [0032]) as well as solve other issues associated with use of protein therapeutics including poor bioavailability, degradation, or aggregation/inactivation caused by storage. Further Mirkin and Brodin teach that protein core spherical nucleic acids are a “core technology” applicable to many proteins and which provides the ability to stabilize/improve the properties of any enzyme and thus could be applied to treatment for many diseases (Para. [0083]).
Mirkin and Brodin is silent regarding a protein core which comprises a gene editing protein.
Lee teaches a CRISPR-gold system comprising a gold nanoparticle core, an oligonucleotide shell, an RNA -guided endonuclease, and guide RNA (Paras. [0004], [0057], [0058]; Claim 1; See Fig 1). Lee teaches that this system can be used to deliver a Cas9 protein and guide RNA for gene editing (Paras. [0052], [0054]), which is considered to reasonably read on a gene editing protein. Additionally, Lee teaches that this system can overcome issues associated with use of viral delivery methods (Para. [0003]).
Therefore, it would have been obvious to one having ordinary skill in the art before the effective filing date of the instant invention, to choose the CRISPR system (e.g. Cas9/guide RNA) comprising a gene editing protein as taught by Lee for use in the protein core spherical nucleic acid as taught by Mirkin and Brodin with a reasonable expectation of success. A skilled artisan would have chosen to use a gene editing protein as taught by Lee in the protein core spherical nucleic acid of Mirkin and Brodin because Mirkin and Brodin teach that their protein core spherical nucleic acid increases cellular uptake, reduces immunogenicity and could be applied to many different proteins for many different treatments and therefore, a skilled artisan would have recognized that the protein core spherical nucleic acid could be used to deliver the gene editing protein of Lee while providing the benefit of eliminating the safety concerns regarding the use of gold nanoparticles. One having ordinary skill in the art would have had a reasonable expectation of success as both Mirkin and Brodin and Lee teach a spherical nucleic acid comprising a core and an oligonucleotide shell which is useful for delivery of proteins and is superior to other commonly used methods and Mirkin and Brodin teach that their protein core spherical nucleic acid is a “core technology” which is widely applicable to many proteins.
With regard to claim 2, Mirkin and Brodin teach that the polynucleotides of the oligonucleotide shell are attached to the protein core covalently (Paras. [0011], [0033], Fig 1).
With regard to claims 30 and 31, as detailed above, Lee teaches that the gene editing protein is CRISPR-associated (Paras. [0005], [0047], and Cas9 (Para. [0052]).
With regard to claim 47, Mirkin and Brodin teach protein core spherical nucleic acids comprising other enzymes, such as catalase, which has a diameter of between about 1nm and about 500 nm (See Fig. 15E). While Mirkin and Brodin do not teach a protein core spherical nucleic acid comprising a gene editing protein (e.g., Cas), it appears based on Fig. 15E that attachment of the oligonucleotide shell results in an approximately 13nm increase in size. As Cas9 is known to be approximately 10nm in size, the combination of Mirkin and Brodin and Lee as detailed above would result in a protein core spherical nucleic acid having a diameter between about 1 nm and 500 nm.
With regard to claim 49, Mirkin and Brodin teach that that protein core spherical nucleic acid can comprise a targeting moiety (Para. [0082]) which can be attached to one or more of the shell oligonucleotides (Para. [0147]), which is considered to reasonably read on a targeting oligonucleotide.
Additionally, Mirkin and Brodin teach that the oligonucleotides comprising the shell can comprise a sequence which is complimentary to a target polynucleotide (Para. [0111]), which is considered to reasonably read on a targeting oligonucleotide.
With regard to claims 49 and 50, Mirkin and Brodin teach that the protein core spherical nucleic acid comprises an oligonucleotide shell which can comprises an antisense oligonucleotide or an siRNA (Paras. [0110], [0137]), which is considered to reasonably read on both a targeting oligonucleotide (claim 49) and an inhibitory oligonucleotide (claim 50).
With regard to claim 55, Mirkin and Brodin teach a composition comprising the protein core spherical nucleic acid (Para. [0023]). Lee also teaches a composition comprising the CRISPR-gold system (Para. [0056]).
With regard to claim 56, as detailed above, Lee teaches that the composition comprising the CRISPR-gold system (Para. [0056]) comprises a guide RNA (Claim 1, See Fig 1).
With regard to claims 83 and 84, as detailed above, the combination of Mirkin and Brodin and Lee teach a protein core spherical nucleic acid comprising a CRISPR system which comprises a gene editing protein (Cas9) and a guide RNA, which is considered to reasonably read on a DNA or RNA gene editor substrate. Lee teaches that Cas9 requires two RNA molecules to cut DNA (Para. [0063]) and further teaches that the Cas9 system requires an sgRNA (Ex. 1, Paras. [0117], [0118]; Ex. 2, Paras. [0133], [0137]), which would be understood to one having ordinary skill in the art to comprise a crRNA and a tracrRNA (also see Table 4 and Para. [0139]).
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 1-2, 30-31, 47, 49-50, 55-56, and 83-84 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3 and 5-21 of U.S. Patent No. US 12,264,344 in view of Lee.
The subject matter claimed in the instant application is disclosed in the reference application as follows: the method of inhibiting gene expression comprising use of a nanoparticle comprising a protein core, and a plurality of polynucleotides comprising a shell which are covalently linked to the protein core, makes obvious the instant composition of a protein core spherical nucleic acid (ProSNA) comprising a gene editing protein and a covalently linked oligonucleotide shell, wherein the gene editing protein is a Cas (e.g. Cas9), has a diameter of about 1 nm to about 500 nm, comprises a targeting, inhibitory, or immunostimulatory oligonucleotides or a guide RNA which comprises a crRNA and tracrRNA and compositions comprising the ProSNA and guide RNA. The difference between the instant claims and the reference claims lies in the fact that the instant application claims are more specific as to the type of protein (gene editing) which is to be used in the composition.
With regard to claims 1-2, 30-31, 47, 49-50, 55-56, and 83-84, as detailed above and incorporated herein, Lee teaches a CRISPR-gold system comprising a gold nanoparticle core, an oligonucleotide shell, an RNA-guided endonuclease, and guide RNA (Paras. [0004], [0057], [0058]; Claim 1; See Fig 1). Lee teaches that this system can be used to deliver a Cas9 protein and guide RNA for gene editing (Paras. [0052], [0054]). Lee teaches that Cas9 requires two RNA molecules to cut DNA (Para. [0063]) and further teaches that the Cas9 system requires an sgRNA (Ex. 1, Paras. [0117], [0118]; Ex. 2, Paras. [0133], [0137]), which would be understood to one having ordinary skill in the art to comprise a crRNA and a tracrRNA (also see Table 4 and Para. [0139]). Lee also teaches compositions comprising the spherical nucleic acids (Para. [0056]). Thus, based on the teachings of Lee, a gene editing protein comprising a Cas9 and guide RNA comprising a crRNA and tracrRNA would be an obvious type of protein to use in the method of inhibiting gene expression comprising use of a nanoparticle comprising a protein core, and a plurality of polynucleotides comprising a shell which are covalently linked to the protein core of U.S. Patent No. 12,264,344. Since the instant application protein core spherical nucleic acid composition is made obvious by claims 1-3 and 5-21 of U.S. Patent No. 12,264,344, the claims are not patentably distinct.
Claims 1-2, 30-31, 47, 49-50, 55-56, and 83-84 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 46-51 of copending Application No. 19/062,421 in view of Mirkin and Brodin (US 2017232109) and Lee US 20200405884.
This is a provisional nonstatutory double patenting rejection.
The subject matter claimed in the instant application is disclosed in the reference application as follows: the pharmaceutical composition comprising a core-shell nanoparticle comprising a protein core and a covalently attached polynucleotide shell, wherein the density of polynucleotides on the surface is at least 10 pmol/cm2 and wherein the protein is catalytically active or therapeutic is made obvious by the instant composition of a protein core spherical nucleic acid (ProSNA) comprising a Cas protein and a covalently linked oligonucleotide shell comprising a gene editing protein and a covalently linked oligonucleotide shell, wherein the gene editing protein is a Cas (e.g. Cas9) has a diameter of about 1 nm to about 500 nm, comprises a targeting, inhibitory, or immunostimulatory oligonucleotides or a guide RNA which comprises a crRNA and tracrRNA and compositions comprising the ProSNA and guide RNA. The difference between the instant claims and the reference claims lies in the fact that the instant application claims are more specific as to the type of protein (Cas) which is to be used in the nanoparticle and the reference claims are more specific as to the structural features of the nanoparticle.
With regard to claims 1-2, 30-31, 47, 49-50, 55-56, and 83-84, as detailed above and incorporated herein, Mirkin and Brodin teach protein based materials comprising a protein core and oligonucleotide shell (Paras. [0010], [0085], which is considered to reasonably read on protein core spherical nucleic acid (See Fig 1). Additionally, Mirkin and Brodin teach that this structure is generalizable to any protein (Para. [0010]) and that the protein core can be an enzyme (Para. [0095]). Mirkin and Brodin teach that the protein core spherical nucleic acids provide reduced immunogenic response and increased cellular uptake (Para. [0032]) as well as solve other issues associated with use of protein therapeutics including poor bioavailability, degradation, or aggregation/inactivation caused by storage. Mirkin and Brodin also teach that these protein core spherical nucleic acids can be used in a pharmaceutical composition (See Pg. 20, left col.). Lee teaches a CRISPR-gold system comprising a gold nanoparticle core, an oligonucleotide shell, an RNA-guided endonuclease, and guide RNA (Paras. [0004], [0057], [0058]; Claim 1; See Fig 1). Lee teaches that this system can be used to deliver a Cas9 protein and guide RNA for gene editing (Paras. [0052], [0054]) and that this system can be used in pharmaceutical compositions (Para. [0103], [104]). Further, the structural features of the polynucleotide shell are taught by Mirkin and Brodin. Mirkin and Brodin teach wherein the density of the polynucleotides is at least 10 pmol/cm2 and is 10 pmol/cm2 to 100 pmol/cm2 (claim 5), wherein each polynucleotide of the plurality is the same (claim 3), wherein at least two of the polynucleotides of the plurality are different (claim 4), wherein the polynucleotides are attached via a surface amino group of a protein (claim 12), and where the amino group is from a Lys residue (claim 13)
Thus, based on the teachings of Mirkin and Brodin and Lee, a Cas comprising protein core spherical nucleic acid would be an obvious type to use in the pharmaceutical composition of copending application 19/062,421 and the structural features of the nanoparticle are known in the art. Since based on the teachings of Mirkin and Brodin and Lee, the instant application protein core spherical nucleic acid makes obvious the pharmaceutical composition of claims 46-51 of copending application 19/062,421, the claims are not patentably distinct.
Citation of Pertinent Prior Art
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. Brodin et al. (2015, DNA-Mediated Cellular Delivery of Functional Enzymes, JACS, 137(47):14838-14841, found in IDS dated 02/17/2025).
Brodin et al. teaches protein core spherical nucleic acid (ProSNA) comprising a protein core and a shell of oligonucleotides which promote cellular uptake (Pg. 14838, right col.) and an exemplary embodiments where the ProSNA comprises a β-galactosidase protein as the core (Abstract, Fig. 1). Brodin et al. teaches that the architecture of ProSNAs (e.g., the oligonucleotide shell) significantly enhances cellular uptake and physiological stability (Abstract; Pg. 14838, left col., last para. and right col.; Fig. 3) without affecting enzyme structure (Pg. 14839, right col., last para.) or enzymatic activity (Pg. 14840, right col., 1st para.). Additionally Brodin et al. teaches that this strategy (i.e., protein core and oligo shell) could be used to turn proteins which are normally cell membrane impermeable into ProSNAs for cellular delivery (Pg. 14840, right col., last para.) and further indicates that the ProSNA comprising a β-galactosidase core is a “proof-of-concept” and this strategy could be used to create biologically active materials from a “nearly limitless” library of proteins which can function as a ProSNA core (Pg. 14841).
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ERIN V PAULUS whose telephone number is (571)272-6301. The examiner can normally be reached Mon-Fri 8 AM-5 PM.
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/ERIN V PAULUS/Examiner, Art Unit 1631
/ARTHUR S LEONARD/Examiner, Art Unit 1631
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