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
Priority
This application is a Continuation of International Patent Application No. PCT/US2022/079505, filed November 8, 2022, which claims the benefit of U.S. Provisional Application No. 63/277,116 filed November 8, 2021, that is hereby acknowledged by the Examiner.
Status of the Claims
The amendment dated 12/19/2024 is acknowledged. Claims 2, 5, 7, 24, 35-36, 45, 50, 52, 70, 75, 81, 144 and 155 are pending and under examination.
Information Disclosure Statement
There was no information disclosure statement (IDS) submitted at the time of this Office action.
Drawings
The drawing filed on 05/08/2024 are acknowledged and accepted by the Examiner.
Claim Objections
Claim 70 is objected to for the following informalities:
Claim 70 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
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.
Claims 2 and 144 are rejected under 35 U.S.C. 112(b), as being indefinite for failing to particularly point out and distinctly claim the subject matter which applicant regards as the invention.
Claim 2 recites “e.g.”. The phrase "for example" or “e.g.” renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Claim 144 recites “likelihood”. It is unclear to a skilled artisan what the recitation means such that the specification does not clearly define “likelihood”. The concept it represents remains mathematically indefinite as the actual probability changes leaving the mathematical meaning unclear. A skilled artisan would not know the metes and bounds of the varied numerical ranges, thus, rendering the claim vague and indefinite.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims under 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of 35 U.S.C. 103(c) and potential 35 U.S.C. 102(e), (f) or (g) prior art under 35 U.S.C. 103(a).
Claims 2, 5, 7, 24, 35-36, 45, 50, 52, 75, 81 and 155 are rejected under 35 U.S.C. 103(a) as being unpatentable over Baiersdorfer et al. “Baiersdorfer” (WO2017/182524) in view of Jooss et al. “Jooss” (WO2021/216776, international filing date of April 21, 2021).
The claims are directed to a composition for delivery of a self-amplifying expression system comprising a single-stranded RNA (ssRNA) vector, wherein the ssRNA vector comprises a 7- methylguanylate (m⁷G cap), a polyadenylation (polyA) tail, a self-amplifying backbone, and one or more modified nucleosides, optionally wherein:
(a) the self-amplifying backbone comprises a polynucleotide selected from a self-replicating RNA virus, optionally wherein the self-replicating RNA virus is selected from the group comprising an alphavirus, a flavivirus, a measles virus, and a rhabdovirus;
(b) the ssRNA vector is purified, optionally wherein the ssRNA vector is purified by chromatography, optionally wherein the chromatography comprises a cellulose chromatography system or an affinity-based separation system; optionally wherein the affinity-based separation system is a deoxythymidine (dT) oligonucleotide (Oligo(dT)) system;
(c) greater than 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% of adenine, guanine, cytidine, and/or uridine nucleosides of the ssRNA vector are modified nucleosides;
(d) the composition comprises less than 30%, less than 25%, less than 20%, less than 15%. less than 10%, less than 5%, less than 2%, less than 1%, less than 0.5%, or less than 0.1% of a contaminant, optionally wherein the contaminant comprises salt, detergent, and/or double stranded RNA (dsRNA);
(e) the ssRNA vector comprises 70% or more, 80% or more. 85% or more, 90% or more, or 95% or more, 97% or more, 98% or more, 99% or more, or 99.5% or more of the total RNA present in the composition;
(I) the ssRNA vector is the only RNA species present in the composition,
(g) the ssRNA vector is produced by in vitro transcription, optionally wherein the m⁷G cap comprises an m⁷G cap analog, optionally wherein the m⁷G cap analog comprises a trinucleotide m⁷G-ppp-A-U cap analog or dinucleotide m⁷G-ppp-A cap analog;
(h) the ssRNA vector comprises a cassette comprising at least one nucleic acid sequence for delivery, optionally wherein the at least one nucleic acid sequence comprises a polypeptide- encoding nucleic acid sequence, optionally wherein the polypeptide-encoding nucleic acid sequence is an antigen-encoding nucleic acid sequence, and wherein the cassette is operably linked to or operably inserted into the self-amplifying backbone;
(i) the self-amplifying backbone comprises a polynucleotide selected from a self-replicating RNA virus comprising at least one nucleic acid sequence, from 5' to 3', described by the formula:
m⁷G-ppp-N₁-N₂-Nv, wherein m⁷G is a 7-methylguanylate (m⁷G) cap,
ppp is a triphosphate bridge,
N₁ is a first nucleotide of the self-amplifying backbone corresponding to a first endogenous 5' nucleotide of the self-replicating RNA virus,
N₂ is a second nucleotide of the self-amplifying backbone corresponding to a second endogenous 5' nucleotide of the self-replicating RNA virus, and
Nv comprises (1) one or more additional nucleic acid sequences of the self- amplifying backbone, and (2) a cassette comprising at least one nucleic acid sequence for delivery, optionally wherein the at least one nucleic acid sequence comprises a polypeptide-encoding nucleic acid sequence, optionally wherein the polypeptide-encoding nucleic acid sequence is an antigen-encoding nucleic acid sequence, and wherein the cassette is operably linked to or operably inserted into the self-amplifying backbone; and/or
(j) the composition further comprising a nanoparticle delivery vehicle, optionally wherein the nanoparticle delivery vehicle is a lipid nanoparticle (LNP). It is noted that the claims recite “optionally”, therefore, it is understood by the Office that the limitations are not required by said claims.
Regarding claims 2, 5, 7, 24, 45, 75 and 81, Baiersdorfer discloses methods for providing single-stranded RNA (ssRNA); and a composition for delivery of a self-amplifying expression system comprising a single-stranded RNA (ssRNA) vector (comprising a particular RNA to be expressed in a cell, a single-stranded self-replicating RNA, wherein the self-replicating RNA is single stranded RNA of positive sense) (page 47, lines 11-13); further comprising delivery systems, known to those skilled in the art, whereby ssRNA ... can be formulated to ensure proper distribution in vivo, (page 62, lines 26-28), wherein the ssRNA vector comprises a 7-methylguanylate (m7G cap) (a conventional 5'-cap ... preferably the 7-methylguanosine cap, m7G) (page 36, Lines 29-30), a polyadenylation (polyA) tail (a long poly-A sequence having a length of about 120 nucleotides results in an optimal transcript stability and translation efficiency of an RNA, preferably ssRNA, such as mRNA) (page 38, lines 18-19), and one or more modified nucleosides (altered/modified nucleotides) (page 33, lines 31-34; such as modified naturally occurring nucleotides, non-naturally occurring nucleotides and/or modified non-naturally occurring nucleotides (page 34, lines 18-19), wherein one or more modified nucleosides comprises m5C (incorporation of one or more 3'-UTRs and replacing one or more naturally occurring nucleotides with synthetic nucleotides, e.g., 5-methylcytidine for cytidine) (page 39, lines 1-2), wherein the said m7G cap comprises an m7G cap analog wherein the ssRNA comprises an RNA 5'-cap, preferably the 7-methylguanosine cap [m7G], and wherein the term "5'-cap" includes a 5'-cap analog that resembles the RNA cap structure and is modified to possess the ability to stabilize RNA (page 36, lines 29-32). Baiersdorfer further discloses wherein the self-replicating RNA is single stranded RNA of positive sense, wherein the self-replicating RNA.is alphaviral genomic RNA or is derived from alphaviral genomic RNA, and wherein the self-replicating RNA is a viral gene expression vector (page 47, lines 12-15), whereby assessment is done by dot blotting (Figures 1-2).
Baiersdorfer does not explicitly disclose a self-amplifying backbone.
Jooss, however, discloses non-natural nucleotides useful as 5' caps for RNA nucleotides and compositions and methods using delivery and vaccine RNA nucleotide compositions that include non-natural nucleotides as 5' caps (Abstract). Jooss is in the field of compositions and methods that allow for large scale synthesis of mRNAs (Para. [0004]), and teaches a self-amplifying backbone (wherein the self-amplifying expression system comprises a self-amplifying backbone, wherein the self-amplifying backbone comprises one or more polynucleotide sequences of a self-replicating RNA virus (Para. [0011]).
It would have been obvious to one of ordinary skill in the art, at the time of the claimed invention, to modify the composition of Baiersdorfer to further comprise the self-amplifying backbone of Jooss. One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success in order to obtain a composition comprising a nucleic acid sequence encoding an infectious disease organism peptide selected from the group consisting of ... a virus-derived peptide (Para. [0052]) for “delivery and vaccine RNA nucleotide compositions that include natural nucleotides as 5' caps (Abstract) for large scale synthesis of mRNAs (Para. [0004]). Therefore, the claimed invention would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention.
Regarding claims 35-36 and 155, Baiersdorfer discloses a pharmaceutical composition and a pharmaceutically acceptable carrier for administration of the composition to a subject (pages 48 lines33-36 to page 49 lines 1-21) such as priming expansion (page 46 lines 11-14).
Regarding claims 45, 50 and 52, Baiersdorfer discloses a method of reducing double stranded RNA (dsRNA) in a nucleic acid mixture (a positive purification procedure ... comprising [1] mixing the RNA preparation comprising ssRNA with the cellulose material under shaking and or stirring, preferably for at least 5 min. more preferably for at least 10 min; and [2] separating the cellulose material to which dsRNA and ssRNA are bound from the remainder, page 4, lines 3-6), the method comprising (A) purifying the self-amplifying expression system through a cellulose system (separating the cellulose material to which dsRNA and ssRNA are bound from the remainder, page 4, lines 3-6); and/or (B) producing the self-amplifying expression system such that the self-amplifying expression system comprises modified nucleosides (wherein RNA is in vitro transcribed RNA [IVT RNA], providing modified RNA {with} correspondingly modified nucleotides, such as modified naturally occurring nucleotides, non-naturally occurring nucleotides and/or modified non-naturally occurring nucleotides, page 34, lines 16-18; wherein these altered/modified nucleotides can be referred to as analogs of naturally-occurring nucleotides, and the corresponding RNAs containing such altered/modified nucleotides [i.e., altered/modified RNAs] can be referred to as analogs of naturally-occurring RNA page 33, lines 31-34); and wherein the self-amplifying expression system comprises a single-stranded RNA (ssRNA) vector, wherein the ssRNA vector comprises an m7G cap, and a polyA tail (wherein the self-replicating RNA is alphaviral genomic RNA or is derived from alphaviral genomic RNA, and wherein the self-replicating RNA is a viral gene expression vector, page 47, lines 12-15; wherein the ssRNA comprises an RNA 5'-cap, preferably the 7-methylguanosine cap [m7G], page 36, lines 29-30; a long poly-A sequence having a length of about 120 nucleotides results in an optimal transcript stability and translation efficiency of an RNA, preferably ssRNA, such as mRNA, page 38, lines 18-19). Baiersdorfer discloses methods for the removal of dsRNA contaminants from IVT mRNA (page 25 entirety and page 29, lines 16-37), and teaches cellulose chromatography (cellulose chromatography represents a new, alternative method to HPLC for the purification of IVT mRNA for removal of long dsRNA from IVT mRNA by cellulose chromatography, pages 29-30) and discloses the efficiency of dsRNA removal from IVT RNA by cellulose (20% or less of dsRNA, Examples 2-6); and purification of ssRNA, (Examples 6-9). Baiersdorfer teaches out of 100% of the pharmaceutical composition that the amount of the ssRNA will rang from about 0.01% to about 99% (page 60 lines 16-21). It would have been obvious for one of ordinary skill to determine the appropriate percentage of the protein in the composition of the methods disclosed by the prior art by routine experimentation procedures known in the art in order to achieve the maximum (production or activity or therapeutic) response from the composition. In view of Jooss, discloses large scale synthesis of mRNAs (Para. (0004]), and teaches a self-amplifying backbone (wherein the self-amplifying expression system comprises a self-amplifying backbone, wherein the self-amplifying backbone comprises one or more polynucleotide sequences of a self-replicating RNA virus, Para. [0011]). It would have been obvious to one of ordinary skill in the art, at the time of the claimed invention, to modify the method of Baiersdorfer to further comprise the self-amplifying backbone of Jooss. One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success to provide a proper method that is both cost effective and simple. Therefore, the claimed invention would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Barry Chestnut whose telephone number is (571)270-3546. The examiner can normally be reached on M-Th 8:00 to 4:00.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Thomas Visone can be reached on 571-270-0684. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/BARRY A CHESTNUT/Primary Examiner, Art Unit 1672
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