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 .
DETAILED ACTION
Applicant's preliminary amendment filed on August 13, 2025 is acknowledged. Claims 1-292, 305-323, 329-361, 368, 369, 373, and 390 have been canceled. Claims 293, 299, 304, 328, 362-365, 371, 372, 381, and 392 were amended. Claims 293-304, 324-328, 362-367, 370, 371, 372, 374-389, and 391-429 are pending.
Election/Restrictions
Applicant’s election without traverse of the following species (reproduced below) in the reply filed on August 13, 2025 is acknowledged:
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Claims 324, 326, 394, 395, and 396 are readable on the elected species of a betaine containing substance.
Claims 325, 327, 388, 389, 393, 397, 398, 400, 405-409, 412, 422, 423, 426, 427, 428, and 429 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on August 13, 2025.
Claims 293-304, 324, 326, 328, 362-367, 370, 371, 372, 374-387, 391, 392, 394, 395, 396, 399, 401-404, 410, 411, 413-421, 424, and 425 are examined on the merits herein.
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Information Disclosure Statement
The information disclosure statement (IDS) submitted on December 22, 2022, February 13, 2023, and May 3, 2023 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are 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.
Drawings
The drawings were received on September 16, 2022 and February 7, 2023. These drawings are found acceptable by the examiner.
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: reference 670 in Figure 60. Corrected drawing sheets in compliance with 37 CFR 1.121(d), or amendment to the specification to add the reference character(s) in the description in compliance with 37 CFR 1.121(b) 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. 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:
In the brief description of the drawings section, the letter designations of each figure should be included with the figure number (e.g., FIGS. 1A-1B or FIGS. 50A-50F).
Appropriate correction is required.
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. 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. See pages 358 and 359.
Claim Objections
Claims 294-304, 324, 326, 328, 362-367, 370, 371, 372, 375-387, 391, 392, 394, 395, 396, 399, 401-404, 410, 411, 413-421, 424, and 425 are objected to because of the following informalities:
The word “Claim” in claims 294-304, 324, 326, 328, 362-367, 370, 371, 372, 375-387, 391, 392, 394, 395, 396, 399, 401-404, 410, 411, 413-421, 424, and 425 should not be capitalized.
Claim 304 recites the abbreviation DMSO. The abbreviation should be clearly written out at their first occurrence in the claim and should be followed by the abbreviation in parentheses.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
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 294, 300, and 375 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.
The term “about” in claims 294, 300, and 375 is a relative term which renders the claim indefinite. The term “about” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Therefore, the phrase “about 50% of said RNA molecules” has been rendered indefinite by the use of the term “about”. One of skill cannot know the metes and bounds of the claims because the term “about” is an undefined relative term.
Claim Rejections - 35 USC § 102
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 293, 324, 326, 370, 371, 374, 394, 395, 396, 420, and 421 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Lin et al. (US 11,326,164).
Regarding claims 293, 324, 326, 370, 371, 394, 395, and 396, Lin et al. teaches chemical compositions and their use for formulating RNA- and/or DNA-based medicine drugs/vaccines into stable compound complexes useful for in-vitro, ex-vivo and in-vivo delivery. Lin et al. also teaches the synthesis of trimethylglycyl chemicals and their use for formulating cosmetic, biomedical, therapeutic- and/or pharmaceutical-grade nucleic acid compositions, including but not limited microRNA precursors (pre-miRNA/miRNA), small hairpin RNAs (shRNA), short interfering RNAs (siRNA), ribozymes, antisense synthetic oligonucleotides, RNA-DNA hybrids and DNA-based vectors/vaccines [column 1, third paragraph].
Regarding claims 374, 420, and 421, Lin et al. teaches for miRNA transfection, pri-/pre-miR-302 prepared from Example 1 was dissolved in 0.01˜5.0M, preferably 0.1˜2.0M, of TMGG solution at a desired concentration up to 5 mg/ml and then directly applied to cell culture medium based on the miRNA amount needed [column 18, first full paragraph].
Claims 293-298, 324, 326, 328, 372, 374-379, 384-387, 391, 392, 394-396, 420, and 421 are rejected under 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2) as being anticipated by Huang et al. (WO 2016/196782).
Regarding claims 293, 324, 326, 328, 372, 374, 387, 391, 394-396, 420, and 421, Huang et al. teaches compositions for introducing double-stranded RNA capable of silencing a target gene in a plant [0002] wherein the composition comprises a nucleic acid and glycine betaine (betaine, TMG) [0073]. Further, Huang et al. demonstrates in the working examples embodiments of methods and compositions useful for delivering a nucleic acid into a plant or cells or tissues of a plant.
Regarding claims 294-298 and 375-379, Example 12 of the instant specification demonstrated that following about 48 hours at 60ºC, samples comprising varying concentrations of benzoate with 1M TMG displayed significantly less RNA degradation as compared to a sample with only 50mM Tris-HCl as compared to the -80ºC reference sample. Meanwhile, the sample with only 50mM Tris-HCl displayed significant RNA degradation. Therefore, with regard to the functional language recited in the claims, the structure in the prior art is indistinguishable from the structure that is claimed, and absent evidence to the contrary the recited function is inherent in the structure. See MPEP 2112.
Regarding claims 384-386 and 392, the wherein clauses are interpreted as intended use.
Claim Rejections - 35 USC § 103
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 299-304, 362-365, 399, 401-404, 410, and 411 are rejected under 35 U.S.C. 103 as being unpatentable over Lin et al. (US 11,326,164) as applied to claims 293, 324, 326, 370, 371, 374, 394, 395, 396, 420, and 421 above, and further in view of Hong et al. (US 2004/0037874).
Regarding claims 299-304, 362-365, 399, 401-404, 410, and 411 the
teachings of Lin et al. are discussed above.
However, Lin et al. does not teach a second RNA stabilizing substance
comprising at least one aprotic substance or a cellular uptake agent. Lin et al. does not teach an ionizable lipid. Lin et al. also does not teach the total weight percentage of RNA stabilizing substances or the composition weight percentage.
Hong et al. teaches a process for preparing a microparticulate complex
from a particle-forming component ("PFC") and a nucleic acid-like component ("NAC") and are contacted in a monophasic composition of water and a water-miscible solvent [0031]. The NAC includes nucleic acid (i.e. a polymer that comprises a plurality of nucleic acid bases attached to a backbone of covalently linked repetitive molecular units), DNA, RNA, natural and synthetic oligonucleotides (including antisense oligonucleotides, interfering RNA and small interfering RNA), nucleoprotein, and nucleic acid [0033]. Hong et al. also teaches a water-miscible organic solvent which may be an aprotic solvent wherein the aprotic solvent is preferably dimethylsulfoxide (DMSO) [0036]. Further, Hong et al. teaches using charge-changing lipids which are ionizable lipids whose ionic charge changes with the change in their molecular environment [0072].
Regarding claims 300-303, Example 2 of the instant specification demonstrated that the RNA sample stored in DMSO displayed increased stability and reduced rate of degradation compared to the RNA sample stored in Tris Acetate EDTA (TAE). Specifically, the RNA sample stored in DMSO does not show notable signs of degradation until about 100 days at room temperature. Therefore, with regard to the functional language recited in the claims, the structure in the prior art is indistinguishable from the structure that is claimed, and absent evidence to the contrary the recited function is inherent in the structure. See MPEP 2112.
Regarding claims 304 and 399, Hong et al. teaches that the aprotic solvent may be dimethylsulfoxide (DMSO) [0036].
Regarding claims 362, 363, 410, and 411, Hong et al. teaches that the organic solvent in the mixture is from about 10 vol. % to about 60 vol. % [0051].
Regarding claims 364, 365, 402, and 404, Hong et al. teaches that the PFC (particle-forming component) comprises a lipid [0038].
It would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to incorporate DMSO and a cellular uptake agent to the composition of Lin et al. because it would have amounted to combining prior art elements to yield predictable results. One of skill in the art would have been motivated to do so because Hong et al. taught that a pharmaceutically acceptable organic solvent is advantageous for nucleic acid delivery to skin cells in topical applications [0054].
Claims 366 and 367 are rejected under 35 U.S.C. 103 as being unpatentable over Lin et al. (US 11,326,164) as applied to claims 293, 324, 326, 370, 371, 374, 394, 395, 396, 420, and 421 above, and further in view of Miao et al. (US 2020/0109121).
Regarding claims 366 and 367, the teachings of Lin et al. are discussed above.
However, Lin et al. does not teach a coding RNA such as an mRNA.
Miao et al. teaches lipidoid compounds of various formulas and pharmaceutically acceptable solvate which may include the associated solvent DMSO, to deliver an agent such as RNA, including therapeutic mRNA as a vaccine [abstract], [0003], and [0066]. Miao et al. defines mRNA as “a sequence coding for the protein to be synthesized” [0103].
It would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to incorporate an mRNA as taught by Miao et al. to the composition of Lin et al. because it would have amounted to combining prior art elements to yield predictable results. One of skill in the art would have been motivated to do so because Miao et al. taught delivery of therapeutic mRNA as a vaccine.
Claims 380-383 are rejected under 35 U.S.C. 103 as being unpatentable over Huang et al. (WO 2016/196782) as applied to claims 293-298, 324, 326, 328, 372, 374-379, 384-387, 391, 392, 394-396, 420, and 421 above, and further in view of Knepp et al. (US 6,264,990).
Regarding claims 380-383, the teachings of Huang et al. are discussed above.
However, Huang et al. does not teach storage of the RNA product in an implant.
Knepp et al. teaches methods for treating a subject suffering from or susceptible to a condition which may be alleviated or prevented by administration of a nucleic acid-containing compound, said methods comprising administering to said subject an effective amount of a stable nucleic acid composition comprising a nucleic acid-containing powder wherein the nucleic acid hydration in said powder is less than about 10%; and at least one anhydrous, non-polar, aprotic, hydrophobic, low-reactivity vehicle [column 4, sixth full paragraph]. Further, the formulations are useful in a variety of delivery systems, including, but not limited to, various pumping devices (syringes, infusion sets, syringe pumps, implantable pumps, etc.), transdermal reservoir systems, liquid fill capsules, injectable depot compositions and the like [column 6, first full paragraph].
It would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to formulate the RNA product of Huang et al. in an implant as taught by Knepp et al. because it would have amounted to applying a known technique to yield predictable results. One would have been motivated to do so because Knepp et al. taught compositions in a container as a means for delivery to treat a disease.
Claims 413-415, 418, 419, and 424-425 are rejected under 35 U.S.C. 103 as being unpatentable over Huang et al. (WO 2016/196782) as applied to claims 293-298, 324, 326, 328, 372, 374-379, 384-387, 391, 392, 394-396, 420, and 421 above, and further in view of Hong et al. (US 2004/0037874).
Regarding claims 413-415, 418, 419, and 424-425, the teachings of Huang et al. are discussed above.
However, Huang et al. does not teach a cellular uptake agent or an ionizable lipid. Huang et al. also does not teach an aprotic substance. Huang et al. also does not teach the total weight percentage of RNA stabilizing substances or the RNA product weight percentage.
Hong et al. teaches a process for preparing a microparticulate complex
from a particle-forming component ("PFC") and a nucleic acid-like component ("NAC") and are contacted in a monophasic composition of water and a water-miscible solvent [0031]. The NAC includes nucleic acid (i.e. a polymer that comprises a plurality of nucleic acid bases attached to a backbone of covalently linked repetitive molecular units), DNA, RNA, natural and synthetic oligonucleotides (including antisense oligonucleotides, interfering RNA and small interfering RNA), nucleoprotein, and nucleic acid [0033]. Hong et al. also teaches a water-miscible organic solvent which may be an aprotic solvent wherein the aprotic solvent may be dimethylsulfoxide (DMSO) [0036]. Further, Hong et al. teaches using charge-changing lipids which are ionizable lipids whose ionic charge changes with the change in their molecular environment [0072]. Hong et al. teaches that the organic solvent in the mixture is from about 10 vol. % to about 60 vol. % [0051].
It would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to incorporate an aprotic substance and a cellular uptake agent to the method of Huang et al. because it would have amounted to combining prior art elements to yield predictable results. One of skill in the art would have been motivated to do so because Hong et al. taught that a pharmaceutically acceptable organic solvent is advantageous for nucleic acid delivery to skin cells in topical applications [0054].
Claims 416 and 417 are rejected under 35 U.S.C. 103 as being unpatentable over Huang et al. (WO 2016/196782) as applied to claims 293-298, 324, 326, 328, 372, 374-379, 384-387, 391, 392, 394-396, 420, and 421 above, and further in view of Miao et al. (US 2020/0109121).
Regarding claims 416 and 417, the teachings of Huang et al. are discussed above.
However, Huang et al. does not teach a coding RNA such as an mRNA.
Miao et al. teaches lipidoid compounds of various formulas and pharmaceutically acceptable solvate which may include the associated solvent DMSO, to deliver an agent such as RNA, including therapeutic mRNA as a vaccine [abstract], [0003], and [0066]. Miao et al. defines mRNA as “a sequence coding for the protein to be synthesized” [0103].
It would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to incorporate an mRNA as taught by Miao et al. to the method of Huang et al. because it would have amounted to combining prior art elements to yield predictable results. One of skill in the art would have been motivated to do so because Miao et al. taught delivery of therapeutic mRNA as a vaccine.
Citation of Pertinent Prior Art
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Grotzer et al. (Medical and Pediatric Oncology 2000). Grotzer et al. tested RNAlater, a RNA stabilization solution, to determine whether tumor tissue can be stored for a period of up to 7 days at room temperature without significant RNA degradation. Pieces of tumor were stored for 7 days at room temperature or for 1 day at 37ºC followed by 6 days at room temperature in RNAlater. Total RNA isolated from the tumor samples stored under different conditions was analyzed and compared to the total RNA isolated from snap-frozen tumor samples [page 438, left column, last paragraph bridging to right column].
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHRISTINA TRAN whose telephone number is (571)270-0550. The examiner can normally be reached M-F 7:30 - 5:00pm.
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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.
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/C.T./
Examiner, Art Unit 1637
/Jennifer Dunston/Supervisory Patent Examiner, Art Unit 1637
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