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
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1-2, 4-7, 9, 13, 16-17, 19, 21, 35-36 in the reply filed on 02/25/2026 is acknowledged.
Claims 3, 14, 18, 20, 22-24, 30-33 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 02/25/2026.
Applicant’s election with traverse of species elections in the reply filed on 02/25/2026 is acknowledged. Applicant traverses the species requirement only to the effect of comparing the examiner’s assertions under PCT Rule 13.2 on page 6 of the Requirement and the examiner’s assertion on page 7 that ‘applicant will be entitled to consideration of claims to additional species’. Applicant respectfully disagrees with the former assertion -this is a species requirement – and agrees with the latter assertion -additional species should be considered. Applicant elected from claim 13, i. a polypeptide that comprises SEQ ID NO: 17 and from claim 16, i. the sequence of SEQ ID NO: 8. In response, the species restriction is considered proper according to lack of unity standard as indicated. The claims are examined according to their election; withdrawn species will be considered consistent with Restriction practice as examination proceeds, as appropriate.
Claims 1-2, 4-7, 9, 13, 16-17, 19, 21, 35-36 are under consideration.
Priority
Priority to provisional application 63/129/837 and filing date of 12/23/2020 is acknowledged for examination purposes.
Information Disclosure Statement
The information disclosure statement (IDS) submitted 06/22/2023 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code on page 7. 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.
The disclosure is objected to because of the following informalities:
VP35, N, NS1 viral identities are defined in the text and by their SEQ ID NOs:. However, “E3” is only defined by its SEQ ID NO: 23. Clarify “E3” without adding new matter.
Appropriate correction is required.
Claim Objections
Claims 4, 6, 9, 17, and 19 are objected to because of the following informalities:
Claim 4: Remove the extra space between “1” and the comma. For example, it should read “claim 1,”.
Claim 6: Change “TC83” to “TC-83 for consistency with the specification.”
Claim 9: Add a “the” before “self-replicating mRNA “.
Claim 17: Change “cap 1” to “cap 1 structure” for increased clarity.
Claim 19: Change “N1-methylpseudouridines” to “N1-methylpseudouridine”. 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 1-2, 4-7, 9, 13, 16, 17, 19, 21, 35-36 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.
See claims 1-2, 4-7, 9, 13, 16, 17, 19, 21, 35-36 as submitted 02/25/2026.
Claims 1, 2, 35 all recite different polypeptides like VP35, N, etc. and also recite “or a variant or fragment thereof” but without any indication of the virus, if appropriate, from which they are derived. Additionally, the specification does not provide additional clarity as to the metes and bounds of “variant”, thus making these claims unclear.
Claim 1: As written, especially with the (i) and (ii) numbering, it is unclear if (i) and (ii) are separate components of the mRNA or if the “construct” actually consists of the first heterologous polypeptide interferon effector and a polypeptide antigen-encoding region, an antigen-binding polypeptide encoding region, etc.
Claim 2: Other than providing SEQ ID NO: 23 in the specification, without additional text and explanation, it is unclear what E3 is or from what virus it is derived. E3 appears to be from an Orthopoxvirus based on sequence homology but it is not clear.
Claims 6 and 7: For both claims, the TC-83 comparative sequence, especially for the NSP3 region, is not identified in the claim. As a result, it is not clear what the position numbers are relative to or what/where position 1, for example is located with respect to the amino acid substitutions.
Claim 7: It is unclear if the claim should read “RNA” or “mRNA” sequence encoding.
Claim 13: Claim 13, as written, is dependent on claim 1. However, SEQ ID NO: 17 matches claim 2. c. NS1. The dependency is unclear.
Claim 21: It is unclear if “self-replicating messenger RNA (mRNA)” as recited in claim 1 is being used interchangeably with “self-replicating RNA” as recited in claim 21.
Claim 36: The phrase “the mRNA can be amplified in trans by in the presence of the replicase is unclear. Additionally, it is unclear if the replicase activity refers to a self-amplifying RNA mechanism or a trans-amplifying RNA mechanism. The disclosure does not appear to encompass trans-amplifying mRNA mechanisms such as trans replicons. “Trans-replicated mRNA” is only mentioned on page 1, under the Background to the 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.
Claims 1, 2, 9, 21, 35-36 are rejected under 35 U.S.C. 103 as being unpatentable over Geall et al. (Geall)(US 20110300205A1)(See PTO-892 Notice of References Cited) in view of Hart et al. (Hart)(WO200000617A2) (cited in the IDS submitted on 06/22/2023) in view of Magini et al. (Magini)(See PTO-892 Notice of References Cited) and in view of Hekele et al. (Hekele) (See PTO-892 Notice of References Cited).
See claims 1, 2, 9, 21, 35-36 as submitted 02/25/2026.
Regarding claims 1 and 2, and 9, Geall teaches that self-replicating RNA molecules, which replicate in host cells leading to an amplification of the amount of RNA encoding the desired gene product, can enhance efficiency of RNA delivery and expression of the encoded gene products [0006]. Preferably, the self-replicating RNA molecules contain a heterologous sequence encoding gene product, such as a target protein (e.g., an antigen) or an RNA (e.g., a small RNA). The self-replicating RNA generally contains at least one or more genes selected from the group consisting of viral replicase, viral proteases, viral helicases and other nonstructural viral proteins, and also comprise 5'- and 3'-end cis-active replication sequences, and if desired, a heterologous sequence that encode a desired amino acid sequences (e.g., a protein, an antigen). A subgenomic promoter that directs expression of the heterologous sequence can be included in the self-replicating RNA. If desired, the heterologous sequence may be fused in frame to other coding regions in the self-replicating RNA and/or may be under the control of an internal ribosome entry site (IRES) [0057]. Geall also teaches a self-replicating RNA molecule useful with the invention may have two open reading frames. The first (5') open reading frame encodes a replicase; the second (3') open reading frame encodes a desired gene product. In some embodiments the RNA may have additional (downstream or upstream) open reading frames e.g. that encode further desired gene products, which can be under the control of an IRES.
Geall also teaches “Exemplary gene products that can be encoded by the self-replicating RNA molecule include proteins and peptides from pathogens, such as bacteria, viruses, fungi and parasites, including malarial surface antigens and any antigenic viral protein”…[and] exemplary gene products that can be encoded by the self-replicating RNA molecule include any desired eukaryotic polypeptide such as, for example, a mammalian polypeptide such as an enzyme, e.g., chymosin or gastric lipase; an enzyme inhibitor, e.g., tissue inhibitor of metalloproteinase (TIMP); a hormone, e.g., growth hormone; a lymphokine, e.g., an interferon; a cytokine, e.g., an interleukin (e.g., IL-2, IL-4, IL-6 etc.); a chemokine, e.g., macrophage inflammatory protein-2; a plasminogen activator, e.g., tissue plasminogen activator (tPA) or prourokinase; or a natural, modified or chimeric immunoglobulin…or any desired combinations [0076] (as recited in claim 1. ii.). Geall further teaches [s]uitable antigens include proteins and peptides from a pathogen such as a virus, bacteria, fungus, protozoan, plant or from a tumor. Viral antigens that can be…from a Orthomyxoviruses, such as Influenza A [0130].
Regarding claim 21, Geall teaches “a self-replicating RNA molecule that contains modified nucleotides can be prepared by transcribing (e.g., in vitro transcription) a DNA that encodes the self-replicating RNA molecule using a suitable DNA-dependent RNA polymerase, such as T7 phage RNA polymerase, SP6 phage RNA polymerase, T3 phage RNA polymerase, and the like, or mutants of these polymerases which allow efficient incorporation of modified nucleotides into RNA molecules. The transcription reaction will contain nucleotides and modified nucleotides, and other components that support the activity of the selected polymerase, such as a suitable buffer, and suitable salts. The incorporation of nucleotide analogs into a self-replicating RNA may be engineered, for example, to alter the stability of such RNA molecules, to increase resistance against RNases, to establish replication after introduction into appropriate host cells (“infectivity” of the RNA), and/or to induce or reduce innate and adaptive immune responses” [0077].
Regarding claim 35, Geall teaches “the self-replicating RNA molecule is encapsulated in, bound to or adsorbed on a cationic lipid, a liposome”[0025].
Regarding claim 36, Geall teaches “[o]ne suitable system for achieving self-replication is to use an alphavirus-based RNA replicon. These +-stranded replicons are translated after delivery to a cell to give of a replicase (or replicase-transcriptase). The replicase is translated as a polyprotein which auto-cleaves to provide a replication complex which creates genomic −-strand copies of the +-strand delivered RNA. These −-strand transcripts can themselves be transcribed to give further copies of the +-stranded parent RNA and also to give a subgenomic transcript which encodes the desired gene product. Translation of the subgenomic transcript thus leads to in situ expression of the desired gene product by the infected cell. Suitable alphavirus replicons can use a replicase from a sindbis virus, a semliki forest virus, an eastern equine encephalitis virus, a venezuelan equine encephalitis virus, etc. [0060].
Geall does not teach specific interferon effectors like Ebola’s VP35 or Influenza A’s NS1.
Regarding claims 1 and 2, Hart, however, teaches a self-replicating RNA comprising the VEE virus replicon and any of the Ebola Zaire 1976 (Mayinga isolate) RNAs encoding the GP, NP, VP24, VP30, VP35, and VP40. Proteins (as recited in claim 1). The RNA can be used as a vaccine for protection from Ebola infection. When the RNA is packaged, a VEE virus replicon particle is produced. Hart also teaches: when the replicon RNA or DNA is used as a vaccine, the replicon RNA or DNA can be administered directly using techniques such as delivery on gold beads (gene gun), delivery by liposomes, or direct injection, among other methods known to people in the art. Any one or more DNA constructs or replicating RNA described above can be use in any combination effective to elicit an immunogenic response in a subject.
Hart does not teach proteins from other viruses such as Influenza A or Porcine Reproductive and Respiratory Syndrome Virus (PRRSV).
Magini, however, teaches administration of novel self-amplifying mRNA (SAM) vectors expressing influenza NP (SAM(NP)), M1 (SAM(M1)), and NP and M1 (SAM(M1-NP)) delivered with lipid nanoparticles (LNP) induced robust polyfunctional CD4 T helper 1 cells, while NP- containing SAM also induced cytotoxic CD8 T cells (Abstract, p. 1).
Hekele further teaches the SAM vaccine platform with influenza antigens and also suggests “the SAM vaccine platform could offer a potential solution for a wide range of additional pathogens” (p. 6).
One of ordinary skill in the art would have been motivated, as Hekele suggests, to use the SAM vector with antigens beyond influenza, and instead, use a heterologous polypeptide interferon effector from Ebola, such as VP35 as taught by Hart as well as a heterologous polypeptide from influenza as taught by Magini but with substituting the matrix protein 1("M1") with an interferon effector, the NS1 protein, or a variant or a fragment thereof (as recited in claim 3) in order to effect or modulate an interferon response either to reduce interference or in some cases, elevate an interferon response. Furthermore, one would have been motivated to also make a construct with one or more antigens as taught by Geall and Magini or antigens from additional pathogens as taught by Hekele (See MPEP 2143, Rationale A. Combining prior art elements according to known methods to yield predictable results and Rationale B. Simple substitution of one known element for another to obtain predictable results).
One of ordinary skill in the art would have had a reasonable expectation of success for using the self-replicating RNA molecules or SAM replicons and both Ebola and Influenza antigens within a construct as taught by Geall, Hart, Magini and Hekele. There would have been a reasonable expectation of success given the underlying materials and methods are known, successfully demonstrated in the context of RNA vaccinology, therapeutics and/or immunity, and commonly used as evidenced by the applied prior art.
Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention.
Claims 4-7 are rejected under 35 U.S.C. 103 as being unpatentable over Geall in view of Hart, Magini and Hekele, as applied to claim 1 above, and further in view of Pepini et al. (Pepini)(See PTO-892 Notice of References Cited) and in view of Irvine et al. (Irvine)(US20200224174A1)(See PTO-892 Notice of References Cited).
See claims 4-7 as submitted 02/25/2026.
Geall, Hart, Magini and Hekele teach claim 1. Geall also teaches “self-replicating RNA molecules of the invention contain modified nucleotides and therefore have improved stability and are resistant to degradation and clearance in vivo. The presence of one or more modified nucleotides in the self-replicating RNA also provides other advantages. Unexpectedly, self-replicating RNA molecules that contain modified nucleotides retain the ability to self-replicate in cells and, thus, can be used to induce expression and over expression of encoded gene products, such as RNA or proteins (e.g., an antigen) encoded by the self-replicating RNA...The self-replicating RNA molecules of the invention contain modified nucleotides and have reduced capacity to stimulate the innate immune system. This provides for enhanced safety of the self-replicating RNA molecules of the invention and provides additional advantages. For example, a large dose of the self-replicating RNA molecules of the invention can be administered to produce high expression levels of the encoded gene product before the self-replicating RNA molecule is amplified in the hosts cells, with reduced risk of undesired effects, such as injection site irritation and or pain [0044].
Regarding claim 4, Pepini teaches the SAM vaccine platform technology and that “modulating the early effects of the innate immune response is a key area for further investigation. Potential strategies to facilitate this in a vaccine include RNA sequence modification to generate IFN-insensitive RNA, novel formulations to optimize delivery of RNA vaccines in a way to minimize the consequences of interactions with innate immune sensors, and small-molecule modulators that target various points of the IFN signaling cascade” (p. 4023).
Pepini does not teach the specific amino acid substitutions.
Regarding claim 5, Irvine teaches mutations in the nonstructural genes of an alphavirus replicon, Venezuelan Equine Encephalitis, that increase the strength and persistence of expression of the replicon genome (p.1, Abstract). Irvine also teaches FIG. 1C (p.2) showing amino acid mutations, in the NSP3 region.
Regarding claims 6-7, Irvine references replicons derived from Venezuelan Equine Encephalitis (VEE) as evidenced in Wroblewska et al. (2015)(See PTO-892 Notice of References Cited) who worked with TC-83. Irvine teaches E1595D and V1645M amino acid mutations in the NSP3 region in FIG. 1C (p.2) and Table 1 (p. 83)(as recited in claim 6) and the corresponding G4796T and G4944A nucleotide substitutions in Table 1 (p.83)(as recited in claim 7).
One of ordinary skill in the art would have been motivated to construct a self-replicating mRNA sequence where the NSP3 region has the modifications as taught by Irvine since they appear to be the same as those in the instant application and because Irvine and Geall both suggests that replicon mutations appear to enhance replicon persistence and subgenomic expression of the therapeutic agent (See MPEP 2143, Rationale B. Simple substitution of one known element for another to obtain predictable results).
One of ordinary skill in the art would have had a reasonable expectation of success for making the mutations as taught by Pepini and Irvine. There would have been a reasonable expectation of success given the underlying materials and methods are known, successfully demonstrated in the context of RNA replication, vaccinology, and/or immunity, and commonly used as evidenced by the applied prior art.
Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention.
Claim 13 is rejected under 35 U.S.C. 103 as being unpatentable over Geall in view of Hart, Magini and Hekele, as applied to claim 1 above, and further in view of Crea et al. (Crea)(WO2007127290-A2)(See PTO-892 Notice of References Cited).
See claim 13 as submitted 02/25/2026.
Geall, Hart, Magini and Hekele teach claim 1 but do not teach a peptide that comprises SEQ ID NO: 17.
Crea, however, teaches a method for producing a vaccine or therapeutic composition against infection by an influenza A virus and the Nonstructural protein 1 (NS1) SEQ ID NO: 31, with a 100% identity to instant application SEQ ID NO: 17 (See result #1, ANY92650, us-18-269-120-17.minpct90.rag, in supplemental tab).
One of ordinary skill in the art would have been motivated to use the influenza NS1 polypeptide as taught by Crea since it is a 100% match with that of the instant application and as Crea teaches, “Recent analyses have established that the nonstructural NS1 protein of influenza A virus (termed NS1-A) is a major force that antagonizes activation of PKR and the expression of early defense genes, including IFN-β”(p.12). (See MPEP 2143, Rationale B. Simple substitution of one known element for another to obtain predictable results).
One of ordinary skill in the art would have had a reasonable expectation of success for substituting the NS1 polypeptide as taught by Crea. There would have been a reasonable expectation of success given the underlying materials and methods are known, successfully demonstrated in the context of influenza vaccinology and host immune defense interactions, and commonly used as evidenced by the applied prior art.
Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention.
Claim 17 is rejected under 35 U.S.C. 103 as being unpatentable over Geall, in view of Hart, Magini and Hekele, as applied to claim 1 above, and further in view of Capone et al. (Capone)(WO2020121273A1)(See PTO-892 Notice of References Cited).
See claim 17 as submitted 02/25/2026.
Geall, Hart, Magini and Hekele teach claim 1 and teach encapsulation in a liposome but do not teach comprises a cap 1.
Capone, however, teaches “Self-amplifying RNA,”“self-replicating RNA” and “RNA replicon” are used interchangeably to mean RNA with the ability to replicate itself. The term “self-amplifying RNA vector” refers to a self-amplifying RNA capable of introducing a polynucleotide into a cell. The self-amplifying RNA vectors of the invention comprise mRNA encoding one or more antigens (p. 17). Capone also teaches the “cap 0 structure plays an important role in maintaining the stability and translational efficacy of the RNA molecule. The 5' cap of the RNA molecule may be further modified by a 2 '-O-Methyltransferase which results in the generation of a cap 1 structure (m7Gppp [m2 '-O] N), which may further increase translation efficacy” (p. 12).
One of ordinary skill in the art would have been motivated to modify the RNA molecule to generate a cap 1 structure as taught by Capone in order to increase translation efficacy (See MPEP 2143, Rationale A. Combining prior art elements according to known methods to yield predictable results).
One of ordinary skill in the art would have had a reasonable expectation of success for making the modification to the RNA molecule to generate a cap 1 structure in order to increase translation efficacy as taught by Capone. There would have been a reasonable expectation of success given the underlying materials and methods are known, successfully demonstrated in the context of self-amplifying RNA technology, mRNA therapeutics and RNA delivery, and commonly used as evidenced by the applied prior art.
Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention.
Claim 19 is rejected under 35 U.S.C. 103 as being unpatentable over Geall in view of Hart, Magini and Hekele, as applied to claim 1 above, and further in view of Svitkin et al. (Svitkin)(See PTO-892 Notice of References Cited).
See claim 19 as submitted 02/25/2026.
Geall, Hart, Magini and Hekele teach claim 1 but do not teach that the self-replicating mRNA comprises at least one N1-methylpseudouridine.
Svitkin, however, teaches that N1-methyl-pseudouridine (N1mΨ) outperforms several other nucleoside modifications and their combinations in terms of translation capacity. Svitkin also shows that in addition to turning off the immune/eIF2α phosphorylation-dependent inhibition of translation, the incorporated N1mΨ nucleotides dramatically alter the dynamics of the translation process by increasing ribosome pausing and density on the mRNA…and that the increased ribosome loading of modified mRNAs renders them more permissive for initiation by favoring either ribosome recycling on the same mRNA or de novo ribosome recruitment (p. 6023, Abstract).
One of ordinary skill in the art would have been motivated to make the nucleoside modification as taught by Svitkin because the modifications could confer stability and low immunogenicity and facilitate the expression of desired antigens (See MPEP 2143, Rationale Rationale A. Combining prior art elements according to known methods to yield predictable results).
One of ordinary skill in the art would have had a reasonable expectation of success for making the nucleoside modification as taught by Svitkin. There would have been a reasonable expectation of success given the underlying materials and methods are known, successfully demonstrated in the context of self-amplifying RNA technology, mRNA therapeutics and RNA delivery, and commonly used as evidenced by the applied prior art.
Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention.
Allowable Subject Matter
Claim 16 is objected to as being dependent upon a rejected base claim (claims 1, 4, and 5), but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Conclusion
No claims allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Claire Cornelius whose telephone number is (571)272-0860. The examiner can normally be reached M-F, 0930-1700.
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/C.C./Examiner, Art Unit 1672
/M FRANCO G SALVOZA/Primary Examiner, Art Unit 1672