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 .
Continued Examination Under 37 CFR 1.114
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 27 April 2026 has been entered.
Application Status
The Amendments and Remarks filed 27 April 2026 are acknowledged and have been entered. Claim 165 is amended. Claims 2, 7, 10-13, 18, 21, 23, 24, 26-81, 84, 89-91 and 96-163 are cancelled. Claims 1, 3-6, 8-9, 14-17, 19-20, 22, 25, 82-83, 85-87, 92-95, and 164-172 are under examination on the merits.
Any objection or rejection not reiterated herein has been overcome by applicant’s claim amendments.
Priority
This application is a divisional of application 15/831,230 filed 12/04/2017 which claims priority to 62/587,954 filed 11/17/2017, 62/486,361 filed 4/17/2017, and 62/430,250 filed 12/02/2016.
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, 3-6, 8-9, 16-17, 22, 25, 92-94, 164-165, 170-172 are rejected under 35 U.S.C. 103 as being obvious over Frolov 2014 (US 2014/0079734 A1) in view of Johnston (US 2008/0279891 A1) and Berglund (US 11,135,283; WO2017/083356).
Regarding claim 1, 9 and 164, Frolov 2014 teaches alphavirus RNA replicons and methods of their use in vaccines and producing heterologous proteins [0003, 0013, abstract]. Frolov 2014 teaches Sindbis- and Semliki Forest virus-based vectors (nucleic acid molecule) with modifications in the beginning of the capsid-coding sequence, a sequence that encodes a viral capsid that contains a translational enhancer (i.e., a first nucleic acid sequence) derived from an Old-World alphavirus such as, e.g., Sindbis, Semliki Forest, Ross River or other Old-World alphavirus [0008, 0041, 0129]. Frolov 2014 teaches the translational enhancer is folded into a stable stem-loop structure (i.e., DLP loop motif) [0047]. Frolov 2014 also teaches these modifications to be a part of a recombinant replicon (i.e., modified viral RNA replicon) acid that also includes a first alphavirus 5’ untranslated region (5’UTR) and conserved sequence element (51-nt CSE), a nucleic acid sequence encoding alphavirus (e.g., VEEV) nonstructural proteins nsP1, nsP2, nsP3 and nsP4, a subgenomic promoter, and a heterologous gene for expression of a protein of interest (GOI) (i.e., second nucleic acid sequence) downstream from the nonstructural proteins and a 3’UTR [abstract; 0004-0007; 0041, Figs. 1-3]. Frolov 2014 teaches these nonstructural proteins nsP1, nsP2, nsP3 and nsP4 form the replicative enzyme complex, which amplifies the viral genome and synthesizes additional subgenomic RNA that is a template for synthesis of viral structural proteins [0026]. Frolov 2014 teaches that these RNA modified structures increase expression of heterologous nucleotide sequences of interest [0131]. Frolov also teaches that the present invention provides a method eliciting an immune response to a heterologous protein in a subject, comprising administering to the subject an immunogenic amount of a recombinant replicon nucleic acid of this invention, thereby eliciting an immune response to the heterologous protein encoded by the recombinant replicon nucleic acid [0010]. Frolov further teaches recombinant alphavirus replicons containing additional translational control elements within recombinant expression cassettes. Frolov illustrates a recombinant replicon in which a translational enhancer derived from an alphavirus is positioned adjacent a heterologous expression cassette to enhance translation of the heterologous gene. Frolov explains that the recombinant replicons provide improved protein production efficiency through incorporation of additional translational regulatory elements [Abstract; 0004-0007; Fig. 3]. Frolov therefore teaches a modified alphavirus RNA replicon comprising: a first nucleic acid sequence comprising an alphavirus 5’ untranslated region; a second nucleic acid sequence downstream thereof comprising alphavirus nonstructural protein coding sequences; a heterologous gene downstream of the nonstructural protein coding sequences; and incorporation of alphavirus translational enhancer elements to improve expression.
Frolov 2014 does not teach wherein the first nucleic acid sequence is operably linked upstream to the second nucleic acid sequence, where the translational enhancer is specifically an alphavirus capsid translational enhancer operably associated with the nonstructural protein coding sequences
Johnston teaches alphavirus adjuvants or Venezuelan Equine Encephalitis viral adjuvants, i.e., modified alphavirus genomic nucleic acids, for enhancing an immune response to an immunogen [abstract]. Johnston teaches that replicon vectors that comprise a capsid translational enhancer region of the alphavirus capsid protein can operably associate with the sequences encoding the non-structural proteins to enhance expression thereof [0140]. Thus Johnston expressly teaches that an alphavirus capsid translational enhancer need not remain associated with the capsid coding sequence, but instead may be operably associated with heterologous coding sequences or with sequences encoding the alphavirus nonstructural proteins to enhance expression.
It would have been obvious to one ordinary skilled in the art before the effective filing date of the claimed invention to modify the recombinant alphavirus replicon of Frolov by operably associating Johnston’s known alphavirus capsid translational enhancer with the nonstructural protein coding region of the Frolov replicon because Johnston expressly teaches that such positioning enhances expression of the associated coding sequences. Improving translation of the nonstructural proteins would have predictably increased production of the viral replication machinery, thereby improving amplification of the replicon RNA and ultimately increasing expression of the downstream heterologous gene. Such optimization of known expression-enhancing regulatory elements for improved protein production represents the predictable use of prior-art elements according to their established functions.
Furthermore, Berglund provides evidence that a person of ordinary skill would have had a reasonable expectation of success in making such a modification.
Berglund teaches extensive engineering of the alphavirus 5’ replication region immediately upstream of nsP1 while maintaining functional replicons. Berglund teaches that the RNA packaging signal may be inserted between the 5’ replication signal and the full nsP1 coding sequence and that the packaging signal serves as part of the replication signal while maintaining replicon function [pg. 14, 31]. Berglund further teaches that the packaging signal may be positioned anywhere between the end of the 5’ replication signal and the beginning of the 26S promoter, demonstrating that functional RNA regulatory elements can be repositioned throughout the nonstructural region while preserving replicon activity [pg. 32-33]. Berglund also teaches duplication and codon modification of nsP1 sequences to accommodate insertion of additional functional RNA elements into this region [pg. 14, 32]. Accordingly, Berglund demonstrates that persons of ordinary skill routinely modified the normally conserved 5’ replication signal/nsP1 region by inserting additional functional RNA elements while maintaining alphavirus replicon function.
Regarding claim 165, Berglund teaches a functional RNA regulatory element approximately 141 nucleotides from the 5’ terminus [pg. 14, 32, 88, Fig. 8].
Therefore, a person of ordinary skill in the art would have had a reasonable expectation that Johnston’s known alphavirus capsid translational enhancer likewise could be operably associated with the nonstructural protein coding region of Frolov’s recombinant alphavirus replicon while retaining biological function. The combination merely substitutes one known alphavirus translational regulatory element for another known translational regulatory arrangement to perform the same known function—enhancing translation of associated coding sequences—and therefore would have represented nothing more than the predictable use of prior-art elements according to their established functions.
Regarding claim 3, while Frolov 2014 teaches that a promoter can be used to direct transcription of a subgenomic messenger RNA as part of the alphavirus replication process [0048], Frolov or Johnston do not teach where the nucleic acid molecule comprises a promoter operably linked upstream to the first nucleic acid sequence. It would have been obvious to one ordinary skilled in the art before the effective filing date of the claimed invention to modify the nucleic acid molecule as taught and suggested by Frolov 2014 and Johnston where the molecule comprises a promoter operably linked upstream to the first nucleic acid sequence. One of ordinary skill would be motivated with a reasonable expectation of success to make the modification for the advantage of directing the expression of the viral capsid enhancer and thereby enhancing expression of the non-structural proteins for the purpose of amplifying the viral genome and synthesizing additional subgenomic RNA.
Regarding claim 4, Frolov 2014 teaches a 5' UTR sequence operably linked upstream to the first nucleic acid sequence [0041, Figs 1-3].
Regarding claim 5, although Frolov 2014 teaches a 5' UTR sequence operably linked upstream to the first nucleic acid sequence [0041, Figs 1-2], Frolov 2014 does not teach where the 5' UTR sequence is operably linked downstream to the promoter and upstream to the first nucleic acid sequence. Frolov 2014 does teach a 5’UTR operably linked downstream of a promoter in the DI RNA-encoding alphavirus replicon [Fig. 1-3]. Frolov 2014 teaches that the 5’ UTR has a strong positive effect on replication of these RNAs. It would have been obvious to one ordinary skilled in the art before the effective filing date of the claimed invention to modify the nucleic acid molecule as taught and suggested by Frolov 2014 and Johnston where the molecule comprises a 5' UTR sequence operably linked downstream to the promoter and upstream to the first nucleic acid sequence. One of ordinary skill would be motivated to make the modification for the advantage of directing the strong expression/replication of the viral capsid enhancer and thereby enhancing expression of the non-structural proteins for the purpose of amplifying the viral genome and synthesizing additional subgenomic RNA. One of ordinary skill would have an expectation of success since Frolov 2014 already teaches replicons that comprise a 5' UTR sequence is operably linked downstream of a promoter.
Regarding claim 6, Frolov 2014 teaches the recombinant replicon nucleic acids comprising a nucleic acid sequence encoding a protease [0041]. Frolov 2014 teaches the capsid-coding sequence, which contains a translational enhancer is fused in frame (i.e., operably linked downstream to the first nucleic acid sequence) with a nucleotide sequence encoding a protease (e.g., FMDV-2A protease) [0129]. Frolov 2014 teaches that the protease is included for polyprotein processing [0120]. Frolov 2014 also teaches that the viral genome is translated into the polyprotein precursor of the nonstructural proteins which is sequentially self-processed by the encoded protease [0026]. Frolov 2014 does not teach wherein the coding sequence for an autoprotease peptide is operably linked upstream to the second nucleic acid sequence and downstream to the first nucleic acid sequence. It would have been obvious to one ordinary skilled in the art before the effective filing date of the claimed invention to further modify the nucleic acid molecule as taught and suggested by Frolov 2014 and Johnston wherein the coding sequence for an autoprotease peptide is operably linked between the first and second nucleic acid sequence. One of ordinary skill would be motivated to make this modification with a reasonable expectation of success for the advantage of cleaving the nonstructural proteins from the viral capsid enhancer aiding in the polyprotein processing of the nonstructural proteins.
Regarding claim 8, Frolov teaches a nucleotide sequence encoding a F2A protease [0129].
Regarding claim 16, Frolov 2014 teaches the recombinant replicon nucleic acid comprising a promoter operably linked to and a nucleic acid sequence encoding a heterologous protein (i.e., GOI encoding a polypeptide) [0008, Fig. 1-3].
Regarding claim 17, Frolov teaches that the heterologous protein can be a therapeutic protein [0011, claim 20]. Frolov 2014 teaches that the heterologous nucleic acid of this invention can encode a protein or peptide, which can be, but is not limited to, an antigen, an immunogen or immunogenic polypeptide or peptide, a fusion protein, a fusion peptide, a cancer antigen, etc. [0088].
Regarding claim 22, Frolov teaches that the modified vectors are expression vectors [0133].
Regarding claim 25, Frolov 2014 teaches that the DI RNA-encoding replicons can be cloned into plasmids under control of RNA Pol II promoters [0132].
Regarding claims 92, 170 and 172, Frolov 2014 teaches a modified VEEV RNA replicon [0055, 0120, Fig. 1].
Regarding claims 93 and 171, the combination of Frolov 2014 teaches where the second nucleic acid sequence encodes nonstructural proteins nsp 1-4 [Figs 1-2].
Regarding claim 94, Frolov 2014 teaches that nonlimiting examples of an alphavirus of this invention include eastern equine encephalitis virus (EEEV) [0055].
Claims 14-15 and 166 are rejected under 35 U.S.C. 103 as being unpatentable over Frolov 2014 (US 2014/0079734 A1) in view of Johnston (US 2008/0279891 A1) and Berglund (US 11,135,283; WO2017/083356) as applied above to claim 1 and 164 and further in view of Regts (US 2004/0005711 A1).
The teachings of Frolov 2014, Johnston and Berglund are discussed above as applied to claim 1 and 164. Frolov 2014, Johnston and Berglund teach wherein the viral capsid enhancer comprises a nucleic acid sequence of one of SEQ ID NOs: 1 and 46-52.
Regts teaches alphavirus vector systems used for vaccine purposes [abstract]. Regts teach that the alphavirus vector system comprises a translational enhancer element which helps overcome lower expression or improves expression of heterologous proteins [0019]. Regts teach that the translational enhancer element comprises a viral capsid gene segment, such as from an alphavirus (e.g., Semliki Forest virus (SFV)) [0019]. Regts teaches that this enhancer element is termed SFV-enh6,7 and has a sequence (SEQ ID NO:4) which is 100% identical to SEQ ID NO: 50 of the instant application [0040, Fig. 9 and 19].
It would have been obvious to one ordinary skilled in the art before the effective filing date of the claimed invention to modify the nucleic acid molecule as taught and suggested by Frolov 2014, Johnston and Berglund with the sequence of the SFV-enh6,7 enhancer of Regts. This modification would amount as a simple substitution of one alphavirus capsid translation enhancer for another, both known to improve expression of heterologous proteins. The combination of prior art elements according to known methods to yield predictable results supports can support a conclusion of obviousness. See MPEP 2143(I). One of ordinary skill in the art would have a reasonable expectation of success since both Frolov and Regts teach modified alphavirus replicons used for heterologous protein expression.
Claims 19-20 and 95 are rejected under 35 U.S.C. 103 as being unpatentable over Frolov 2014 (US 2014/0079734 A1) in view of Johnston (US 2008/0279891 A1) and Berglund (US 11,135,283; WO2017/083356) as applied above to claim 1 and further in view of Mir (Mir et. al. 2009. Clinical and Vaccine Immunology Vol. 16, No. 10 p. 1467-1475).
The teachings of Frolov 2014, Johnston and Berglund are discussed above as applied to claim 1 and similarly apply to claim 19-20 and 95.
Frolov 2014, Johnston and Berglund do not teach a nucleic acid molecule further comprising a third nucleic acid sequence encoding one or more RNA stem-loops of a second viral capsid enhancer or a variant thereof; and a fourth nucleic acid sequence operably linked to the third nucleic acid sequence, wherein the fourth nucleic acid sequence comprises a coding sequence for a second gene of interest (GOI) or at least two, three, four, five, or six expression cassettes, and wherein the a second autoprotease peptide is operably linked downstream to the third nucleic acid sequence and upstream to the fourth nucleic acid sequence.
Frolov does teach that the replicon comprises a promoter upstream of a heterologous protein of interest [0041, Figs. 1-3].
Mir teaches the ability to exploited self-splicing 2A sequences of the foot-and-mouth disease virus (FMDV) to generate a DNA vaccine construct expressing multiple full-length antigens from a single open reading frame (ORF). Mir teaches that is possible to coexpress up to four full-length antigens joined by 2A sequences in a single ORF under the control of a single promoter thereby generating a DNA vaccine construct (V-2A) that expresses high levels of full-length and functional antigens which are secreted at different stages of disease development and which induce strong immune responses [pg. 1467, col. 1, para 2].
Therefore, it would have been obvious to one ordinary skilled in the art before the effective filing date of the claimed invention to modify the nucleic acid of as taught and suggested by Frolov 2014, Johnston and Berglund to additionally contain a third nucleic acid sequence encoding one or more RNA stem-loops of a second viral capsid enhancer or a variant thereof; a fourth nucleic acid sequence operably linked to the third nucleic acid sequence, wherein the fourth nucleic acid sequence comprises a coding sequence for a second gene of interest (GOI) and wherein a coding sequence for a second F2A peptide is between the third and fourth sequences, or two or more expression cassettes. One of ordinary skill would be motivated to make this modification for the advantage of coexpressing multiple genes of interest in coordinated manner and/or where the posttranslational modification due to FMDV 2A leads to the segmentation of the long-translated polypeptide into individual proteins. This modification would simply amount to a duplication of parts of the nucleic acid molecule of the current claim 1 and of the expression cassette as disclosed by Frolov 2014.
Claims 82-83, 85-86 and 167-168 are rejected under 35 U.S.C. 103 as being unpatentable over Frolov 2014 (US 2014/0079734 A1) in view of Johnston (US 2008/0279891 A1) and Berglund (US 11,135,283; WO2017/083356) as applied above to claim 1 and 164 and further in view of Lee (US20080131459A1).
Regarding claims 82-83 and 167-168, the teachings of Frolov 2014, Johnston and Berglund are discussed above as applied to claim 1 and 164. Frolov does not teach wherein the modified viral replicon is derived from an arterivirus virus species of Porcine respiratory and reproductive syndrome virus (PRRSV).
Frolov 2014, Johnston and Berglund do not teach where the second nucleic acid sequence encodes the entire pp lab nonstructural protein of the modified arterivirus RNA replicon.
Johnston teaches that the viral adjuvants of the invention can be derived from any suitable virus such as a nidovirus [0098-0099] where the nidovirus includes equine arteritis
virus, lactate dehydrogenase-elevating virus, porcine respiratory and reproductive syndrome virus, and simian hemorrhagic fever virus of the family Arteriviridae [0089].
Lee teaches a luciferase (LUC)-expressing PRRSV viral replicons [0066; Fig. 10] and the use of a PRRSV vector for the expression of a heterologous gene or a genetic vaccine. Lee teaches that two overlapping ORFs, ORF1a and 1b, are expressed from the genomic RNA, processed into 13 mature nonstructural proteins (i.e., the entire pp lab nonstructural protein of the modified arterivirus RNA Replicon), and known to be involved in viral replication [0003].
It would have been obvious to one ordinary skilled in the art before the effective filing date of the claimed invention to modify the nucleic acid molecule as taught and suggested by Frolov 2014, Johnston and Berglund where the modified viral replicon is derived from PRRSV the second nucleic acid sequence encodes the entire pp lab nonstructural protein of the modified arterivirus RNA replicon. This modification would amount as a simple substitution of one modified viral replicon for another, where the replicons are both shown to be used for expression of heterologous proteins. Additionally, one of ordinary skill would be motivated to use the entire pp lab nonstructural protein of the modified arterivirus RNA replicon as the second nucleic acid because Frolov 2014 uses the all 4 non-structural proteins from the alphavirus genome in its viral replicon for the purpose of amplifying the viral genome and synthesizing additional subgenomic RNA. The combination of prior art elements according to known methods to yield predictable results supports can support a conclusion of obviousness. See MPEP 2143(I). One of ordinary skill in the art would have a reasonable expectation of success since both Frolov and Regts teach modified viral replicons for expression of heterologous proteins.
Regarding claim 85, Frolov 2014 teaches where the replicon can comprise nucleotide sequences encoding one or more proteins of interest [0120]. Frolov also teach that the replicon comprises a promoter upstream of a heterologous protein of interest [0041, Figs. 1-3]. However, Frolov 2014, Johnston and Berglund do not teach that the replicon comprises one or more genes of interest are each operably linked to a promoter, thereby comprising one or more expression cassettes. Frolov 2014 teaches that a promoter can be used to direct transcription of a subgenomic messenger RNA as part of the alphavirus replication process [0048]. It would have been obvious to one ordinary skilled in the art before the effective filing date of the claimed invention to modify the nucleic acid molecule as taught and suggested by Frolov 2014, Johnston and Berglund where the molecule comprises at least one to six expression cassettes. One of ordinary skill would be motivated with a reasonable expectation of success to make the modification for the advantage of directing the expression of multiple genes of interest individually.
Regarding claim 86, Frolov teaches a replicon that comprises of an expression cassette (promoter operably linked to a GOI) downstream of the second nucleic acid sequence (comprising the non-structural proteins) [041, Figs. 1-3].
Claims 87 and 169 is rejected under 35 U.S.C. 103 as being unpatentable over Frolov 2014 (US 2014/0079734 A1), in view of Johnston (US 2008/0279891 A1), Berglund (US 11,135,283; WO2017/083356) and Lee (US 20080131459 A1) as applied to claims 1, 82, and 83 and further in view of Stein (US 20050171044 A1) and Sanches (US 2009/0202588 A1).
The teachings of Frolov 2014, Johnston and Berglund, and Lee are discussed above as applied to claims 1, 82, and 83. Frolov 2014, Johnston and Berglund or Lee do not teach where at least one of the one or more expression cassettes is operably positioned downstream to a transcriptional regulatory sequence (TRS) of the modified arterivirus RNA replicon, wherein the TRS is selected from the group consisting of TRS1, TRS2, TRS3, TRS4, TRS5, TRS6, and TRS7.
Stein teaches that nidoviruses, such as Porcine reproductive and respiratory syndrome virus [table 1], comprise a TRS that appear to play a critical role in viral transcription by bringing into close proximity the minus strand body TRS and positive-strand leader TRS in order to complete synthesis of the negative-sense sg RNA templates [0101, Fig. 2B, Table 3]. Stein teaches TRS-1 and TRS-2 [0176, Fig. 6].
Sanches teaches vectors and virus particles comprising sequences encoding at least one neutralizing epitope of ORF5 of porcine reproductive and respiratory syndrome virus (PRRSV) for the preparation of vaccines [abstract]. Sanches teaches that TRS is a sequence or a fragment of a sequence capable of driving the synthesis of subgenomic viral RNAs [0046]. Sanches teaches that protein coding sequences within the nucleic acids of the present invention are preferably linked to sequences controlling the expression of these genes in the host cells or organisms [0078]. Sanches teaches the genes encoding the epitopes or further polypeptides may for example be flanked by transcription regulatory sequences (TRS) to increase transcription and/or translation of the protein coding sequences [0078].
It would have been obvious to one ordinary skilled in the art before the effective filing date of the claimed invention to modify the nucleic acid molecule as taught and suggested by Frolov 2014, Johnston and Berglund where the molecule comprises TRS1 or TRS1 positioned upstream of the expression cassette. One of ordinary skill would be motivated to make the modification with a reasonable expectation of success for the advantage of aiding in transcription of the expression cassette because Stein teaches that TRSs pay a viral role in viral transcription and Sanches teaches that polypeptides are linked to TRS sequences to increase the transcription and/or translation of the protein coding sequences.
Response to Arguments
Additionally, Applicant's arguments filed 04/27/2026 have been fully considered but they are not persuasive.
Applicant’s arguments with respect to the rejection of the independent claims have been fully considered and are persuasive. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of Berglund.
Applicant argues that neither Frolov nor Johnston teaches or suggests a modified viral RNA replicon comprising an alphavirus capsid enhancer positioned upstream of the nonstructural protein coding sequence as presently claimed. Applicant further argues that Johnston merely speculates regarding alternative locations for the capsid translational enhancer and provides no teaching that such a construct would function. Applicant additionally contends that the alphavirus 5’ replication region is highly conserved and that a person of ordinary skill in the art would not have had a reasonable expectation of success in relocating a capsid translational enhancer into this region. Applicant’s arguments have been fully considered but are not persuasive.
Johnston expressly teaches that the alphavirus capsid translational enhancer is not limited to its native capsid coding sequence. Rather, Johnston states: “Replicon vectors that do not encode the alphavirus capsid protein may nonetheless comprise a capsid translational enhancer region operably associated with a heterologous sequence, or the sequences encoding the non-structural proteins and/or encoding the alphavirus structural proteins … so as to enhance expression thereof.” (Johnston ¶[0140]). Thus, Johnston expressly teaches operably associating the alphavirus capsid translational enhancer with sequences encoding the alphavirus nonstructural proteins to enhance expression of those proteins. Accordingly, Johnston is not limited to maintaining the enhancer adjacent the capsid coding sequence and instead affirmatively teaches relocation of the enhancer to alternative coding regions for the same functional purpose.
Applicant additionally argues that neither Frolov nor Johnston contains an actual working example of the claimed arrangement. This argument is not persuasive because obviousness does not require that the prior art disclose the identical claimed construct or provide an express working example of every possible modification. Rather, the relevant inquiry is whether the prior art would have provided a person of ordinary skill with a reason to make the claimed modification together with a reasonable expectation of success.
Here, Frolov teaches recombinant alphavirus replicons designed to improve heterologous protein expression through incorporation of translational regulatory elements. Johnston expressly teaches operably associating the alphavirus capsid translational enhancer with nonstructural protein coding sequences to enhance expression. Berglund further demonstrates that the 5’ replication signal/nonstructural region of alphavirus replicons was known to tolerate insertion and repositioning of functional RNA regulatory elements while maintaining replicon activity. Collectively, these references provide both the motivation to make the claimed modification and a reasonable expectation that the modification would function for its intended purpose.
Applicant has not provided persuasive objective evidence demonstrating that positioning the known alphavirus capsid translational enhancer upstream of the nonstructural protein coding sequence produces any unexpected result or property beyond the predictable enhancement of translation taught by the prior art.
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 filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual 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/apply/applying-online/eterminal-disclaimer.
Claims 1, 3-6, 8-9, 14-17, 19-20, 22, 25, 82-83, 85-87, 92-95 and 164-172 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 8-10, 13, 16, 43 and 48 of U.S. Patent No. US11845939B2 in view of Frolov 2014 (US 2014/0079734 A1), Johnston (US 2008/0279891 A1), Berglund (US 11,135,283; WO2017/083356), Regts (US 2004/0005711 A1), Lee (US 20080131459 A1), Stein (US 20050171044 A1), and Sanches (US 2009/0202588 A1).
Although the claims at issue are not identical, they are not patentably distinct from each other because the claim 8 of the patented claims teach a nucleic acid molecule, comprising a modified viral RNA replicon, wherein the modified viral RNA replicon comprises: a first nucleic acid sequence encoding one or more structural elements of a viral capsid enhancer comprising one or more RNA stem-loops, wherein the viral capsid enhancer is heterologous to the viral RNA replicon; and a second nucleic acid sequence comprising a sequence encoding for at least one viral nonstructural protein of a corresponding unmodified viral RNA replicon, wherein the first nucleic acid sequence is operably linked upstream to the second nucleic acid sequence, wherein the modified viral RNA replicon further comprises one or more expression cassettes, wherein at least one of the one or more expression cassettes comprises a promoter operably linked to a sequence for a gene of interest (GOI). Claim 11 further teaches wherein the native viral nonstructural proteins of the corresponding unmodified viral RNA replicon is from an alphavirus or arterivirus.
The patented claims do not teach that the expression cassette comprising the GOI is a component/operably linked of the second nucleotide sequence.
The teachings of Frolov 2014 are discussed above and provides for a replicon where an expression cassette is operably linked to a second nucleic acid sequence comprising nonstructural proteins [0041, Figs. 1-3].
It would have been to one ordinary skilled in the art before the effective filing date of the claimed invention to combine the teaching of the patented claims and modify the replicon where the expression cassette comprising the GOI is a component/operably linked of the second nucleotide sequence. One of ordinary skill would be motivated for the advantage of GOI expression. The combination of prior art elements according to known methods to yield predictable results supports can support a conclusion of obviousness. See MPEP 2143(I). One of ordinary skill in the art would have a reasonable expectation of success since both the patented claims and Frolov 2014 teach the use of modified viral RNA replicon for gene expression.
For additional limitations of the instant claims, see the additional teachings of the patented claims. To the extent that there are limitations that are not provided for by the patented claims, the teachings of Frolov 2014, Johnston, Berglund, Regts, Lee, Stein and Sanches are discussed above. It would have been obvious to have modified the subject matter of the patented claims to arrive at the subject matter of the instant claims for substantially the same reasons as discussed above in view of the teachings of these references.
Response to Arguments
Applicant's arguments filed 04/27/2025 have been fully considered but they are not persuasive in view of the response as discussed above. Applicant requests that the Examiner hold these rejections in abeyance until claims are deemed allowable in the current application. However, the Examiner lacks the authority to hold rejections in abeyance, and thus the rejections of record are simply maintained.
Conclusion
No claims allowed.
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/TIFFANY NICOLE GROOMS/Examiner, Art Unit 1637
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