DETAILED ACTION
Final Rejection
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of the Claims
2. Claims 1-3, 5, 9, 11, 14-24, and 26-27 are pending in the claim listing 01/14/2026.
3. Claims 1-3, and 9 amended, and new claims 25-26 are added in the claim listing 01/14/2026.
4. Claims 1-3, 5, 9, 11, 14-24, and 26-27 are under examination in this office action.
Information Disclosure Statement
5. The information disclosure statement (IDS) submitted on 07/29/2021, 05/13/2022, 11/07/2024, 05/27/2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Rejections - 35 USC § 103 (Modified)
6. The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
7. (Rejection maintained and extended without adding a new prior art- as necessitated by claim amendment),
Claims 1-2, and 5 are rejected under 35 U.S.C. 103 as being unpatentable over Barnett et al 2003 (US6602705B1, patent published on 5 August 2003), and further in view of Smyth et al 1998 (Journal of Virology, vol 72 (5), pages 4478-4484), Yao et al 2001 (published in Virology, 285, p. 128-137), Coursaget et al 2018 (US 20170368162 A1, published 28 December 2018), Zdanowicz et al 2016 (Acta Biopharmica Polonica, 2016, vol 63), Peretti et al 2006 (Virology 345 (2006) 115 – 126), and Kaczmarczyk et al 2011 (PNAS, 2011, vol 108, No.41).
Claim 1: Barnett et al 2003 (US6602705B1) discloses a human immunodeficiency virus (HIV) virus-like particle (VLP), the invention provides methods of producing VLPs, as well as, uses of the VLPs including, but not limited to, vehicles for the presentation of antigens and stimulation of immune response in subjects to whom the VLPs are administered (See abstract, Col 5, lines 20-25); VLPs are generally composed of one or more viral proteins, such as, but not limited to those proteins referred to as capsid, coat, shell, surface and/or envelope proteins (See, Col 11, lines 11-14); group-specific antigens (Gag) of human immunodeficiency virus type-1 [HIV-1) self-assemble into noninfectious virus-like particles (VLP) that are released from various eucaryotic cells by budding, Col. 28, lines 56-59), wherein said VLP comprises at least one HIV structural protein and HIV envelope protein, VLPs are generally composed of one or more viral proteins, such as, but not limited to those proteins referred to as capsid, coat, shell, surface. and/or envelope proteins, Col. 11, lines 11-14; wherein the VLP does not contain the HIV genome and lacks reverse transcriptase and integrase. Barnett et al (See, Example 15, Col 86-88) teaches co-transfection of Env and Gag as monocistronic or bicistronic plasmid DNA constructs in 293T cells to produce HIV VLP that comprise envelope and Gag (structural protein) reciting VLPs were known to be present through a selected range of sucrose densities. The VLPs were formed using all the tested combinations of constructs containing both Env and Gag, purified Env-Gag VLPs were analyzed by electron microscopy. These produced HIV Env-Gag VLPs does not contain a complete HIV genome (lacks a HIV genome) and lacks reverse transcriptase and integrase.
The sequence is modified by deletions of coding regions corresponding to reverse transcriptase and integrase (See, Col 231, claim 11), further, the HIV polymerase polypeptide may be modified by deletions of coding regions corresponding to reverse transcriptase and integrase. Such a polynucleotide sequence may preserve T-helper cell and CTL epitopes, for example when used in a vaccine application (See Col 5, lines 40-44); because synthetic HIV-1 Gag-polymerase expresses the potentially deleterious functional enzymes reverse transcriptase (RT) and integrase (INT) (in addition to the structural proteins and protease), it is important to inactivate RT and INT functions. Several in-frame deletions in the RT and INT reading frame can be made to achieve catalytic nonfunctional enzymes with respect to their RT and INT activity (See Col. 53, lines 66-67, Col 54 Col. 1-11).
Barnett et al 2003 further teaches the added limitation of instant claim 1, wherein at least one structural protein, wherein said at least one structural protein comprises HIV Gag by disclosing Gag VLPs produced by a synthetic Gag expression cassette (Fig 5. and associated legend), alternate method … P55 Gag VLPs (See, col 72, section D, lines 24, line 58-59, abstract). Barnett et al 2003 teaches suggestion that “uses of the VLPs including, but not limited to, vehicles for the presentation of antigen” (See, abstract). Barnett et al 2003 teaches a wide variety of lentiviruses may be utilized within the context of the present invention (reads on VLP production), including for example, lentiviruses selected from the group consisting of HIV, HIV-1, HIV-2, FIV and SIV.
Barnett et al 2003 (US6602705B1) does not explicitly disclose whether the VLP envelope protein is dual tropic for CCR5 and CXCR4 and the VLP comprising at least one therapeutic agent.
Smyth et al 1998 teaches an HIV-type 1 strain 89.6 is a dual-tropic strain that mediate CD4 dependent fusion and entry in macrophages (CCR5 dependent entry) and T cells (CXCR-4 dependent entry). CCR5 is the principal chemokine receptor used by macrophage-tropic (M-tropic) non-syncytium-inducing strains of HIV-1, while CXCR-4 is used by T-cell line-tropic (T-tropic) syncytium-inducing strains (See, page 4478, abstract, abstract lines 1-3 and column 1, para 2, introduction). HIV type 1 strain 89.6 can enter CCR5-deficient macrophages using CXCR-4, ….. it is possible that entry into wild-type macrophages by HIV type 1 strain 89.6 could be mediated by either CCR5 or CXCR-4 (See page 4483, column 1, last para).
Coursaget et al 2018 is in the field of human virology and VLPs art and their use as therapeutic agents (See page 3, para [00021] and teaches a VLPs of HPV comprises at least one therapeutic and/or at least one molecular imaging agent. Coursaget et al 2018 teaches a method provided that comprise administering to the subject one or more therapeutic agents delivered by a virus-like particle (VLP)-based delivery system (See, page 1, para [00012]); aspects of the invention relate to methods and compositions for delivering one or more compounds to a subject; the compound may be one or more of a therapeutic or medical agent, a nucleic acid or a small molecule, or an imaging or contrast agent (See page 3, para [0022]). In some embodiments, compositions of the invention may be administered to a subject having an immune system deficiency to treat a condition (e.g., infection, cancer, or other condition) associated with the immune system deficiency caused by an infection (e.g., an HIV infection, AIDS) (See, page 4, para [0030]). Accordingly, methods and compositions of the invention may be used to treat other infections such as HSV or HIV infection ……. and/or for example, other infections which are common infections in the genital tract (See, page 16, para [0158]). Coursaget et al 2018 thus provide a suggestion and motivation that the HIV VLPs can comprise a therapeutic agent similar to taught in the prior art for HPV VLPs.
Zdanowicz et al 2016 is in the VLP art and has reviewed Virus-like particles including HIV VLP as drug delivery vectors (See, Zdanowicz et al 2016, abstract, p. 2016 col 2 para 2 delivery of bleomycin, entire article). Zdanowicz et al 2016 teaches VLPs for drug delivery have the potential to drastically improve bioavailability of the cargo. A large variety of active molecules can be encapsulated into the VLPs or attached to it (See, last page -conclusion). The prior art also reads on HIV VLPs as a delivery vectors. The selective elimination of HIV-1 infected cells is by the chimeric VLPs that carried a cargo of ganciclovir drug (drug delivery) to the HIV-1 infected human macrophages cells (See, page 2015 col 2 -2016 col 1, Selective elimination of HIV-1-infected cells).
Peretti et al 2006 is in the HIV VLP art and teaches (CD4-CXCR4) and (CD4- CCR5) Nef7-based VLPs efficiently enter cells infected by X4- or R5-tropic HIV-1 strains. The delivery of the VLP associated Nef7/TK led to cell death upon GCV treatment. Of interest, VLPs were effective also against non-replicating, HIV-1-infected primary human monocyte-derived macrophages. HIV-targeted VLPs represent a promising candidate for the treatment of persistently HIV-1-infected cells that are part of virus reservoirs resistant to HAART therapies (See, Peretti et al 2006, abstract, entire article). Thus, Peretti et al 2006 teaches inventive concept of dual-tropic (CD4-CXCR4 and CD4- CCR5) HIV VLPs in anti-HIV treatment.
Kaczmarczyk et al 2011 is in the HIV VLP art and teaches Cre recombinase delivery using a cell-penetrating peptide fusion (HIV TAT) and VLPs; generation of functional VLPs and mode of action (See, abstract, Fig. 1, 3-4, entire article).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the prior art teaching of Barnett et al 2003 on the VLP with the teachings of the additional prior arts, as applied and recited supra, to incorporate dual-tropic (CCR5 and CXCR4 tropic) envelope derived from a well-studied HIV-1 dualtropic strain 89.6, and further comprise at least one therapeutic, wherein said VLP does not contain a complete HIV genome and lacks reverse transcriptase and integrase to arrive at the invention of claim 1. The motivation would have been to produce a HIV VLP comprising an envelope having dual tropism to CCR5 to infect macrophages and CXCR-4 to infect CD4 positive T cells (Smyth et al, page 4482, column 1, para. 2; page. 4482, column 2, para. 3; page 4482, column 2, para 4; page. 4483, column 1, para 3). The HIV type 1 strain VLP comprising dualtropic envelope from strain 89.6 would offer an advantage to deliver a therapeutic agent by binding to CCR5 chemokine receptor on macrophages (M-tropic) and CXCR-4 on CD4 positive T cells (T-tropic). Peretti et al 2006 teaches inventive concept of dual-tropic (CD4-CXCR4 and CD4- CCR5) HIV VLPs in anti-HIV treatment. The motivation to comprise at least one therapeutic agent would be for treatment of the HIV infection/disease administering the VLPs for targeted delivery of the therapeutics. There would have been a reasonable expectation of success given the teachings of Barnett et al on HIV- VLPs suggest that “uses of the VLPs including, but not limited to, vehicles for the presentation of antigen” (See, abstract, prior art), Smyth et al on HIV-1 strain 89.6 dualtropic envelope, and additionally, Yao et al teaches producing a SHIV VLP comprising dualtropic strain 89.6 envelope, and additional prior arts as applied and recited in areas of VLPs for delivery of therapeutics One of the ordinary skills in the art would have a reasonable expectation of success with the applied prior art teachings to the claim 1 as recited supra, there would have been no technical constraint to arrive at the claimed inventions. Thus, the invention of claim 1 as a whole was clearly prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention. This is analogous to some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the invention as claimed in claims 1. See KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007) (see MPEP § 2143, example of rationales, A-G).
Claim 2: The VLP of claim 1 (dependent on claim 1), wherein said VLP comprises HIV protease (Pro).
The combined teachings of Barnett et al 2003, Smyth et al 1998, Yao et al 2001, Coursaget et al 2018, Zdanowicz et al 2016, Peretti et al 2006, and Kaczmarczyk et al 2011, teaches the HIV-1 VLP of claim 1 as recited supra.
Barnett et al 2003 (US6602705B1) further teaches the added limitation of instant claim 2, wherein said VLP comprises HIV protease (Pro) expression cassettes may further include a polynucleotide sequence encoding an HIV protease polypeptide (Col 2, lines 48-50, claim 4). It is known in the art that the function of the HIV protease is to mature or cleave Gag to into four smaller proteins: matrix (MA; pi 7), capsid (CA; p24), nucleocapsid (NC; p7), and p6. Barnett et al 2003 (US6602705B1) teaches, wherein said Gag is cleaved into capsid because a subset of aliquots was also subjected to Western blot analysis using monoclonal antibody ... specific for HIV p24 (a subunit of HIV p55), (See, Col. 71, Line 46-48) and the results from the SDS PAGE ... show that the ... visible protein band that migrated at a molecular weight of-72,000 Kd was reactive with the HIV p24-specific monoclonal antibody (See Col 71, lines 55-61). It would have been obvious to one of ordinary skill in the art, at the time of the claimed invention, to further modify the VLP of claim 1 as taught by combined teachings as applied to claim 1 as recited supra to further incorporate additional teachings of Barnett et al on protease (Pro) to arrive at the invention of claim 2. The motivation to incorporate HIV protease in the VLP would be for cleavage of Gag is necessary for the assembly of virus-like particle during expression (See, Barnett et al US6602705B1, col 1, lines 59-65). There would have been a reasonable expectation of success given the teachings of Barnett et al on HIV- VLPs and the knowledge and skills of the ordinary in the art. Thus, the invention of claim 2 as a whole was clearly prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention. This is analogous to some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the invention as claimed in claim 2. See KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007) (see MPEP § 2143, example of rationales, A-G).
Claim 5: The VLP of claim 1, wherein said HIV envelope protein is from HIV-189.6.
The combined teachings of Barnett et al 2003, Smyth et al 1998, Yao et al 2001, Coursaget et al 2018, Zdanowicz et al 2016, Peretti et al 2006, and Kaczmarczyk et al 2011 that renders obvious claim 1 as recited supra are incorporated by reference here in entirety.
The added limitation of the claim 5, wherein said HIV envelope protein is from HIV-189.6 is taught by Smyth et al 1998 by disclosing an HIV-type 1 strain 89.6 is a dual-tropic strain that mediate CD4 dependent fusion and entry in macrophages (CCR5 dependent entry) and T cells (CXCR-4 dependent entry) as recited supra (See, page 4478, abstract, abstract lines 1-3 and column 1, para 2, introduction, page 4483, column 1, last para). It would have been obvious to one of ordinary skill in the art, at the time of the claimed invention, to modify the combined prior arts teachings HIV VLP of claim with additional teachings of Smyth et al 1998 arrive at the invention of claim 5 comprising a HIV VLP with dual-tropic HIV envelope. The motivation would have been CCR5 is the principal chemokine receptor used by macrophage-tropic (M-tropic) non-syncytium-inducing strains of HIV-1, while CXCR-4 is used by T-cell line-tropic (T-tropic) syncytium-inducing strains (See, page 4478, abstract, abstract lines 1-3 and column 1, para 2, introduction). HIV type 1 strain 89.6 can enter CCR5-deficient macrophages using CXCR-4, ….. it is possible that entry into wild-type macrophages by HIV type 1 strain 89.6 could be mediated by either CCR5 or CXCR-4 (See page 4483, column 1, last para). One of the ordinary skills in the art would have a reasonable expectation of success to arrive at the invention of claim 5 given the combined teachings applied to render obvious the claim 5 as recited supra. Thus, the invention of claims 5 as a whole was clearly prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention. This is analogous to some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the invention as claimed in claim 5. See KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007) (see MPEP § 2143, example of rationales, A-G).
8. (Rejection maintained and extended without adding a new prior art- as necessitated by claim amendment), Claim 3 is rejected under 35 U.S.C. 103 as being unpatentable over combined teachings of Barnett et al 2003 (US6602705B1, patent published on 5 August 2003), Smyth et al 1998 (Journal of Virology, vol 72 (5), pages 4478-4484), Yao et al 2001 (published in Virology, 285, p. 128-137), Coursaget et al 2018 (US 20170368162 A1, published 28 December 2018), Zdanowicz et al 2016 (Acta Biopharmica Polonica, 2016, vol 63), Peretti et al 2006 (Virology 345 (2006) 115 – 126), and Kaczmarczyk et al 2011 (PNAS, 2011, vol 108, No.41), as applied to claim 1 above, and further in view of Kim et al 2004 (US 20040131592 A1, published 8 July 2004).
Claim 3: The VLP of claim 1, wherein said HIV Gag is cleaved into at least matrix and capsid.
The combined teachings of Barnett et al 2003, Smyth et al 1998, Yao et al 2001, Coursaget et al 2018, Zdanowicz et al 2016, Peretti et al 2006, and Kaczmarczyk et al 2011, teaches the VLP of claim 1 as recited above. However, does not explicitly teach the instant claim 3 limitation wherein said Gag is cleaved into at least matrix and capsid.
Kim et al 2004 is in the field of HIV virus-like particles (See, abstract) and teaches that Gag protein of HIV and its proteolytic cleavage products are the major structural components of the virion. The Gag itself is sufficient to direct assembly and release of virus-like particles without any other viral proteins. Gag protein is cleaved by viral protease (PR) encoded by pol gene, generating matrix (MA, p17), capsid (CA, p24), nucleocapsid (NA, p9), and p6, which are assembled to produce mature viral particles (See, para [0093] lines 1-8). Therefore, it would have been obvious to one of ordinary skill in the art, at the time of the claimed invention, to modify the VLP of the combined teachings of the recited prior art as applied to claim 1 and further incorporate teachings of Kim et al regarding the HIV protease for mediating cleavage of the HIV Gag. The motivation would have been providing a Gag gene encoding both matrix protein and capsid protein thereby providing a vector with the necessary components for VLP assembly (See, Kim et al, para [0041] and Fig 21). One of the ordinary skills in the art would have a reasonable expectation of success to arrive at the invention of claim 3 given the combined teachings as recited supra. Thus, the invention of claim 3 as a whole was clearly prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention. This is analogous to some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the invention as claimed in claim 3. See KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007) (see MPEP § 2143, example of rationales, A-G).
9. (Rejection maintained and extended without adding a new prior art- as necessitated by claim amendment), Claims 9 and 11 are rejected under 35 U.S.C. 103 as being unpatentable over combined teachings of Barnett et al 2003 (US6602705B1, patent published on 5 August 2003), Smyth et al 1998 (Journal of Virology, vol 72 (5), pages 4478-4484), Yao et al 2001 (published in Virology, 285, p. 128-137), Coursaget et al 2018 (US 20170368162 A1, published 28 December 2018), Zdanowicz et al 2016 (Acta Biopharmica Polonica, 2016, vol 63), Peretti et al 2006 (Virology 345 (2006) 115 – 126), and Kaczmarczyk et al 2011 (PNAS, 2011, vol 108, No.41) as applied to claim 1, above, and further in view of Thrane et al 2015 (published in PLoS ONE 10(11): e0143071), Fisher et al 2016 (US 2016/0108429 A1 published 21 April 2016), Dundas et al 2013 (Appl Microbiol Biotechnol (2013) 97:9343–9353), and Theophile Ohlmann et al 2017 (WO2017068077A1 published 27 April 2017, listed on IDS filed on 07/29/2021).
The combined teachings of the prior arts as applied and recited above teaches the VLP of claim 1; however, does not teach the added limitations of instant claims 9 and 11.
Thrane et al 2015 is in the field of virus and VLP and teaches HPV VLP and a plasmid construct that encodes/express a fusion protein of monomeric streptavidin (mSA) at the N-terminus of VAR2CSA antigen and further incorporation on surface of fused mSA- VAR2CSA antigen on the surface of VLP to obtain HPV L1 VLP. Prior to incorporation of fused mSA- VAR2CSA antigen on the VLP, the VLP shell protein subunits express a genetic AviTag sequence (GLNDIFEAQKIEWHE) inserted at four different positions in the HPV16 L1 sequence that correspond to surface exposed loops in the assembled VLP structure (See, page 5, Results, para 1) that is biotinylated using BirA ligase enzyme reaction creating biotinylated AviTag to conjugate the fused mSA- VAR2CSA antigen, (See, page 6, figure 1, a, b and associated legends). Thrane et al 2015 do not teach an HIV VLP with at least one structural protein and envelope.
Fisher et al 2016 is in the field of streptavidin and biotin-based imaging (See page 1, para [0008]) and teaches a molecular imaging agent is conjugated to monomeric streptavidin or an analogue thereof by disclosing a method of imaging and treating cancerous cells in a subject is provided, comprising... contacting the avidin or streptavidin with a biotinylated adduct comprising an imaging agent (See page 1, para [0008], [0021]). This Fisher at al 2016 teaches the concept of using streptavidin and biotin conjugation for an imaging agent.
Fisher et al 2016 does not teach a therapeutic agent conjugation to a monomeric streptavidin or an analogue thereof.
Dundas et al 2013 is in the art and teaches the streptavidin–biotin interaction is frequently used in drug delivery for cancer and gene therapy, because it separates the targeting agent from the actual drug to improve the therapeutic index of a treatment. For example, streptavidin was used to develop a cancer therapy based on pre-targeting, in which biotinylated antibodies against known cancer biomarkers are used to recruit radiolabeled streptavidin (See, page 9349, col 1, section on Targeted Drug Therapy, Figure 3, page 9349). Dundas et al 2013 teaches the concept of conjugating a therapeutic agent antibody to streptavidin and the streptavidin can bind to a biotin label on a virus (read on the HIV VLPs) (See, Fig. 3, and associated legends).
Theophile Ohlmann et al 2017 (WO2017068077A1, 04/27/2017) is in the field of gene targeting by CRISPR systems and teaches HIV-1- based VLPs (See, Fig 14A and legends), the virus-derived particle (reads on HIV VLPs), further comprising, or further being complexed with, two CRISPR-Cas system guide RNAs that both hybridize with a target nucleic acid, respectively (See, claims 4-5). In some other embodiments part of all of the said one or more guide RNAs are ….. complexed with these virus-derived particles (VLPs). According to these other embodiments, the guide RNAs which are complexed with the virus- derived particles also enter into the target cells with the virus-derived particles to which these guide RNAs are complexed targeting nucleic acids.
Theophile Ohlmann et al 2017 teaches VLPs ensure a transient and dose-dependent delivery of the CRISPR-RNPc (also termed "CRISPR-RiboNucleoProtein complex") into target cells and induce a robust and rapid cleavage of the desired targeted gene (See, Theophile Ohlmann et al 2017, page 14, lines 14-16); the guide RNAs can also be incorporated successfully in virus-derived particles, creating a fully active CRISPR-RNPc within viral like particles that can be transmitted into recipient cells. The experimental results of the inventors illustrate the high efficiency of these Cas-containing virus-derived particles. These virus-derived particles are fully able to deliver CRISPRs in different cells types, including primary cells, without apparent toxicity (See, Theophile Ohlmann et al 2017 page 19, lines 18-23); 'all in one' VLPs delivering the Cas9 protein, the gRNAs and the repair primer (See, page 10 line 14) ; virus-derived particles ... efficiently transfer the CRISPR-RNPc into the desired target cells (See, page 16, lines 9-10); results indicate that HIV-1 based VLPs are efficient in delivering the CRISPR/CAS9 system; the said virus-derived particles comprise one or more kinds of complexes of a Cas protein and a guide RNA, wherein each CRISPR-Cas complex comprise a single Cas protein complexed with a single guide RNA. In some of these embodiments wherein a plurality of cleavages of a target nucleic acid is sought, the said virus-derived particles comprise the same number of kinds of CRISPR-Cas complexes, each kind of CRIPSR-Cas complex being specific for generating a DNA cleavage at a desired location of a target nucleic acid to which the corresponding guide RNA hybridize (See, page 31, lines 29-33; page 32, lines 1-2); types of diseases and disorders that can be treated by methods of the present invention include, but are not limited to, infectious diseases e.g., HIV (See page 44, lines 16-18); SEQ ID 34, Nucleic acid encoding HIV-1 GAG-CAS9 polypeptide (may be termed "KLAP229" (See page 71, SEQ ID 34).
It would have been obvious to one of ordinary skill in the art, at the time of the claimed invention, to modify the combined teachings of the prior arts applied to claim 1 as recited supra and incorporate the teachings of Thrane et al 2015, Fisher et al 2016, Dundas et al 2013 on conjugating at least one therapeutic agent to monomeric streptavidin or an analogue thereof to arrive at claim 9. Modification of prior art teachings as applied to claim 1 by incorporation of teachings of Theophile Ohlmann et al 2017 regarding therapeutic is a CRISPR ribonucleoprotein, wherein the guide RNA of the CRISPR ribonucleoprotein targets the HIV genome would arrive at the invention of claim 11. The motivation would have been to provide thereby a therapeutic VLP that can specifically target the genes (HIV genome) of infectious virus such as HIV (See, Theophile Ohlmann et al 2017, page 1, lines 10-30; page 44, lines 16-18). One of the ordinary skills in the art would have a reasonable expectation of success to arrive at the invention of claims 9 and 11 given the combined prior art teachings applied to the claims 9 and 11 as recited supra. It is similar to combining prior art elements according to known methods to yield predictable results. See, KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007), examples of rationales, A-G.
10. (Rejection modified- as necessitated by claim amendment) Claim 14 is rejected under 35 U.S.C. 103 as being unpatentable over combined teachings of Barnett et al 2003 (US6602705B1, patent published on 5 August 2003), Smyth et al 1998 (Journal of Virology, vol 72 (5), pages 4478-4484), Yao et al 2001 (published in Virology, 285, p. 128-137), Coursaget et al 2018 (US 20170368162 A1, published 28 December 2018), Zdanowicz et al 2016 (Acta Biopharmica Polonica, 2016, vol 63), Peretti et al 2006 (Virology 345 (2006) 115 – 126), and Kaczmarczyk et al 2011 (PNAS, 2011, vol 108, No.41) as applied to claims 1, above, and further in view of Arnaldo Caruso et al 2013 (US 20130028908 A1 published 31 January 2013).
Claim 14: The VLP of claim 1, wherein said VLP comprises a biotinylated HIV structural protein.
The combined teachings of the prior arts as applied to claim 1 and recited above teaches the VLP of claim 1 as recited, supra, but fails to teach the claim 14 limitation wherein said VLP comprises a biotinylated HIV structural protein.
Arnaldo Caruso et al 2013 is in the field of monoclonal antibodies directed against HIV p17 protein, the said antibody being capable of neutralizing the binding between the p17 protein and the p17 protein receptor (p17R) expressed on the surface of immunocompetent cells (See, para [0001]). Arnaldo Caruso et al 2013 teaches a biotinylated HIV structural protein p17 that bind to Mab MBA-1 neutralizing or blocking the interaction between the p17 proteins and the cellular receptor, p17R (See, para [0026], [0032]); on Raji cells (See, para [0034]); a further incubation with streptavidin to detect, by cytofluorimetric analysis, for the possible presence of the protein bound to the surface receptor, not neutralized by the monoclonal antibody (See, para. [0034]); as shown in Fig. 3 ... the Mab MBA-1 bound all the denatured p17 BH10, S75X, S85X, S92X and S012X proteins with the same affinity (See, para [0036]).
Therefore, it would have been obvious to one of ordinary skill in the art, at the time of the claimed invention, to modify the combined prior art teachings as applied to claim 1 and recited supra to incorporate the teachings of Arnaldo Caruso et al 2013 to further comprise the biotinylated HIV structural protein. The motivation would have been to use the teachings of Arnaldo Caruso et al 2013 to biotinylate the p17 HIV structural protein to identify or confirm binding with the therapeutic Mab MBA-1 (Arnaldo Caruso et al, para [0036]). The teachings could also be used to biotinylate another HIV VLP structural protein recognized by a specific Mab. One of the ordinary skills in the art would have a reasonable expectation of success to arrive at the invention of claim 14 given the combined prior art teachings applied to the claim 14 as recited supra. It is similar to combining prior art elements according to known methods to yield predictable results. See, KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007), examples of rationales, A-G.
11. (Rejection modified- as necessitated by claim amendment) Claim 15 is rejected under 35 U.S.C. 103 as being unpatentable over combined teachings of Barnett et al 2003 (US6602705B1, patent published on 5 August 2003), Smyth et al 1998 (Journal of Virology, vol 72 (5), pages 4478-4484), Yao et al 2001 (published in Virology, 285, p. 128-137), Coursaget et al 2018 (US 20170368162 A1, published 28 December 2018), Zdanowicz et al 2016 (Acta Biopharmica Polonica, 2016, vol 63), Peretti et al 2006 (Virology 345 (2006) 115 – 126), Kaczmarczyk et al 2011 (PNAS, 2011, vol 108, No.41), and Arnaldo Caruso et al 2013 (US 2013/0028908 A1 published 31 January 2013) as applied to claim 14, above, and further in view of Arnaldo Caruso et al 2015 (US9090675B2, patent granted/published on 28 July 2015).
Claim 15: The VLP of claim 14, wherein said biotinylated HIV structural protein is biotinylated matrix.
The combined prior art teachings as applied to claim 14 and recited supra teaches the VLP of claim 14; however, does not to teach the instant claim 15 limitation wherein the said biotinylated HIV structural protein is biotinylated matrix.
Arnaldo Caruso et al 2015 teaches a biotinylated HIV structural protein is biotinylated matrix /p17 matrix; the antibody was incubated with the p17 BH10 protein or the biotinylated African variants thereof, to allow for the formation of the antigen-antibody complex, and then the Raji cells were added with an incubation for 30′ at 4° C (See, title reciting matrix protein is p17 and claim 1, col 5, lines 28-31); figure 1 shows the binding reactivity of the MBA1 antibody towards the different matrix proteins. The diagram shows that the MBA1 monoclonal antibody recognizes and binds the proteins of interest, unlike the non-related protein. These results were also confirmed by Western Blot. The MBA1 monoclonal antibody was actually shown to bind the p17 BH10 protein and the African variants thereof even in the denatured form; the obtained monoclonal antibody was also subjected to an optimized neutralization test to verify its ability to block the interaction between p17 proteins (BH10 and African variants thereof) and p17R receptor. To this end, the Raji cell line, a neoplastic B lymphocyte line expressing the surface receptor that binds the p17 protein (p17R), was used. Firstly, the antibody was incubated with the p17 BH10 protein or the biotinylated African variants thereof, to allow for the formation of the antigen-antibody complex, and then the Raji cells were added with an incubation for 30′ at 4° C. After several washes, a further incubation with streptavidin was carried out to detect, by cytofluorimetric analysis, the possible presence of the protein bound to the p17R surface receptor, not neutralized by the monoclonal antibody (See, Arnaldo Caruso et al 2015 (US9090675B2, column 5, lines 23-36). Monoclonal antibodies MBA-1 and MBS-3 were also subjected to an optimized neutralization test to verify their ability to block the interaction between the p17 BH10 proteins and African variants and their cellular receptor (p17R) (See, Arnaldo Caruso et al 2015 (US9090675B2 column 7, lines 27-30).
It would have been obvious to one of ordinary skill in the art, at the time of the claimed invention, to modify the invention of claim 14 as taught by the applied combined teachings of the prior arts to the claim 14 by incorporating the teachings of Arnaldo Caruso et al 2015 (US9090675B2) to comprise the biotinylated HIV structural protein matrix (p17/matrix) to arrive at instant claim 15. The motivation would have been to apply biotinylate HIV structural protein matrix to confirm binding with the therapeutic monoclonal antibody MBA-1 (See Arnaldo Caruso et al 2015 (US9090675B2) column 2, lines 50-65) and neutralization test to verify their ability to block the interaction between the p17 BH10 proteins and African variants and their cellular receptor p17R (See, Arnaldo Caruso et al 2015 (US9090675B2 column 7, lines 27-30). One of the ordinary skills in the art would have a reasonable expectation of success to arrive at the invention of claim 15 given the combined prior art teachings applied to the claim 15 as recited supra. It is similar to combining prior art elements according to known methods to yield predictable results. See, KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007), examples of rationales, A.
12. (Rejection modified- as necessitated by claim amendment) Claim 19 is rejected under 35 U.S.C. 103 as being unpatentable over combined teachings of Barnett et al 2003 (US6602705B1, patent published on 5 August 2003), Smyth et al 1998 (Journal of Virology, vol 72 (5), pages 4478-4484), Yao et al 2001 (published in Virology, 285, p. 128-137), Coursaget et al 2018 (US 20170368162 A1, published 28 December 2018), Zdanowicz et al 2016 (Acta Biopharmica Polonica, 2016, vol 63), Peretti et al 2006 (Virology 345 (2006) 115 – 126), Kaczmarczyk et al 2011 (PNAS, 2011, vol 108, No.41), and Arnaldo Caruso et al 2013 (US 2013/0028908 A1 published 31 January 2013) as applied to claim 14, above, and further in view of Shirbaghaee et al 2015 (published in Biopolymers (15) 3, pages 113-132), Thrane et al 2015 (PLoS ONE 10 (11): e0143071, pages 1-16) and Dundas et al 2013 (Appl Microbiol Biotechnol (2013) 97:9343–9353).
Claim 19: The VLP of claim 14, wherein said VLP further comprises a therapeutic conjugated to monomeric streptavidin or an analogue thereof.
The combined prior art teachings as applied to claim 14 above teaches the HIV VLP that has a biotinylated HIV structural protein; however, does not teach the instant claim 19 limitation wherein said VLP further comprises a therapeutic conjugated to monomeric streptavidin or an analogue thereof.
Shirbaghaee et al 2015 published a review on different applications of virus-like particles in biology and medicine: vaccination and delivery systems, and includes HIV VLPs (page 118, column 2, para 2). Shirbaghaee et al 2015 discloses drug (therapeutic) delivery application (See, page 114, figure 1) by using a non-covalent conjugation strategy that uses streptavidin as linkers to attach biotinylated antigens and VLPs through their efficient and specific interactions (See, entire research paper, page 123, column 1, last para VLPs as Delivery Systems); drug delivery, protein and peptide delivery, DNA delivery, SiRNA delivery, cell targeting (See, pages 123-127); enveloped HIV VLPs with Pr55 Gag are recited (page 118, column 2, para 2).
Thrane et al 2015 is in the field of virus and VLP and teaches HPV VLP and a plasmid construct that encodes/express a fusion protein of monomeric streptavidin (mSA) at the N-terminus of VAR2CSA antigen and further incorporation on surface of fused mSA- VAR2CSA antigen on the surface of VLP to obtain HPV L1 VLP. Prior to incorporation of fused mSA- VAR2CSA antigen on the VLP, the VLP shell protein subunits express a genetic AviTag sequence (GLNDIFEAQKIEWHE) inserted at four different positions in the HPV16 L1 sequence that correspond to surface exposed loops in the assembled VLP structure (See, page 5, Results, para 1) that is biotinylated using BirA ligase enzyme reaction creating biotinylated AviTag to conjugate the fused mSA- VAR2CSA antigen, (See, page 6, figure 1, a, b and associated legends). Thrane et al 2015 do not teach an HIV VLP with at least one structural protein and envelope.
Dundas et al 2013 teaches use of monomeric or monovalent streptavidin fused to other molecule to create a biotin binding site and display of the streptavidin monomer on cell surface for conjugating with biotinylated fluorescent reporter molecule for imaging purpose without problem of aggregation of imaging agent by use of conventional quadrivalent avidin or streptavidin (See, page 9344, and entire research paper for result and figures).
Therefore, it would have been obvious to one of ordinary skill in the art at the time of the claimed invention to modify the VLP of claim 14 taught by combined prior art teachings as applied to claim 14 and incorporate the teachings of Shirbaghaee et al 2015 on using a non-covalent, efficient and specific interactions conjugation property between therapeutic conjugated streptavidin and biotinylated VLPs and monomeric streptavidin approach of Thrane et al 2015 and Dundas et al 2013 to arrive at VLP of claim 19 that comprises a therapeutic conjugated to monomeric streptavidin. The motivation would have been to obtain HIV VLPs displaying consistently oriented therapeutic or drugs in a high-density repetitive manner for superior treatment outcomes as taught for high-density repetitive display of vaccine antigen on VLP by Thrane et al 2015 (See, page 6, figure 1, b) and overcoming the problem of four high affinity binding sites of wild type Streptavidin that binds to multiple biotinylated ligand/proteins and cause target aggregation that can affect biological functions, live cell imaging. A structural monomer corresponding to a single streptavidin subunit binds one biotin molecule at a time and thus offers the simplest solution for biotin recognition that does not result in target aggregation. The smaller size of the mutant (~14 kDa or approximately 25 % of a tetramer) that would be advantageous for in vivo applications by increasing access to various tissues (See, Dundas et al 2013 research paper, pages 9344-9345, figure 1, Engineered variants, monovalent streptavidin, monomeric streptavidin). One of the ordinary skills in the art would have a reasonable expectation of success to arrive at the invention of claim 19 given the combined prior art teachings applied to the claim 19 as recited supra. It is similar to combining prior art elements according to known methods to yield predictable results. See, KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007), examples of rationales, A.
13. (Rejection modified- as necessitated by claim amendment) Claims 20 is rejected under 35 U.S.C. 103 as being unpatentable over combined teachings of Barnett et al 2003 (US6602705B1, patent published on 5 August 2003), Smyth et al 1998 (Journal of Virology, vol 72 (5), pages 4478-4484), Yao et al 2001 (published in Virology, 285, p. 128-137), Coursaget et al 2018 (US 20170368162 A1, published 28 December 2018), Zdanowicz et al 2016 (Acta Biopharmica Polonica, 2016, vol 63), Peretti et al 2006 (Virology 345 (2006) 115 – 126), Kaczmarczyk et al 2011 (PNAS, 2011, vol 108, No.41), and Arnaldo Caruso et al 2013 (US 2013/0028908 A1 published 31 January 2013) as applied to claim 14 above, and further in view of Shirbaghaee et al 2015 (published in Biopolymers (15) 3, pages 113-132), Fisher et al 2016 (US 2016/0108429 A1 published 21 April 2016) and Thrane et al 2015 (published in PLoS ONE 10(11): e0143071).
Claim 20: The VLP of claim 14, wherein said VLP further comprises a HIV structural protein conjugated to avidin, streptavidin, or an analogue thereof.
The combined prior art teachings as applied to claim 14 above teaches the HIV VLP that has a biotinylated HIV structural protein as recited supra; however, do not disclose the instant claim 20 limitation, wherein said VLP further comprises a HIV structural protein conjugated to avidin, streptavidin, or an analogue thereof.
Shirbaghaee et al 2015 published a review on different applications of virus-like particles in virology, biology and medicine: vaccination and delivery systems, and includes HIV VLPs (page 118, column 2, para 2). Shirbaghaee et al 2015 discloses drug (therapeutic) delivery application (See, page 114, figure 1) by using a non-covalent conjugation strategy that uses streptavidin as linkers to attach biotinylated antigens and VLPs through their efficient and specific interactions (See, entire research paper, page 123, column 1, last para VLPs as Delivery Systems); drug delivery, protein and peptide delivery, DNA delivery, SiRNA delivery, cell targeting (See, pages 123-127); enveloped HIV VLPs with Pr55 Gag are recited (page 118, column 2, para 2).
Fisher et al 2016 is in the field of cell surface expression of avidin or streptavidin for imaging, treatment or combined imaging and treatment protocols for cancer using retroviral/lentiviral vectors. Fisher et al teaches a gene construct (See, figure 3-B) with a avidin or streptavidin nucleic acid sequence linked to a PEG-Prom promoter and membrane targeting sequence (See, para [0002], para [0007], and para [0021]); avidin is expressed on ….. cells (See, figure 2-B). Fisher et al 2016 do not explicitly teach HIV VLP.
Arnaldo Caruso et al 2013 teaches use of a fluorescent reporter molecule labelled streptavidin for imaging purpose/probing of a biotinylated HIV structural protein p17 binding to Mab MBA-1 that block the interaction between the p17 proteins and the cellular receptor, p17R (See, para [0026], [0032]); on Raji cells (See, para [0034]); by cytofluorimetric analysis (See, para. [0034]).
Thrane et al 2015 is in the field of virology and VLP. Thrane teaches a VLP vaccine display platform and expression of monomeric streptavidin (mSA) fused to N-terminus of VAR2CSA vaccine antigen to obtain mSA-VAR2CSA. Using AviTag amino acid sequence GLNDIFEAQKIEWHE expressed on VLP shell protein and in vitro biotinylation of AviTag, the mSA-VAR2CSA antigen is conjugated to biotinylated VLP for surface displaying on VLP consistently oriented mSA-VAR2 antigens in a high-density repetitive manner (See, abstract, and page 6, figure 1). Thrane et al 2015 do not teach the HIV VLP. It would have been obvious to one of ordinary skill in the art, at the time of the claimed invention, to modify the combined prior art teachings as applied to the HIV VLP of claim 14 to incorporate teachings of Fisher et al 2016 to develop a nucleic acid construct encoding avidin or streptavidin fused to HIV structural protein to arrive at invention of claim 20, a HIV VLP comprising structural protein conjugated to avidin, streptavidin. Thrane et al 2015 teaches N-terminal expression of monomeric streptavidin (mSA) fused to VAR2CSA antigen and that teaching could have been used for N-terminal fusion expression of avidin or streptavidin with HIV structural protein in VLP. The motivation for fusion expression of avidin or streptavidin with HIV structural protein in VLP would have been to directly conjugate biotinylated therapeutic or imaging agent to avidin or streptavidin that is fused to HIV structural protein avoiding use of AviTag and in vitro biotinylating step to conjugate avidin. A desired biotinylated molecular imaging or reporter molecule or therapeutic molecules could be specifically bind to HIV structural protein conjugated to avidin or streptavidin to enable incorporation at a high-density repetitive manner for superior imaging output purposes or treatment purpose, respectively. The HIV VLP of instant claim 20 would have two types of structural proteins, one conjugated to biotin and second conjugated to streptavidin. A motivation would have been to use HIV VLPs of instant claim 20 for two different purposes (i) delivery of therapeutics via HIV structural protein conjugated to biotin and (ii) streptavidin conjugated HIV structural protein could be used for fluorescent labeling of streptavidin for imaging purpose as taught by Arnaldo Caruso et al 2013 or for binding a different biotinylated therapeutic. Another motivation would have been to obtain HIV VLPs displaying consistently oriented two different types of therapeutics or drugs or one therapeutic and one fluorescent reporter molecule for imaging purpose in a high-density repetitive manner, to better understand of the location in body and trafficking of the VLPs, as taught for high-density repetitive display of vaccine antigen on VLP by Thrane et al 2015 (See, page 6, figure 1, b). There would have been a reasonable expectation of success to arrive at the invention of claim 20 given the combined teachings of the prior arts as applied to arrive at instant claim 20 as recited supra. It is similar to combining prior art elements according to known methods to yield predictable results. See, KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007), examples of rationales, A.
14. (Rejection modified- as necessitated by claim amendment) Claims 21 is rejected under 35 U.S.C. 103 as being unpatentable over combined teachings of Barnett et al 2003 (US6602705B1, patent published on 5 August 2003), Smyth et al 1998 (Journal of Virology, vol 72 (5), pages 4478-4484), Yao et al 2001 (published in Virology, 285, p. 128-137), Coursaget et al 2018 (US 20170368162 A1, published 28 December 2018), Zdanowicz et al 2016 (Acta Biopharmica Polonica, 2016, vol 63), Peretti et al 2006 (Virology 345 (2006) 115 – 126), Kaczmarczyk et al 2011 (PNAS, 2011, vol 108, No.41), and Arnaldo Caruso et al 2013 (US 2013/0028908 A1 published 31 January 2013) as applied to claim 14 above, and further in view of Shirbaghaee et al 2015 (published in Biopolymers (15) 3, pages 113-132), Fisher et al 2016 (US 2016/0108429 A1 published 21 April 2016) and Thrane et al 2015 (published in PLoS ONE 10(11): e0143071) as applied to claim 20, above, and further in view of Kamo et al 2016 (Bioorg. Med. Chem. Lett. 26, 2016, pages 43–45).
Claim 21. The VLP of claim 20, wherein said VLP further comprises a biotinylated therapeutic and/or a therapeutic conjugated monomeric streptavidin or an analogue thereof.
The combined prior art teachings as applied to claim 20 above teaches the HIV VLP of claim 20 as recited supra; however, does not teach a biotinylated therapeutic and/or a therapeutic conjugated monomeric streptavidin or an analogue thereof.
Kamo et al 2016 is in the field of anti-HIV therapeutics. Kamo et al teaches a biotinylated anti-HIV therapeutic drug/compound BMMP [2-(benzothiazol-2-ylmethylthio)-4-methylpyrimidine], an inhibitor of HIV-1 replication, linked to biotin. By performing surface plasmon resonance experiments, the biotinylated BMMP was used to identify the HIV-1 virus target components with which the drug interacts (See, pages 43-46, title, abstract, methods, results, and conclusion).
Thrane et al 2015 is in the field of virus and VLP and further teaches HPV VLP and a plasmid construct that encodes/express a fusion protein of monomeric streptavidin (mSA) at the N-terminus of VAR2CSA antigen and further incorporation on surface of fused mSA- VAR2CSA antigen on the surface of VLP to obtain HPV L1 VLP. Prior to incorporation of fused mSA- VAR2CSA antigen on the VLP, the VLP shell protein subunits express a genetic AviTag sequence (GLNDIFEAQKIEWHE) inserted at four different positions in the HPV16 L1 sequence that correspond to surface exposed loops in the assembled VLP structure (See, page 5, Results, para 1) that is biotinylated using BirA ligase enzyme reaction creating biotinylated AviTag to conjugate the fused mSA- VAR2CSA antigen, (See, page 6, figure 1, a, b and associated legends). Thrane et al 2015 do not teach an HIV VLP with at least one structural protein and envelope.
It would have been obvious to one of ordinary skill in the art, at the time of the claimed invention, to modify the combined prior art teachings as applied to the claim 20 above and incorporate the teachings of Kamo et al 2016 on biotinylated BMMP drug/therapeutic as recited, supra, recognize reasonable success of avidin/streptavidin specific binding with biotinylated therapeutic to arrive at the instant claim 21 invention comprising HIV VLP comprising a biotinylated therapeutic/drug. One of the ordinary skills in the art would have been motivated for a drug discovery, to assess the specific interaction of biotinylated BMMP drug for HIV-1 virus structural /non-structural components target identification for drug discovery as recited by Kamo et al 2016 (See page 44, column 2, para 2). Another motivation would have been to obtain HIV VLPs displaying consistently oriented therapeutics or drug at high-density repetitive display on VLP as taught for antigen by Thrane et al 2015 (See, page 6, figure 1, b). The motivation to use monomeric streptavidin would be to avoid VLP aggregation because a monomeric form of streptavidin has advantageous to native streptavidin or avidin as the latter contains four biotin binding sites and cause aggregation of streptavidin conjugated imaging agent or therapeutics (See, Thrane et al 2015, page 6, last para on Construction of the displayed antigen VAR2CSA, lines 4-6; Dundas et al 2013, page 9344, section on Engineered variants and entire research paper). There would have been a reasonable expectation of success to arrive at the invention of claim 21 given the combined teachings of the prior arts as applied to arrive at instant claim 21 as recited supra. It is similar to combining prior art elements according to known methods to yield predictable results. See, KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007), examples of rationales, A.
15. (Rejection modified- as necessitated by claim amendment) Claim 16 is rejected under 35 U.S.C. 103 as being unpatentable over combined teachings of
Barnett et al 2003 (US6602705B1, patent published on 5 August 2003), Smyth et al 1998 (Journal of Virology, vol 72 (5), pages 4478-4484), Yao et al 2001 (published in Virology, 285, p. 128-137), Coursaget et al 2018 (US 20170368162 A1, published 28 December 2018), Zdanowicz et al 2016 (Acta Biopharmica Polonica, 2016, vol 63), Peretti et al 2006 (Virology 345 (2006) 115 – 126), Kaczmarczyk et al 2011 (PNAS, 2011, vol 108, No.41), as applied to claims 1, above, and further in view of Fisher et al 2016 (US 2016/0108429 A1 published 21 April 2016) and Thrane et al 2015 (published in PLoS ONE 10(11): e0143071).
Claim 16: The VLP of claim 1, wherein said VLP comprises a HIV structural protein conjugated to avidin, streptavidin, or an analogue thereof.
The combined teachings of prior art as applied to claim 1 above teaches the VLP of claim 1, however, does not teach the instant claim 16 limitation wherein said VLP comprises a HIV structural protein conjugated to avidin, streptavidin, or an analogue thereof.
Fisher et al 2016 is in the field of cell surface expression of avidin or streptavidin for imaging, treatment or combined imaging and treatment protocols for cancer using retroviral/lentiviral vectors. Fisher et al teaches a gene construct (See, figure 3-B) with a avidin or streptavidin nucleic acid sequence linked to a PEG-Prom promoter and membrane targeting sequence (See, para [0002], para [0007], and para [0021]); avidin is expressed on ….. cells (See, figure 2-B). Fisher et al 2016 do not explicitly teach HIV VLP.
Thrane et al 2015 is in the field of virology and VLP. Thrane teaches a VLP vaccine display platform and expression of monomeric streptavidin (mSA) fused to N-terminus of VAR2CSA vaccine antigen to obtain mSA-VAR2CSA. Using AviTag amino acid sequence GLNDIFEAQKIEWHE expressed on VLP shell protein and in vitro biotinylation of AviTag, the mSA-VAR2CSA antigen is conjugated to biotinylated VLP for surface displaying on VLP consistently oriented mSA-VAR2 antigens in a high-density repetitive manner (See, abstract, and page 6, figure 1). Thrane et al 2015 do not teach HIV VLP.
It would have been obvious to one of ordinary skill in the art, at the time of the claimed invention, to modify the teachings of the combined prior art teachings as applied to the VLP of claim 1 and incorporate teachings of Fisher et al 2016 to develop a nucleic acid construct encoding avidin or streptavidin fused to HIV structural protein to arrive at invention of claim 16, a HIV VLP comprising structural protein conjugated to avidin, streptavidin. Thrane et al 2015 teaches N-terminal expression of monomeric streptavidin (mSA) fused to VAR2CSA antigen and that teaching could have been used for N-terminal fusion expression of avidin or streptavidin with HIV structural protein in VLP. The motivation for fusion expression of avidin or streptavidin with HIV structural protein in VLP would have been to directly conjugate biotinylated therapeutic or imaging agent to avidin or streptavidin that is fused to HIV structural protein avoiding use of AviTag and in vitro biotinylating step to conjugate avidin. A desired biotinylated molecular imaging or reporter molecule or therapeutic molecules could be incorporated at a high-density repetitive manner for superior imaging output purposes or treatment purpose, respectively. There would have been a reasonable expectation of success to arrive at the invention of claim 16 given the combined teachings of the prior arts as applied to arrive at instant claim 16 as recited supra. It is similar to combining prior art elements according to known methods to yield predictable results. See, KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007), examples of rationales, A.
16. (Rejection modified- as necessitated by claim amendment) Claim 17 is rejected under 35 U.S.C. 103 as being unpatentable over combined teachings of
Barnett et al 2003 (US6602705B1, patent published on 5 August 2003), Smyth et al 1998 (Journal of Virology, vol 72 (5), pages 4478-4484), Yao et al 2001 (published in Virology, 285, p. 128-137), Coursaget et al 2018 (US 20170368162 A1, published 28 December 2018), Zdanowicz et al 2016 (Acta Biopharmica Polonica, 2016, vol 63), Peretti et al 2006 (Virology 345 (2006) 115 – 126), Kaczmarczyk et al 2011 (PNAS, 2011, vol 108, No.41), Fisher et al 2016 (US 2016/0108429 A1 published 21 April 2016) and Thrane et al 2015 (published in PLoS ONE 10(11): e0143071) as applied to claim 16 above, and further in view of Kim et al 2004 (US 2004/0131592 A1, published 8 July 2004) and Dundas et al 2013 (Appl Microbiol Biotechnol (2013) 97:9343–9353).
Claim 17: The VLP of claim 16, wherein said VLP comprises capsid conjugated to monomeric streptavidin or an analogue thereof.
The combined teachings of prior art as applied to claim 16 above teaches the VLP of claim 16, however, does not teach a capsid conjugated to monomeric streptavidin or an analogue thereof.
Barnett et al (US6602705B1) further teaches a HIV VLP, wherein Gag is cleaved into capsid because a subset of aliquots was also subjected to Western blot analysis using monoclonal antibody ... specific for HIV p24 (a subunit of HIV p55), (See, Col. 71, Line 46-48) and the results from the SDS PAGE ... show that the ... visible protein band that migrated at a molecular weight of-72,000 Kd was reactive with the HIV p24-specific monoclonal antibody (See Col 71, lines 55-61).
Kim et al 2004 is in the field of HIV virus-like particles (See, abstract) and teaches that Gag protein of HIV is cleaved by viral protease (PR) encoded by pol gene, generating matrix (MA, p17), capsid (CA, p24), nucleocapsid (NA, p9), and p6, which are assembled to produce mature viral particles (See para [0093] lines 1-8).
Fisher et al 2016 is in the field of cell surface expression of avidin or streptavidin for imaging, treatment or combined imaging and treatment protocols for cancer using retroviral/lentiviral vectors and teaches a gene construct (See, figure 3-B) with a avidin or streptavidin nucleic acid sequence linked to a PEG-Prom promoter and membrane targeting sequence (See, para [0002], para [0007], and para [0021]); avidin is expressed on ….. cells (See, figure 2-B).
Fisher et al 2016 does not explicitly teach HIV VLP.
Thrane et al 2015 is in the field of virology and VLP. Thrane teaches a VLP vaccine display platform and expression of monomeric streptavidin (mSA) fused to N-terminus of VAR2CSA vaccine antigen to obtain mSA-VAR2CSA. Using AviTag amino acid sequence GLNDIFEAQKIEWHE expressed on VLP shell protein and in vitro biotinylation of AviTag, the mSA-VAR2CSA antigen is conjugated to biotinylated VLP for surface displaying on VLP consistently oriented mSA-VAR2 antigens in a high-density repetitive manner (See, abstract, and page 6, figure 1).
Thrane et al 2015 does not teach HIV VLP.
It would have been obvious to one of ordinary skill in the art, at the time of the claimed invention, to modify the combined teaching of the prior arts as applied to claim 16 to incorporate the teachings of Thrane et al 2015 on N-terminal expression of monomeric streptavidin (mSA) fused to VAR2CSA antigen and develop a nucleic acid construct of HIV capsid protein to which monomeric streptavidin is fused to N-terminal of HIV capsid protein and is expressed as “monomeric streptavidin-capsid” fusion protein to arrive at invention of claim 17. The motivation for fusion expression of monomeric streptavidin with HIV capsid protein in HIV VLP would have been to use capsid for conjugation with biotinylated therapeutic or imaging agent to monomeric streptavidin that is fused to HIV capsid protein avoiding use of AviTag and in vitro biotinylating step to conjugate avidin. Monomeric streptavidin overcomes the problem of four high affinity binding sites of wild type Streptavidin that binds to multiple biotinylated ligand/proteins and cause target aggregation that can affect biological functions, live cell imaging. A structural monomer corresponding to a single streptavidin subunit binds one biotin molecule at a time and thus offers the simplest solution for biotin recognition that does not result in target aggregation. The smaller size of the mutant (~14 kDa or approximately 25 % of a tetramer) that would be advantageous for in vivo applications by increasing access to various tissues (See, Dundas et al 2013 research paper, pages 9344-9345, figure 1, Engineered variants, monovalent streptavidin, monomeric streptavidin). A desired biotinylated molecular imaging or reporter molecule or therapeutic molecules could be incorporated at a high-density repetitive manner for superior imaging output purposes or treatment purpose, respectively. There would have been a reasonable expectation of success to arrive at the invention of claim 17 given the combined teachings of the prior arts as applied to arrive at instant claim 17 as recited supra. It is similar to combining prior art elements according to known methods to yield predictable results. See, KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007), examples of rationales, A.
17. (Rejection modified- as necessitated by claim amendment) Claim 18 is rejected under 35 U.S.C. 103 as being unpatentable over combined teachings of
Barnett et al 2003 (US6602705B1, patent published on 5 August 2003), Smyth et al 1998 (Journal of Virology, vol 72 (5), pages 4478-4484), Yao et al 2001 (published in Virology, 285, p. 128-137), Coursaget et al 2018 (US 20170368162 A1, published 28 December 2018), Zdanowicz et al 2016 (Acta Biopharmica Polonica, 2016, vol 63), Peretti et al 2006 (Virology 345 (2006) 115 – 126), Kaczmarczyk et al 2011 (PNAS, 2011, vol 108, No.41), Fisher et al 2016 (US 2016/0108429 A1 published 21 April 2016) and Thrane et al 2015 (published in PLoS ONE 10(11): e0143071) as applied to claim 16 above, and further in view of Kamo et al 2016 (Bioorg. Med. Chem. Lett. 26, 2016, pages 43–45).
Claim 18: The VLP of claim 16, wherein said VLP further comprises a biotinylated therapeutic.
The combined teachings of prior arts as applied to claim 16 above teaches the HIV VLP of claim 16; however, do not teach the instant claim 18 limitation wherein said VLP further comprises a biotinylated therapeutic.
Kamo et al 2016 is in the field of anti-HIV therapeutics. Kamo et al teaches a biotinylated anti-HIV therapeutic drug/compound BMMP [2-(benzothiazol-2-ylmethylthio)-4-methylpyrimidine], an inhibitor of HIV-1 replication, linked to biotin. By performing surface plasmon resonance experiments, the biotinylated BMMP was used to identify the HIV-1 virus target components with which the drug interacts (See, pages 43-46, title, abstract, methods, results, and conclusion).
It would have been obvious to one of ordinary skill in the art, at the time of the claimed invention, to modify the combined teaching of the prior arts as applied to claim 16 above to the HIV VLP of claim 16 to incorporate the teachings of Kamo et al 2016 on biotinylated BMMP drug/therapeutic as recited, supra, by recognizing a reasonable success of avidin/streptavidin specific binding with biotinylated therapeutic to arrive at the instant claim 18 invention comprising HIV VLP structural protein conjugated to biotinylated therapeutic. The motivation would be a drug discovery, to assess the specific interaction of biotinylated BMMP drug for HIV-1 virus structural /non-structural components target identification for drug discovery as recited by Kamo et al 2016 (See page 44, column 2, para 2). Another motivation would have been to obtain HIV VLPs displaying consistently oriented therapeutics or drug at high-density repetitive display on VLP as taught for antigen by Thrane et al 2015 (See, page 6, figure 1, b). A motivation could be a desired biotinylated therapeutic conjugated to HIV structural protein and incorporated on HIV VLP at a high-density repetitive manner for efficacious treatment purpose as taught by Thrane et al 2015 (See, page 6, figure 1 b and legends). There would have been a reasonable expectation of success to arrive at the invention of claim 18 given the combined teachings of the prior arts as applied to arrive at instant claim 18 as recited supra. It is similar to combining prior art elements according to known methods to yield predictable results. See, KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007), examples of rationales, A.
18. (Rejection modified- as necessitated by claim amendment) Claim 22 is rejected under 35 U.S.C. 103 as being unpatentable over combined teachings of Barnett et al 2003 (US6602705B1, patent published on 5 August 2003), Smyth et al 1998 (Journal of Virology, vol 72 (5), pages 4478-4484), Yao et al 2001 (published in Virology, 285, p. 128-137), Coursaget et al 2018 (US 20170368162 A1, published 28 December 2018), Zdanowicz et al 2016 (Acta Biopharmica Polonica, 2016, vol 63), Peretti et al 2006 (Virology 345 (2006) 115 – 126), Kaczmarczyk et al 2011 (PNAS, 2011, vol 108, No.41), as applied to claim 1 above and further in view of Raska et al 2010 (published in The Journal of of Biological Chemistry, 285, (27), pp. 20860 –20869).
Claim 22: A method of synthesizing a VLP of claim 1, said method comprising expressing said HIV structural proteins and envelope protein in mammalian cells.
The combined teachings of prior arts as applied to claim 1 above teaches HIV-1 VLP of claim 1 comprising strain 89.6 dualtropic CCR5 and CXCR-4 dualtropic envelope as recited supra; however, does not teach instant claim 22 added limitation, said method comprising expressing said HIV structural proteins and envelope protein in mammalian cells (instant claim 22 limitation).
Barnett et al (US6602705B1) further teaches the added limitation of instant claim 22, a method of synthesizing a HIV VLP comprising expressing HIV structural proteins and envelope protein in mammalian cells. The expression cassette of interest is incubated under conditions for producing VLPs and the VLPs are purified to produce a composition of VLP (See Col5, lines 15-25). The mammalian cell lines used to produce VLPs can be BHK, VERO, HT1080, 293, RD, COS-7, or CHO cells, an antigen presenting cell e.g., primary, immortalized or tumor-derived lymphoid cells such as macrophages, monocytes, dendritic cells, B-cells, T-cells, stem cells, and progenitor cells thereof, (See, col 4, lines 33-43; Col 29, lines 24-67, See example 15- Col. 86-88) discloses a human immunodeficiency virus (HIV) virus-like particle (VLP) (See abstract, Col 5, lines 20-25); VLPs are generally composed of one or more viral proteins, such as, but not limited to those proteins referred to as capsid, coat, shell, surface and/or envelope proteins (See, Col 11, lines 11-14); group-specific antigens (Gag) of human immunodeficiency virus type-1 (HIV-1) self-assemble into noninfectious virus-like particles (VLP) that are released from various eucaryotic cells by budding, Col. 28, lines 56-59), wherein said VLP comprises at least one HIV structural protein and HIV envelope protein, VLPs are generally composed of one or more viral proteins, such as, but not limited to those proteins referred to as capsid, coat, shell, surface. and/or envelope proteins, Col. 11, lines 11-14; wherein the VLP does not contain the HIV genome and lacks reverse transcriptase and integrase because the sequence is modified by deletions of coding regions corresponding to reverse transcriptase and integrase (See, Col 231, claim 11), further, the HIV polymerase polypeptide may be modified by deletions of coding regions corresponding to reverse transcriptase and integrase. Such a polynucleotide sequence may preserve T-helper cell and CTL epitopes, for example when used in a vaccine application (See Col 5, lines 40-44); because synthetic HIV-1 Gag-polymerase expresses the potentially deleterious functional enzymes reverse transcriptase (RT) and integrase (INT) (in addition to the structural proteins and protease), it is important to inactivate RT and INT functions. Several in-frame deletions in the RT and INT reading frame can be made to achieve catalytic nonfunctional enzymes with respect to their RT and INT activity (See Col. 53, lines 66-67, Col 54 Col. 1-11). HIV VLP comprises HIV Gag, Pro, gp120, and gp41 by disclosing antigens and polypeptides derived from ... HIV-1 ... including but not limited to antigens such as gp120, gp41, gp160, Gag and pol (See, Col 2, lines 37-40, See, Col. 42, Ln. 8-20; expression cassettes may further include a polynucleotide sequence encoding an HIV protease polypeptide (Col 2, lines 48-50).
It would have been obvious to one of ordinary skill in the art, at the time of the claimed invention, to further modify the VLP of claim 1 as taught by applied combined prior art teachings as recited supra to further incorporate additional teachings of Barnett et al regarding expression of HIV proteins/envelope protein in mammalian cells to arrive at the invention of claim 22. The motivation to incorporate HIV Gag protein in the VLP would be the Gag is necessary for the assembly of virus-like particle, HIV-1 envelope protein is a glycoprotein of 160 kD (gp160) and during expression /infection in host cell, gp160 is cleaved by host cell protease to form gp120 and gp41 and thus these are envelope protein (See, Barnett et al US6602705B1, col 1, lines 59-65) and as known in the art protective immune response inducing epitopes reside on gp140 and gp120 and Pro is required for processing of Gag. The motivation to perform a method to comprise expression of said HIV structural proteins and envelope protein in mammalian cells would be efficient expression of the structural protein and envelope glycoproteins in mammalian cell lines and assembly of the VLPs, Gag polypeptides /structural polypeptides would be free of baculovirus contaminants; production by established methods approved by the FDA; increased purity and greater yields, a novel method of producing the Gag-containing polypeptides in CHO or other mammalian cells. Other mammalian cell lines include, but are not limited to, BHK, VERO, HT1080, 293, 293T, RD, COS-7, CHO, Jurkat, HUT, SUPT, C8166, MOLT4/clone8, MT-2, MT-4, H9, PM1, CEM, myeloma cells (e.g., SB20 cells) and CEMX174, such cell lines are available, for example, from the A.T.C.C. (See, Barnett et al US6602705B1, col 23, lines 38-52).
Another motivation would be, the HIV VLPs are directed to be used in mammalian species human or animal model for treatment or prevention of HIV and the expression of the HIV structural polypeptides Gag, Pro, gp120, and gp41 in mammalian cells would largely preserve glycosylation pattern of the HIV envelope glycoprotein gp120 and gp41 to comprise VLPs. Raska 2010 teaches glycosylation patterns of HIV-1 gp120 depend on the type of expressing cells (different mammalian cells or insect cells) and affect antibody recognition (See, Raska et al, abstract,entire article; page 20861, for insect cells- col 1, para 2). There would have been a reasonable expectation of success given the applied prior art teachings to arrive at the invention of claim 22 to express the HIV structural proteins and envelope protein in mammalian cells. Thus, the invention of claim 22 as a whole was clearly prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention.
19. (Rejection modified- as necessitated by claim amendment) Claim 23 is rejected under 35 U.S.C. 103 as being unpatentable over combined teachings of
Barnett et al 2003 (US6602705B1, patent published on 5 August 2003), Smyth et al 1998 (Journal of Virology, vol 72 (5), pages 4478-4484), Yao et al 2001 (published in Virology, 285, p. 128-137), Coursaget et al 2018 (US 20170368162 A1, published 28 December 2018), Zdanowicz et al 2016 (Acta Biopharmica Polonica, 2016, vol 63), Peretti et al 2006 (Virology 345 (2006) 115 – 126), Kaczmarczyk et al 2011 (PNAS, 2011, vol 108, No.41), as applied to claim 1 above, and further in view of Santangelo et al 2015 (Nat Methods, 12(5): 427–432), Milenic et al 2004 (Nature Reviews, Vol 3, 490-498), Rasaneh et al 2009 (Nuclear Medicine and Biology 36, 363–369), Joo et al 2008 (ACS Nano, Vol 2 (8)1553-1562) and Walling et al 2009 (Int. J. Mol. Sci. 2009, 10, 441-491).
Claim 23: A method of monitoring a viral infection in a subject in need thereof, said method comprising administering at least one VLP of claim 1 further comprising a molecular imaging agent to the subject and detecting the presence of the molecular imaging agent.
The combined prior art teachings as applied to claim 1 above teaches the HIV VLP of claim 1, however, does not teach added limitations of instant claim 23, method comprising administering at least one VLP of claim 1 further comprising a molecular imaging agent to the subject and detecting the presence of the molecular imaging agent.
Santangelo et al 2015 is in the field of in vivo molecular imaging of virus infection using non-invasive approach.
Santangelo et al 2015 discloses a method to capture total-body simian immunodeficiency virus (SIV) replication using immunoPET, an antibody-targeted positron emission tomography (See, abstract); SIV Env protein–specific monoclonal antibody (mAb) clone 7D3 was used to develop the probe because of its broad SIV Env specificity. 7D3 binds the CCR5 binding site of Gp120 and prevents syncytia formation in vitro with SIVMACCP-MAC, and it does not affect soluble CD4 binding or neutralize SIVmac239. In vitro validation studies demonstrated that 7D3-64CuPEG-DOTA probe bound specifically to SIV infected cells (See pages 2-3, para on Development of the immunoPET probe). The monkeys were administered 200 TCID50 (50% tissue culture infective dose) of SIVMAC239 intravenously (See methods, Monkeys, lines 6-7); 64Cu-labeled SIV Gp120–specific antibody (radiolabel 64Cu) that contains conjugated 7D3 Mab binds specifically to SIV envelope on the SIV virus in monkeys led to readily detectable signals in the gastrointestinal and respiratory tract, lymphoid tissues and reproductive organs of viremic monkeys. Viral signals were reduced in aviremic antiretroviral-treated monkeys but detectable in colon, select lymph nodes, small bowel, nasal turbinates, the genital tract and lung. In elite controllers, virus was detected primarily in foci in the small bowel, select lymphoid areas and the male reproductive tract, as confirmed by quantitative reverse-transcription PCR (qRT-PCR) and immunohistochemistry (See page 15, 17-19, figures 1-4, for immunoPET and immunohistochemistry). The real-time, in vivo viral imaging method has broad applications to the study of immunodeficiency virus pathogenesis, drug and vaccine development, and the potential for clinical translation (See, abstract).
Santangelo et al 2015 does not specifically teach administration of HIV VLP of instant claim 1.
Milenic et al 2004 teaches linking β emitter 177Lu radionucleotides using DOTA/PA-DOTA to the protein including target specific antibody (See page 491-492, page 494 figure 4, page 495, figure 5) for in vivo noninvasive imaging.
Rasaneh et al 2009 teaches radiolabeling of a monoclonal antibody, specific to human epidermal growth factor receptor 2 (HER2) used in patients with tumors that overexpress HER2 receptor, trastuzumab with 177Lu via DOTA using the NHS-DOTA chemistry to obtain 177Lu–DOTA–trastuzumab for cancer treatment (See, page 363-364, abstract, introduction, methods).
Joo et al 2008 and Walling et al 2009 are in the field of live cell and in vivo imaging using Quantum Dots, (fluorescent particles) labelled target proteins. Quantum Dots labeling specificity for HIV/virus envelope is achieved by site specific biotinylating of viral envelope medicated by Bir A ligase enzyme and coupling QD525-Streptavidin (See, Joo et al 2008, page 1552, figure 1); or specific monoclonal antibodies conjugated with Quantum Dots, inter alia, other approaches (See, Walling et al 2009, page 462, last para).
Joo et al 2008 teaches site-specific labeling of enveloped viruses with Quantum Dots for single virus tracking in cell cultures including labeling of HIV envelope with Quantum dots (See, page 1557, column 2, last para and page 1558, see entire research paper with figures 1-7, and methods).
Walling et al 2009 teaches application of Quantum Dots for live cell and In vivo imaging (See, page 460, 447, figure 4 and legends) showing use of Quantum Dots tagged to cancer cells in molecular imaging in a mouse model.
It would have been obvious to one of ordinary skill in the art, at the time of the claimed invention, to modify the teachings of the prior arts as applied to claim 1 as recited supra to incorporate teachings of Santangelo et al 2015 on 7D3-64CuPEG-DOTA and substitute 7D3 antibody with HIV VLP to arrive at the radiolabeled VLP-64CuPEG-DOTA and use it to administer to a subject and detect the presence of the molecular imaging agent as taught by Santangelo et al 2015 to arrive at the invention of claim 23.
Alternatively, the teachings of Milenic et al 2004 and Rasaneh et al 2009 would have been reasonably expected to be successful to modify the VLP of Barnett et al using 177Lu radiolabel to produce 177Lu–DOTA–VLP and use it to administer to a subject and detect the presence of the molecular imaging agent as taught by Santangelo et al 2015 to arrive at the invention of claim 23.
Alternatively, fluorescent reporter approach (a non-radioactive label) the teachings of Joo et al 2008 would have been reasonably expected to be successful to modify the VLP of Barnett et al using QD525 Quantum Dots as label to produce QD525-Streptavidin-Biotin–VLP and its use to administer to a subject and detect the presence of the molecular imaging agent QD525 as taught by and Walling et al 2009 to arrive at the invention of claim 23.
The motivation to use 177Lu and 64Cu over the Quantum Dots for VLP labeling would be high level of tissue penetration and high-quality imaging. Quantum Dots labeling of VLP at specific site based on using Bir A ligase and Streptavidin or analogues would offer flexibility of different color spectra and no risk of exposure to radiolabel (Joo et al 2008). There would have been a reasonable expectation of success given the applied prior art teachings to arrive at the invention of claim 23. It is similar to combining prior art elements according to known methods to yield predictable results. See, KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007), examples of rationales, A.
20. (Rejection modified- as necessitated by claim amendment),Claim 24 is rejected under 35 U.S.C. 103 as being unpatentable over Barnett et al 2003 (US6602705B1, patent published on 5 August 2003), Smyth et al 1998 (Journal of Virology, vol 72 (5), pages 4478-4484), Yao et al 2001 (published in Virology, 285, p. 128-137), Coursaget et al 2018 (US 20170368162 A1, published 28 December 2018), Zdanowicz et al 2016 (Acta Biopharmica Polonica, 2016, vol 63), Peretti et al 2006 (Virology 345 (2006) 115 – 126), Kaczmarczyk et al 2011 (PNAS, 2011, vol 108, No.41), as applied to claim 1, above, and further in view of McBurneya et al 2009 (published in 2009 in Vaccine (27) pages 4337-4379), Kirkegaard et al 2011 (published in Virology Journal (8): 38), and Notka et al 2000 (published in Vaccine (18) 291-301).
Claim 24: A method of treating, inhibiting, and/or preventing an HIV infection in a subject in need thereof, said method comprising administering at least one VLP of claims 1 to the subject.
The combined teachings as applied to claim 1 teaches the HIV VLP of claim 1, however, does not teach sufficient details on added limitations of instant claim 24 on a method of treating, inhibiting, and/or preventing an HIV infection in a subject in need thereof, said method comprising administering at least one VLP of claims 1 to the subject.
McBurneya et al 2009 teaches Human immunodeficiency virus-like particles with consensus envelopes elicited broader cell-mediated peripheral and mucosal immune responses than polyvalent and monovalent Env vaccines including antibody response (See entire research paper, abstract, See page 4344 fig 3, fig 4).
Kirkegaard et al 2011 teaches Induction of antibody and cellular immune responses against the HIV-1 envelope protein using γ-retroviral virus-like particles (See, entire research paper, abstract, see pages 3-5 figures 1-5).
Barnett et al (US6602705B1), McBurneya et al 2009 and Kirkegaard et al 2011 teaches induction of humoral (antibody) and cellular immune response in animal model administering HIV VLP however does not teach a viral challenge experimental studies in animal models or subjects following HIV VLP administration.
Notka et al 2000 teaches HIV-1 gp160 based VLP immunization /administration, induction of immune response and challenge of the immunized rhesus macaques with Simian human immunodeficiency virus SHIV-4 and induced protection by reduced SHIV-4 detection and clearance of challenge SHIV-4 virus faster than nonimmunized controls (See entire research paper, abstract). Notka et al 2000 is considered to be analogous to the claimed invention because it is in the similar field of retrovirus and retrovirus VLP (HIV VLP/SHIV VLP) immunogenic composition.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the combined prior art teachings as applied to the claim 1 to incorporate the teachings of McBurneya et al and Kirkegaard et al and Notka et al on a method of treating, inhibiting, and/or preventing a viral (SHIV-4) infection and apply the teachings to the HIV VLP of claim 1 to a method of treating, inhibiting, and /or preventing an HIV infection in a subject in need thereof. One of ordinary skill in the art would have a reasonable expectation of success to reasonably treat or reasonably inhibit SHIV-4 virus infection in animals immunized with VLP comprising HIV gp160 given the knowledge in the art that SHIV-4 and HIV induces cross protective immune responses (See, Notka et al 2000, page 298 discussion, page 299 column 1 first paragraph lines 6-8). There would have been a reasonable expectation of success given the applied prior art teachings to arrive at the invention of claim 24. It is similar to combining prior art elements according to known methods to yield predictable results. See, KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007), examples of rationales, A.
21. (New Rejection - as necessitated by claim amendment), Claim 26 is rejected under 35 U.S.C. 103 as being unpatentable over combined teachings of Barnett et al 2003 (US6602705B1, patent published on 5 August 2003), Smyth et al 1998 (Journal of Virology, vol 72 (5), pages 4478-4484), Yao et al 2001 (published in Virology, 285, p. 128-137), Coursaget et al 2018 (US 20170368162 A1, published 28 December 2018), Zdanowicz et al 2016 (Acta Biopharmica Polonica, 2016, vol 63), Peretti et al 2006 (Virology 345 (2006) 115 – 126), and Kaczmarczyk et al 2011 (PNAS, 2011, vol 108, No.41), as applied to claim 1 above, and further in view of Melikyan et al 2005 (PNAS, vol 102 (24) p. 8728-8733), Markosyan et al 2005 (Molecular Biology of the Cell, vol 16, p. 5502-5513), Cubas et al 2009 (J Immunother. 2009; 32(2): 118–128).
Claim 26: The VLP of claim 1, further comprising at least one molecular imaging agent.
The combined teachings of Barnett et al 2003, Smyth et al 1998, Yao et al 2001, Coursaget et al 2018, Zdanowicz et al 2016, Peretti et al 2006, and Kaczmarczyk et al 2011, teaches the VLP of claim 1 as recited above. However, does not explicitly teach the instant claim 1 limitation further comprising at least one molecular imaging agent.
Melikyan et al 2005 is in the HIV art and teaches viral particles /viral membranes were labeled with a lipophilic dye [1,1_-dioctadecyl-3,3,3_,3_-tetramethylindodicarbocyanineperchlorate (DiD)]; and gag YFP/DiD labeled virions (See, abstract, p.8732, col 1, para 3).
Markosyan et al 2005 is in the HIV VLP art and teaches imaging of lipid dye DiD (1,1’-dioctadecyl-3,3,3’,3’tetramethylindodicarbocyanine perchlorate) labelled HIV-1 Env-mediated fusion using labeled viral particles comprising pseudotyped with an MLV core and an HIV-1 Env (See, Markosyan et al 2005, abstract, Fig. 1, 3).
Cubas et al 2009 is in the retrovirus art and teaches labeling or conjugation of SHIV VLPs with IRDye® 800CW, the dye can be efficiently conjugated to VLPs without disrupting particle structure, imaging in vitro, in situ and in v mouse model (See, Cubas et al 2009, abstract, methods, results, Fig 1 A-C, Fig 2-3).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, to modify the combined prior art teaching as applied to claim 1 above with additional prior arts teachings of Melikyan et al 2005, Markosyan et al 2005, and Cubas et al 2009 on a molecular imaging agent labelling of HIV or HIV VLPs to arrive at the invention of instant claim 26. The motivation to comprise at least one molecular imaging agent would be for tracking of delivery of therapeutic agent for treatment of the HIV infection/disease with HIV VLPs comprising therapeutic agent and the VLPs having fluorescent imaging label/markers that would facilitate in vitro and in vivo tracking of the administered VLPs and monitor targeted delivery of the therapeutics. There would have been a reasonable expectation of success given the prior arts as applied to claim 26. One of the ordinary skills in the art would have a reasonable expectation of success with the applied prior art teachings to the claim26 as recited supra, there would have been no technical constraint to arrive at the claimed inventions. Thus, the invention of claim 26 as a whole was clearly prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention. It is similar to combining prior art elements according to known methods to yield predictable results. See, KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007), examples of rationales, A.
22. (New Rejection - as necessitated by claim amendment), Claim 27 is rejected under 35 U.S.C. 103 as being unpatentable over combined teachings of Barnett et al 2003 (US6602705B1, patent published on 5 August 2003), Smyth et al 1998 (Journal of Virology, vol 72 (5), pages 4478-4484), Yao et al 2001 (published in Virology, 285, p. 128-137), Coursaget et al 2018 (US 20170368162 A1, published 28 December 2018), Zdanowicz et al 2016 (Acta Biopharmica Polonica, 2016, vol 63), Peretti et al 2006 (Virology 345 (2006) 115 – 126), and Kaczmarczyk et al 2011 (PNAS, 2011, vol 108, No.41), as applied to claim 1 above, and further in view of Melikyan et al 2005 (PNAS, vol 102 (24) p. 8728-8733), Markosyan et al 2005 (Molecular Biology of the Cell, vol 16, p. 5502-5513), Cubas et al 2009 (J Immunother. 2009; 32(2): 118–128), Shirbaghaee et al 2015 (published in Biopolymers (15) 3, pages 113-132), Thrane et al 2015 (PLoS ONE 10 (11): e0143071, pages 1-16) and Dundas et al 2013 (Appl Microbiol Biotechnol (2013) 97:9343–9353).
Claim 27: The combined prior art teachings as applied to claim 1 and recited supra teaches claim 1. However, does not teach added limitation of instant claim 27, wherein said VLP comprises biotinylated matrix, and wherein said therapeutic agent is conjugated to monomeric streptavidin or an analogue thereof.
The prior art teachings as applied to claims 14-15 as recited supra teaches HIV VLP of claim 1 comprises biotinylated matrix are incorporated here in entirety.
The prior art teachings as applied to claim 19 as recited supra teaches a said therapeutic agent is conjugated to monomeric streptavidin or an analogue thereof are incorporated here in entirety.
It would have been obvious to one of ordinary skill in the art, at the time of the claimed invention to modify the combined prior art teachings as applied to claim 1 as recited supra with additional teachings of Arnaldo Caruso et al 2015 to comprise the biotinylated HIV structural protein matrix (p17/matrix) and incorporate the teachings of Shirbaghaee et al 2015, Thrane et al 2015, Dundas et al 2013 to conjugate the therapeutic agent with monomeric streptavidin or an analogue thereof to obtain a HIV VLP with biotinylated matrix-monomeric streptavidin therapeutic agent complex for HIV therapy. The motivation would have been to obtain HIV VLPs displaying consistently oriented therapeutic or drugs in a high-density repetitive manner for superior treatment outcomes as taught for high-density repetitive display of vaccine antigen on VLP by Thrane et al 2015 (See, page 6, figure 1, b) and overcoming the problem of four high affinity binding sites of wild type Streptavidin that binds to multiple biotinylated ligand/proteins and cause target aggregation that can affect biological functions, live cell imaging. A structural monomer corresponding to a single streptavidin subunit binds one biotin molecule at a time and thus offers the simplest solution for biotin recognition that does not result in target aggregation. The smaller size of the mutant (~14 kDa or approximately 25 % of a tetramer) that would be advantageous for in vivo applications by increasing access to various tissues (See, Dundas et al 2013 research paper, pages 9344-9345, figure 1, Engineered variants, monovalent streptavidin, monomeric streptavidin). One of the ordinary skills in the art would have a reasonable expectation of success to arrive at the invention of claim 27 given the combined prior art teachings applied to the claim 27 as recited supra. It is similar to combining prior art elements according to known methods to yield predictable results. See, KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007), examples of rationales, A-G.
Response to Applicants Arguments/Remarks (filed 01/14/2026)
Applicant’s Arguments:
CLAIMS 1-3, 5, 6, 9, 11, AND 14-24 ARE NOT RENDERED OBVIOUS BY THE REFERENCES CITED BY THE EXAMINER
The Examiner has rejected claims 1, 2, 5, and 6 under 35 U.S.C.§103(a) as allegedly unpatentable over Barnett et al. in view of Smyth et al., Yao et al., Coursaget et al., Zdanowicz et al., Peretti et al., Kaczmarczky et al., Melikyan et al., Markosyan et al., and Cubas et al. It is the Examiner's position that it would have been obvious to a skilled artisan to combine these ten (10) references to arrive at the instantly claimed invention.
Applicant respectfully disagrees with the Examiner's position for at least the following reasons.
Claim 1 recites a human immunodeficiency virus (HIV) virus-like particle (VLP), comprising: (a) at least one HIV structural protein, wherein the at least one structural protein comprises HIV Gag, (b) at least one HIV envelope protein that is dual-tropic for CCR5 and CXCR4, and (c) at least one therapeutic agent, wherein the VLP does not contain a complete HIV genome and lacks reverse transcriptase and integrase. As explained throughout the present application, the use of an HIV Env protein which is dual-tropic for CXCR4 and CCR5 allows for the targeting of a therapeutic agent to "all major HIV-1 cellular targets/reservoirs which include both CD4+ effector memory and regulatory T cells as well as mononuclear phagocytes (MP; monocytes, macrophages and dendritic cells) using the CCR5 co-receptor and broad populations of CD4+ T cells (using the CXCR4 co-receptor)" (page 7 and the Example). By targeting both monocyte/macrophage and CD4+ T cell populations, the instantly claimed VLPs allows for superior therapeutic delivery to all HIV reservoirs to increase the efficacy of the therapeutic agent being delivered.
In contrast to the VLPs of the instant invention, the VLPs of Barnett et al. are used as "vehicles for the presentation of antigens and stimulation of immune response in subjects to whom the VLPs are administered" (Abstract). The Examiner references Example 15 of Barnett et al. as allegedly disclosing VLPs with Env and Gag. However, Barnett et al. fail to teach or suggest that these VLPs are infectious or could deliver a therapeutic agent. Indeed, as noted above, Barnett et al. are concerned only with the presentation of antigens on VLPs for stimulating an immune response - not with delivering therapeutic agents. Even in Example 15, Barnett et al. note that Env proteins with deleted variable domains V1 and V2 were incorporated into VLPs at higher levels than WT Env. Env proteins with deleted V1 and V2 domains are known to deficient for infectivity while providing superior antibody production compared to wild-type. This further shows that the VLPs of Barnett et al. are only taught to be used as agents for presenting antigens for antibody production rather than delivering a therapeutic agent.
The Examiner cites Smyth et al. for allegedly teaching that HIV strain 89.6 is a dual tropic strain. However, Applicant notes that Smyth et al. utilize replication-competent HIV chimera viruses, in contrast to the instantly claimed VLPs. Moreover, Smyth et al. fail to teach or suggest any therapeutic benefit for utilizing the dual tropic Env protein from HIV strain 89.6. Certainly, Smyth et al. fail to teach or suggest using the dual tropic Env protein to deliver therapeutic agents to HIV reservoirs.
The Examiner has also cited Yao et al. However, the Examiner appears to have failed to specifically address the relevance of this reference in the Official Action. Yao et al. disclose Simian-Human Immunodeficiency Virus (SHIV) VLPs which comprise an HIV Env protein and the simian immunodeficiency virus (SIV) Gag (see page 135). Notably, Yao et al. teach that a SHIV VLP comprising the dual-tropic 89.6 Env induces apoptosis in CXCR4- and CCR5-containing cells (Abstract). Yao et al. fail to teach or suggest using the dual tropic Env protein to deliver therapeutic agents to HIV reservoirs.
Based on the foregoing, Applicant submits that the skilled artisan would have neither the motivation nor expectation of success in combining the disclosures of Barnett et al., Smyth et al., and Yao et al. Indeed, Barnett et al. only disclose using VLPs for presenting antigens to a host and inducing antibody production. The teaching by Smyth et al. that the Env protein from HIV strain 89.6 is dual tropic is irrelevant to Barnett et al., which is simply trying to trigger an immune response. Similarly, the teaching of Yao et al. that SHIV VLP comprising the Env protein from HIV strain 89.6 induce apoptosis is irrelevant to Barnett et al. Indeed, apoptosis is not part of the process of triggering an immune response to an antigen. Accordingly, it is clear that there is no reasonable motivation to combine these references.
There is nothing in the teachings of Barnett et al., Smyth et al., and Yao et al. that directs or suggests a skilled artisan to an HIV VLP that comprises (a) at least one HIV structural protein, wherein the at least one structural protein comprises HIV Gag, (b) at least one HIV envelope protein that is dual-tropic for CCR5 and CXCR4, and (c) at least one therapeutic agent, as instantly claimed.
The other references cited by the Examiner fail to overcome the deficiencies in the teachings of Barnett et al., Smyth et al., and Yao et al.
1) Coursaget et al. - The Examiner contends that
Coursaget et al. disclose the use of VLPs for administering a therapeutic agent. However, Coursaget et al. only provide human papilloma virus (HPV) VLPs. The only reference to HIV in Coursaget et al. is at paragraph [0158] which states:
However, it should be appreciated that HPV-based particles of the invention may be used as general
delivery vehicles to treat mucosal diseases or conditions
regardless of whether they are caused by HPV infection.
Accordingly, methods and compositions of the invention
may be used to treat other infections such as HSV or HIV
infection... [Emphasis added]
Thus, Coursaget et al. suggest using HPV VLPs to deliver therapeutics to treat HIV. However, Coursaget et al. clearly fail to teach or suggest the use of HIV VLPs to deliver therapeutics.
2)Zdanowicz et al. - The Examiner states that
Zdanowicz et al. disclose the use of HIV VLPs as drug delivery vehicles. Applicant respectfully disagrees. The only mention of HIV is at the section entitled "Selective elimination of HIV-1-infected cells" at pages 471-472. However, this paragraph discloses the use of vesicular stomatitis virus G glycoprotein (VSV-G) VLPs.
3) Peretti et al. - The reference discloses VLPs "pseudotyped with the CD4 and CXCR4 or CCR5 HIV cell receptors" (page 124; emphasis added). Peretti et al. fail to disclose the use of a VLP with HIV Env on the surface. Moreover, Peretti et al. fail to disclose a dual-tropic VLP - as the VLPs contain either CXCR4 or CCR5. Certainly, Peretti et al. do not teach or suggest a VLP with a dual tropic Env.
4) Kaczmarcyk et al. - The reference discloses VLPs comprising either the VSV-G envelope or influenza neuraminidase (NA) or hemmagglutinin (HA) fusions (see Fig. 1). Kaczmarcyk et al. teach that the VSV-G Env was necessary for intracellular delivery (whole document). 5) Melikyan et al. - The reference discloses
pseudotyped murine leukemia virus (MLV) vectors bearing avian sarcoma and leukosis virus (ASLV) envelope protein. The reference has nothing to do with HIV VLPs.
6) Markosyan et al. - The reference discloses
pseudotyped murine leukemia virus (MLV) vectors bearing HIV-1 Env and is only concerned with imaging lipid and content mixing.
7) Cubas et al. - As with Yao et al., Cubas et al. disclose SHIV VLPs. Additionally, as with Barnett et al., Cubas et al. is only concerned with triggering an immune response by presenting antigen.
In view of all of the foregoing, Applicant submits that the combined teachings of the ten (10) references cited by the Examiner fails to direct the skilled artisan to the instantly claimed VLPs having HIV Gag and a dual-tropic HIV Env along with a therapeutic agent. The only references to disclose dual tropic HIV Env proteins are Smyth et al. and Yao et al. However, Smyth et al. merely identify dual tropism and fail to teach or suggest using such an Env protein to increase the delivery of therapeutic agents to HIV reservoirs, as taught by the instant application. Moreover, Yao et al. merely disclose that SHIV VLPs can induce apoptosis.
Applicant submits that it is impermissible to pick and choose aspects of the ten (10) cited references and use them with hindsight to find obviousness. Moreover, there is nothing in the ten (10) cited references, alone or in combination, that would guide the skilled artisan to arrive at the claimed VLP with any reasonable expectation of success.
As stated in the last Official Action response, Applicant also submits that the claimed VLPs possess unexpectedly superior properties. The claimed VLPs target HIV-infectable cells in vitro and in vivo and target all major HIV-1 cellular targets/reservoirs including both CD4+ effector memory and regulatory T cells as well as mononuclear phagocytes. Such benefits were not predictable based on the cited references. For example, Figs. 4A-4D of the present applications show specific targeting of monocyte/macrophages and CD4+ T cells in vitro. Further, Figs. 5A-5D and 6 show that the claimed VLPs effectively targeted blood, lymph nodes, liver, and spleen, which are HIV reservoirs in humanized mice. It was unexpected and surprising to find that the claimed VLPs demonstrated improved targeting and delivery of therapeutics as well as enhanced uptake and improved antiviral responses in CD4+ T cells and monocyte/macrophage cells, which are principal targets of HIV infection, over non-dual tropic VLPs. Nothing in the references cited by the Examiner teach or suggest such superior results with the claimed VLPs.
Accordingly, Applicant submits that the rejection under 35 U.S.C. §103 cannot be reasonably maintained. Withdrawal of the rejection is respectfully requested.
In addition to the above, the Examiner has cited further references against certain dependent claims in combination with the above ten (10) references. The other references cited by the Examiner fail to overcome the deficiencies in the teachings of the above ten (10) references.
In addition to the above, the Examiner has cited further references against certain dependent claims in combination with the above ten (10) references. The other references cited by the Examiner fail to overcome the deficiencies in the teachings of the above ten (10) references.
1) Kim et al. - The reference provides HIV VLPs, but discloses that they are "useful as an antigen for a diagnostic kit for HIV infection as well as for vaccine composition" (Abstract). As explained at paragraph [0078], Kim et al. teach that the VLPs induce a desired immune response, as with Barnett et al.
2) Thrane et al., Dundas et al., and Fisher et al. - These references were cited by the Examiner only to demonstrate avidin or streptavidin conjugations.
3) Theophile et al. - The Examiner has cited the reference only for teaching the CRISPR system.
4) Caruso et al. (2013) - The Examiner has cited the reference only for disclosing biotinylated HIV p17.
5) Caruso et al. (2015) - The Examiner has cited the reference only for disclosing biotinylated HIV p17 matrix.
6) Shirbaghee et al. - The reference discloses the use of VLPs to deliver various compounds (pages 124-126). Notably, HIV VLPs are not disclosed for delivering compounds. Rather, Shirbaghee et al. disclose that HIV VLPs induce a strong immune response, as with Barnett et al.
7) Kamo et al. - The reference has been cited by the Examiner only to demonstrate the biotinylation of an HIV therapeutic.
8) Raska et al. - The reference has been cited by
the Examiner only to teach the use of mammalian cells for HIV production.
9) Santangelo et al., Milenic et al., Rasaneh et al., Joo et al., and Walling et al. - The references were cited by the Examiner only to demonstrate in vivo imaging of HIV pathogenesis.
10) McBurneya et al., Kirkegaard et al., and Notka et al. - These references were cited by the Examiner only to demonstrate methods of treating HIV.
In view of all of the foregoing, Applicant submits that the rejections under 35 U.S.C. §103 cannot be reasonably maintained. Withdrawal of the rejections is respectfully requested.
In summary, the Applicant argues that the prior art by Barnett et al and other additional prior art results in the use of multiple references for the rejection; the prior art does not teach VLP to deliver therapeutic agents, prior art only teaches VLP for immune response stimulation/induction; Smyth et al fail to teach or suggest HIV strain 89.6 Env for therapeutic benefit; Yao et al teach HIV Env and SIV Gag; Coursaget et al teach HPV VLP. Applicant has argued all the prior arts applied does not render obvious claim 1 and other dependent claims.
In Response: The 103 rejection(s) has been modified in this office action, in view of applicant’s amendment of the claims 1 and dependent claims.
Initially, in response to applicant’s arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Further, in response to applicant's argument that the examiner has combined an excessive number of references, reliance on a large number of references in a rejection does not, without more, weigh against the obviousness of the claimed invention. See In re Gorman, 933 F.2d 982, 18 USPQ2d 1885 (Fed. Cir. 1991).
Both the prior office action and instant rejection under 35 U.S.C. 103 as part of the obviousness analysis, necessitates a number of references since the claims contain multiple claim elements and interdisciplinary concepts. Accordingly, for that reason it was not unreasonable to use ten prior art references to render obvious the claims. For example, some prior arts are used to indicate the VLPs are known in the art for drug delivery vectors and not only limited to HIV VLPs and the use of the HIV VLPs is obvious as taught by the prior art that is a review. Coursaget et al teach HPV VLP and the prior arts is not in HIV, but it is in the field of virology e.g. VLPs of HPV for therapeutic agent cargo delivery applications.
For example, Barnett et al 2003 teaches HIV VLP that can be produced from different HIV proteins (See, entire prior art). Barnett et al 2003 teaches and provides suggestion that the VLPs has additional uses and not just for immune stimulation “The invention provides methods of producing Virus-Like Particles (VLPs), as well as uses of the VLPs including, but not limited to, vehicles for the presentation of antigens and stimulation of immune response in subjects to whom the VLPs are administered. Even if the HIV VLPs of instant application are claimed only for drug delivery, the HIV VLPs when administered to a subject would stimulate and induce immune response which the invention is not intending to measure immune stimulation and response. The HIV VLPs of present invention are “not inert” the HIV VLPs are seen as an antigen or immunogen by the mammalian subject immune system.
Smyth et al HIV strain 89.6 provides a required dual-tropic Env and it would target the cells based on the dual tropic nature of the HIV strain 89.6 and does not limit from performing therapeutic agent delivery. Yao et al teach HIV Env and SIV Gag, as mentioned earlier, the this is an obviousness rejection, and the prior art in the field provides unexplicit suggestions and motivations. Peretti et al teaches the HIV-targeted VLPs concept “We here report that (CD4-CXCR4) and (CD4-CCR5) Nef7-based VLPs efficiently enter cells infected by X4- or R5-tropic HIV-1 strains, respectively (See, abstract, entire prior art, and rejection in the office action). The VLPs are dual-tropic because even vesicular stomatitis virus G glycoprotein pseudotyped HIV-1-based virus-like particles (VLPs) retain dual tropism due to incorporated CD4-CXCR4 and CD4-CCR5 that enables the VLPs efficiently enter cells infected by X4- or R5-tropic HIV-1 strains. Kaczmarczyk et al 2011 teaches the concept of VLP based therapeutic delivery and provides a suggestion or motivation for the instant invention. The prior art regarding conjugation of imaging agents to a VLP or a virus teaches the concept of labelling of VLP with an imaging agent. Cubas et al teaches virus-like particle (VLP) lymphatic trafficking, imaging approach to directly visualize the trafficking of SHIV VLPs (abstract, Fig 1 A, B, C, entire article).
The prior art references cited and as applied to the dependent claims teaches the added limitations and renders obvious the dependent claims as recited in the office action. The applied prior art teachings render obvious the claimed compound that is HIV-VLP structure, and the HIV-VLP structure conjugation or linked therapeutic agent or imaging agent using an approach of avidin-biotin affinity and linkage that is taught and commonly used in the art. When the structure of a compound is rendered obvious the results or effects are reasonably expected.
Accordingly, Applicant’s arguments addressing the prima facie case, have been considered but were not persuasive.
Applicant’s Arguments: regarding Secondary Consideration:
As stated in the last Official Action response, Applicant also submits that the claimed VLPs possess unexpectedly superior properties. The claimed VLPs target HIV-infectable cells in vitro and in vivo and target all major HIV-1 cellular targets/reservoirs including both CD4+ effector memory and regulatory T cells as well as mononuclear phagocytes. Such benefits were not predictable based on the cited references. For example, Figs. 4A-4D of the present applications show specific targeting of monocyte/macrophages and CD4+ T cells in vitro. Further, Figs. 5A-5D and 6 show that the claimed VLPs effectively targeted blood, lymph nodes, liver, and spleen, which are HIV reservoirs in humanized mice. It was unexpected and surprising to find that the claimed VLPs demonstrated improved targeting and delivery of therapeutics as well as enhanced uptake and improved antiviral responses in CD4+ T cells and monocyte/macrophage cells, which are principal targets of HIV infection, over non-dual tropic VLPs. Nothing in the references cited by the Examiner teach or suggest such superior results with the claimed VLPs.
In Response: Applicant’s arguments regarding claimed VLPs possess unexpectedly superior properties have been considered but are not persuasive, because the 35 U.S.C. 103 obviousness rejection rendered provides a strong prim facie obviousness case for the instant claimed HIV VLPs and their conjugation to a therapeutic or an imaging agents and independent and dependent claims, including the amended claim in this rejection as recited supra.
In this regard, courts have held that where “"the record establish[ed] such a strong case of obviousness" that allegedly unexpectedly superior results were ultimately insufficient to overcome obviousness conclusion). See MPEP 2145; and See, e.g., Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1372, 82 USPQ2d 1321, 1339 (Fed. Cir. 2007) ("the record establish[ed] such a strong case of obviousness" that allegedly unexpectedly superior results were ultimately insufficient to overcome obviousness conclusion); Leapfrog Enterprises Inc. v. Fisher-Price Inc., 485 F.3d 1157, 1162, 82 USPQ2d 1687, 1692 (Fed. Cir. 2007).
Additionally, Applicant's argument of "unexpected result" is not persuasive, since the references teachings applied/cited in the 103 rejections (as modified) provide reasonable expectation for achieving the claimed invention and suggests what applicant is alleging is unexpected.
Even assuming arguendo "unexpected” properties of the claims (or claimed HIV VLPs) the evidence is not sufficient since it fails to provide a representative showing commensurate to the claimed scope. See, MPEP 2145. “… in determining the relative weight to accord to rebuttal evidence, considerations such as whether a nexus exists between the claimed invention and the proffered evidence, and whether the evidence is commensurate in scope with the claimed invention, are appropriate. See also Example 2 in MPEP 2145.
It is also noted that, to the extent that Applicant is attributing statements regarding unexpected results that are not supported by evidence on the record, arguments presented by applicant cannot take the place of factually supported objective evidence. See, e.g., In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965); See also MPEP 2145 I.
23. Applicant’s arguments with respect to amended claims 1-3, 5, 9, 11, 14-24, and 26-27 have been considered but are deemed moot because the obviousness rejections above have been modified to address these newly added limitations. Accordingly , the amended claims 1-3, 5, 9, 11, 14-24, and 26-27 are rendered obvious under 35 U.S.C. 103 the additional teachings of the prior arts as recited supra. The rejection is maintained.
Thus, the rejection as recited in the office action supra is maintained.
24. The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
The prior art below is to be read in context to the claimed inventions and added claim limitations/elements.
Belshan et al (2009). In vivo biotinylation and capture of HIV-1 matrix and integrase proteins. Journal of Virological Methods 159, p 178–184. The report describes the adaptation of the biotin ligase BirA-biotin acceptor sequence (BAS) labeling system to biotinylate specific human immunodeficiency virus 1 (HIV-1) proteins in vivo.
Gray et al (2009). Tissue-Specific Sequence Alterations in the Human Immunodeficiency Virus Type 1 Envelope Favoring CCR5 Usage Contribute to Persistence. Journal of Virology. Vol. 83, No. 11.
Epelman et al (2014). Origin and functions of tissue macrophages. Immunity. 2014 Jul 17;41(1):21-35.
Zhen et al (2014). CD4 ligation on human blood monocytes triggers macrophage differentiation and enhances HIV infection. J Virol. 2014 Sep 1;88(17):9934-46.
Carlson-Stevermer et al (2017). Assembly of CRISPR ribonucleoproteins with biotinylated oligonucleotides via an RNA aptamer for precise gene editing. Nat. Commun. 2017; 8:1711.
Conclusion
25. No claim is allowed.
26. Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
27. A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SAMADHAN J JADHAO whose telephone number is (703)756-1223. The examiner can normally be reached M-F 8:00-5:00.
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/SAMADHAN JAISING JADHAO/Examiner, Art Unit 1672
/BENNETT M CELSA/Primary Examiner, Art Unit 1600