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 .
Applicant’s amendment filed on 05/19/2026 has been entered.
Claims 1-2, 4-10, 12, 17-19, 23, 25-27, 29, 34 and 38 are pending in the present application.
Applicant's election with traverse of Group I (claims 1-2, 4-10, 12 and 17-18) in the reply filed on 05/19/2026 is acknowledged.
The traversal is on the ground(s) that the cited combination of Glorioso, Federoff and Das does not teach or suggest a packaging cell line in claim 1 of the present application (a shared special technical feature in Groups I-VI) because Glorioso and Federoff teach away from one another, and a person of ordinary skill in the art would not combine the selected teachings of Glorioso and Federoff with a reasonable expectation of success. Specifically, Glorioso describes a packaging cell line which is capable of producing HSV-like particles without vhs, and describes why this is advantageous (see Glorioso, paragraph [0044]). However, Federoff on the other hand strongly emphasizes expression systems which do include vhs (e.g., UL41) for VP16 to have any beneficial effect on HSV titers (see Federoff, paragraph [0020]). Additionally, Applicant argued that an ordinary skill in the art would not have expected with a reasonable expectation of success, that introducing VP16 along with additional features including ICP0, ICP4, and ICP27, would yield a further cumulative benefit or synergy; and there is no teaching or suggestion as to why a person having ordinary skill in the art would select VP16 (while not including vhs), and adding VP16 to ICP0, ICP4, and ICP27.
This is not found persuasive because although Glorioso taught that desirably the non-toxic HSV vector does not express UL41 (i.e., the host shut-off (vhs) gene); Glorioso did not teach nor suggest that a complementing/packing host cell could not contain a vhs expression vector encoding a virion host shutoff protein under any condition. Similar to the teachings of Glorioso, Federoff also generated HSV amplicon particles that do not express UL41 in a system comprising a complementing/packaging cell line containing a vhs expression vector encoding a virion host shutoff protein. Thus, there is no teaching away whatsoever between Glorioso and Federoff. Moreover, Federoff taught clearly to enhance packaging efficiency of generated HSV amplicon particles, the HSV transcriptional activator VP16 was introduced into packaging cells. Please refer to the 103 rejection that is set forth below for more details along with the provided motivation why an ordinary skill in the art would have combined the cited arts to arrive at the presently claimed invention with a reasonable expectation of success.
The requirement is still deemed proper and is therefore made FINAL.
Accordingly, claims 19, 23, 25-27, 29, 34 and 38 were withdrawn from further consideration because they are drawn to non-elected inventions.
Therefore, claims 1-2, 4-10, 12 and 17-18 are examined on the merits herein.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1, 2, 4, 6, 8-10, 12 and 17-18 are rejected under 35 U.S.C. 103 as being unpatentable over Glorioso, III et al (US 2019/0276845; IDS) in view of Federoff et al (US 2004/0105844; IDS) and Das et al (Current Gene Therapy 16:156-167, 2016; IDS).
The instant claims are drawn to a packaging cell line (e.g., a mammalian cell line, claim 18) comprising: (a) a helper virus genome (e.g., does not contain an origin of replication or a packaging signal, claim 10; does not express one or more of ICP0, ICP4, and ICP27, claim 12; does not contain an internal repat region, claim 17); (b) a nucleic acid sequence encoding reverse tetracycline transactivator (rtTA); (c) a nucleic sequence encoding VP16 (e.g., under the control of a Tet-On system, claim 4) ; (d) a nucleic acid sequence encoding ICP0 (e.g., under the control of a Tet-On system, claim 6); (e) a nucleic sequence encoding ICP4 (under the control of its cognate viral promoter, claim 8); and (f) a nucleic acid sequence encoding ICP27 (under the control of its cognate viral promoter, claim 9).
Glorioso, III et al already disclosed at least a complementing/packaging cell line that complements ICP0, ICP4 and ICP27 for the growth, production and propagation of a non-toxic HSV vector that does not express toxic HSV genes (e.g., ICP0, ICP4 and ICP27) in non-complementing cells and which HSV vector genome comprises one or more transgenes (see at least Abstract; Brief Summary of the Invention; particularly paragraphs [0042]-[0043], and [0064]). Glorioso, III et al stated clearly “[a]n aspect of the invention provides a complementing cell line, which complements ICP0 and ICP4, desirably ICP0, ICP4 and ICP27” (first sentence of paragraph [0064]); and taught that the cell line can be engineered to express these genes via expression cassettes and that the introduced ICP4/ICP27 coding sequences are preferably under the control of their cognate viral promoters (last complete sentence of paragraph [0064]). Glorioso, III et al also disclosed a novel cell line, based on U2OS human osteosarcoma cells, was engineered to conditionally express the essential genes ICP4 and ICP27 under the control of their cognate viral promoters via retrovirus-mediated insertion, and as such these genes may remain silent until HSV infection delivers the HSV tegument protein VP16 to the nucleus where it promotes high level expression of the integrated ICP4 and ICP27 genes by activation of their promoters (paragraph [0082]). Glorioso, III et al also stated “In addition to the perturbation of ICP0, ICP4, ICP22, ICP27, and ICP47 expression, desirably the inventive vector also does not express UL41 (i.e., the host shut-off (vhs) gene). UL41 is an RNAse that degrades many host and viral mRNAs, causes rapid shutoff of host cell protein synthesis, and enters cells as a virion tegument component” (paragraph [0044]); and “In addition to the foregoing, the inventive HSV vector also desirably comprises a deletion of the internal repeat (Joint) region, comprising IRs and IRL. Deleting this region can contribute to the stability of the vector genome, and deleting this sequence of HSV DNA also allows for the vector to accommodate large transgenes (at least 15 kb) and still be packaged correctly into mature virions. Deletion of the Joint eliminates one copy each of the IE genes ICP0 and ICP4 such that the remaining copies can be easily manipulated. It also deletes the promoter for the ICP22 or ICP47 immediate early genes” (paragraph [0060]). Glorioso, III et al further taught the use of an inducible promoter (e.g., TRE3G combined with rtTA3G expression from a separate promoter in LAT or other known inducible promoters known in the art) or a constitutive mammalian promoter (e.g., SV40, CMV, CAG, EF1α, UbC, RSV, β-actin, PGK, and the like) to express a transgene in an expression cassette that is inserted into the non-toxic HSV vector (paragraph [0055]).
Glorioso, III et al did not teach specifically a complementing/packaging cell line that further comprises a helper virus genome, a nucleic acid sequence encoding rtTA, and a nucleic acid sequence encoding VP16 for the production of a HSV amplicon particle.
Before the effective filing date of the present application (04/21/2021), Federoff et al already taught a method for producing HSV amplicon particles which includes co-transfecting a host cell (e.g., mammalian cells such as BHK cells, NIH 3T3 cells, 2-2 cells, 293 cells, and RR1 cells) with: (i) an amplicon vector comprising an HSV origin of replication, an HSV cleavage/packaging signal, and a heterologous transgene expressible in a patient, (ii) one or more vectors individually or collectively encoding all essential HSV genes (constituting a helper virus genome) but excluding all cleavage/packaging signals, and (iii) a vhs expression vector encoding a virion host shutoff protein; and then isolating HSV amplicon particles produced by the host cell (Abstract and paragraph [0072])). Federoff et al stated “To further enhance packaging efficiency, the HSV transcriptional activator VP16 was introduced into packaging cells prior to the packaging components. Preloading of packaging cells with VP16 led to an additional enhancement of amplicon titers, an effect that did not occur in the absence of vhs” (paragraph [0020]); and disclosed in an exemplification that VP16 expression is regulated via a glucocorticoid-controlled VP16 expression vector (Example 2, paragraphs [0122]-[0123]). Federoff et al taught that stable expression of VP16 can be achieved either using a stable plasmid which is copied and partitioned among dividing host cells with acceptable fidelity or by integration of the VP16 into the host cell genome (paragraph [0069]). Federoff et al also stated “The one or more vectors individually or collectively encoding all essential HSV genes but excluding all cleavage/packaging signals can either be in the form of a set of vectors or a single bacterial-artificial chromosome (“BAC”), which is formed, for example by combining the set of vectors to create a single, double-stranded vector” (paragraph [0053]); and “By “essential HSV genes”, it is intended that one or more vectors include all genes which encode polypeptides that are necessary for replication of the amplicon vector and structural assembly of the amplicon particles. Thus, in the absence of such genes, the amplicon vector is not properly replicated and packaged within a capsid to form an amplicon particle capable of adsorption” (paragraph [0054]). Table 1 listed all essential HSV-1 genes that include UL54 gene (encodes ICP27), and α4 gene (encodes ICP4). Federoff et al also prepared Helper Virus-free HSV amplicon particles and Helper Virus HSV amplicon particles in Example 4 for comparison.
Additionally, Das et al already reviewed Tet-On systems for doxycycline-inducible gene expression in eukaryotic cells in diverse settings, varying from basic biological research to biotechnology and gene therapy applications, with optimized rtTA variants that require less dox for activation, which will reduce side effects and allow gene control in tissues where a relatively low dox level can be reached, such as the brain (Abstract). Das et al also taught that a rtTA variant does not bind tetO in the absence of an effector, and binding of dox triggers a conformational switch in rtTA, which allows tetO binding (an advantage relative to the Tet-Off system in that dox is not required to be administered continuously outside of a small time window in which only transient expression of a gene-of-interest is needed) (see section titled “The Eukaryotic Tet-On System” at page 157; and Fig. 1).
Accordingly, it would have been obvious for an ordinary skill in the art to modify the teachings of Glorioso, III et al by also preparing a complementing/packaging cell line that further comprising a nucleic acid sequence encoding VP16; a nucleic acid sequence encoding rtTA of a Tet-On system under the control of a constitutive promoter for regulating the expression of said VP16 and/or ICP0; and all other essential HSV genes apart from genes encoding ICP4 and/or ICP27 in the form of a helper virus genome or a single BAC, that is useful for the production of a HSV amplicon particles; wherein the helper virus genome also does not contain an origin of replication (ori) and/or a packaging signal (pac), and/or an internal repeat (Joint) region, in light of the teachings of Federoff et al and Das et al as set forth above.
An ordinary skill in the art would have been motivated to carry out the above modifications because: (i) Federoff et al already taught that the HSV transcriptional activator VP16 was introduced into packaging cells (e.g., VP16 expression is regulated via a glucocorticoid-controlled VP16 expression vector) prior to the packaging components to enhance packaging efficiency and amplicon titers in the presence of vhs; the one or more vectors individually or collectively encoding all essential HSV genes but excluding all cleavage/packaging signals can either be in the form of a set of vectors or a single bacterial-artificial chromosome (“BAC”); and (ii) Das et al already reviewed well known Tet-On systems for doxycycline-inducible gene expression in eukaryotic cells in diverse settings, varying from basic biological research to biotechnology and gene therapy applications, which is also useful for regulating a controlled expression of VP16 and/or the toxic ICP0 in a complementing/packaging cell line. Please also note that the primary Glorioso, III reference already taught the introduced ICP4/ICP27 coding sequences are preferably under the control of their cognate viral promoters which are also activated by VP16; and that a deletion of the internal repeat (Joint) region comprising IRs and IRL can contribute to the stability of a vector genome and in this instance a helper virus genome. Furthermore, an ordinary skill in the art would readily recognize that the helper virus genome containing all essential HSV genes other than the genes encoding ICP4, ICP27 and/or ICP0 (already provided by other expression cassettes in one or more vectors in the complementing/packaging cell line), without an origin of replication and/or a packaging signal, and with a deleted internal repeat (Joint) region would be more stable and less likely to replicate and be packaged to contaminate the desired HSV amplicon particles. With respect to dependent claim 2, since Das et al already taught that a rtTA variant does not bind tetO in the absence of an effector in a Tet-On system, it would have been obvious for an ordinary skill in the art to operably link a nucleic acid encoding rtTA under the control of a constitutive promoter such that expressed rtTA variant is ready available for binding to added dox; and Glorioso, III et al also taught using a constitutive mammalian promoter (e.g., SV40, CMV, CAG, EF1α, UbC, RSV, β-actin, PGK, and the like) to express a transgene in an expression cassette.
An ordinary skilled artisan would have a reasonable expectation of success in light of the teachings of Glorioso, III et al, Federoff et al and Das et al; coupled with a high level of skill for an ordinary skilled artisan in the relevant art.
The modified complementing/packaging cell line for the production of HSV amplicon particles resulting from the combined teachings of Glorioso, III et al, Federoff et al and Das et al as presented above is indistinguishable from and encompassed by a packaging cell line of claim 1 of the present application.
Therefore, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
Claim 5 is rejected under 35 U.S.C. 103 as being unpatentable over Glorioso, III et al (US 201/0276845; IDS) in view of Federoff et al (US 2004/0105844; IDS) and Das et al (Current Gene Therapy 16:156-167, 2016; IDS) as applied to claims 1, 2, 4, 6, 8-10, 12 and 17-18 above, and further in view of La Boissiere et al (J. Virol. 78:8002-8014, 2004; IDS).
The combined teachings of Glorioso, III et al, Federoff et al and Das et al were presented above. However, none of the cited references teach specifically that VP16 is expressed as a fusion polypeptide comprising a reporter.
Before the effective filing date of the present application (04/21/2021), La Boissiere et al already prepared and successfully characterized recombinant HSV viruses expressing VP16 linked to a green fluorescent protein (GFP) to track and visualize the multifunctional VP16 protein that plays important roles in immediate-early transcriptional regulation, in the modulation of the activities of other viral components, and in the pathway of assembly and egress of infectious virions (see at least Abstract; and section titled “Construction of HSV-1 VP16-GFP viruses” at page 8003).
Accordingly, it would have been obvious for an ordinary skill in the art to further modify the combined teachings of Glorioso, III et al, Federoff et al and Das et al by also expressing VP16-GFP protein in the complementing/packaging cell line, in light of the teachings of La Boissiere et al as set forth above.
An ordinary skill in the art would have been motivated to carry out the above modification because La Boissiere et al already successfully characterized recombinant HSV viruses expressing VP16 linked to a green fluorescent protein (GFP) to track and visualize the multifunctional VP16 protein, and in this instance to monitor its expression via a Tet-On system as well as its regulation of ICP4 and/or ICP27 expression under the control of their respective cognate viral promoters, and the production of HSV amplicon particles in the complementing/packaging cell line.
An ordinary skilled artisan would have a reasonable expectation of success in light of the teachings of Glorioso, III et al, Federoff et al, Das et al and La Boissiere et al; coupled with a high level of skill for an ordinary skilled artisan in the relevant art.
The modified complementing/packaging cell line for the production of HSV amplicon particles resulting from the combined teachings of Glorioso, III et al, Federoff et al, Das et al and La Boissiere et al as presented above is indistinguishable from and encompassed by a packaging cell line of the present application.
Therefore, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
Claim 7 is rejected under 35 U.S.C. 103 as being unpatentable over Glorioso, III et al (US 201/0276845; IDS) in view of Federoff et al (US 2004/0105844; IDS) and Das et al (Current Gene Therapy 16:156-167, 2016; IDS) as applied to claims 1, 2, 4, 6, 8-10, 12 and 17-18 above, and further in view of Miller et al (US 2015/0159172; IDS).
The combined teachings of Glorioso, III et al, Federoff et al and Das et al were presented above. However, none of the cited references teach specifically that the nucleic acid encoding VP16, the nucleic acid encoding ICP0, the nucleic acid sequence encoding ICP4, helper virus genome, and/or the nucleic acid sequence encoding ICP27 is in a safe harbor site of the packaging cell line.
Before the effective filing date of the present application (04/21/2021), Miller et al already taught methods and compositions for targeted integration of a transgene encoding a functional protein into a “safe harbor” locus (e.g., CCR5, AAVS1, HPRT, Rosa or albumin locus) in a cell; and they also taught that a “safe harbor” locus is a locus within the genome wherein a gene may be inserted without any deleterious effect on the host cell and at which locus expression of the inserted gene is not perturbed by any read-through expression from neighboring genes (see at least Summary; particularly paragraphs [0015], , [0027] and [0100]).
Accordingly, it would have been obvious for an ordinary skill in the art to further modify the combined teachings of Glorioso, III et al, Federoff et al and Das et al by also at least inserting the nucleic acid encoding VP16, the nucleic acid encoding ICP0, the nucleic acid sequence encoding ICP4, helper virus genome, and/or the nucleic acid sequence encoding ICP27 in a safe harbor site of the complementing/packaging cell line, in light of the teachings of Miller et al as set forth above.
An ordinary skill in the art would have been motivated to carry out the above modification because Miller et al already taught successfully methods and compositions for targeted integration of a transgene encoding a functional protein into a “safe harbor” locus (e.g., CCR5, AAVS1, HPRT, Rosa or albumin locus) in a cell; and disclosed that a “safe harbor” locus is a locus within the genome wherein a gene may be inserted without any deleterious effect on the host cell and at which locus expression of the inserted gene is not perturbed by any read-through expression from neighboring genes. Please note that Federoff et al already taught at least that stable expression of VP16 could be achieved either using a stable plasmid which is copied and partitioned among dividing host cells with acceptable fidelity or by integration of the VP16 into the host cell genome.
An ordinary skilled artisan would have a reasonable expectation of success in light of the teachings of Glorioso, III, Federoff et al, Das et al and Miller et al; coupled with a high level of skill for an ordinary skilled artisan in the relevant art.
The modified complementing/packaging cell line for the production of HSV amplicon particles resulting from the combined teachings of Glorioso, III et al, Federoff et al, Das et al and Miller et al as presented above is indistinguishable from and encompassed by a packaging cell line of the present application.
Therefore, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
Claims 1-2, 4-10, 12 and 17-18 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 5-6, 9-11, 13-14, 16-18, 20-27 of copending Application No. 19/121,300 in view of Glorioso, III et al (US 2019/0276845; IDS), Federoff et al (US 2004/0105844; IDS), Das et al (Current Gene Therapy 16:156-167, 2016; IDS) and La Boissiere et al (J. Virol. 78:8002-8014, 2004; IDS).
Claims 1, 3, 5-6, 9-11, 13-14, 16-18, 20-27 of copending Application No. 19/121,300 are drawn to a packaging cell line comprising a recombinant genome (e.g., U2OS cell line comprising ICP0, ICP4 and ICP27 genes; dependent claim 25), wherein the recombinant genome comprises: a) a first nucleic acid sequence comprising one or more Herpes Simplex Virus (HSV) Class I genes (e.g., ICP4, ICP27, ICP0, ICP34.5, VP16, or a combination thereof; dependent claim 5) and a first one or more regulatory elements comprising a promoter; and b) a second nucleic acid sequence comprising one or more HSV Class I and Class II genes (equivalent to a helper virus genome of the present application), wherein the promoter is an inducible promoter (e.g., tetracycline-inducible promoter or a doxycycline-inducible promoter, or comprising a Tet-On promoter comprising TRE3G or TRE-tight; dependent claims 9-10); the same packaging cell line wherein the first nucleic acid sequence is in a first genomic safe harbor site of the recombinant genome, wherein the first genomic safe harbor site comprises a Rosa26 homolog locus (dependent claim 3); or wherein the second nucleic acid sequence is in a second genomic safe harbor site of the recombinant genome, wherein the second genomic safe harbor comprises an AAVS1 locus (claim 11); or wherein the recombinant genome does not comprise a nucleic acid comprising an HSV origin of replication (ori), an HSV packing signal (pac), a nucleic acid sequence comprising oriL/S, or a combination thereof (dependent claim 18).
The claims of the present application differ from claims 1, 3, 5-6, 9-11, 13-14, 16-18, 20-27 of copending Application No. 19/121,300 in reciting specifically that the packaging cell line comprising a nucleic acid sequence encoding reverse tetracycline transactivator (rtTA) that is under the control of a constitutive promoter; the nucleic acid sequence encoding VP16 is under the control of a Tet-On system and/or VP16 is expressed as a fusion polypeptide comprising a reporter; the nucleic acid sequence encoding ICP0 is under the control of a Tet-On system; the nucleic acid sequence encoding ICP4 or ICP27 is under the control of its cognate viral promoter; and the helper virus genome does not contain an internal repeat region (joint).
Before the effective filing date of the present application (04/21/2021), Glorioso, III et al already disclosed at least a complementing/packaging cell line that complements ICP0, ICP4 and ICP27 for the growth, production and propagation of a non-toxic HSV vector that does not express toxic HSV genes (e.g., ICP0, ICP4 and ICP27) in non-complementing cells and which HSV vector genome comprises one or more transgenes (see at least Abstract; Brief Summary of the Invention; particularly paragraphs [0042]-[0043], and [0064]). Glorioso, III stated clearly “[a]n aspect of the invention provides a complementing cell line, which complements ICP0 and ICP4, desirably ICP0, ICP4 and ICP27” (first sentence of paragraph [0064]); and taught that the cell line can be engineered to express these genes via expression cassettes and that the introduced ICP4/ICP27 coding sequences are preferably under the control of their cognate viral promoters (last complete sentence of paragraph [0064]). Glorioso, III also disclosed a novel cell line, based on U2OS human osteosarcoma cells, was engineered to conditionally express the essential genes ICP4 and ICP27 under the control of their cognate viral promoters via retrovirus-mediated insertion, and as such these genes may remain silent until HSV infection delivers the HSV tegument protein VP16 to the nucleus where it promotes high level expression of the integrated ICP4 and ICP27 genes by activation of their promoters (paragraph [0082]). Glorioso, III et al stated “In addition to the foregoing, the inventive HSV vector also desirably comprises a deletion of the internal repeat (Joint) region, comprising IRs and IRL. Deleting this region can contribute to the stability of the vector genome, and deleting this sequence of HSV DNA also allows for the vector to accommodate large transgenes (at least 15 kb) and still be packaged correctly into mature virions. Deletion of the Joint eliminates one copy each of the IE genes ICP0 and ICP4 such that the remaining copies can be easily manipulated. It also deletes the promoter for the ICP22 or ICP47 immediate early genes” (paragraph [0060]). Glorioso, III et al further taught the use of an inducible promoter (e.g., TRE3G combined with rtTA3G expression from a separate promoter in LAT or other known inducible promoters known in the art) or a constitutive mammalian promoter (e.g., SV40, CMV, CAG, EF1α, UbC, RSV, β-actin, PGK, and the like) to express a transgene in an expression cassette that is inserted into the non-toxic HSV vector (paragraph [0055]).
Additionally, Federoff et al already taught a method for producing HSV amplicon particles which includes co-transfecting a host cell (e.g., mammalian cells such as BHK cells, NIH 3T3 cells, 2-2 cells, 293 cells, and RR1 cells) with: (i) an amplicon vector comprising an HSV origin of replication, an HSV cleavage/packaging signal, and a heterologous transgene expressible in a patient, (ii) one or more vectors individually or collectively encoding all essential HSV genes (constituting a helper virus genome) but excluding all cleavage/packaging signals, and (iii) a vhs expression vector encoding a virion host shutoff protein; and then isolating HSV amplicon particles produced by the host cell (Abstract and paragraph [0072])). Federoff et al stated “To further enhance packaging efficiency, the HSV transcriptional activator VP16 was introduced into packaging cells prior to the packaging components. Preloading of packaging cells with VP16 led to an additional enhancement of amplicon titers, an effect that did not occur in the absence of vhs” (paragraph [0020]); and disclosed in an exemplification that VP16 expression is regulated via a glucocorticoid-controlled VP16 expression vector (Example 2, paragraphs [0122]-[0123]). Federoff et al taught that stable expression of VP16 can be achieved either using a stable plasmid which is copied and partitioned among dividing host cells with acceptable fidelity or by integration of the VP16 into the host cell genome (paragraph [0069]). Federoff et al also stated “The one or more vectors individually or collectively encoding all essential HSV genes but excluding all cleavage/packaging signals can either be in the form of a set of vectors or a single bacterial-artificial chromosome (“BAC”), which is formed, for example by combining the set of vectors to create a single, double-stranded vector” (paragraph [0053]); and “By “essential HSV genes”, it is intended that one or more vectors include all genes which encode polypeptides that are necessary for replication of the amplicon vector and structural assembly of the amplicon particles. Thus, in the absence of such genes, the amplicon vector is not properly replicated and packaged within a capsid to form an amplicon particle capable of adsorption” (paragraph [0054]). Table 1 listed all essential HSV-1 genes that include UL54 gene (encodes ICP27), and α4 gene (encodes ICP4). Federoff et al also prepared Helper Virus-free HSV amplicon particles and Helper Virus HSV amplicon particles in Example 4 for comparison.
Moreover, Das et al already reviewed Tet-On systems for doxycycline-inducible gene expression in eukaryotic cells in diverse settings, varying from basic biological research to biotechnology and gene therapy applications, with optimized rtTA variants that require less dox for activation, which will reduce side effects and allow gene control in tissues where a relatively low dox level can be reached, such as the brain (Abstract). Das et al also taught that a rtTA variant does not bind tetO in the absence of an effector, and binding of dox triggers a conformational switch in rtTA, which allows tetO binding (an advantage relative to the Tet-Off system in that dox is not required to be administered continuously outside of a small time window in which only transient expression of a gene-of-interest is needed) (see section titled “The Eukaryotic Tet-On System” at page 157; and Fig. 1).
Furthermore, La Boissiere et al already prepared and successfully characterized recombinant HSV viruses expressing VP16 linked to a green fluorescent protein (GFP) to track and visualize the multifunctional VP16 protein that plays important roles in immediate-early transcriptional regulation, in the modulation of the activities of other viral components, and in the pathway of assembly and egress of infectious virions (see at least Abstract; and section titled “Construction of HSV-1 VP16-GFP viruses” at page 8003).
Accordingly, it would have been obvious for an ordinary skilled artisan to modify the packaging cell line in claims 1, 3, 5-6, 9-11, 13-14, 16-18, 20-27 of copending Application No. 19/121,300 by also having the recited features of the instant claims; in light of the teachings of Glorioso, III et al, Federoff et al, Das et al and La Boissiere et al as set forth above with a reasonable expectation of success.
An ordinary skilled artisan would have been motivated to carry out the above modifications because: (i) Federoff et al already taught that the HSV transcriptional activator VP16 was introduced into packaging cells (e.g., VP16 expression is regulated via a glucocorticoid-controlled VP16 expression vector) prior to the packaging components to enhance packaging efficiency and amplicon titers in the presence of vhs; the one or more vectors individually or collectively encoding all essential HSV genes but excluding all cleavage/packaging signals can either be in the form of a set of vectors or a single bacterial-artificial chromosome (“BAC”); (ii) Das et al already reviewed well known Tet-On systems for doxycycline-inducible gene expression in eukaryotic cells in diverse settings, varying from basic biological research to biotechnology and gene therapy applications, which is also useful for regulating a controlled expression of VP16 and/or the toxic ICP0 in a complementing/packaging cell line; (iii) Glorioso, III et al also taught the introduced ICP4/ICP27 coding sequences are preferably under the control of their cognate viral promoters which are also activated by VP16; and that a deletion of the internal repeat (Joint) region comprising IRs and IRL can contribute to the stability of a vector genome and in this instance a helper virus genome; and (iv) La Boissiere et al already successfully characterized recombinant HSV viruses expressing VP16 linked to a green fluorescent protein (GFP) to track and visualize the multifunctional VP16 protein, and in this instance to monitor its expression via a Tet-On system as well as its regulation of ICP4 and/or ICP27 expression under the control of their respective cognate viral promoters, and the production of HSV amplicon particles in the complementing/packaging cell line. Moreover, an ordinary skill in the art would readily recognize that the helper virus genome containing all essential HSV genes other than the genes encoding ICP4, ICP27 and/or ICP0 (already provided by other expression cassettes in one or more vectors in the complementing/packaging cell line), without an origin of replication and/or a packaging signal, and with a deleted internal repeat (Joint) region would be more stable and less likely to replicate and be packaged to contaminate the desired HSV amplicon particles. With respect to dependent claim 2, since Das et al already taught that a rtTA variant does not bind tetO in the absence of an effector in a Tet-On system, it would have been obvious for an ordinary skill in the art to operably link a nucleic acid encoding rtTA under the control of a constitutive promoter such that expressed rtTA variant is ready available for binding to added dox; and Glorioso, III et al already taught using a constitutive mammalian promoter (e.g., SV40, CMV, CAG, EF1α, UbC, RSV, β-actin, PGK, and the like) to express a transgene in an expression cassette.
The modified packaging cell line resulting from claims 1, 3, 5-6, 9-11, 13-14, 16-18, 20-27 of copending Application No. 19/121,300 along with the teachings of Glorioso, III et al, Federoff et al, Das et al and La Boissiere et al as set forth above is indistinguishable and is encompassed by the presently claimed invention.
Therefore, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
This is a provisional nonstatutory double patenting rejection.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Gossen M et al (Science 268:1766-1769, 1995) disclosed the reverse Tet system with the gene encoding rtTA is composed of rtetR and the VP16 moiety, driven by the constitutive human cytomegalovirus IE promoter (Abstract; last paragraph of left column continues to first paragraph of middle column at page 1768; and Fig. 1).
Conclusions
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Quang Nguyen, Ph.D., at (571) 272-0776.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s SPE, James Douglas (Doug) Schultz, Ph.D., may be reached at (571) 272-0763.
To aid in correlating any papers for this application, all further correspondence regarding this application should be directed to Group Art Unit 1631; Central Fax No. (571) 273-8300.
Any inquiry of a general nature or relating to the status of this application or proceeding should be directed to (571) 272-0547.
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/QUANG NGUYEN/Primary Examiner, Art Unit 1631
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