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 without traverse of claims 5-9 (Group II) in the reply filed on 03/27/2026 is acknowledged.
Claims 1-4 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 03/27/2026.
Accordingly, claims 5-9 are pending and under consideration.
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55. The earliest effective filing date to which the instant application is entitled is 01/13/2021.
Information Disclosure Statement
Receipt of an information disclosure statement on 07/11/2023 is acknowledged. The signed and initialed PTO-1449 has been mailed with this action.
Drawings
The drawings are objected to because:
Figures 3C, 4C, 5C-E, 6C-H, and 7C are of insufficient quality to be clearly legible/interpretable. It would be remedial to increase the image quality such that they are clearly legible/interpretable.
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.
Claim Objections
Claims 5-9 are objected to because of the following informalities:
Claim 5 recites (in part) “a gene delivery method, comprising: providing a composition comprising a gene delivery…” (bolded emphasis added), which does not comport with standard grammatical and/or linguistic conventions. The term “a gene delivery” is awkward and improper. It would be remedial to amend the instant claim language such that it is easily readable/interpretable by comporting with standard grammatical and/or linguistic conventions, for example by reciting “a gene delivery method, comprising: providing a composition comprising a gene delivery agent…” (bolded and underlined emphasis added). This is merely and example set forth by the Examiner and is not intended to be limiting.
Claim 6 recites “the gene [of the method of claim 5] is selected from the group consisting of gDNA, cDNA, plasmid DNA, mRNA, tRNA, rRNA, antisense nucleotide, missense nucleotide, and protein-producing nucleotide” (bolded emphasis added), which does not comport with standard grammatical and/or linguistic conventions. Conventionally, the bolded terms are referred to in the plural when there is no singular article preceding the recited list (i.e. “an”). It would be remedial to amend the instant claim language such that is comports with standard grammatical and/or linguistic conventions, for example by reciting “the gene [of the method of claim 5] is selected from the group consisting of gDNA, cDNA, plasmid DNA, mRNA, tRNA, rRNA, antisense nucleotides, missense nucleotides, and protein-producing nucleotides” (bolded and underlined emphasis added) or “the gene [of the method of claim 5] is selected from the group consisting of a gDNA, cDNA, plasmid DNA, mRNA, tRNA, rRNA, antisense nucleotide, missense nucleotide, and protein-producing nucleotide” (bolded and underlined emphasis added). These are merely examples set forth by the Examiner and are not intended to be limiting.
Claim 7 recites (in part) “the gene delivery and the gene…” (bolded emphasis added), which, as set forth above, does not comport with standard grammatical and/or linguistic conventions. The term “the gene delivery” is awkward and improper. It would be remedial to amend the instant claim language such that it is easily readable/interpretable by comporting with standard grammatical and/or linguistic conventions, for example by reciting “the gene delivery agent and the gene…” (bolded and underlined emphasis added). This is merely an example set forth by the Examiner and is not intended to be limiting.
Claim 8 also recites (in part) “a gene delivery…” (bolded emphasis added), which, as set forth above, does not comport with standard grammatical and/or linguistic conventions. The term “a gene delivery” is awkward and improper. It would be remedial to amend the instant claim language such that it is easily readable/interpretable by comporting with standard grammatical and/or linguistic conventions, for example by reciting “a gene delivery agent…” (bolded and underlined emphasis added). This is merely an example set forth by the Examiner and is not intended to be limiting. Furthermore, claim 8 also recites (in part) “carry out reaction…” and “carrying out reaction…”, the recitations of which do not comport with standard grammatical and/or linguistic conventions. Per these conventions, an article such as “a” or “the” is required preceding “reaction.” It would be remedial to amend the instant claim language to include an article such as “a” or “the” preceding “reaction.”
Finally, while the recitation of claim 9 is not strictly grammatically improper, it nonetheless does not comport with standard linguistic conventions. The recitation of “adjusting the pH of the solution in which polyethylenimine and cholic acid are included to 6.9 to 7.1” (bolded emphasis added) reads awkwardly, as “included” is not the typical word used in such recitations. For ease of interpretation, it would be remedial to amend the instant claim to “adjusting the pH of the solution comprising polyethylenimine and cholic acid to 6.9 to 7.1,” or some similar recitation. This is merely an example set forth by the Examiner and is not intended to be limiting.
Appropriate correction is required.
The Examiner has noted those grammatical and/or linguistic informalities that most impact claim interpretation, but this is not an exhaustive accounting of every possible grammatical and/or linguistic informality. The instant claim set would benefit from careful grammatical and/or linguistic review and revision in order to place the instant application in condition for allowance.
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.
Claims 5-7 are rejected under 35 U.S.C. 103 as being unpatentable over Cheng et al., 2016 (hereinafter Cheng; as cited in the IDS filed 07/11/2023; of record) in view of WO 2018/232502 A1 (hereinafter Uludag) and Sang et al., 2015 (hereinafter Sang).
With regard to claim 5, which recites “a gene delivery method, comprising:
providing a composition comprising a gene delivery [agent] in which polyethylenimine and cholic acid are ionically bonded and which is represented by the following Chemical Formula 1 and a gene,…wherein in the Chemical Formula 1, m is an integer of 2 to 930, and n is an integer of 58 to 930; and contacting the composition with cells,” as set forth in the restriction requirement dated 02/26/2026, gene delivery agents wherein polyethylenimine and cholic acid are ionically bonded are known in the art. As previously set forth, Cheng discloses nanohemostats formed by cholic-acid-mediated self-assembly of polyethylenimine (PEI), wherein said assembly process is dominated by electrostatic (i.e. ionic) interactions (abstract; page 9961, column 1, paragraph 2; page 9968, column 1, paragraph 1; Figures 1 and 2). The cholic acid structure disclosed in Figure 1B of Cheng is identical to the instantly claimed cholic acid molecule bonded to PEI. While Cheng does not disclose that the nanohemostat structures taught therein may be used as a gene (or nucleic acid) carrier, this deficiency is cured by Uludag. Uludag discloses gene delivery compositions and methods of using the same (abstract), wherein said gene delivery compositions comprise PEI and cholic acid (page 5, lines 14-17). Per Uludag, these compositions may be administered to cells in order to deliver the nucleic acid cargo carried therein (page 1, lines 4-6). Uludag further discloses that the PEI of said gene delivery compositions is of variable weight (page 5, lines 17-20), which is impacted by variable numbers of repeating PEI units/subunits (page 50, claim 5). Per Uludag, x, y, and z are repeating units, wherein “x” corresponds to the instantly claimed “m” and is disclosed to have 7 to 22 repeating units (which falls within the instantly claimed range of 2 to 930), and wherein “y” corresponds to the instantly claimed “n” and is disclosed to have 14 to 44 repeating units (which does not fall within the instantly claimed range of 58 to 930). Thus, the disclosure of Uludag establishes that it is within the realm of routine optimization/experimentation to vary the number of subunits within PEI to generate effective gene delivery compositions. Per MPEP § 2144.05(I)(A), “it is not inventive to discover the optimum or workable ranges by routine experimentation” (In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)). Therefore, based on the disclosure of Uludag and MPEP § 2144.05(I)(A) it would have been obvious to someone of ordinary skill in the art prior to the effective filing date of the instant application to vary the number of PEI subunits, as disclosed in Uludag, to optimize the gene delivery agents comprising PEI and cholic acid taught therein. Thus, it is considered that Cheng and Uludag disclose each and every limitation of instant claim 5.
With regard to claim 6, which recites “the method of claim 5, wherein the gene is selected from the group consisting of gDNA, cDNA, plasmid DNA, mRNA, tRNA, rRNA, antisense nucleotide, missense nucleotide, and protein-producing nucleotide,” as set forth above, Uludag discloses gene delivery compositions and methods of using the same (abstract), wherein said gene delivery compositions comprise PEI and cholic acid (page 5, lines 14-17). Uludag further discloses that the nucleic acid delivered by the agents taught therein may be an antisense oligonucleotide or plasmid DNA (page 7, lines 1-6), as instantly claimed. Thus, Uludag discloses each and every additional limitation of instant claim 6.
With regard to claim 7, which recites “the method of claim 5, wherein the gene delivery and the gene are included in a weight ratio of 4 to 6:1,” as set forth above, Uludag discloses gene delivery compositions and methods of using the same (abstract), wherein said gene delivery compositions comprise PEI and cholic acid (page 5, lines 14-17). Uludag further discloses that it is essential to understand the cellular uptake of polyplexes to gain better insight into the overall efficacy of carriers, teaching a ratio of 12:1 of a similar gene delivery agent to assay said cellular uptake (page 32, lines 20-30). However, Uludag does not specifically teach that a weight ratio of 4 to 6:1 is the most effective ratio of gene delivery agent:gene, particularly when said gene delivery agent comprises PEI and cholic acid. This deficiency is cured by Sang, which discloses that transfection efficiency of PEI-DNA particles is directly influenced by the ratio of PEI to DNA, teaching that a ratio of 4:1 of PEI:DNA achieves optimal transfection efficiency. Furthermore, as set forth above, per MPEP § 2144.05(I)(A), “it is not inventive to discover the optimum or workable ranges by routine experimentation” (In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)). Based on the collective disclosures of Uludag and Sang, it is clearly within the realm of routine optimization via routine experimentation to vary the ratio of gene delivery agent:gene being delivered in order to optimize transfection efficiency. Therefore, it would have been obvious to someone of ordinary skill in the art prior to the effective filing date of the instant application to vary the ratio of gene delivery agent:gene being delivered, as disclosed in both Uludag and Sang, in order to optimize transfection efficiency of the agents taught therein. Thus, Uludag and Sang are considered to collectively disclose each and every additional limitation of instant claim 7.
Given that Cheng discloses ionically bonded PEI and cholic acid, that Uludag discloses that PEI and cholic acid compositions (wherein the number of subunits and ratio of PEI are optimized to facilitate the function thereof) may be used to delivery nucleic acid species such as antisense oligonucleotides or plasmid DNA, and that Sang discloses further optimization of PEI to DNA ratios for purposes of optimizing transfection efficiency thereof, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to ionically bond PEI and cholic acid (as disclosed in Cheng), wherein the subunits and ratio of PEI are optimized to facilitate the function thereof (as disclosed in Uludag and Sang) to predictably form an optimized nucleic acid delivery agent capable of delivering said nucleic acid species (i.e. antisense oligonucleotide as per Uludag) to a cell. One would have been motivated to make such a modification in order to receive the expected benefit of effectively delivering a nucleic acid species such as an antisense oligonucleotide to a cell.
Claims 8-9 are rejected under 35 U.S.C. 103 as being unpatentable over Cheng et al., 2016 (hereinafter Cheng; as cited in the IDS filed 07/11/2023; of record) in view of WO 2018/232502 A1 (hereinafter Uludag), Wei et al., 2018 (hereinafter Wei), and Gallops et al., 2019 (hereinafter Gallops).
With regard to claim 8, which recites “a method of preparing a gene delivery [agent], the method comprising:
dissolving polyethylenimine in an alcohol solution and adding an acid solution to carry out [the] reaction; and
mixing cholic acid with the solution and carrying out [the] reaction followed by sonicating to obtain the gene delivery [agent] in which the polyethylenimine and the cholic acid are ionically bonded and which is represented by the following Chemical Formula 1…wherein, in the Chemical Formula 1,
m is an integer of 2 to 930, and n is an integer of 58 to 930,
as set forth above, Cheng and Uludag collectively disclose Chemical Formula 1. As set forth above, Cheng discloses nanohemostats formed by cholic-acid-mediated self-assembly of polyethylenimine (PEI), wherein said assembly process is dominated by electrostatic (i.e. ionic) interactions (abstract; page 9961, column 1, paragraph 2; page 9968, column 1, paragraph 1; Figures 1 and 2). The cholic acid structure disclosed in Figure 1B of Cheng is identical to the instantly claimed cholic acid molecule bonded to PEI. While Cheng does not disclose that the nanohemostat structures taught therein may be used as a gene (or nucleic acid) carrier, this deficiency is cured by Uludag. Uludag discloses gene delivery compositions and methods of using the same (abstract), wherein said gene delivery compositions comprise PEI and cholic acid (page 5, lines 14-17). Per Uludag, these compositions may be administered to cells in order to deliver the nucleic acid cargo carried therein (page 1, lines 4-6). Uludag further discloses that the PEI of said gene delivery compositions is of variable weight (page 5, lines 17-20), which is impacted by variable numbers of repeating PEI units/subunits (page 50, claim 5). Per Uludag, x, y, and z are repeating units, wherein “x” corresponds to the instantly claimed “m” and is disclosed to have 7 to 22 repeating units (which falls within the instantly claimed range of 2 to 930), and wherein “y” corresponds to the instantly claimed “n” and is disclosed to have 14 to 44 repeating units (which does not fall within the instantly claimed range of 58 to 930). Thus, the disclosure of Uludag establishes that it is within the realm of routine optimization/experimentation to vary the number of subunits within PEI to generate effective gene delivery compositions. Per MPEP § 2144.05(I)(A), “it is not inventive to discover the optimum or workable ranges by routine experimentation” (In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)). Therefore, based on the disclosure of Uludag and MPEP § 2144.05(I)(A) it would have been obvious to someone of ordinary skill in the art prior to the effective filing date of the instant application to vary the number of PEI subunits, as disclosed in Uludag, to optimize the gene delivery agents comprising PEI and cholic acid taught therein. Thus, it is considered that Cheng and Uludag disclose the structure of Chemical Formula 1. However, neither Cheng nor Uludag fully disclose the instantly claimed method of preparing said gene delivery agent. This deficiency is cured by Wei.
Wei discloses ionically bonded PEI utilized to modify perovskite films (abstract). While Wei is not drawn to usage of PEI for purposes of gene delivery, Wei is drawn to ionic compounds comprising PEI, and Uludag discloses usage of PEI for purposes of gene delivery, as set forth above. As disclosed in the “Experimental” section of Wei, ionically bonded PEI was prepared by dissolving PEI in a solution comprising hydroiodic acid and methanol (page 653, column 2, paragraph 2), which constitute an alcohol and acid solution, as recited at (a) of instant claim 8.
Regarding the cholic acid limitations of (b) of instant claim 8, as set forth above, Cheng discloses ionically bonded PEI and a cholic acid species (abstract). As shown in Figure 1 of Cheng, these cholic acid species include cholic acid and ursodeoxycholic acid (UDCA). Per the methods of Cheng, such ionically bonded PEI and cholic acid species (i.e. cholic acid or UDCA) are produced by sonicating a solution comprising PEI to which the cholic acid species is added (page 9969, column 2, paragraph 3).
Thus, it is considered that Cheng, Uludag, and Wei collectively disclose each and every limitation of instant claim 8.
With regard to claim 9, which recites “the step (b) [of the method of claim 8] further comprises adjusting the pH of the solution in which polyethylenimine and cholic acid are included to 6.9 to 7.1,” as set forth above, Cheng, Uludag, and Wei collectively disclose each and every limitation of instant claim 8. However, these disclosures do not teach the instantly claimed pH range. This deficiency is cured by Gallops. Gallops discloses that PEI is a highly studied vector for nonviral gene delivery with a high transfection efficiency that has been linked with its pH responsiveness (abstract; graphical abstract). Gallops further discloses that a key feature underlying the mechanism of PEI-mediated gene delivery is that PEI is not fully protonated at physiological pH of ~7.4 and becomes increasingly protonated (i.e. cationic) in acidic environments, such as endosomal environments encountered by gene delivery polyplexes (page 7255, column 1, paragraph 1). As shown in the graphical abstract, as pH increases, PEI becomes more weakly charged, meaning it is less able to participate in ionic bonds as a cation. On the other hand, as pH decreases, PEI becomes more highly charged, meaning it is more able to participate in ionic bonds as a cation. As set forth above, per MPEP § 2144.05(I)(A), “it is not inventive to discover the optimum or workable ranges by routine experimentation” (In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)). Based on the disclosure of Gallops, one of ordinary skill in the art would have been motivated to optimize the pH of the reaction to generate ionically bonded PEI and cholic acid such that PEI is able to participate in ionic bonds as a cation, thereby facilitating delivery of nucleic acids, as disclosed in Uludag and Gallops. The graphical abstract of Gallops discloses that pH influences the protonation state and charge of PEI, with PEI becoming more highly charged as pH decreases from a physiological pH of ~7.4 (page 7255, column 1, paragraph 1). Given that the claimed pH range of 6.9 to 7.1 is lower than said physiological pH of ~7.4, one of ordinary skill in the art would reasonably predict that PEI would be more highly charged, and therefore more able to participate in ionic bonds, at a pH of 6.9 to 7.1 as depicted in the graphical abstract of Gallops.
Given that Cheng discloses ionically bonded PEI and cholic acid (said bond facilitated by sonication of a mixture thereof), that Uludag discloses that PEI and cholic acid compositions (wherein the number of subunits of PEI are optimized to facilitate the function thereof) may be used to delivery nucleic acid species such as antisense oligonucleotides or plasmid DNA, that Wei discloses preparation of ionically bonded PEI by dissolving PEI in a solution comprising hydroiodic acid and methanol, and that Gallops discloses that PEI becomes more highly charged as pH decreases and that PEI is not fully protonated at a physiological pH of ~7.4, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention treat PEI with a mixture of alcohol and acid (as disclosed in Wei) followed by sonication with a mixture of PEI and cholic acid (as disclosed in Cheng) at a pH that facilitates more highly charged PEI (as disclosed in Gallops) to predictably generate an optimized ionically bonded PEI and cholic acid (as disclosed in Cheng) that is capable of delivering nucleic acids to a cell (i.e. an antisense oligonucleotide as per Uludag). One would have been motivated to make such a modification in order to receive the expected benefit of producing an optimized gene delivery agent capable of effectively delivering a nucleic acid species such as an antisense oligonucleotide to a cell.
Conclusion
No claims are allowed.
Claims 5-9 are objected to.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Sarah E Allen whose telephone number is (571)272-0408. The examiner can normally be reached M-F 8-5.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jennifer Dunston can be reached at 571-272-2916. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
879
/SARAH E ALLEN/ Examiner, Art Unit 1637
/J. E. ANGELL/ Primary Examiner, Art Unit 1637
Prosecution Insights