The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on March 9, 2026 has been entered.
Rejections and/or objections not reiterated from previous office actions are hereby withdrawn.
Claims 2-15, 17, 22-24, 26, 30-32, 34-41, 43-62, 64-77 are canceled. Claims 1, 16, 18-21, 25, 27-29, 33, 42, 63, 78-81, 82-85, 86-88 are pending and under consideration.
Priority: This application is a 371 of PCT/US2020/050910, filed September 15, 2020, which claims benefit to provisional applications 62/970628, filed February 5, 2020, and 62/901043, filed September 16, 2019.
Objections and Rejections
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, 16, 18-21, 25, 27-29, 33, 42, 63, 78-81, 82-85, 86-88 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.
Claims 1, 33, 42 recite the limitation "the L protein of EMCV" in the claims. There is insufficient antecedent basis for this limitation in the claims.
Claims 16, 18-21, 25, 27-29, 33, 42, 63, 78-81, 82-85, 86-88 are included in this rejection because they are dependent on the above claims.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 86 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 86 is a product claim dependent on claim 1. The claim does not recite any additional components to the product that further limit the claims. The recitation of an intended use (i.e. vaccine composition) in a product claim does not further limit the claim. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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.
Claims 1, 16, 25, 33, 42, 82-84, 86-87 are rejected under 35 U.S.C. 103 as being unpatentable over Salvatore et al. (2002 Journal of Virology 76(3): 1206-1212; IDS 12.13.22, previously cited) in view of Borghese et al. (2019 Journal of Virology 93(19):e01010-19, 13 pages; IDS 12.13.22, previously cited) and Paul et al. (2006 Journal of General Virology 87: 1237-1246).
Salvatore et al. disclose the NS1 protein of influenza A1 virus inhibits nucleocytoplasmic transport (at least p. 1210). Salvatore et al. disclose that NS1 protein enhances translation (at least p. 1206) and surprisingly, expression of NS1 protein resulted in an enhancement and not a decrease of reporter gene activity (at least p. 1207). Salvatore et al. disclose 293 cells are transfected with a plasmid comprising nucleic acid molecules encoding luciferase (a target protein) and a plasmid comprising nucleic acid molecules encoding NS1, where the plasmids are under the control of a promoter (at least p. 1207). Salvatore et al. disclose that the NS1 protein enhances gene expression due to an increase in translation through the inhibition of PKR (at least p. 1208-1209). Salvatore et al. do not explicitly teach a picornavirus leader (L) protein.
Borghese et al. disclose Theiler’s murine encephalomyelitis virus (TMEV or Theiler’s virus) belongs to the species Theilovirus, within the genus Cardiovirus for the family Picornaviridae (at least p. 1). Borghese et al. disclose cardiovirus leader (L) proteins are closely related multifunctional proteins shown to interfere with cellular processes,, including type I interferon and chemokine production, nucleocytoplasmic trafficking (at least p. 2). Borghese et al. disclose that the Theiler’s virus L protein acts on PKR by an indirect mechanism to render this kinase nonresponsive to dsRNA (at least p. 9-10). Borghese et al. also disclose a system or HeLa cells transfected with a plasmid comprising nucleic acid molecules encoding wildtype Theiler’s virus leader (L) protein and a plasmid comprising nucleic acid molecules encoding GFP (a target protein) (at least p. 7, 10-11). Borghese et al. disclose other known cardiovirus L proteins besides Theiler’s virus L protein, include the L protein of encephalomyocarditis virus (EMCV), including the mengovirus strain (at least p. 1). Borghese et al. further disclose that both mengovirus and TMEV L wildtype inhibited PKR phosphorylation, contrary to mutants (p. 5-6).
Paul et al. disclose cardiovirus leader proteins are functionally interchangeable in vitro and in vivo (at least p. 1237). Paul et al. disclose the L protein encoded by cardioviruses, include TMEV and EMCV (at least p. 1237). Paul et al. disclose the proteins of EMCV and Mengo virus (a slightly divergent strain of EMCV) are almost identical (at least p. 1238, also Fig. 1). Paul et al. disclose that the L protein encoded by EMCV and Mengo virus shares about 35% sequence identity with that of TMEV; however, in spite of these differences, the L protein of Mengo virus shares, with that of TMEV, the ability to inhibit transcription of type I interferon, cytokine and chemokine genes, and to interfere with nucleocytoplasmic trafficking (at least p. 1237-1238).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to incorporate or substitute a EMCV L protein or functional variant thereof as disclosed in Borghese et al./Paul et al. for the NS1 protein in the system comprising nucleic acid molecules encoding a NCT inhibitor protein and a target protein of Salvatore et al noted above (instant claims 1, 16, 25, 33, 42, 83-84). The motivation to do so is given by Salvatore et al., which disclose that expressing NCT inhibitor proteins enhances protein translation in a system. One of ordinary skill would have a reasonable expectation of success because Salvatore et al. disclose systems expressing a NCT inhibitor protein enhances translation of a protein and the prior art recognizes that EMCV L protein is a NCT inhibitor protein.
Regarding instant claims 82, 87, since Salvatore et al. in view of Borghese et al. and Paul et al. reasonably disclose a system comprising nucleic acid molecules encoding the same proteins recited, it would be obvious that the nucleic acid molecules can alternatively be RNA molecules because the same result of encoding said proteins is achieved.
Regarding instant claim 86, MPEP 2111.02 notes that if the body of a claim fully and intrinsically sets forth all of the limitations of the claimed invention, and the preamble merely states, for example, the purpose or intended use of the invention, rather than any distinct definition of any of the claimed invention’s limitations, then the preamble is not considered a limitation and is of no significance to claim construction. In this instance, the recitation of vaccine composition is an intended use of the composition. The cited art references Salvatore et al. and Borghese et al. disclose the cells are in a medium (Salvatore et al. p. 1207; Borghese et al. p. 10) and therefore can be deemed to disclose a composition comprising the system noted above.
Reply: In view of Applicants’ amendments/remarks, the previous 102(a)(1) and 103 rejections have been withdrawn. However, the claims are rejected under new 103 rejections over Salvatore et al., Borghese et al. and newly cited Paul et al. for the reasons noted above and herein.
Applicants assert that the office action asserts that it would have been obvious to substitute a Theiler’s virus L protein as described in Borghese et al. for the NS1 protein of Salvatore et al. because both proteins inhibit PKR activation. Applicants assert that even if this assertion were correct, which Applicants do not concede, a person of skill in the art would not have expected that an EMCV L protein would produce the same translational enhancement as the NS1 protein due to significant differences in the structure and activity of the NS1 protein, Theiler’s virus L protein, and EMCV L protein. Applicants assert that Borghese et al. only present data for PKR inhibition data for Theiler’s virus L protein and not for the EMCV L protein. Applicants assert that the Theiler’s virus L protein is structurally distinct from the EMCV L protein – the Theiler’s virus L protein includes a carboxy-terminal Theilo domain, whereas EMCV L protein does not. Applicants assert that Borghese et al. show that cells infected with a Theiler’s virus L protein having a mutation in the Theilo domain (LM60V) exhibit stress granule formation , which is correlated with PKR activation, whereas cells infected with the wildtype Theiler’s virus L protein do not (Borghese et al. p. 2-3). Applicants assert that these results indicate that the Theilo domain is needed for the PKR inhibitory activity of the Theiler’s L protein and since the EMCV L protein lacks a Theilo domain, a person of skill in the art would not have expected the EMCV L protein to exhibit the same PKR inhibitory activity as the Theiler’s virus L protein.
Applicants’ remarks are not persuasive. As previously noted, Borghese et al. disclose other known cardiovirus L proteins besides Theiler’s virus L protein, include the L protein of encephalomyocarditis virus (EMCV) (at least p. 1). Borghese et al. further disclose that both mengovirus and TMEV L wildtype inhibited PKR phosphorylation, contrary to mutants (p. 5-6).
Paul et al. also disclose that the L protein encoded by cardioviruses, include TMEV and EMCV (at least p. 1237). Paul et al. disclose the proteins of EMCV and Mengo virus (a slightly divergent strain of EMCV) are almost identical (at least p. 1238, also Fig. 1). Paul et al. disclose that the L protein encoded by EMCV and Mengo virus shares about 35% sequence identity with that of TMEV; however, in spite of these differences, the L protein of Mengo virus shares, with that of TMEV, the ability to inhibit transcription of type I interferon, cytokine and chemokine genes, and to interfere with nucleocytoplasmic trafficking (at least p. 1237-1238).
Therefore, one of ordinary skill would have a reasonable expectation of success that an EMCV L protein also exhibits the same PKR inhibitory activity as the Theiler’s virus L protein because Borghese et al. disclose that mengovirus L protein (an EMCV strain), like TMEV L protein, inhibits PKR phosphorylation and Paul et al. disclose that the L protein of EMCV/Mengo share the same functions as TMEV L protein, despite having only about 35% sequence identity with that of TMEV L protein.
As previously noted, Salvatore et al. disclose that NS1 protein, while having a dsRNA binding domain, still enhances gene expression by its ability to inhibit PKR (see also the reasons noted on at least p. 6-8 of the October 8, 2025 final office action).
Borghese et al. disclose that viral proteins such as the NS1 protein (of Salvatore et al.) or E3L, were shown to block dsRNA-mediated PKR activation, and that these proteins possess a dsRNA binding domain (DRBD) that competes with PKR for dsRNA binding (p. 9). As also noted by Applicants, Borghese et al. disclose that in the case of cardioviruses (such as Theiler’s virus leader (L) protein), the leader sequence does not contain a dsRNA binding domain (p. 9). However, Borghese et al. still disclose that both mengovirus and TMEV L wildtype inhibited PKR phosphorylation (p. 5-6).
Therefore, even if the mechanism of inhibiting PKR is different between NS1 and Theiler’s virus L protein, and the structures of NS1, TMEV L protein, and EMCV L protein are different, it is still recognized that NS1, Theiler’s virus L protein, and EMCVL protein still have the same ultimate effect of inhibiting PKR, which Salvatore et al. recognize as contributing to enhanced gene expression.
Therefore, one of ordinary skill would have a reasonable expectation of success that co-expression of the EMCV L protein of Borghese et al./Paul et al. with the target protein in the eukaryotic cell of Salvatore et al. enhances translation of the target protein because the EMCV L protein, like Theiler’s virus L protein and the NS1, has the same effect of inhibiting PKR activity.
For at least these reasons, the 103 rejection is maintained.
Claims 1, 16, 18-21, 25, 27, 33, 42, 63, 78-81, 82-84, 85, 86-87, 88 are rejected under 35 U.S.C. 103 as being unpatentable over Salvatore et al. (2002 Journal of Virology 76(3): 1206-1212; IDS 12.13.22, previously cited) in view of Borghese et al. (2019 Journal of Virology 93(19):e01010-19, 13 pages; IDS 12.13.22, previously cited), Paul et al. (2006 Journal of General Virology 87: 1237-1246), and Szymczak et al. (2005 Expert Opin Biol Ther 5(5): 627-638; previously cited). The teachings of Salvatore et al. in view of Borghese et al./Paul et al. over at least instant claims 1, 25, 33, 42 are noted above.
As noted above, Salvatore et al. in view of Borghese et al. and Paul reasonably disclose a eukaryotic cell transfected with a plasmid comprising nucleic acid molecules encoding a target protein and a plasmid comprising nucleic acid molecules encoding a EMCV L protein, where the plasmids are under the control of a promoter. Salvatore et al. and/or Borghese et al. do not explicitly teach one vector to comprise the nucleic acid molecules encoding the virus L protein and target protein.
Szymczak et al. disclose various strategies to express multiple proteins on a single vector (at least p. 627-628).
Regarding instant claims 18-19, Szymczak et al. disclose one technique is through the use of two independent transcriptional units, each with its own promoter (at least p. 628). It would have been obvious to one of ordinary skill to incorporate the nucleic acid molecules encoding the EMCV L protein and target protein in the system of Salvatore et al. and Borghese et al./Paul et al. into a vector comprising two promoters where the nucleic acid molecules encoding the virus L protein is operatively linked to one promoter and the nucleic acid molecules encoding the target protein is operatively linked to the second promoter, as suggested in Szymczak et al. The motivation to do so is given by Szymczak et al., which disclose multiple proteins can be expressed in a single vector. One of ordinary skill would have a reasonable expectation of success because strategies to express multiple proteins in a single vector were known in the prior art.
Regarding instant claim 20, Szymczak et al. disclose other known strategies include a single promoter in the vector for expressing the multiple proteins (p. 628-629). It would have been obvious to one of ordinary skill to incorporate a vector comprising a single promoter as suggested in Szymczak et al. operatively linked to the nucleic acid molecules encoding the EMCV L protein and target protein in the system of Salvatore et al. and Borghese et al./Paul et al. The motivation to do so is given by Szymczak et al., which disclose multiple proteins can be expressed in a single vector comprising one promoter. One of ordinary skill would have a reasonable expectation of success because strategies to express multiple proteins in a single vector comprising one promoter were known in the prior art.
Regarding instant claim 21, Szymczak et al. disclose another known strategy includes incorporating 2A peptide sequences in the single vector to express multiple proteins (at least p. 629-631). It would have been obvious to one of ordinary skill to incorporate a vector comprising nucleic acid molecules encoding a 2A peptide sequence element linked to the nucleic acid molecules encoding the EMCV L protein and target protein in the system of Salvatore et al. and Borghese et al./Paul et al. The motivation to do so is given by Szymczak et al., which disclose multiple proteins can be expressed in a single vector utilizing 2A peptide sequences. One of ordinary skill would have a reasonable expectation of success because strategies to express multiple proteins in a single vector utilizing 2A peptide sequences were known in the prior art.
Regarding instant claim 27, Szymczak et al. disclose another known technique includes an internal ribosome entry site (IRES) in the single vector to express multiple proteins (at least p. 628-629). It would have been obvious to one of ordinary skill to incorporate a vector comprising a IRES as suggested in Szymczak et al. linked to the nucleic acid molecules encoding the EMCV L protein and target protein in the system of Salvatore et al. and Borghese et al./Paul et al. The motivation to do so is given by Szymczak et al., which disclose multiple proteins can be expressed in a single vector utilizing an IRES. One of ordinary skill would have a reasonable expectation of success because strategies to express multiple proteins in a single vector utilizing IRESs were known in the prior art.
Regarding instant claim 63, Szymczak et al. disclose known vectors include adeno-associated virus vectors and lentivirus vectors (at least p. 630, 637).
Regarding instant claims 78-81, 85, 88, Szymczak et al. disclose expressing various proteins with vectors, including immunoglobulins, cell surface receptors, transcription factors, enzymes, cytokines (at least p. 627, 635).
Reply: Applicants’ amendments/remarks have been considered but they are not persuasive. The reasons for maintaining Salvatore et al. and Borghese et al., in view of newly cited Paul et al., are the same as noted above.
Claims 1, 16, 18-21, 25, 27-29, 33, 42, 63, 78-81, 82-85, 86-88 are rejected under 35 U.S.C. 103 as being unpatentable over Salvatore et al. (2002 Journal of Virology 76(3): 1206-1212; IDS 12.13.22, previously cited) in view of Borghese et al. (2019 Journal of Virology 93(19):e01010-19, 13 pages; IDS 12.13.22, previously cited), Paul et al. (2006 Journal of General Virology 87: 1237-1246), Szymczak et al. (2005 Expert Opin Biol Ther 5(5): 627-638; previously cited), and Zheng et al. (2007 Chinese Journal of Bacteriology 23(5): 947-952, abstract only; previously cited). The teachings of Salvatore et al., Borghese et al./Paul et al., and Szymczak et al. over at least instant claims 1, 16, 18-21, 25, 27, 33, 42, 63, 78-81, 82-84, 85, 86-87, 88 are noted above.
Regarding instant claims 28-29, Zheng et al. disclose expressing a target gene driven by T7 RNA polymerase in eukaryotic cells (abstract p. 1). Zheng et al. disclose utilizing a vector expressing T7 RNA polymerase and comprising the T7 promoter sequence (p. 1-2). It would have been obvious to one of ordinary skill in the art to incorporate a T7 promoter and/or nucleic acids encoding T7 RNA polymerase into the vector comprising the nucleic acid molecules encoding the EMCV L protein and target protein in the system of Salvatore et al., Borghese et al./Paul et al., and Szymczak et al. noted above. The motivation to do so is given by Zheng et al., which disclose expressing a target gene in eukaryotic cells can be achieved by the T7 RNA polymerase expression system. One of ordinary skill would have a reasonable expectation of success because the prior art disclose that protein expression in cells can be achieved by a vector utilizing the T7 promoter and T7 RNA polymerase expression system.
Reply: Applicants’ amendments/remarks have been considered but they are not persuasive. The reasons for maintaining Salvatore et al. and Borghese et al., in view of newly cited Paul et al., are the same as noted above.
No claim is allowed.
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/Marsha Tsay/Primary Examiner, Art Unit 1656
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