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 .
Claim Status
Claims 1-2, 4-5, 8, 15-16, 24-25, 29, 32-33, 36-37, 42-43 and 45 are currently pending in this application.
Election/Restrictions
Election was made without traverse of Group I, claims 1-2, 4-5, 8, 15-16, 24-25, 29, 32-33, 36-37, and 42-43, in the reply filed on July 13, 2026, and claim 45 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected subject matter, there being no allowable generic or linking claim. Claims 1-2, 4-5, 8, 15-16, 24-25, 29, 32-33, 36-37, and 42-43 have been considered on the merits.
Claim Objections
Claim 16 and 25 recites “CSE1” or “conserved sequence element 1 (CSE1)” whereas the same term throughout the claim set is “CSE 1” or abbreviated as “(CSE 1)”. Claim 32 recites “N1-methyl-pseudouridine” while all other instances in the other claims recites “1mΨ,” presumably meaning the exact same; it would be more logically consistent to use a single term or to denote somewhere in the claim set these are synonymous, if that is the intent. Appropriate correction is required.
Claim Interpretation
In the claims, the term “in vitro transcribed RNA molecule” is interpreted as a product-by-process limitation with no implied structure distinguishing such an RNA molecule from another RNA molecule made by a different process.
In the claims, the phrase “of interest” regarding the gene product or gene is interpreted as encompassing any gene product or gene as “of interest” is subjective as a personal view, preference or intention.
In claim 36, the phrase “nucleotide or nucleoside” is interpreted as modifying the word “modification” as in “nucleotide modification” or “nucleoside modification,” instead of “nucleotide” or “nucleoside modification” relative to the canonical four RNA residues.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1, 4, 15-16, 24-25, 29, 33, 37, and 42-43 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural product without significantly more. Based upon an analysis with respect to the claim as a whole, claims do not recite something significantly different than a judicial exception. The rationale for this determination is explained below.
The claims are to a composition (STEP 1: YES)
The claims are directed to compositions consisting primarily of nature-based products, an RNA molecule having a plurality of uridine bases, 5’ cap, 5’ regulatory region of an alphavirus, an open reading frame encoding a gene product, and one or more modified uridine bases wherein the very first 5’ occurring uridine is unmodified and wherein the RNA is replicable.
The preamble attempts to limit the claimed RNA molecule to only those which are “modified,” which could suggest a limitation to an anthropogenic intervention (manufacture) that causes the RNA to be modified (see e.g., instant pg. 26, lines 17-22; pg. 16, lines 23-34). However, the scope of “modified” as a limitation regarding a replicable RNA molecule is neither defined in the claims nor the instant specification. Rather, all the express limitations in the claims fail to exclude all naturally occurring RNA molecules as explained below. Furthermore, the instant application makes clear that the required “modified” uridine(s) of the RNA is the only “modification” needed to render the replicable RNA molecule to be categorized as “modified” (i.e., containing a modified nucleotide, see e.g., instant pg. 5, lines 14-20 and 6-9, pg. 1, lines 19-21; pg. 43-50), and as explained below, many of these “modified” uridines are naturally occurring modifications.
The art teaches that naturally occurring alphaviruses, such as Sindbis viruses (SINV), have native RNA genomic RNA molecules that are replicable and comprising a plurality of uridine bases, 5’ cap (m7GpppA), 5’ regulatory regions of an alphavirus (5’ UTRs), and two open reading frames encoding gene products of interest (e.g., nsP1-4 replicase and CP (CP, E3, E2, 6K/TF, and E1)) (Sokoloski et al., Virulence 17(1):2609389 (2026) at pg. 8, right col., to pg. 10, left col.; Fig. 3).
Regarding uridine modifications, in nature the alphavirus RNA is modified by host cell encoded pseudouridine synthases (e.g., dyskerin) and can result in pseudouridine (Ψ) located at positions throughout the genome from positions 89-11625, with the majority positioned 3’ of nsp4, e.g., at positions 9468, 9469 and 9470 (Stark et al., mBio 16(7):e0132925 (2025) at Abstract, Fig. 3-4; Table S2). Therefore, the balance of the evidence points to naturally occurring, SINV virus-infected host cells comprising replicable viral RNAs comprising modified uridines positioned 3’ to the dozen or so 5’ unmodified uridines (NC_001547 (NCBI reference 2018)). Thus, claim 1 encompass products of nature and lack any markedly different characteristic (STEP 2A prong 1: YES).
Regarding claims 15 and 25, the first modified uridine is at position 89 as noted above, which is past the CSE1 in the 5’ regulatory region of the NSP reading frame (first 44 nucleotide bases (see instant pg. 36, lines 14-23)), and thus there is no pseudouridine in the CSE1 (such as the first ten 5’ nucleotides thereof). Regarding claim 16, naturally occurring alphaviruses (Sindbis) have a 5’ cap within ten nucleotides of the CSE 1 as evidenced by NC_001547. Regarding claim 29, the art teaches the natural SINV genome comprises a 5’ cap with the sequence AU (NC_001547.1). Regarding claim 33, the art teaches the 5’ cap involves a modified G having a modified backbone (e.g., triphosphate bridge) (Sokoloski et al., (2026) at pg. 8, right col., last para.).
When examining Step 2A prong 2, the answer is ‘NO’ because the invention of claims 1, 4, 15-16, 24-25, 29, 33, 37, and 42-43 does not integrate the judicial exception into a practical application, such as when considered in the alternative as drafted for claims 16, 33 and 37. There are no other additional claim limitations recited in the dependent claims that would amount to significantly more than the judicial exception except in dependent claims 2, 5, 32, and 36.
Claim Rejections - 35 USC § 112(a), Written Description
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-2, 4-5, 8, 15-16, 24-25, 29, 32-33, 36-37, and 42-43 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The claimed invention as a whole is not adequately described if the claims require essential or critical elements that are not adequately described in the specification and that is not conventional in the art as of applicant’s effective filing date. Possession may be shown by actual reduction to practice, clear depiction of the invention in a detailed drawing, or by describing the invention with sufficient relevant identifying characteristics such that a person skilled in the art would recognize that the inventor had possession of the claimed invention. Pfaff v. Wells Electronics, Inc., 48 USPQ2d 1641,1646 (1998).
In making a determination of whether the application complies with the written description requirement under 35 U.S.C. 112(a) or 35 U.S.C. 112, first paragraph, it is necessary to understand what Applicant is claiming and what Applicant has possession of.
Claims 1, 5, and 15 are each directed to a modified replicable RNA molecule comprising at least one uridine that is a modified uridine so long as the 5’ most uridine is unmodified. It must be emphasized that for such an RNA comprising three or more uridines, the uridine modification patterns include wherein all but the 5’ most uridine is modified or any combination of modified and unmodified remaining uridines. As noted in claims 2, 5 and 25, patterns encompass sub-combinations wherein 5-99% of the remaining uridines are modified or unmodified.
The genus of “modified uridines” is broad encompassing any modified uridine and/or uridine analogue known in the prior art, which at least encompasses: N1-methyl-pseudouridine (1mΨ), pseudouridine (ψ), 5-methyl-uridine (m5U), 3-methyl-uridine (m3U), 5-methoxy-uridine (mo5U), 5-aza-uridine, 6-aza-uridine, 2-thio-5-aza-uridine, 2-thio-uridine (s2U), 4-thio-uridine (s4U), 4-thio-pseudouridine, 2-thio-pseudouridine, 5-hydroxy-uridine (ho5U), 5-aminoallyl-uridine, 5-halo-uridine (e.g., 5-iodo-uridine or 5-bromo-uridine), uridine 5-oxyacetic acid (cmo5U), uridine 5-oxyacetic acid methyl ester (mcmo5U), 5-carboxymethyl-uridine (cm5U), 1-carboxymethyl-pseudouridine, 5-carboxyhydroxymethyl-uridine (chm5U), 5-carboxyhydroxymethyl-uridine methyl ester (mchm5U), 5-methoxycarbonylmethyl-uridine (mcm5U), 5-methoxycarbonylmethyl-2-thio-uridine (mcm5s2U), 5-aminomethyl-2-thio-uridine (nm5s2U), 5-methylaminomethyl-uridine (mnm5U), 1-ethyl-pseudouridine, 5-methylaminomethyl-2-thio-uridine (mnm5s2U), 5-methylaminomethyl-2-seleno-uridine (mnm5se2U), 5-carbamoylmethyl-uridine (ncm5U), 5-carboxymethylaminomethyl-uridine (cmnm5U), 5-carboxymethylaminomethyl-2-thio-uridine (cmnm5s2U), 5-propynyl-uridine, 1-propynyl-pseudouridine, 5-taurinomethyl-uridine (τm5U), 1-taurinomethyl-pseudouridine, 5-taurinomethyl-2-thio-uridine (τm5s2U), 1-taurinomethyl-4-thio-pseudouridine), 5-methyl-2-thio-uridine (m5s2U), 1-methyl-4-thio-pseudouridine (m1s4ψ), 4-thio-1-methyl-pseudouridine, 3-methyl-pseudouridine (m3ψ), 2-thio-1-methyl-pseudouridine, 1-methyl-1-deaza-pseudouridine, 2-thio-1-methyl-1-deaza-pseudouridine, dihydrouridine (D), dihydropseudouridine, 5,6-dihydrouridine, 5-methyl-dihydrouridine (m5D), 2-thio-dihydrouridine, 2-thio-dihydropseudouridine, 2-methoxy-uridine, 2-methoxy-4-thio-uridine, 4-methoxy-pseudouridine, 4-methoxy-2-thio-pseudouridine, 3-(3-amino-3-carboxypropyl)uridine (acp3U), 1-methyl-3-(3-amino-3-carboxypropyl)-pseudouridine (acp3 ψ), 5-(isopentenylaminomethyl)uridine (inm5U), 5-(isopentenylaminomethyl)-2-thio-uridine (inm5s2U), α-thio-uridine, 2′-O-methyl-uridine (Um), 5,2′-O-dimethyl-uridine (m5Um), 2′-O-methyl-pseudouridine (ψm), 2-thio-2′-O-methyl-uridine (s2Um), 5-methoxycarbonylmethyl-2′-O-methyl-uridine (mcm5Um), 5-carbamoylmethyl-2′-O-methyl-uridine (ncm5Um), 5-carboxymethylaminomethyl-2′-O-methyl-uridine (cmnm5Um), 3,2′-O-dimethyl-uridine (m3Um), 5-(isopentenylaminomethyl)-2′-O-methyl-uridine (inm5Um), 1-thio-uridine, deoxythymidine, 2′-F-ara-uridine, 2′-F-uridine, 2′-OH-ara-uridine, 5-(2-carbomethoxyvinyl) uridine, and 5-[3-(1-E-propenylamino) uridine (instant pg. 48-50). The modified uridine genus also comprises wherein the uridine base comprises a sugar modification (e.g., arabinose, alkoxy or aryloxy (—OR, e.g., R═H, alkyl, cycloalkyl, aryl, aralkyl, or heteroaryl); polyethyleneglycols (PEG), -O(CH2CH2 O)nCH2CH2 OR, methylene bridge; -O -alkylamino, dialkylamino, heterocyclyl, arylamino, diarylamino, heteroarylamino, or diheteroaryl amino; ethylene diamine, polyamino) or aminoalkoxy; or a thiol group, an alkyl group, or a halo group (pg. 43-50).
In analyzing whether the written description requirement is met for genus claims, it is first determined whether a representative number of species have been described.
In the instant case, the instant specification provides methods of incorporating modified uridines into an RNA molecule during in vitro transcription by controlling the presence of UTP options (exemplified with only a single species, N1-methyl-pseudouridine) (Example 2); however this description is silent as to how to achieve the scope of partial incorporation patterns encompassed by the claims such as between 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% of the uridines in the molecule except for the 5' most uridine or how to achieve selective modifications of one or more most 5’ uridines of a sub-element (e.g., CSE 1, cap, and/or 5’ regulatory region).
While the prior art teaches making RNA molecules with modified uridine bases, such as during polymerization in vitro or via chemical side chain reactions (e.g., methylation or acetylation) or a uridine-modifying enzyme (synthase) and/or combined with enzymatic RNA ligation (see e.g., Pardi et al., Methods Mol Biol 969: 29-42 (2013) at pg. 31; Depmeier et al., Chembiochem 22: 2826-47 (2021) at Fig. 1, pgs. 2829 and 2831), the instant description lacks any guidance as to how to use prior art methods to achieve the full scope of the genus of aforementioned patterns and modified uridines.
The prior art directly teaches the above approaches for a few species described in the instant disclosure, namely N1-methyl-pseudouridine (1mΨ), pseudouridine (ψ), 5-methyl-uridine (m5U), and 2-thiouridine (s2U), the prior art does not address every individual uridine modification species proposed by the written description. While in vitro transcription using mixed pools of uridine species (unmodified and modified) can produce RNAs comprising randomly blended unmodified and modified uridine bases, this has no precise control in the prior art or as taught in the instant disclosure. Similarly, while solid phase synthesis can be used to make a synthetic RNA with any sequence of modified uridines desired, the length of such RNAs are limited to sizes (e.g., <100 bases) excluding the vast majority of open reading frames of interest (id.). Thus, while incorporating modified uridines/uridine analogues of various structures into an in vitro transcribed RNA was understood by the skilled worker, this understanding falls short of the full variety of modified uridine species and diverse unlimited patterns of modified and unmodified uridine distributions throughout the RNA encompassed by the claims.
For example, the prior art does not provide routine methods of making RNAs having, inter alia, isopentenyl-derivatized uridines, 5-taurinomethyluridine, 1-taurinomethyl-pseudouridine, 5-taurinomethyl-2-thiouridine, cm5U, cmnm5U, or chm5U. Further, the prior art does not teach incorporating such modifications in a site-specific manner, e.g., avoiding the first 5’ uridine or the first 2 to 10 5’ uridines within a subregion (e.g., 5’ regulatory region or CSE 1). The instant description does not provide this missing information over the scope of modified uridines encompassed by the claims. However, applicant is invited to furnish evidence to the contrary.
The skilled artisan could not rely upon the disclosure in the specification such that the specification would sufficiently describe that Applicant was in possession of the entire scope of the invention as claimed.
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 1-2, 4-5, 8, 15-16, 24-25, 29, 32-33, 36-37, and 42-43 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 pre-AIA the applicant regards as the invention.
Claims 1, 5, and 15, each recites a “modified” replicable RNA molecule, which is ambiguous and unclear as the term “modified” is a relative term and modified compared to what is not specified, such as regarding a reference or parental RNA molecule for comparison. Claims 2, 4, 8, 16, 24-25, 29, 32-33, 36-37, and 42-43 are included in the rejection for depending from an indefinite claim.
Claims 2, 4-5, 8, 24-25, 29, and 33 each recite the term “preferably,” which is ambiguous and unclear as to whether the language after “preferably” is a limitation or optional feature.
Claim 4, 8, and 24 each recites “RNA-dependent RNA polymerase (replicase),” which is not clear if what is within the parenthesis recites a claim limitation or an optional feature(s).
Claim 5 recites “the remaining,” which is not clear, it implies there is already antecedent for at least one uridine in addition to the single uridine in the recited sequence; however, this is ambiguous as neither the 5’ regulatory region nor the ORF is expressly required to comprise a single uridine. Moreover “remaining” appears to be an idiomatic expression for all the other uridines, the unmentioned uridines, yet to be specified uridines, etc. or perhaps any other uridine, if present. Claim 8 is included in this rejection for depending from an indefinite claim.
Claim 8 recites “in conserved sequence element 1 (CSE1)”, which lacks sufficient antecedent basis.
Claims 15 recites “the ten 5’ nucleotides” and “of conserved sequence element 1 (CSE 1),” which lack sufficient antecedent basis.
Claim 29 recites “NpppNU” and “NpppAU” as RNA sequences, however the symbols or nomenclature used like ‘N’ and ‘p’ are not clearly defined in the claims (in contrast, ‘A’ and ‘U’ are both unambiguous).
Claim 33 recites “optionally and/or wherein,” which is ambiguous and unclear as to whether the language after optionally is a wherein limitation or optional feature.
Claim 37 recites the terms “SFV” and “VEEV,” which is unclear. These terms are not defined in the claims. If these are abbreviations, then each needs to be spelled out at least once in the claim set.
Claim 37 recites “antigen (tumor, viral, bacterial, fungal, allergen),” which is not clear if what is within the parenthesis recites a claim limitation or an optional feature(s), such as in the form of non-limiting examples.
Claim 37 recites “the gene of interest,” which lacks sufficient antecedent basis in the claim or a claim from which it depends. Claim 37 also recites “the encoded RNA-dependent RNA polymerase,” which lacks sufficient antecedent basis in the claim or claim 1 from which it depends.
Claim 42 recites “formulated” with lipids, which is not defined in the claims or the specification and thus is unclear as to the metes and bounds of a composition comprising a lipid and the recited RNA molecule that is formulated versus one that is not considered “formulated.”
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 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 1, 4, 15-16, 24-25, 32-33, 37, and 42-43 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Sahin (WO2020144295A1; IDS ref.) as evidenced by Stark (Stark et al., mBio 16: e0132925 (2025)) and NC_001547 (NCBI Reference Sequence: NC_001547 (2018)).
Regarding claim 1, Sahin discloses a self-replicating RNA molecule expression vector derived from a natural RNA alphavirus which replicates in a host cell (e.g, an insect, mammalian, or human cell) (such as a Sindbis, Semliki Forest, or Venezuelan equine encephalitis virus) wherein the RNA has a 5’ regulatory region of the alphavirus at the natural region including four conserved sequence elements, two or more ORFs encoding products (pg. 26-29 and 32-33) (such as those native to the alphavirus and/or a peptide or polypeptide of interest) (pg. 9, 40), and a 5’ cap (pg. 18), wherein the RNA is made with pseudouridines, e.g., substituted partially for uridine to reduce immunogenicity (pg. 19-21).
Although Sahin does not expressly disclose the first 5’ uridine in the RNA is not modified, Stark teaches alphavirus genomes are modified by host cell synthases (e.g., dyskerin) to have pseudouridines (Ψ) located at positions dispersed throughout the RNA, and in the case of a prototype Sindbis viruses from positions 89-11625 (Abstract, Fig. 3-4; Table S2) but leaving the first dozen or so 5’ uridines unmodified (prior to position 89) in view of NC_001547. Sahin discloses alphavirus genomes in host cells are naturally provided with a 5’ cap. Thus, Sahin discloses an RNA molecule with all the features recited in instant claim 1.
Regarding claim 4, Sahin discloses the alphavirus genome inherently has a ORF encoding non-structural proteins 1, 2, 3, and 4 (nsp1234 and nsp123 polyproteins) forming an RNA-dependent RNA polymerase (alphavirus replicase) (pg. 27-28).
Regarding claims 15 and 24, as evidenced by NC_001547, the first ten 5’ uridines of the CSE 1 all occur in the unmodified region 5’ to position 89; and as mentioned just prior, Sahin discloses the alphavirus genome inherently has a ORF encoding non-structural proteins 1, 2, 3, and/or 4 forming an RNA-dependent RNA polymerase (alphavirus replicase) (pg. 27-28).
Regarding claim 16, naturally occurring alphaviruses (Sindbis) have a 5’ cap within ten nucleotides of the CSE 1 as evidenced by NC_001547.
Regarding claim 25, Stark and NC_001547 teaches alphavirus Sindbis genomic RNAs are modified by host cell synthases to have pseudouridines (Ψ) located at numerous positions throughout positions 89-11625 (Abstract, Fig. 3-4; Table S2) but leaving the first dozen or so 5’ uridines unmodified prior to position 89, which includes the entire CSE 1 5’ regulatory region.
Regarding claim 32, Sahin discloses including N1-methyl-pseudouridine in the RNA, as partially replacing some uridines (pg. 19-21).
Regarding claim 33, Sahin discloses wherein the RNA has a 5’ cap comprising a modified backbone of a guanosine bonded to the neighboring nucleotide via a 5’ to 5’ triphosphate linkage (pg. 16, 18).
Regarding claim 37, Sahin discloses including an ORF encoding a therapeutic polypeptide or nucleic acid as well as, or alternatively, wherein the 5’ regulatory region and alpha virus replicase are from the same alphavirus (Sindbis) (pg. 58, pg. 26-33).
Regarding claims 42-43, Sahin discloses manufacturing the RNA in a host cell and preparing the RNA in a pharmaceutical composition comprising pharmaceutically acceptable carriers and/or excipients formulated for administering to a recipient, such as a lipid-based delivery vehicle (pg. 48-49).
Thus, Sahin as evidenced by Stark and NC_001547 anticipates the claimed invention.
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, 4-5, 8, 15-16, 24-25, 32-33, 36-37, and 42-43 are rejected under 35 U.S.C. 103 as being unpatentable over Sahin as evidenced by Stark and NC_001547, and in view of Nance (Nance and Meier, ACS Cent Sci. 7: 748-56 (2021)).
As set forth fully above, Sahin as evidenced by Stark and NC_001547 anticipates claims 1, 4, 15-16, 24-25, 32-33, 37 and 42-43 and, thus, renders obvious the subject matter of claims1, 4, 15-16, 24-25, 32-33, 37 and 42-43.
Sahin teaches making self-replicating RNA molecules derived from RNA alphavirus in a host cell (e.g., an insect or mammalian cell) and having a 5’ cap, a 5’ regulatory region of the alphavirus, and an ORF encoding a product of interest (e.g., a therapeutic polypeptide) as an engineered expression vector wherein modified uridines are substituted partially for some of the unmodified uridines to reduce immunogenicity (pg. 9, 18-21, 26-29, 32-33, and 40).
Regarding claims 2 and 32, Sahin (pg. 19-21) teaches modifying the bases of the RNA non-immunogenic so as not to induce a response by the immune system upon administration, e.g., to a mammal, such as by incorporating modified uridine or uracil nucleotides suppressing RNA-mediated activation of innate immune receptors into the RNA, including selecting 1mΨ (N-1-methyl-pseudouridine). Regardless, Sahin does not expressly teach wherein at least 5% of the uridines in the RNA are 1mΨ (N1-methylpseudouridine) excluding the single most 5’ uridine.
However Nance teaches the modified uridine residue 1mΨ (m1Ψ) specifically provides less immunogenic potential for expression vectors used in mammals (enhancing immune evasion) while also improving expression/production (pg. 751-752; Fig. 2, 4). In particular, Nance teaches 1mΨ has less innate immune receptor activation via TLR3/TLR7 and does not suggest having 1mΨ at the most extreme 5’ end of a therapeutic RNA (id.).
It would have been prima facie obvious to one of ordinary skill in the art before the effective time of filing to design the RNA taught by Sahin to comprise a large number of 1mΨ residues in lieu of unmodified uridines to reduce chances of triggering innate immune responses, such as by substituting 5-50% or more of unmodified uridines. One of ordinary skill in the art would be motivated by Sahin teaching suppressing innate immune receptor activation and Nance touting 1mΨ as a very successful structure for achieving this as already demonstrated in the prior art while simultaneous improving expression (such as over natural uridine analogues like methoxyuridine).
Regarding claim 5, although the combination Sahin, Nance, Stark and NC_001547 does not teach wherein the RNA expressly comprises the sequence AUGGCGGA or AUGGGCGG, as it is obvious to engineer into the RNA vector an exogenous ORF of interest encoding any gene product of interest, it would have been prima facie obvious to one of ordinary skill in the art before the effective time of filing to design the RNA with an ORF having the starting sequence AUGGCGGA or AUGGGCGG as the translation initiation start site wherein the gene product of interest is a polypeptide beginning with the sequence methionine-alanine or methionine-guanine, respectively.
Regarding claim 8, the natural Sindbis viral genome comprises another ORF encoding an alphavirus replicase, which is required for replication and so would be maintained when deriving a replicable vector therefrom, and, in a host cell, the RNA vector would comprise at least one additional nucleotide 5’ to the start site in the guanosine residue of the 5’ cap due to the host capping modifications mentioned already herein.
Regarding claim 36, Sahin teaches including 1mΨ residues but does not expressly teach wherein there is no other uridine modification present. However, it would have been prima facie obvious to one of ordinary skill in the art before the effective time of filing to design the RNA taught by Sahin to comprise 1mΨ residues to reduce chances of triggering innate immune responses and improve expression by substituting every pseudouridine with 1mΨ thereby preserving the naturally evolved alphavirus modified-U pattern taught by Stark. One of ordinary skill in the art would be motivated by Sahin teaching suppressing innate immune receptor activation and Nance touting 1mΨ as superior to pseudouridine, which already occurs in a specific pattern in host cells.
Thus, the claimed invention as a whole is prima facie obvious before the effective filing date in the absence of evidence to the contrary.
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 USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The 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/process/file/efs/guidance/eTD-info-I.jsp.
Claims 1-2, 4, 32-33, 36-37, and 42-43 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 13, 20, 23, 27, 38, 54, 58, and 68 of the “reference” application US 18/702,287 as evidenced by Sokoloski (Sokoloski et al., Virulence 17(1):2609389 (2026)).
Claim 38 of the reference patent is directed to a replicable RNA (rRNA) molecule comprising a modified 5' regulatory region of a self-replicating alphavirus (e.g., a Sindbis virus, SFV, EEEV or VEEV), such as encoding (ORF) a replicase or gene of interest (as in claim 27 or 54) and comprising at least one modified nucleotide (claim 27 or 36) wherein the modified nucleotide is N1-methyl-pseudouridine (1mΨ), such as at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% of all uridines of the molecule (claims 62 and 13).
Claims 1-2, 32 and 36-37 in the instant application differ from the claims of the reference patent in that there must be a 5’ cap and the first 5’ uridine is unmodified. However, the reference claims teach wherein only a small percentage (e.g., between one residue and just 10%) of the uridines are modified (e.g., as 1mΨ). Thus, this teaches wherein the only modified uridine is in the middle or end of the molecule and the first 5’ uridine is unmodified. Regarding the presence of a 5’ cap, based on the prior art methods of making alphavirus RNA vectors like Sindbis vectors, such as in an infected host cell, a 5’ cap would inherently be present as evidenced by Sokoloski teaching a host factor added 5’ cap (m7GpppA) (pg. 8; Fig. 3).
Regarding instant claim 4, reference claims 20, 23, 54, and 58 teach wherein the molecule comprises two ORFs (as in claim 27 or 54) for the gene of interest and an alphaviral replicase from or derived from an alphavirus (SFV, VEEV, EEEV or Sindbis virus), which is comprised of non-structural proteins 1, 2, 3 and 4.
Regarding instant claim 33, reference claim 13 teaches wherein the modified nucleotide includes a modified adenine, guanine or cytosine residue.
Regarding instant claim 42-43, reference claim 68 teaches the molecule in a pharmaceutical composition comprising a pharmaceutically acceptable carrier, pharmaceutically acceptable excipient, and/or formulated with lipids.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ERIC J ROGERS whose telephone number is (571)272-8338. The examiner can normally be reached Monday - Friday 9:00-6:00.
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/ERIC J ROGERS/
Examiner, Art Unit 1638
/Tracy Vivlemore/Supervisory Primary Examiner, Art Unit 1638
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