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 .
Election/Restrictions
Applicant’s election without traverse of Group I, corresponding to claims, 1, 4-6, 8, 14, 17, 21, 26, 27, 33, 34, 36-38, 43, 48-50, 52, 57, 58, 60, 62, and 64- 66 in the reply filed on 07/22/2026 is acknowledged. Claims 1 and 37 have been amended. Claim 4 is cancelled.
Examiner also acknowledges applicant’s election of species:
Species I: pp71 – SEQ ID NOs: 14
Claims 21, 64, 65, and 66 are withdrawn from further consideration pursuant to 37
CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or
linking claim.
Claims 1, 5, 6, 8, 14, 17, 26, 27, 33, 34, 36 – 38, 43, 48-50, 52, 57, 58, 60, and 62 are under consideration.
Priority
This is a National Stage Entry under 35 U.S.C. 371 of International Patent Application
No. PCT/US2022/075647, filed August 30, 2022. This application also claims priority to US Provisional Application No. 63/239,269, filed on August 31, 2021.
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, 6, 33, 34, 36 – 38, 50, 58, and 62 are rejected under 35 U.S.C. 103 as being unpatentable over Caposio et al (Sci Rep, 2019, 10.1038/s41598-019-55508-w, hereinafter, “Caposio”), in view of Baldick et al (J Virology, 1997, 10.1128/jvi.71.6.4400-4408.1997, hereinafter, “Baldick”) and Perkel et al (Biocompare, 2015, hereinafter, “Perkel”), as evidenced by Lonza (Designing an RNAi Experiment Using Nucleofection™ Technical Reference Guide, 2012, hereinafter, “Lonza”) and Andronikou (Questions: Is transfection with mRNA faster? What are standard incubation times?, Cell Culture DISH, Retrieved 2020, hereinafter, “Andronikou”).
Caposio teaches designing CMV vaccines that demonstrate protection in animal models of infectious disease and cancer (Abstract). Caposio teaches that live attenuated viruses were generated by deleting genes required to counteract intrinsic and innate immune responses (Abstract). Caposio also teaches that attenuated viruses can be grown in known and common cell lines and increase viral production when anti-viral host factors are knocked down using small interfering RNA (Abstract). Caposio teaches that this method of generating attenuated virus removes the need for a complementing cell line (Abstract).
Regarding claim 1, Caposio teaches a method of producing progeny CMV by introducing siRNA to knockdown death-domain associated protein 6 (DAXX) and introducing a CMV wherein UL82, which encodes the pp71 protein, is deleted (Section: Generation of a live-attenuated HCMV vector platform by deletion or inactivation of UL82 (pp71)). Caposio teaches that a major function of pp71 is to counteract the host repressor DAXX which limits viral immediate early gene expression (Section: Generation of a live-attenuated HCMV vector platform by deletion or inactivation of UL82 (pp71)). Caposio teaches that by targeting DAXX with siRNA results in an increase in CMV production and recovery (Section: Generation of a live-attenuated HCMV vector platform by deletion or inactivation of UL82 (pp71), Figure 1E).
Caposio does not teach introducing mRNA encoding pp71 to cells to produce CMV.
However, regarding claim 1, Baldick teaches the identification of proteins involved in stimulating and increasing production of progeny CMV in human diploid fibroblasts (Abstract). Baldick teaches a method of producing the progeny CMV through transfection as well as though viral spread of parent CMV (Section: Late gene expression and virus spread). Baldick also teaches the introduction or omission of genes that are essential for augmenting CMV replication (Introduction: ¶ 3-5). Regarding claim 1, Baldick teaches that co-transfecting viral DNA with a plasmid expressing pp71 increased HCMV DNA production by 30 – 80-fold (Abstract, Figure 1).
Both Caposio and Baldick do not teach introducing a mRNA encoding a pp71 protein.
However, Perkel teaches the advantages and disadvantages of DNA, RNA, and protein transfection into cells (See document). Perkel teaches the advantages of DNA transfection include expense and continuous production of mRNA and protein long after transfection (Section: DNA ¶3). Perkel teaches that the disadvantages of DNA transfection include transport into the nucleus and possible genome integration (Section: DNA ¶4). Perkel teaches the advantages of RNA transfection include an increase in transfection efficiency, no need for nucleus transport, and quicker protein production compared to DNA transfections (Section: RNA ¶1). Perkel also teaches that mRNA transfection will only result in produced protein as long as the mRNA is not degraded (Section: RNA ¶2). Additionally, Perkel teaches that DNA transfection will result in mRNA as mRNA is transcribed from a DNA template (Section: RNA ¶4).
Together, the prior art teaches a method of producing progeny CMV by infecting cells with a parent CMV, incubating the cell, and collecting the progeny CMV through the overproduction of pp71 within cells to increase viral titers. The prior art also teaches that the use of mRNA transfection would result in quicker protein production. The transfection of pp71 mRNA would reasonably achieve the same result as knocking down the host repressor DAXX in a shorter amount of time because protein production due to mRNA transfection operates at a faster time scale than protein reduction caused by siRNA. Proteins are produced as quickly as 90 minutes after mRNA transfection, as evidenced by Andronikou, while it can take at least 24 hours for adequate knockdown of target proteins using siRNA, as evidenced by Lonza (Section: 4. Determine Optimal Analysis Time points). Therefore, it would have been prima facie obvious before the effective filing date of the claimed invention to use introduce mRNA encoding pp71 into a cell along with a parent CMV to produce progeny CMV because doing so would enable generate high titers of CMV in shorter amount of time. One of ordinary skill in the art would have had a reasonable expectation of success in using mRNA to produce pp71 in a cell line to produce CMV given the increase in viral titers by the overproduction of pp71 is well known, has been successfully demonstrated, and commonly used in the prior art.
Regarding claim 6, Caposio teaches the use of MRC-5 cells to produce CMV (Section: In vitro growth of live-attenuated TR3).
Regarding claim 33, Caposio teaches the progeny CMV is a HCMV (Abstract).
Regarding claim 34, Caposio teaches the progeny CMV is comprised of a TR3 backbone (Section: In vitro growth of live-attenuated TR3).
Regarding claims 36 – 38 and 62, Caposio teaches the generation of a UL82-deleted HCMV by replacing the pp71-encoding ORF with that of HIVgag (Figure 1D, Section: Generation of a live-attenuated HCMV vector platform by deletion or inactivation of UL82 (pp71)).
Regarding claims 50 and 58, Caposio teaches the deletion of UL82 in the parent CMV (Figure 1D, Section: Generation of a live-attenuated HCMV vector platform by deletion or inactivation of UL82 (pp71)).
Together, the prior art teaches a method of producing progeny CMV by infecting cells with a parent CMV, incubating the cell, and collecting the progeny CMV through the overproduction of pp71 to increase viral titers. The prior art also teaches the use of a TR3 backbone to express HIVgag antigen. Therefore, it would have been prima facie obvious before the effective filing date of the claimed invention to use introduce mRNA encoding pp71 into a cell along with a parent CMV comprising a TR3 backbone encoding a HIVgag antigen to produce progeny CMV because doing so would enable generate high titers of CMV in shorter amount of time. One of ordinary skill in the art would have had a reasonable expectation of success in using mRNA to produce pp71 in a cell line to produce CMV given the increase in viral titers by the overproduction of pp71 is well known, has been successfully demonstrated, and commonly used in the prior art.
Accordingly, the claimed invention was prima facie obvious to one of ordinary skill in the art at the time of filing especially in the absence of evidence to the contrary.
Claim 5 is rejected under 35 U.S.C. 103 as being unpatentable over Caposio, Baldick, and Perkel as applied to claims 1, 6, 33, 34, 36 – 38, 50, 58, and 62 above, and further in view of Paredes et al (Curr Protoc Microbiol, 2012, 10.1002/9780471729259.mc14e04s24, hereinafter, “Paredes”).
As discussed above, claims 1, 6, 33, 34, 36 – 38, 50, 58, and 62 were rendered prima facie obvious by Caposio, Baldick, and Perkel. While the references teach a method of producing HCMV by overexpression of pp71, the references fail to teach wherein the progeny CMV comprises pp71 protein.
However, Parades teaches the development of a bacterial artificial chromosome (BAC) system that allows for the production of full length HCMV (Abstract). Parades teaches the protocol of using a BAC system to produce progeny CMV (Section: Basic Protocol 1). Parades teaches the AD169 was propagated using this system without the need for deletion of any viral sequence (Section: Basic Protocol 1 ¶1). Furthermore, Parades teaches the co transfection of the HCMV viral DNA and HCMV pp71 plasmid which increases virus reconstitution (Section: Construction of recombinant HCMV virus carrying the BAC capture plasmid, Step 21).
Regarding claim 5, Parades teaches the reconstitution of CMV AD169 by transfecting HCMV viral DNA and HCMV pp71 plasmid, resulting in full length CMV that are not missing viral components such as pp71 (Section: Basic Protocol 1 ¶1).
Together, the prior art teaches a method of producing progeny CMV by infecting cells with a parent CMV, incubating the cell, and collecting the progeny CMV that is comprised of pp71 through the overproduction of pp71 to increase viral titers. Therefore, it would have been prima facie obvious before the effective filing date of the claimed invention to produce CMV that express pp71 by transfecting a mRNA encoding pp71 into a cell along with a parent CMV to produce progeny CMV because doing so would enable the generation of full length CMV in a shorter amount of time. One of ordinary skill in the art would have had a reasonable expectation of success in using mRNA to produce pp71 in a cell line to produce full length CMV given the increase in viral titers by the overproduction of pp71 is well known, has been successfully demonstrated, and commonly used in the prior art.
Accordingly, the claimed invention was prima facie obvious to one of ordinary skill in the art at the time of filing especially in the absence of evidence to the contrary.
Claims 8, 14, and 17 are rejected under 35 U.S.C. 103 as being unpatentable over Caposio, Baldick, and Perkel as applied to claims 1, 6, 33, 34, 36 – 38, 50, 58, and 62 above, and further in view of Hager et al (Human gene therapy, 2008, 10.1089/hum.2007.165, hereinafter, “Hager”) and Eichhorn et al (eLife, 2016, 10.7554/eLife.16955, hereinafter, “Eichhorn”).
As discussed above, claims 1, 6, 33, 34, 36 – 38, 50, 58, and 62 were rendered prima facie obvious by Caposio, Baldick, and Perkel. While the references teach a method of producing HCMV by overexpression of pp71, the references fail to teach the exact sequence of SEQ ID NO: 14, a mRNA molecule further comprising a poly(A) tail, or a mRNA molecule produced using a double-stranded DNA template encoding the poly(A) tail from a plasmid.
However, Hager teaches the optimization of transgene expression cassettes encoded by lentiviruses (Abstract). Hager teaches that poly(A) tails increase mRNA stability and translation efficiency (Section: LENTIVIRAL VECTOR INTERNAL POLY(A) SIGNAL ¶2). Hager teaches that poly(A) signal enhances transgene expression (Section: LENTIVIRAL VECTOR INTERNAL POLY(A) SIGNAL ¶3). Hager also teaches that viral promoters can affect viral titers (Abstract).
Additionally, Eichhorn teaches that the poly(A) tail influences the translation of mRNA (Abstract). Eichhorn teaches the profiling of translational efficiencies and poly(A) tail lengths throughout Drosophila oocyte maturation and early embryonic development (Abstract). Eichhorn teaches that longer poly(A) tail have higher translation efficiency in multiple stages of developments (Section: A conserved switch in the nature of translational control ¶2, 3).
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Regarding claims 8 and 14, Caposio teaches a 100% sequence identity to the first 2034 nucleotides of SEQ ID NO: 14 (reproduced below, Query is SEQ ID NO: 14, Sbjct is Caposio- note only the first 483 nucleotides are shown). Eichhorn teaches an 80 nt poly(A) tail increases translation efficiency, which corresponds to nucleotides 2035 – 2114 of SEQ ID NO: 14 (Section: A conserved switch in the nature of translational control ¶2, 3). Thus, the claimed sequence is reasonably encompassed by Caposio and Eichhorn.
Regarding claim 17, Caposio teaches the production of a mRNA encoding pp71 using a DNA plasmid.
Caposio, Baldick, Perkel, Hager, and Eichhorn are considered to be analogous to the claim invention because they deal with the expression of proteins within a cell. Caposio teaches a method of producing progeny CMV by introducing siRNA to knockdown death-domain associated protein 6 (DAXX) along with a CMV with the UL82, encoding the pp71 protein, deleted (Section: Generation of a live-attenuated HCMV vector platform by deletion or inactivation of UL82 (pp71)). Baldick teaches that co-transfecting viral DNA with a plasmid expressing pp71 increased HCMV DNA production by 30 – 80-fold (Abstract, Figure 1). Perkel also teaches that mRNA transfection will only result in produced protein as long as the mRNA is not degraded (Section: RNA ¶2). Additionally, Perkel teaches that DNA transfection will result in mRNA as mRNA is transcribed from a DNA template (Section: RNA ¶4). Hager teaches that poly(A) signal enhances transgene expression (Section: LENTIVIRAL VECTOR INTERNAL POLY(A) SIGNAL ¶3). Eichhorn teaches an 80 nt poly(A) tail increases translation efficiency (Section: A conserved switch in the nature of translational control ¶2, 3).
Together, the prior art teaches a method of producing progeny CMV by infecting cells with a parent CMV, incubating the cell, and collecting the progeny CMV by using a transgene with a poly(A) tail. Therefore, it would have been prima facie obvious before the effective filing date of the claimed invention to use introduce mRNA encoding pp71 and a poly(A) tail into a cell along with a parent CMV to produce progeny CMV because doing so would enable stabilize the exogenous mRNA. One of ordinary skill in the art would have had a reasonable expectation of success in using mRNA with a poly(A) tail to produce pp71 in a cell line to produce CMV given the function of poly(A) tails to increase transgene expression is well known, has been successfully demonstrated, and commonly used in the prior art.
Accordingly, the claimed invention was prima facie obvious to one of ordinary skill in the art at the time of filing especially in the absence of evidence to the contrary.
Claims 26 and 27 are rejected under 35 U.S.C. 103 as being unpatentable over Caposio, Baldick, and Perkel as applied to claims 1, 6, 33, 34, 36 – 38, 50, 58, and 62 above, and further in view of Life TechnologiesTM (Lipofectamine® 2000 Reagent Protocol 2013, 2013, hereinafter, “Life Technologies”).
As discussed above, claims 1, 6, 33, 34, 36 – 38, 50, 58, and 62 were rendered prima facie obvious by Caposio, Baldick, and Perkel. While the references teach a method of producing HCMV by overexpression of pp71, the references fail to teach the mRNA is introduced using transfection.
However, Life Technologies teaches Lipofectamine 2000 can be used to transfect mRNA in cells (Section: mRNA Transfection). Additionally, Caposio teaches using Lipofectamine 2000 to transfect cells with siRNA (Section: HCMV ¶5).
Therefore, it would have been prima facie obvious before the effective filing date of the claimed invention to use a lipid transfection reagent introduce mRNA encoding pp71 into a cell along with a parent CMV to produce progeny CMV because doing so would improve mRNA uptake from the cell. One of ordinary skill in the art would have had a reasonable expectation of success in using a lipid transfection reagent to introduce mRNA in a cell line produce CMV given the lipid transfection reagents are well known to be used to transfect mRNA, has been successfully demonstrated, and commonly used in the prior art.
Accordingly, the claimed invention was prima facie obvious to one of ordinary skill in the art at the time of filing especially in the absence of evidence to the contrary.
Claim 43 is rejected under 35 U.S.C. 103 as being unpatentable over Caposio, Baldick, and Perkel as applied to claims 1, 6, 33, 34, 36 – 38, 50, 58, and 62 above, and further in view of Bruening et al (US20170319679A1, hereinafter, “Bruening”).
As discussed above, claims 1, 6, 33, 34, 36 – 38, 50, 58, and 62 were rendered prima facie obvious by Caposio, Baldick, and Perkel. While the references teach a method of producing HCMV by overexpression of pp71, the references fail to teach a pathogen specific antigen for HIV comprised of SEQ ID NO: 12.
However, Bruening teaches HIV-1 vaccines comprising a carrier and a population episensus antigen that was determined using an EpiGraph approach (Abstract). Bruening teaches that the HIV antigens can be fusion proteins and be delivered using a HCMV viral vector (¶0008, ¶0052). Bruening teaches that the HCMV can lack UL82 (¶0072). Bruening also teaches that the HIV antigens can be fusions of gag, nef, and pol proteins (¶0010).
Regarding claim 43, SEQ ID NO: 12 is an amino acid sequence comprised of a M conserved gag/nef/pol fusion episensus 1 protein. Bruening teaches that the HIV antigen can be a fusion of gag, nef, and pol proteins (¶0010, Claim 9). Bruening teaches that the HIV antigen can be comprised of SEQ ID NOs: 719, 723, and 710 (¶0060). Bruening teaches SEQ ID NO: 719 has a 100% sequence identity to amino acids 2 – 232 of instant application SEQ ID NO: 12 (reproduced below, Qy is SEQ ID NO: 12, Db is Bruening).
SEQ ID NO:12 2 – 232 vs BRUENING SEQ ID NO: 719
US-15-516-491-719
Query Match 24.9%; Score 1214; DB 1; Length 231;
Best Local Similarity 100.0%;
Matches 231; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 2 PIVQNLQGQMVHQAISPRTLNAWVKVVEEKAFSPEVIPMFSALSEGATPQDLNTMLNTVG 61
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 PIVQNLQGQMVHQAISPRTLNAWVKVVEEKAFSPEVIPMFSALSEGATPQDLNTMLNTVG 60
Qy 62 GHQAAMQMLKETINEEAAEWDRLHPVHAGPIAPGQMREPRGSDIAGTTSTLQEQIGWMTN 121
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 GHQAAMQMLKETINEEAAEWDRLHPVHAGPIAPGQMREPRGSDIAGTTSTLQEQIGWMTN 120
Qy 122 NPPIPVGEIYKRWIILGLNKIVRMYSPVSILDIRQGPKEPFRDYVDRFYKTLRAEQATQE 181
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 NPPIPVGEIYKRWIILGLNKIVRMYSPVSILDIRQGPKEPFRDYVDRFYKTLRAEQATQE 180
Qy 182 VKNWMTETLLVQNANPDCKTILKALGPAATLEEMMTACQGVGGPGHKARVL 232
|||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 VKNWMTETLLVQNANPDCKTILKALGPAATLEEMMTACQGVGGPGHKARVL 231Bruening teaches SEQ ID NO: 723 has a 100% sequence identity to amino acids 233 – 314 of instant application SEQ ID NO: 12 (reproduced below, Qy is SEQ ID NO: 12, Db is Bruening).
SEQ ID NO:12 233 – 314 vs BRUENING SEQ ID NO: 723
US-15-516-491-723
Query Match 9.6%; Score 465; DB 1; Length 82;
Best Local Similarity 100.0%;
Matches 82; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 233 VGFPVRPQVPLRPMTYKGALDLSHFLKEKGGLEGLIYSKKRQEILDLWVYHTQGYFPDWQ 292
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 VGFPVRPQVPLRPMTYKGALDLSHFLKEKGGLEGLIYSKKRQEILDLWVYHTQGYFPDWQ 60
Qy 293 NYTPGPGIRYPLTFGWCFKLVP 314
||||||||||||||||||||||
Db 61 NYTPGPGIRYPLTFGWCFKLVP 82
Bruening teaches SEQ ID NO: 710 has a 100% sequence identity to amino acids 315 – 912 of instant application SEQ ID NO: 12 (reproduced below, Qy is SEQ ID NO: 12, Db is Bruening).
SEQ ID NO: 12 315 – 912 vs BRUENING SEQ ID NO: 710
US-15-516-491-710
Query Match 65.4%; Score 3184; DB 1; Length 599;
Best Local Similarity 100.0%;
Matches 598; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 315 PQITLWQRPLVTIKIGGQLKEALLADDTVLEDINLPGKWKPKMIGGIGGFIKVRQYDQIL 374
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 2 PQITLWQRPLVTIKIGGQLKEALLADDTVLEDINLPGKWKPKMIGGIGGFIKVRQYDQIL 61
Qy 375 IEICGKKAIGTVLVGPTPVNIIGRNLLTQIGCTLNFPISPIETVPVKLKPGMDGPKVKQW 434
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 62 IEICGKKAIGTVLVGPTPVNIIGRNLLTQIGCTLNFPISPIETVPVKLKPGMDGPKVKQW 121
Qy 435 PLTEEKIKALVEICTEMEKEGKISKIGPENPYNTPVFAIKKKDSTKWRKLVDFRELNKRT 494
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 122 PLTEEKIKALVEICTEMEKEGKISKIGPENPYNTPVFAIKKKDSTKWRKLVDFRELNKRT 181
Qy 495 QDFWEVQLGIPHPAGLKKKKSVTVLDVGDAYFSVPLDKDFRKYTAFTIPSINNETPGIRY 554
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 182 QDFWEVQLGIPHPAGLKKKKSVTVLDVGDAYFSVPLDKDFRKYTAFTIPSINNETPGIRY 241
Qy 555 QYNVLPQGWKGSPAIFQSSMTKILEPFRKQNPDIVIYQLYVGSDLEIGQHRTKIEELRQH 614
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 242 QYNVLPQGWKGSPAIFQSSMTKILEPFRKQNPDIVIYQLYVGSDLEIGQHRTKIEELRQH 301
Qy 615 LLKWGFTTPDKKHQKEPPFLWMGYELHPDKWTVQPIVLPEKDSWTVNDIQKLVGKLNWAS 674
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 302 LLKWGFTTPDKKHQKEPPFLWMGYELHPDKWTVQPIVLPEKDSWTVNDIQKLVGKLNWAS 361
Qy 675 QIYHGQVDCSPGIWQLCTHLEGKVILVAVHVASGYIEAEVIPAETGQETAYFLLKLAGRW 734
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 362 QIYHGQVDCSPGIWQLCTHLEGKVILVAVHVASGYIEAEVIPAETGQETAYFLLKLAGRW 421
Qy 735 PVKVIHTNGSNFTSAAVKAACWWAGIKQEFGIPYNPQSQGVVSMNKELKKIIGQVRDQAE 794
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 422 PVKVIHTNGSNFTSAAVKAACWWAGIKQEFGIPYNPQSQGVVSMNKELKKIIGQVRDQAE 481
Qy 795 HLKTAVQMAVFIHNFKRKGGIGGYSAGERIIDIIATDIQTKLQKQITKIQNFRVYYRDSR 854
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 482 HLKTAVQMAVFIHNFKRKGGIGGYSAGERIIDIIATDIQTKLQKQITKIQNFRVYYRDSR 541
Qy 855 DPIWKGPAKLLWKGEGAVVIQDNSDIKVVPRRKAKIIRDYGKQMAGDDCVAGRQDEDQ 912
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 542 DPIWKGPAKLLWKGEGAVVIQDNSDIKVVPRRKAKIIRDYGKQMAGDDCVAGRQDEDQ 599
Together, Bruening teaches the sequences of gag, nef, and pol used to form the fusion amino acid sequence of SEQ ID NO: 12 (see above). Bruening also teaches gag, nef, and pol can be fused in a single antigen and delivered in a HCMV lacking UL82 (¶0008, ¶0052, ¶0072, ¶0010). Therefore, it would have been prima facie obvious before the effective filing date of the claimed invention to encode a HIV antigen with the exact sequence of SEQ ID NO: 12 in a CMV and produce progeny CMV by introducing mRNA encoding pp71 into a cell along with a parent CMV to produce CMV because doing so would quickly produce CMV that can be used to stimulate an immune response towards HIV. One of ordinary skill in the art would have had a reasonable expectation of using the exact sequence of SEQ ID NO: 12 given that the fusion of the individual protein in a singular antigen is well known, has been successfully demonstrated, and commonly used in the prior art.
Accordingly, the claimed invention was prima facie obvious to one of ordinary skill in the art at the time of filing especially in the absence of evidence to the contrary.
Claim 48 is rejected under 35 U.S.C. 103 as being unpatentable over Caposio, Baldick, and Perkel as applied to claims 1, 6, 33, 34, 36 – 38, 50, 58, and 62 above, and further in view of Evans et al (US20180016599A1, hereinafter, “Evans”).
As discussed above, claims 1, 6, 33, 34, 36 – 38, 50, 58, and 62 were rendered prima facie obvious by Caposio, Baldick, and Perkel. While the references teach a method of producing HCMV by overexpression of pp71, the references fail to teach a pathogen specific antigen for Mycobacterium tuberculosis (Mtb) comprising SEQ ID NO: 13.
However, Evans teaches CMV vectors encoding fusion proteins comprising Mtb antigens that elicit an immune response against tuberculosis (Abstract). Evans teaches the deletion of UL82 of the CMV and the inclusion of Mtb antigens (¶0150, Claim 1). Regarding claim 48, Evans teaches a 100% sequence identity to SEQ ID NO:13 (reproduced below, Qy is SEQ ID NO: 13, Db is Evans).
Query Match 100.0%; Score 6246; Length 1200;
Best Local Similarity 100.0%;
Matches 1190; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 MAFSRPGLPVEYLQVPSPSMGRDIKVQFQSGGANSPALYLLDGLRAQDDFSGWDINTPAF 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 MAFSRPGLPVEYLQVPSPSMGRDIKVQFQSGGANSPALYLLDGLRAQDDFSGWDINTPAF 60
Qy 61 EWYDQSGLSVVMPVGGQSSFYSDWYQPACGKAGCQTYKWETFLTSELPGWLQANRHVKPT 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 EWYDQSGLSVVMPVGGQSSFYSDWYQPACGKAGCQTYKWETFLTSELPGWLQANRHVKPT 120
Qy 121 GSAVVGLSMAASSALTLAIYHPQQFVYAGAMSGLLDPSQAMGPTLIGLAMGDAGGYKASD 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 GSAVVGLSMAASSALTLAIYHPQQFVYAGAMSGLLDPSQAMGPTLIGLAMGDAGGYKASD 180
Qy 181 MWGPKEDPAWQRNDPLLNVGKLIANNTRVWVYCGNGKPSDLGGNNLPAKFLEGFVRTSNI 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 MWGPKEDPAWQRNDPLLNVGKLIANNTRVWVYCGNGKPSDLGGNNLPAKFLEGFVRTSNI 240
Qy 241 KFQDAYNAGGGHNGVFDFPDSGTHSWEYWGAQLNAMKPDLQRALGATPNTGPAPQGATEQ 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 KFQDAYNAGGGHNGVFDFPDSGTHSWEYWGAQLNAMKPDLQRALGATPNTGPAPQGATEQ 300
Qy 301 QWNFAGIEAAASAIQGNVTSIHSLLDEGKQSLTKLAAAWGGSGSEAYQGVQQKWDATATE 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 301 QWNFAGIEAAASAIQGNVTSIHSLLDEGKQSLTKLAAAWGGSGSEAYQGVQQKWDATATE 360
Qy 361 LNNALQNLARTISEAGQAMASTEGNVTGMFARATVGLVEAIGIRELRQHASRYLARVEAG 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 361 LNNALQNLARTISEAGQAMASTEGNVTGMFARATVGLVEAIGIRELRQHASRYLARVEAG 420
Qy 421 EELGVTNKGRLVARLIPVQAAERSREALIESGVLIPARRPQNLLDVTAEPARGRKRTLSD 480
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 421 EELGVTNKGRLVARLIPVQAAERSREALIESGVLIPARRPQNLLDVTAEPARGRKRTLSD 480
Qy 481 VLNEMRDEQTTARDIMNAGVTCVGEHETLTAAAQYMREHDIGALPICGDDDRLHGMLTDR 540
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 481 VLNEMRDEQTTARDIMNAGVTCVGEHETLTAAAQYMREHDIGALPICGDDDRLHGMLTDR 540
Qy 541 DIVIKGLAAGLDPNTATAGELARDSIYYVDANASIQEMLNVMEEHQVRRVPVISEHRLVG 600
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 541 DIVIKGLAAGLDPNTATAGELARDSIYYVDANASIQEMLNVMEEHQVRRVPVISEHRLVG 600
Qy 601 IVTEADIARHLPEHAIVQFVKAICSPMALASSGRHRKPTTSNVSVAKIAFTGAVLGGGGI 660
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 601 IVTEADIARHLPEHAIVQFVKAICSPMALASSGRHRKPTTSNVSVAKIAFTGAVLGGGGI 660
Qy 661 AMAAQATAATDGEWDQVARCESGGNWSINTGNGYLGGLQFTQSTWAAHGGGEFAPSAQLA 720
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 661 AMAAQATAATDGEWDQVARCESGGNWSINTGNGYLGGLQFTQSTWAAHGGGEFAPSAQLA 720
Qy 721 SREQQIAVGERVLATQGRGAWPVCGRGLSNATPREVLPASAAMDAPLDAAAVNGEPAPLA 780
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 721 SREQQIAVGERVLATQGRGAWPVCGRGLSNATPREVLPASAAMDAPLDAAAVNGEPAPLA 780
Qy 781 PPPADPAPPVELAANDLPAPLGEPLPAAPADPAPPADLAPPAPADVAPPVELAVNDLPAP 840
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 781 PPPADPAPPVELAANDLPAPLGEPLPAAPADPAPPADLAPPAPADVAPPVELAVNDLPAP 840
Qy 841 LGEPLPAAPADPAPPADLAPPAPADLAPPAPADLAPPAPADLAPPVELAVNDLPAPLGEP 900
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 841 LGEPLPAAPADPAPPADLAPPAPADLAPPAPADLAPPAPADLAPPVELAVNDLPAPLGEP 900
Qy 901 LPAAPAELAPPADLAPASADLAPPAPADLAPPAPAELAPPAPADLAPPAAVNEQTAPGDQ 960
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 901 LPAAPAELAPPADLAPASADLAPPAPADLAPPAPAELAPPAPADLAPPAAVNEQTAPGDQ 960
Qy 961 PATAPGGPVGLATDLELPEPDPQPADAPPPGDVTEAPAETPQVSNIAYTKKLWQAIRAQD 1020
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 961 PATAPGGPVGLATDLELPEPDPQPADAPPPGDVTEAPAETPQVSNIAYTKKLWQAIRAQD 1020
Qy 1021 VCGNDALDSLAQPYVIGTPGLLTTAGAGRPRDRCARIVCTVFIETAVVATMFVALLGLST 1080
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1021 VCGNDALDSLAQPYVIGTPGLLTTAGAGRPRDRCARIVCTVFIETAVVATMFVALLGLST 1080
Qy 1081 ISSKADDIDWDAIA QCESGGNWAANTGNGLYGGLQISQATWDSNGGVGSPAAASPQQQIE 1140
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1081 ISSKADDIDWDAIA QCESGGNWAANTGNGLYGGLQISQATWDSNGGVGSPAAASPQQQIE 1140
Qy 1141 VADNIMKTQGPGAWPKCSSCSQGDAPLGSLTHILTFLAAETGGCSGSRDD 1190
||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1141 VADNIMKTQGPGAWPKCSSCSQGDAPLGSLTHILTFLAAETGGCSGSRDD 1190
Together, the prior art teaches a method of producing progeny CMV encoding a Mtb antigen by infecting cells with a parent CMV, incubating the cell, and collecting the progeny CMV. Therefore, it would have been prima facie obvious before the effective filing date of the claimed invention to encode a Mtb antigen with the exact sequence of SEQ ID NO: 13 in a CMV and produce progeny CMV by introducing mRNA encoding pp71 into a cell along with a parent CMV to produce CMV because doing so would quickly produce CMV that can be used to stimulate an immune response towards Mtb antigens. One of ordinary skill in the art would have had a reasonable expectation of using the exact sequence of SEQ ID NO: 13 given the sequence is well known, has been successfully demonstrated, and commonly used in the prior art.
Accordingly, the claimed invention was prima facie obvious to one of ordinary skill in the art at the time of filing especially in the absence of evidence to the contrary.
Claim 49 is rejected under 35 U.S.C. 103 as being unpatentable over Caposio, Baldick, and Perkel as applied to claims 1, 6, 33, 34, 36 – 38, 50, 58, and 62 above, and further in view of Klyushnenkova et al (J immunother, 2013, 10.1097/CJI.0b013e3182585d50, hereinafter, “Klyushnenkova”).
As discussed above, claims 1, 6, 33, 34, 36 – 38, 50, 58, and 62 were rendered prima facie obvious by Caposio, Baldick, and Perkel. While the references teach a method of producing HCMV by overexpression of pp71, the references fail to teach wherein the heterologous antigen comprises a prostate cancer antigen.
However, Klyushnenkova teaches the use of CMV as a virus-based vaccine delivery platform (Abstract). Klyushnenkova teaches mouse CMV based vaccines expressing human prostate-specific antigen (PSA) for prostate cancer immunotherapy in mice (Abstract). Klyushnenkova teaches the immunization of animals with the CMV based vaccine delayed growth and increased PSA-specific CD8 T cell responses (Abstract).
Regarding claim 49, Klyushnenkova teaches CMV expressing PSA antigens (Section: Vector construction).
Together, the prior art teaches a method of producing progeny CMV encoding a prostate cancer antigen by infecting cells with a parent CMV, incubating the cell, and collecting the progeny CMV. Therefore, it would have been prima facie obvious before the effective filing date of the claimed invention to encode a prostate cancer antigen in a CMV and produce progeny CMV by introducing mRNA encoding pp71 into a cell along with a parent CMV because doing so would quickly produce CMV that can be used to stimulate an immune response towards prostate cancer antigen. One of ordinary skill in the art would have had a reasonable expectation of encoding prostate cancer antigen in CMV given the expression of prostate cancer antigen delivered with CMV is well known, has been successfully demonstrated, and commonly used in the prior art.
Accordingly, the claimed invention was prima facie obvious to one of ordinary skill in the art at the time of filing especially in the absence of evidence to the contrary.
Claim 52, 57, and 60 are rejected under 35 U.S.C. 103 as being unpatentable over Caposio, Baldick, and Perkel as applied to claims 1, 6, 33, 34, 36 – 38, 50, 58, and 62 above, and further in view of Picker et al (US20180133321A1, hereinafter, “Picker”).
As discussed above, claims 1, 6, 33, 34, 36 – 38, 50, 58, and 62 were rendered prima facie obvious by Caposio, Baldick, and Perkel. While the references teach a method of producing HCMV by overexpression of pp71, the references fail to teach a CMV vector that does not express UL128, UL130, UL146, UL147, and UL82. The reference also fails to teach the a CMV vector that encodes a miRNA recognition element (MRE).
However, Picker teaches CMV vectors that lack active UL128, UL130, UL146 and UL147 proteins that may also comprise one or more MRE that restrict expression of the CMV (Abstract). Picker teaches the modifications to CMV allow for immunization and the selection of different CD8+ T cell responses—CD8+ T cells restricted by MHC-Ia, MHC-II, or by MHC-E (Abstract). Picker teaches CMV vectors comprising MRE that silences expression in the presence of miRNA expressed by myeloid lineage cells (¶0007).
Regarding claim 52, Picker teaches CMV vectors that lack active UL128, UL130, UL146, UL147, and UL82 (Abstract, Claim 1, ¶0082).
Regarding claim 57, Picker teaches CMV vectors comprising a MRE such as miR-142-3p that targets myeloid cells (¶0073).
Regarding claim 60, Picker teaches Picker teaches CMV vectors that lack active UL128, UL130, UL146, UL147, and UL82 that further comprise a MRE such as miR-142-3p that targets myeloid cells (Abstract, Claim 1, ¶0073, ¶0082).
Together, the prior art teaches a method of producing progeny CMV encoding a prostate cancer antigen by infecting cells with a parent CMV, incubating the cell, and collecting the progeny CMV wherein the CMV lack active UL128, UL130, UL146, UL147, and UL82 and further comprise a MRE such as miR-142-3p that targets myeloid cells. Therefore, it would have been prima facie obvious before the effective filing date of the claimed invention to encode a MRE targeting myeloid cells in a CMV that lack active UL128, UL130, UL146, UL147, and UL82 and produce progeny CMV that retain these characteristics by introducing mRNA encoding pp71 into a cell along with a parent CMV because doing so would quickly produce CMV that can be used for immunization and the selection of different CD8+ T cell responses. One of ordinary skill in the art would have had a reasonable expectation of producing progeny CMV that lack active UL128, UL130, UL146, UL147, and UL82 and encode a MRE such as miR-142-3p given it is well known, has been successfully demonstrated, and commonly used in the prior art.
Accordingly, the claimed invention was prima facie obvious to one of ordinary skill in the art at the time of filing especially in the absence of evidence to the contrary.
Conclusion
NO CLAIMS ARE ALLOWED
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Danyal H Alam whose telephone number is (571)272-1102. The examiner can normally be reached M - F 9am - 5pm.
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/DANYAL HASSAN ALAM/ Examiner, Art Unit 1672
/THOMAS J. VISONE/ Supervisory Patent Examiner, Art Unit 1672
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