DETAILED ACTION
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, 30, and 32 are amended.
Claims 40-41 are withdrawn.
Claims 1-2, 11-13,15,17-20, 30, 32 and 36-38 are under examination.
Withdrawn Objections
The objection raised against the disclosure for containing embedded hyperlink is withdrawn in light of the amendment to the specification to remove the hyperlinks.
Withdrawn Rejections
Claim Rejections under 35 USC § 112
The rejection of claims 2, 30 and 32 under 35 U.S.C. § l 12(b), as being indefinite for use of "preferably" phrases is withdrawn in light of claims amendment that removes this recitation, thereby obviating the rejection.
Claim Rejections under 35 USC § 102
The rejection of claims 1-2, 11-12, 18, 20, 30 and 32 under 35 U.S.C. 102(a)(1) as being anticipated by Robinson et al (Antimicrobial Agents and Chemotherapy, 2010), as evidenced by Shi et al (Horizon Bioscience; 2006. Chapter 2) is withdrawn in light of claim 1 amendment. Applicants amended claim 1 to recite “ wherein the self-replicating virus is an alphavirus and wherein the functional non-structural protein is a functional alphaviral replicase”. Robinson describes an HCV (Hepatitis C Virus) subgenomic replicon comprising coding regions for HCV non-structural proteins. By contrast, the amended claims specify that the self-replicating virus is an alphavirus. Thus, Robinson does not teach or suggest all of the limitations of the currently pending claims and the claims are not anticipated by the disclosure of Robinson.
Claim Interpretation
It should be noted that the optional recitations in claims 13,15,20,22, 25, 28,30,32, and 38 are not given patentable weight as they are not required by the subject claim.
Edited Rejections Necessitated by Claims Amendment
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 text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
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.
Claims 1-2,8,11-12,20,22, 24-25,27-28,30, and 32 are rejected under 35 U.S.C. 103 as being unpatentable over Kim et al ( PNAS, 2014), in view of Spuul et al ( Journal of Virology, 2011), Robinson et al (Antimicrobial Agents and Chemotherapy, 2010), and Mizuguchi et al ( Molecular Therapy, 2000).
Regarding claim 1, Kim et al teach an Alphavirus genome-based, self-replicating RNA replicon that can be used for the delivery and expression of heterologous genes, such as those derived from the Venezuelan Equine Encephalitis Virus (VEEV), hence the name VEEV-based replicon. The replicon of Kim et al comprises two open reading frames (ORFs). The first ORF comprises of the viral genome RNA encoding for four nonstructural protein (i.e. nsP1-4), wherein the nsPs are from a self-replicating virus and which together constitute the functional alphavirus replicase. The second ORFs comprises of the subgenomic RNA (SG) encoding the heterologous gene of interest under the control of the alphavirus subgenomic promoter. ( See Fig. 1C, and the section entitled “ Design of More Efficient VEEV-Based Expression System” on page 10709). Thus, Kim et al teach an RNA replicon comprising an open reading frame encoding functional non-structural protein from a self-replicating virus, wherein the self-replicating virus is an alphavirus and the functional non-structural protein is a functional alphavirus replicase.
It is noted that the expression of the functional nonstructural protein in Kim et al’s replicon is driven by a promoter found in the 5’ end of the positive-sense genomic RNA. This differs from the replicon in the instant claim, wherein the expression of the functional nonstructural protein is driven by an IRES.
Spuul et al supplement Kim et al by teaching an Alphavirus derived trans-replication systems comprising of two nucleic acid molecules (i.e. trans replicon), wherein one nucleic acid molecule encodes the nonstructural proteins (i.e. the viral replicase) and the other nucleic acid molecule can be replicated by said replicase in trans.( See abstract). Spuul et al teach that the first nucleic acid is an RNA construct encoding for four nonstructural protein from a self-replicating virus, wherein the expression of these proteins is controlled by an upstream IRES. Spuul et al teach that the RNA construct can be prepared in vitro in the absence of the cap structure m7G(5')ppp(5')G. ( See page 4741, 2nd column, lines 4-6). The second nucleic acid is an RNA template that is provided in trans, wherein the template contains the known conserved sequence elements including those located at the 5’ UTR and at the end of the 3’UTR , which are required for a full alphavirus replication cycle (i.e. 5’RRS and 3’RRS). The RNA template may also contains florescent marker proteins inserted either under the control of the subgenomic promoter (termed Stluc) or directly at the 5’ end of the genome (Nsluc). ( See abstract, and Fig.1, and section “ Replication of RNA template on page 4742). To achieve high-level of expression, Spuul et al teach that the nonstructural protein in the RNA construct is inserted after the internal ribosome entry site (IRES) element of encephalomyocarditis virus (EMCV). Taken together, Spuul et al teach an advantage for placing the nonstructural protein under the control of an IRES element, wherein the advantage being to enhance the expression level of these protein, as these protein once expressed they assemble into a replicase that replicate the RNA replicon provided in trans in Spuul system. ( See 2nd column on page 4741 lines 4-6). Thus, Spuul demonstrates the recognized advantage of using ECMV IRES to efficiently express viral nonstructural proteins required for RNA replication.
Robinson et al further supplement Kim and Spuul et al by demonstrating that the use of ECMV IRES to direct the expression of viral nonstructural protein in a self-replicating viral RNA system was well known in the art. Specifically, Robinson et al disclose an HCV subgenomic replicon comprising of a self-replicating, bicistronic viral RNA, in which the first cistron typically encodes a reporter gene and/or a selectable marker, while the second cistron encodes the HCV nonstructural proteins, and expression is driven by the encephalomyocarditis virus (EMCV) IRES. According to Robinson, the nonstructural proteins are translated as a polyprotein, proteolytically processed by the viral NS3/4A protease, and form a replication complex in which the NS5B RNA-dependent RNA polymerase replicates the entire replicon RNA. ( See Figure.1, and page 3099-1st column-2nd paragraph). Robinson, therefore, confirms that employing an EMCV IRES to drive the expression of viral nonstructural proteins necessary for viral RNA replication was a conventional strategy independent of the particular viral replicon employed.
Therefore, claim 1 is combining prior art elements according to known methods to yield
predictable results, namely the predictable result being the use of IRES element to drive the expression of functional nonstructural protein in the RNA replicon of claim 1. Kim et al teach a cis-RNA replicon comprising an ORF encoding for functional nonstructural protein from a self-replicating alphavirus, but fail to teach a replicon comprising an IRES element driving the expression of the functional nonstructural protein. Spuul et al supplement Kim et al by demonstrating that inserting an IRES element into RNA template encoding for nonstructural protein has the advantage of increasing the expression of these proteins, and hence enhancing the amplification of the replicon. Robinson et al further supplement Kim and Spuul by teaching a cis- RNA replicon comprising ORF encoding for functional nonstructural protein, wherein the expression of these proteins is under the control of IRES element. Therefore, one with ordinary skill in the art would be motivated to modify the alphavirus RNA replicon of Kim et al by placing the alphavirus nonstructural protein coding sequence under IRES-mediated translation control as taught by Spuul, and further evidenced by Robinson et al, in order to achieve efficient cap-independent translation of the alphavirus nonstructural proteins while preserving the known self-replicating properties of the alphavirus replicon. Because Spuul demonstrate that an upstream, IRES provides efficient cap-independent expression of the alphavirus replicase. Robinson further evidences that the use of an IRES to direct the expression of viral nonstructural proteins within a self-replicating viral RNA replicon was well known in the art. Thus, incorporating the known IRES-mediated translational control strategy into Kim’s et al alphavirus replicon would merely substitute one known mechanism of translation initiation for another while preserving the self-replicating alphavirus RNA architecture of Kim and predictably yielding an alphavirus RNA replicon in which the expression of the functional nonstructural protein is controlled by an IRES.
.
Regarding claims 2 and 8, following the discussion of claim 1 above, both Spuul and Robinson teach using a viral IRES element that is derived from EMCV, and hence the expression of the functional nonstructural protein is independent of the cellular translation initiation factors, this reads on claims 2 and 8.
Regarding claim 11, following the discussion of claim 1 above, the expression of the nonstructural protein in the RNA construct of Spuul et al and Robinson et al does not contain a 5’ cap. ( See page 4741, 2nd column, lines 4-6).
Regarding claim 12, following the discussion of claim 1 above, the combined teachings of Kim et al in view of Robinson and Spuul render obvious the RNA replicon of claim 1. The RNA replicon of Kim et al also comprises a 5' replication recognition sequence (5’ RRS) ( also known as CSE). ( See Fig.1, and section “ Design of More Efficient VEEV-Based Expression System.” On page 10709).
Regarding claim 20, as discussed above with respect to claim 12, Kim’s replicon comprises of an RNA replicon containing a 5’ replication recognition sequence, and an open reading frame encoding the nonstructural proteins. Furthermore, the combined teachings of Kim, Spuul, and Robinson render obvious an RNA replicon comprising an open reading frame encoding a functional nonstructural protein and an IRES element driving the expression of the functional nonstructural proteins. However, neither Kim nor Spuul teach an RNA replicon, that further comprises another open reading frame encoding a protein of interest downstream from the 5' replication recognition sequence and upstream from the IRES.
Robinson et al’s teach RNA replicon comprising an open reading frame encoding a protein of interest downstream from the 5' replication recognition sequence and upstream from the IRES, wherein the protein of interest is neomycin, this reads on claim 20. ( See Fig.1A). Therefore, it would have been obvious to one with ordinary skill in the art at the time the invention was filed to modify the RNA replicon of Kim, as modified by Spuul, and to incorporate the arrangement taught by Robinson by positioning an open reading frame encoding a protein of interest downstream of the 5’RRS and upstream of the IRES. Such modification represents the use of known structural arrangement in a self-replicating RNA replicon to permit expression of a heterologous protein while maintain an IRES-mediated expression of the downstream nonstructural proteins, thereby yielding predictable results of co-expression of the protein of interest and the viral replicase protein from the same RNA replicon.
Regarding claim 22, as discussed above with claim 20, the teachings of Kim in view of Spuul and Robinson render obvious an RNA replicon comprising of an open reading frame encoding a protein of interest positioned downstream of the 5’RRS and upstream of the IRES.
Kim et al further teaches that the 5’ RRS required for replication includes native initiation codon and N-terminal coding region of the nsP1 nonstructural protein (See Kim, Fig.1 and discussion of the 5’ replication recognition sequence). Accordingly, incorporation of the protein of interest open reading frame in the portion taught by Robinson et al necessarily preserves the native nsp1 initiation region required for replication. As a result, translation is initiated at the native nsp1 initiation codon, thereby producing fusion protein comprising the protein of interest fused to a fragment of the nonstructural protein encoded by nsp1 open reading frame, namely the N-terminal portion of nsP1. Thus, it would have been obvious to one with ordinary skill in the art to combine the teachings of Kim, Spuul and Robinson because Robinson teaches the placement of a protein of interest coding sequence within a self-replicating RNA replicon upstream of the IRES element, while Kim teaches preserving the native 5’ RRS required for replication. The resulting construct predictably expresses the protein of interest as a fusion protein with a fragment of the nonstructural protein while maintain replication competence of the RNA replicon.
Regarding claim 24, following the discussion of claim 20 above, neither Kim nor Spuul or Robinson expressly teach that the expression of protein of interest is initated at the initiation codon of the open reading frame encoding the protein of interest as required by the limitation recited in claim 24.
Mizuguchi et al teach a bicistronic construct comprising of two ORFs. The first ORF encodes for a protein of interest, which is expressed in a cap-dependent manner. The second ORF encodes for a second protein of interest, whose expression is driven by an IRES element. ( See abstract). Mizuguchi et al demonstrate, when a vector comprising the two ORFs is expressed in an eukaryotic cell such as Hela, L, and CHO cells, the expression of the protein driven by the IRES element is less efficient compared to the level of protein driven by the cap-dependent pathway. In other words, Mizuguchi et al demonstrate that the positioning of a gene upstream or downstream of the IRES determines the mechanism and efficiency of translation and should therefore be selected based on the desired expression characteristics. It is noted that Mizuguchi do not teach an RNA replicon, however Mizuguchi et al teach a favorable design that can be incorporated in an RNA replicon. For example, an ORF encoding for a protein of interest could be inserted alongside the ORF encoding the nonstructural protein. In addition, one with ordinary skill in the art, upon reviewing Mizuguchi et al, would also be motivated to incorporate such design, in an RNA replicon where the expression level of a protein of interest is preferable over the expression of the nonstructural protein.
Therefore, claim 24 is combining prior art elements according to known methods to yield predictable results, namely the predictable result being the insertion of an ORF encoding for a protein of interest between the 5’ replication recognition sequence and the IRES sequence, and wherein the protein of interest is expressed in a cap-dependent manner, whereas the expression of the nonstructural protein is driven by the IRES element. It would have been obvious for one with ordinary skill in the art at the time the invention was filed to modify the RNA replicon of Kim, as modified by Spuul and Robinson, in accordance with the bicistronic expression strategy taught by Mizuguchi so that the upstream protein of interest open reading frame is translated from its own initiation codon while the downstream nonstructural protein open reading frame is translated through the IRES. Such modification merely applies known translational arrangement to known self-replicating RNA construct to achieve the predictable result of independent expression of the protein of interest while maintaining IRES-mediated translation of the downstream nonstructural proteins.
Regarding claim 25, 27-28, 30, and 32, the replicon of Kim et al further contains a subgenomic RNA comprising a subgenomic promoter (i.e. SG promoter) driving the expression of a protein of interest (i.e. Het.gene), wherein the gene of interest is inserted in the subgenomic RNA template, and wherein the subgenomic promotor is located downstream from the open reading frame encoding a functional nonstructural protein from a self-replicating virus, this reads on claims 25, and 27-28. (See abstract, and Fig.1B-C). The RNA replicon of Kim et al also comprises a 5' and 3' replication recognition sequences, as well as subgenomic promotor that are derived from a self-replicating virus, this reads on claim 30. ( See Fig.1 and section “ Design of More Efficient VEEV-Based Expression System” on page 10709). The RNA replicon of Kim et al can be replicated by an RNA-dependent RNA polymerase (also known as replication enzyme) derived from a functional nonstructural protein from a self-replicating virus, this reads on claim 32. (See abstract).
Claims 13,15, 17-19, and 36-38 are rejected under 35 U.S.C. 103 as being unpatentable over Kim et al ( PNAS, 2014), in view of Spuul et al, Robinson et al, and Mizuguchi et al, as applied to claims 1-2,8,11-12,20,22, 24-25,27-28,30, and 32 above, and further in view of Beissert et al ( WO 2017/162460 A1).
The teachings of Kim, Spuul, and Robinson are set forth above.
Regarding claim 13, 15, Kim in view of Spuul, and Robinson render obvious claim1. Kim et al teach RNA replicon containing a 5’ RRS comprising a 51-nt conserved sequence element (51-nt CSE), wherein the 51-nt CSE ,is located in the nsP1-coding sequence, and functions as an enhancer of alphavirus genome replication. It should be noted that the 51-nt CSE reads on an open reading frame that is homologous to a fragment of a nonstructural protein, as it contains an AUG start codon for nsP1 ( e.g. nsp1). ( See Fig.1, and section “ Design of More Efficient VEEV-Based Expression System” on page 10709). Neither Kim et al nor Spuul or Robinson teach the removal of at least one initiation codon form the 51-nt CSE.
Beissert et al teach a RNA replicon that can be replicated by a replicase of alphavirus origin. In particular, the RNA replicon of Beissert comprises a 5' replication recognition sequence, wherein the 5' replication recognition sequence is characterized in that it comprises the removal of at least one initiation codon compared to a native alphavirus 5' replication recognition sequence, this reads on claim 13. Beissert et al state that “ The fact that the replication recognition sequence required for RNA replication comprises an AUG start codon for nsP1 and thus overlaps with the coding sequence for the N-terminal fragment of the alphavirus nonstructural protein represents a serious bottle-neck for the engineering of alphavirus-based vectors because a replicon comprising the 5' replication recognition sequence will typically encode (at least) a part of alphavirus nonstructural protein, typically the N-terminal fragment of nsP1”. Therefore, Beissert et al teach that the removal of at least one initiation codon from the 5’replication recognition sequence prevents the undesired production of fragments of alphavirus nonstructural protein, and therefore enables efficient and safe expression of a protein of interest in a cell or organism. ( See abstract, claim 5, and page 6 lines 10-25).
Therefore, claim 13 is combining prior art elements according to known methods to yield
predictable results, namely the predictable result being the removal of at least one initiation codon from the ORF of a nonstructural protein or a fragment thereof to produce the replicon of claim1. Beissert et al teach RNA replicon that is modified by the removal of at least one initiation codon from the 5’ RRS, and strongly suggest that such removal would be advantageous, as it would prevent the undesired production of a fusion protein comprising a fragment of alphavirus nonstructural protein. The combined teachings of Kim, Robinson and Spuul render obvious the replicon of claim 1. Therefore, one with ordinary skill in the art who had reviewed Kim, Robinson, and Spuul, as discussed above, could have come across Beissert et al and immediately noticed the strong possibility of modifying the 5’ replication recognition sequence in the RNA replicon of Kim et al, as taught by Beissert et al, would have the predictable result of generating an effective RNA replicon that enables efficient and safe expression of a protein of interest in a cell or organism.
Regarding claim 15, following the discussion of claim 13 above. Beissert et al also state that “ In a preferred embodiment, the sequence homologous to an open reading frame of a non-structural protein or a fragment thereof from an alphavirus is characterized in that it comprises the removal of one or more initiation codons other than the native start codon of the open reading frame of a nonstructural protein”. ( See page 9, lines 19-25)
Regarding claim 17, Beissert et al also teach that the RNA replicon comprises one or more nucleotide changes compensating for nucleotide pairing disruptions within one or more stem loops introduced by the removal of at least one initiation codon. ( See page 10 lines 1-3).
Regarding claim 18, Beissert et al further teach that the RNA replicon does not comprise an open reading frame encoding a truncated alphavirus nonstructural protein.( See page 10 lines 5-6).
Regarding claim 19, Beissert et al RNA replicon comprising an open reading frame encoding functional Alphavirus nonstructural protein that does not overlap with the 5' replication recognition sequence. ( See page 11 lines 11-12).
Regarding claims 36-38, Beissert et al also teach a DNA comprising the nucleic acid encoding RNA replicon and a composition comprising RNA replicon and a pharmaceutically acceptable carrier. ( See page 103 lines 17-20, and page 105 lines 3-12).
Response to Arguments
Applicant's arguments filed 06/03/2026 have been fully considered but they are not persuasive.
Applicants argue that Kim is directed to increasing the expression of subgenomic RNA rather than increasing the expression of the alphavirus replicase and therefore fail to teach the claimed invention.
Examiner’s Response to Traversal: Applicant’s arguments have been carefully considered but are not found persuasive. This is because the rejection of claim 1 does not rely on Kim et al for teaching the expression of the replicase through an IRES. Rather, Kim et al are relied upon for teaching the self-replicating alphavirus RNA replicon comprising the alphavirus nonstructural proteins that function as the viral replicase. Spuul specifically is relied upon for teaching the expression of nonstructural proteins from an ECMV IRES and for recognizing the benefit of increasing expression of those protein to form a functional replication complex. Robinson et al was also relied upon to further demonstrate that the use of an ECMV IRES to express viral nonstructural proteins in a self-replicating viral RNA replicon was well known in the art . Accordingly, Applicants arguments against Kim individually is not persuasive as one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., Inc., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Where a rejection of a claim is based on two or more references, a reply that is limited to what a subset of the applied references teaches or fails to teach, or that fails to address the combined teaching of the applied references may be considered to be an argument that attacks the reference(s) individually. This is because “[T]he test for obviousness is what the combined teachings of the references would have suggested to [a PHOSITA].” In re Mouttet, 686 F.3d 1322, 1333, 103 USPQ2d 1219, 1226 (Fed. Cir. 2012). The fact that Kim itself does not expressly describe IRES-mediated enhancement of replicase expression does not negate the obviousness of the claimed invention because the rejection is based on the combined teachings of the prior arts, not on any single reference in isolation.
Applicants further argue that Kim’s observation that an IRES decreased the expression of GFP reporter under particular experiments configuration is considered a teaching away from the subject matter of claim1.
Examiner’s Response to Traversal: Applicant’s arguments have been carefully considered but are not found persuasive. Because Kim et al neither criticize nor discredit the use of an IRES element for the translation of alphavirus replicase proteins. Indeed, the reported result concerns expression of a downstream reporter gene under Kim’s specific construct design and does not discourage use of an IRES in the different configuration taught by Spuul and Robinson. Applicants are reminded that a reference teaches away only when it discourages or criticizes the claimed approach, not merely because it reports different performance under different experimental conditions.
Applicants further argue that Kim’s and Spuul are incompatible because one is reporting a cis replicon and the other is trans replicon. Specifically, Applicants argue that Spuul et al employs a trans-replication system in which the replicase mRNA is intentionally non-replicating, whereas Kim employs a cis-replicating replicon, and therefore the references cannot be combined.
Examiner’s Response to Traversal: Applicant’s arguments have been carefully considered but are not found persuasive. This is because the rejection does not propose incorporating the entirety of Spuul’s trans-replicating system into Kim’s replicon. Rather, the rejection relies only on Spuul’s teaching that an ECMV IRES positioned upstream of the alphavirus replicase coding sequence efficiently drives the translation of the replicase proteins. Furthermore, Robinson et al is cited to further demonstrate that the use of an ECMV IRES to express viral nonstructural proteins in a self-replicating viral RNA replicon with a cis configuration was well known in the art. Although Robinson et al employs an HCV RNA replicon utilizing ECMV IRES rather than an alphavirus replicon, however Robinson demonstrates that incorporating an IRES into a self-replicating viral RNA replicon with a cis configuration was a recognized and conventional translational strategy. In other words, Robinson et al support the general applicability of IRES-mediated translation in a cis- RNA replicon and rebuts Applicants assertion that IRES-driven translation is inherently limited to non-replicating or trans-replication systems. Accordingly, an ordinary skill in the art would have recognized that an IRES element taught by Spuul et al could be applied to Kim’s RNA replicon without importing Spuul’s entire trans-replication methodology or altering Kim’s cis-replication mechanism.
Applicants further argue that Robinson et al do not cure the alleged deficiencies of Kim and Spuul because Robinson does not suggest using a heterologous IRES to launch an alphavirus replicon, but instead, merely employ the natural translation strategy of the HCV virus.
Examiner’s Response to Traversal: Applicant’s arguments have been carefully considered but are not found persuasive. This is because the argument does not address the rejection as made. As stated above, the rejection does not rely on Robinson to teach launching an alphavirus replicon or to teach the specific IRES arrangement recited in the claims. Rather, Kim is relied upon for teaching the self-replicating alphavirus replicon, while Spuul is relied upon for teaching the use of an IRES positioned upstream of the alphavirus replicase coding sequence to direct the translation of the alphavirus nonstructural proteins. Robinson is cited as additional evidence to demonstrate that the use of heterologous ECMV IRES element within a self-replicating viral RNA replicon to initiate translation of nonstructural viral protein was well known in the art. The fact that Robinson’s replicon is based on HCV rather than alphavirus does not diminish the relevance of its teachings regarding the use of heterologous IRES. An ordinary skill in the art would have recognized that IRES elements are modular translational control elements that can be incorporated into different viral RNA replicon systems to direct translation of downstream open reading frames. Therefore, the combination of Kim, Spuul and Robinson would have been obvious to one of ordinary skill in the art.
Applicants also argue that the claimed invention exhibits unexpected results because IRES-mediated expression provides robust RNA replication and transgene expression and that multiple IRES (i.e. ECMV and IAPV) produce desired downstream expression.
Examiner’s Response to Traversal: Applicant’s arguments have been carefully considered but are not found persuasive. First, Applicants has not established that the asserted results are unexpected relative to the closest prior art. The rejection relies upon Kim in view of Spuul et al, which already teaches the use of an IRES to direct the translation of viral replicase proteins in a self-replicating RNA system. Robinson et al further demonstrate that heterologous ECMV IRES, were known for use in self-replicating viral RNA replicon. Thus, the prior art already recognizes that IRES-mediated translation can be successfully employed in a self-replicating viral RNA replicon. Thus, the evidence presented by Applicants demonstrates that the claimed replicon function as intended, and does not establish that such functionality would have been surprising to one with ordinary skill in the art. Also, Applicants have not demonstrated that the alleged unexpected results are commensurate in scope with the claims. The claims broadly encompass RNA replicons employing IRES element, whereas the cited experimental data are limited to specific constructs, specific viral construct, and selected IRES sequences.
Accordingly, the evidence is insufficient to outweigh the prima facie case of obviousness established by the combined teachings of Kim, Spuul and Robinson.
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/FATIMAH KHALAF MATALKAH/Examiner, Art Unit 1638
/Tracy Vivlemore/Supervisory Primary Examiner, Art Unit 1638
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