DETAILED ACTION
Applicant’s response filed March 23, 2026 has been received and entered into the application file. Applicant’s arguments and amendments to the claims have been fully considered.
Claims 1, 6, 7, 19, 24, 25, 31-33, 36-41, 44, 59-64, and 66-68 from the listing filed March 23, 2026 are pending. Claims 6-7, 19, 25, 37, and 39-41 are withdrawn. Claims 2-5, 8-18, 20-23, 26-30, 34-35, 42-43, 45-58, and 65 are cancelled. Thus, claims 1, 24, 31-33, 36, 38, 44, 59-64, and 66-68 are being examined on the merits herein.
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Information Disclosure Statement
The information disclosure statements (IDS) submitted on March 23, 2026 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
REJECTION(S) MAINTAINED, UPDATED FOR AMENDMENT
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
RE: Claims 1, 24, 31, 32,36, 38, 44, 59, 60, 63, and 65 are rejected under 35 U.S.C. 103 as being unpatentable over Verhoeyen, in view of Zhang (Zhang and Roth, J Gene Medicine (2010) 12: 945-955; previously cited), Ziegler (Ziegler, L. A., A dissertation presented to the Faculty of the Graduate School, University of Southern California (2008); previously cited), Heffner, and Kingsman.
Examiner notes Applicant amendment has cancelled claim 65, thus making the rejection of said claim moot.
Applicant amended claim 1 to now require a re-targeted paramyxoviral fusogen. The underlined amendment is de minimis as said amendment is merely the incorporation of now cancelled claim 65 into claim 1. Examiner respectfully notes claim 65 was previously rejected using the same references.
Thus, the previously filed rejections are maintained and updated below for amendment.
Re: Claims 33 and 42 are rejected under 35 U.S.C. 103 as being unpatentable over Verhoeyen, in view of Zhang, Ziegler, Heffner, and Kingsman, and further in view of Lieber.
Re: Claims 61 and 62 are rejected under 35 U.S.C. 103 as being unpatentable over Verhoeyen, in view of Zhang, Ziegler, Heffner, and Kingsman, and further in view of Zhang ‘2824.
Re: Claims 64 and 66 are rejected under 35 U.S.C. 103 as being unpatentable over Verhoeyen, in view of Zhang, Ziegler, Heffner, and Kingsman, and further in view of Wertz.
Re: Claim 68 is rejected under 35 U.S.C. 103 as being unpatentable over Verhoeyen, in view of Zhang, Ziegler, Heffner, and Kingsman, and further in view of Fejoz.
Re: Claim 67 is rejected under 35 U.S.C. 103 as being unpatentable over Verhoeyen, in view of Zhang, Ziegler, Heffner, and Kingsman, and further in view of Maltzahn.
Examiner notes Applicant amendment has cancelled claim 42 thus making the rejection of said claim moot.
Examiner notes claims 64 and 66-68 are additionally amended. However, said amendments are solely to update said claims for the amendment to claim 1 of the fusogen being a paramyxoviral fusogen. As such, said amendments are merely de minimis. The updated rejections of claims 64 and 66-68 are included below, updated for Applicant amendment.
Examiner notes no other claims have been amended via Applicant amendment. As such, the previously filed rejections are maintained.
Claims 1, 24, 31, 32,36, 38, 44, 59, 60, and 63 are rejected under 35 U.S.C. 103 as being unpatentable over Verhoeyen, in view of Zhang (Zhang and Roth, J Gene Medicine (2010) 12: 945-955; previously cited), Ziegler (Ziegler, L. A., A dissertation presented to the Faculty of the Graduate School, University of Southern California (2008); previously cited), Heffner, and Kingsman.
In regards to claim 1, Verhoeyen teaches for the correction of many inherited or acquired defects of the hematopoietic system, the therapeutic gene must be delivered to cells that are able to both self-renew and differentiate into all hematopoietic lineages. As such, these gene therapies must be targeted to the hematopoietic stem cell (HSC) without modifying its properties (p3, 1st paragraph). Verhoeyen further teaches of engineering recombinant membrane proteins (i.e., fusogens) and incorporating them into lentiviral vector particles (i.e., fusosomes) to display “early acting” cytokines on their surface (p4, last paragraph).
As can be seen in Fig 1 below, HIV-1 lentiviral vectors (i.e., fusosomes) were engineered to display recombinant envelope glycoproteins (i.e., fusogens) N-terminally fused to stem cell factor (SCF) or thrombopoietin (TPO), two cytokines that can specifically target the vector particles to hematopoietic stem cells (HSCs) because HSCs express the receptor for SCF, c-kit, and the TPO receptor, c-mpl. In addition, the vectors contain the vesicular stomatitis virus G (VSV-G) glycoproteins, which allow vector-cell fusion (Fig 1). Thus, Verhoeyen teaches of a fusosome comprising a lipid bilayer (a POSITA will appreciate lentiviral vectors comprise a lipid bilayer) comprising a re-targeted fusogen (i.e., the envelope glycoproteins fused to SCF or TPO), wherein the re-targeted fusogen comprises a targeting moiety that binds to a target cell and wherein the target cell is a HSC. Thus, Verhoeyen teaches of point (a) of claim 1, with the exception of the re-targeted fusogen being a “paramyxoviral fusogen” and with the exception of “wherein the targeting moiety is an antibody or an antigen-binding portion of an antibody”.
FIG 1, Verhoeyen
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Verhoeyen additionally teaches the recombinant LVs allowed for superior gene transfer in the most immature of CD34+ cells as compared with conventional LVs. Further, said LVs are able to selectively transduce the HSCs in the CD34+ population with high efficacy and without disturbing their cell function or their capacity to differentiate (p5).
Verhoeyen does not teach of point (b).
Zhang teaches of antibody-directed lentiviral gene transduction in early immature hematopoietic progenitor cells (Abstract). Zhang teaches pseudotyping HIV-1 (Table 1) lentiviral particles with Sindbis virus envelope (Env) proteins modified with an immunoglobulin Fc-binding domain presents a method of selecting cells within a mixed population through antibody (Ab)-mediated targeting. Zhang teaches of targeting lentiviral gene delivery to hematopoietic progenitor cells via Ab-conjugated envelopes (Methods, p945). Specifically, Zhang teaches of optimizing gene delivery using ABCG2 as the cell surface target. Zhang further teaches the conjugation of viral particles with anti-CD133 and anti-ABCG2, both known hematopoietic stem cell-associated Ab, resulted in targeted gene transfer into early immature hematopoietic progenitor cells (Results, p945). Zhang teaches both ABCG2 and CD133 are early markers of HSCs/progenitor cells (p950, 2nd column, last paragraph).
Thus, Zhang teaches a fusosome (i.e., a lentiviral HIV-1 vector) comprising a lipid bilayer comprising a re-targeted fusogen (i.e., Sindbis virus envelope (Env) proteins modified with an immunoglobulin Fc-binding domain), wherein the re-targeted fusogen comprises a targeting moiety that binds to a target cell, wherein the targeting moiety is an antibody or an antigen-binding portion of an antibody (i.e., re-targeted fusogen ABCG2), and wherein the target cell is a hematopoietic progenitor cell, as the cell surface target. Zhang does not per se teach the target cell is a hematopoietic stem cell.
Ziegler teaches of targeting lentivector gene delivery to hematopoietic stem and progenitor cells in vivo (Abstract xiii). Specifically, Ziegler teaches the use of lentiviral vectors to target specific cell types in vivo and further teaches of the co-incorporation of fusogens and antibodies into said vectors (p48, p50). Ziegler teaches using an anti-CD34 antibody or stem cell factor as a targeting molecule and a binding-deficient, fusion competent mutant of the Sindbis virus glycoprotein as a fusogen and teaches targeting CD34+ and CD117+ cells (i.e., hematopoietic stem cells) in vitro. Ziegler additionally teaches both the antibody and fusogen are required for targeted transduction of CD34 and CD117 (i.e., hematopoietic stem cells) cell lines (Abstract, xiii). Ziegler does not teach a fusogen comprising an antibody but rather teaches a 2 count system to target hematopoietic stem cells in which the viral envelope comprises an envelope protein, i.e., fusogen, and also comprises a binding molecule, i.e., an antibody (Figure 1.7, p36). Thus, Ziegler teaches of separating binding and fusion (Abstract).
Thus, Ziegler and Zhang teach gene delivery, via antibodies fused to a lentiviral vector to HSCs/hematopoietic progenitor cells. Ziegler teaches the separation of the antibody and the envelope protein whereas Zhang teaches the fusion of the antibody and the envelope protein. Verhoeyen teaches the fusion of the hematopoietic stem cell targeting moiety (stem cell factor or TPO) with the envelope protein. Examiner notes Ziegler also teaches the use of stem cell factor as the targeting moiety.
As Verhoeyen and Zhang teach the fusion of the HSCs specific targeting moiety (i.e., stem cell factor or TPO [Verhoeyen]/ anti-CD133 and anti-ABCG2[Zhang]) with the envelope protein and Ziegler teaches the specific targeting of hematopoietic cells via a HSCs specific antibody or stem cell factor as the targeting molecule, it would have been obvious, before the effective filing date of the claimed invention, to combine the teachings of Verhoeyen, Zhang and Ziegler. A POSITA would have been motivated and had a reasonable expectation of success in combining the teachings of Verhoeyen, Zhang and Ziegler due to all studying lentiviral vector gene transduction into HSCs/hematopoietic progenitor cells. As Verhoeyen teaches of targeting HSCs via lentiviral vectors comprising fusogens comprising a hematopoietic stem cell specific cytokine and Zhang teaches of lentiviral vectors comprising fusogens comprising hematopoietic stem cell specific antibodies and further teaches said lentiviral vectors allow for targeted gene transduction, and Ziegler teaches of the transduction of HSCs via a lentiviral vector comprising a HSC specific antibody, a POSITA would have been motivated to combine said teachings in order to have a specific system for targeted gene transduction to HSCs via lentiviral vector transduction comprising a fusogen comprising an antibody as the targeting moiety.
Thus, Verhoeyen, Zhang, and Ziegler teach of claim 1(a), minus the re-targeted fusogen being a paramyxoviral fusogen.
Heffner teaches of methods and compositions for improving the efficacy of gene delivery such as viral transduction of cells and specifically teaches of transducing human hematopoietic stem cells (HSCs) with viruses and/or viral vectors. Heffner additionally teaches said compositions and methods are useful for therapeutic indications amenable to treatment with hematopoietic stem cell gene therapies (Abstract).
Heffner teaches of gene delivery vehicles such as retroviruses or lentiviruses or retroviral/lentiviral vectors. In particular, Heffner teaches the gene delivery vehicle is a Human immunodeficiency virus (HIV) virus or a retrovirus (i.e., fusosome) which may be pseudotyped with a vesicular stomatitis virus G-protein (VSV-G) envelope protein (i.e., fusogen) [0018].
In regards to the newly added limitation of a re-targeted fusogen being a paramyxoviral fusogen, Examiner respectfully notes Heffner teaches envelope proteins (i.e., fusogens) for pseudotyping a virus may include such viruses as Paramyxoviridae such as Hendra virus and Nipah virus [0156]. Thus, Heffner teaches wherein the fusogen is a paramyxovirus fusogen.
Further, Heffner teaches said retroviruses comprise a beta-globin promoter and a beta globin locus control region (LCR) (known by those in the art to be a “super enhancer”) operably linked to a gene of interest (claim 28) and additionally teaches said gene of interest may be a gene that encodes a polypeptide that provides a therapeutic function for the treatment of a hemoglobinopathy [0120] (i.e., a nucleic acid that comprises a payload gene encoding an exogenous agent). Further, Heffner teaches the vector of the present invention comprises one or more hematopoietic cell or tissue specific promoters and/or enhancers, such as a human ß-globin promoter and human ß-globin LCR [0129] and moreover teaches the expression control sequence (i.e., a promoter and/or enhancer) may be a stem cell specific expression control sequence that directs stem cell specific expression of the polynucleotide of interest in, for example, a hematopoietic stem cell [0177]. Additionally, the ß-globin promoter is taught in Table 3 of the instant specification which provides examples of exemplary promoters to be used, for example, HSC-specific promoters. Thus, Heffner teaches of a fusosome comprising a nucleic acid that comprises a payload gene encoding an exogenous agent and a positive hematopoietic stem cell (HSC)-specific regulatory element operatively linked to the payload gene.
Heffner does not teach “wherein the positive HSC-specific regulatory element increases expression of the payload gene in an HSC relative to an otherwise similar fusosome lacking the positive HSC-specific regulatory element.” However, said functional limitation recitation is interpreted as functional language and is not given patentable weight because the said functional recitation does not appear to add additional structural limitations to the instant claimed product. See MPEP 2106 (II) (C) and 2111.02 (II). Additionally, “Where the claimed and prior art products are identical or substantially identical in structure or composition, or are produced by identical or substantially identical processes, a prima facie case of either anticipation or obviousness has been established. In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433 (CCPA 1977).” See MPEP 2112.01 (I).
As both Heffner, Verhoeyen, Zhang and Ziegler teach of HIV1 fusosomes for gene transfer/gene delivery to HSCs and additionally both Heffner, Ziegler and Verhoeyen teach of said fusosomes comprising the fusogen VSV-G, and further, Verhoeyen teaches the re-targeted fusogens allowed for superior gene transfer to HSCs, it would have been obvious to a POSITA, before the effective filing date of the claimed invention, to combine the teachings of Heffner and the above discussed references in order to have a fusosome comprising re-targeted fusogens to allow for superior gene transfer to the HSCs. A POSITA would have had a reasonable expectation of success in combining said teachings, and would have been motivated in combing said teachings, due to both Heffner and the above cited references teaching of gene transfer/gene delivery through the use of fusosomes to HSCs.
In regards to the newly added limitation of the re-targeted fusogen being a paramyxoviral fusogen, Examiner respectfully notes Heffner teaches of paramyxoviral fusogens. Thus, it would have been obvious to a POSITA, before the effective filing date of the claimed invention, to combine the teachings of Heffner and the above discussed references in order to have a fusosome comprising re-targeted fusogens to allow for superior gene transfer to the HSCs. A POSITA would have had a reasonable expectation of success in combining said teachings, and would have been motivated in combining said teachings, due to both Heffner and the above cited references teaching of gene transfer/gene delivery through the use of fusosomes to HSCs.
Thus, Heffner, in combination with Verhoeyen, Zhang and Ziegler, teaches of claim 1(a) and 1(b)(i)-(ii). Heffner does not teach of claim 1 (b)(iii).
Neither Verhoeyen, Zhang, Ziegler nor Heffner teach a non-target cell-specific regulatory element (NTCSRE). However, a person of ordinary skill in the art would have been motivated to include NTCSREs in the fusosome of claim 1, due to Kingsman teaching that a concern with the use of vectors as potential therapeutic agents is background expression in non-target cells (p5, last sentence). Further, Kingsman teaches an approach for restricting expression of a transgene to a target cell population by silencing transgene expression in non-target cell types by using endogenous microRNA (miRNA) species (p6, top paragraph). Kingsman further teaches of retroviral vectors (i.e., fusosomes) comprising a miRNA target site. Additionally, Kingsman teaches a “miRNA” target site” is a sequence to which an endogenous miRNA binds. The miRNA target site is complementary to the endogenous miRNA. Expression of one or more NOIs (i.e., nucleotide sequence of interest, i.e., a payload gene encoding an exogenous agent) can be reduced in cells containing miRNAs by including a sequence encoding a miRNA target site in a vector comprising the NOI. Binding of the miRNA to the miRNA target site suppresses expression of the one or more NOIs. If the miRNA is tissue-specific, NOI expression is suppressed only in cell types comprising endogenous miRNAs that bind to the miRNA target site while the NOI is expressed in cell types that do not express such miRNA (i.e., target cells) (p36, miRNA).
Kingsman teaches of a vector (i.e., fusosome) pseudotyped with a rabies G-protein (i.e., a fusogen), wherein the vector comprises a muscle cell-specific microRNA target sequence (NTCSRE) wherein the microRNA sequence is operably linked to a nucleotide sequence of interest (i.e., an exogenous agent). Thus, it would have been obvious to one of ordinary skill in the art, and further a POSITA would have been motivated to combine the teachings of Kingsman, Verhoeyen, Zhang, Ziegler and Heffner, in order to have a fusosome comprising a fusogen and further comprising a nucleic acid comprising a payload gene, such as it taught by both Heffner and Kingsman. One would have been motivated to further combine said teachings in order to have an HSC-specific regulatory element operably linked to a payload gene (as taught by Heffner) as well as a miRNA (as taught by Kingsman) to restrict expression of said payload gene to HSC target cells by silencing transgene expression in non-target cell types. One would have had a reasonable expectation of success in combining said teachings due to all working in the fields of vector-based gene therapy.
Therefore, the combined teachings of Verhoeyen, Zhang, Ziegler, Heffner and Kingsman render the invention obvious and as such, said claim is properly rejected.
In regards to claim 63, Examiner notes said claim is not further limiting. It is noted that the claim language states “wherein, when contacted with a target cell population, the fusosome delivers the payload agent via a non-endocytic pathway.” This functional limitation recitation is interpreted as functional language and is not given patentable weight because the said functional recitation does not appear to add additional structural limitations to the instant claimed product. See MPEP 2106 (II) (C) and 2111.02 (II). Additionally, “Where the claimed and prior art products are identical or substantially identical in structure or composition, or are produced by identical or substantially identical processes, a prima facie case of either anticipation or obviousness has been established. In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433 (CCPA 1977).” See MPEP 2112.01 (I).
Thus, the claim is obvious and is properly rejected.
In regards to claim 24, the above cited references teach the fusosome of claim 1. Further, Heffner teaches hematopoietic stem cells are capable of forming all cells of the blood cell lineage, e.g., lymphoid and myeloid cells [0148]. Additionally, Heffner teaches of long-term HSCs and short-term HSCs [0318]. This reads on “wherein the HSC is a myeloid-lymphoid balanced HSC, a myeloid-biased HAS, a lymphoid-biased HSC, a platelet-biased HSC, a platelet-myeloid-biased HSC, a long-term repopulating HSC, and intermediate-term repopulating HSC or a short-term repopulating HSC.”
Thus, the claim is obvious and is properly rejected.
In regards to claim 31, the above cited references teach the fusosome of claim 1. Further, Heffner teaches retroviruses which comprise a beta-globin promoter and a beta globin locus control region (LCR) (known by those in the art to be a “super enhancer”) operably linked to a gene of interest (claim 28) and additionally teaches said gene of interest may be an exogenous gene [0124] (i.e., a nucleic acid that comprises a payload gene encoding an exogenous agent). Further, Heffner teaches the vector of the present invention comprises one or more hematopoietic cell or tissue specific promoters and/or enhancers, such as a human ß-globin promoter and human ß-globin LCR [0129] and moreover teaches the expression control sequence (i.e., a promoter and/or enhancer) may be a stem cell specific expression control sequence that directs stem cell specific expression of the polynucleotide of interest in, for example, a hematopoietic stem cell [0177]. Additionally, the ß-globin promoter is taught in Table 3 of the instant specification which provides examples of exemplary promoters to be used, for example, HSC-specific promoters. Thus, Heffner teaches “wherein the positive HSC-specific regulatory element comprises an HSC-specific promoter.
Therefore, the claim is obvious and is properly rejected.
In regards to claim 32, the above cited references teach the fusosome of claim 31. Additionally, Heffner teaches retroviruses which comprise a beta-globin promoter and a beta globin locus control region (LCR) (known by those in the art to be a “super enhancer”) operably linked to a gene of interest (claim 28) and additionally teaches said gene of interest may be an exogenous gene [0124] (i.e., a nucleic acid that comprises a payload gene encoding an exogenous agent). Further, Heffner teaches the vector of the present invention comprises one or more hematopoietic cell or tissue specific promoters and/or enhancers, such as a human ß-globin promoter and human ß-globin LCR [0129] and moreover teaches the expression control sequence (i.e., a promoter and/or enhancer) may be a stem cell specific expression control sequence that directs stem cell specific expression of the polynucleotide of interest in, for example, a hematopoietic stem cell [0177]. Additionally, the ß-globin promoter is taught in Table 3 of the instant specification which provides examples of exemplary promoters to be used, for example, HSC-specific promoters. Thus, Heffner teaches “wherein the positive HSC-specific regulatory element comprises an HSC-specific promoter.
Therefore, the claim is obvious and is properly rejected.
In regards to claim 36, the above cited references teach the fusosome of claim 1. Further, Kingsman teaches wherein the NTCSRE comprises a non-HSC-specific miRNA recognition sequence. Kingsman teaches the vector (i.e., fusosome) comprises a muscle cell specific miRNA target sequence (i.e., recognition sequence) (claim 1). Thus, Kingsman teaches of a non-HSC-specific miRNA.
Therefore, the claim is obvious and is properly rejected.
In regards to claim 38, the above cited references teach the fusosome of claim 36. Further, Kingsman teaches wherein the NTCSRE is incorporated into the 3’-untranslated region (UTR) of a GFP expression cassette within a lentiviral vector backbone (p6, second paragraph). As a POSITA will appreciate, the 3’ UTR is transcribed from DNA but is not translated into protein. Thus, Kingsman teaches wherein the NTCSRE is situated or encoded within a transcribed region encoding the exogenous agent (i.e., GFP).
Therefore, the claim is obvious and is properly rejected.
In regards to claim 44, the above cited references teach the fusosome of claim 1. Further, Heffner teaches of a pharmaceutical composition comprising the fusosome and a pharmaceutically acceptable carrier [0274].
Therefore, the claim is obvious and is properly rejected.
In regards to claim 59, the above cited references teach the fusosome of claim 1. Further, Heffner teaches retroviruses which comprise a beta-globin promoter (claim 28). As indicated in claim 60 of the instant application, an example of an erythroid lineage-specific promoter is a beta-globulin promoter.
Thus, the claim is obvious and is properly rejected.
In regards to claim 60, the above cited references teach the fusosome of claim 59. Further, Heffner teaches retroviruses which comprise a beta-globin promoter (claim 28).
Thus, the claim is obvious and is properly rejected.
In regards to claim 65, the above cited references teach the fusosome of claim 1. Further, Heffner teaches envelope proteins (i.e., fusogens) for pseudotyping a virus may include such viruses as Paramyxoviridae such as Hendra virus and Nipah virus [0156]. Thus, Heffner teaches wherein the fusogen is a paramyxovirus fusogen.
Thus, the claim is obvious and is properly rejected.
Claim 33 is rejected under 35 U.S.C. 103 as being unpatentable over Verhoeyen, in view of Zhang, Ziegler, Heffner, and Kingsman, and further in view of Lieber.
In regards to claim 33, the above cited references teach the fusosome of claim 32. The above cited references do not teach wherein the positive HSC-specific regulatory elements comprises a promoter chosen from a vav regulatory element, CD34, CD59, CD90, CD49f, EMCN, or TIE2 promoter.
Lieber teaches of recombinant Adenoviral vectors for cell specific infection and genome integration (Title). Additionally, Lieber teaches of potential candidate promoters to drive expression with high specificity for HSC includes the CD34 promoter [162].
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to do a simple substitution of one known element for another to obtain predictable results. It would have been obvious to substitute the beta-globin promoter as taught by Heffner for the CD34 promoter as taught by Lieber in order to have a vector with a promoter driving expression with high specificity for the HSCs.
The skilled artisan would have had a reasonable expectation of successfully substituting said promoters. Substitution of one element for another known in the field is considered to be obvious, absent a showing that the result of the substitution yields more than predictable results. See KSR International Co. v Teleflex Inc 82 USPQ2d 1385 (US 2007) at page 1395.
Thus, the claim is obvious and is properly rejected.
Claims 61 and 62 are rejected under 35 U.S.C. 103 as being unpatentable over Verhoeyen, in view of Zhang, Ziegler, Heffner, and Kingsman, and further in view of Zhang ‘2824.
In regards to claim 61, the above cited references teach the fusosome of claim 1. Neither Verhoeyen nor Heffner teach wherein the exogenous agent comprises a site-specific nuclease. Heffner does however teach that a gene of interest (i.e., an exogenous agent) may be a gene that encodes a polypeptide that provides a therapeutic function for the treatment of a hemoglobinopathy [0120].
Zhang ‘2824 teaches of system, methods, and compositions for altering expression of target gene sequences and related gene products. Zhang further teaches of the CRISPR-Cas system in combination with vectors and vector systems which encode one or more components of a CRISPR complex (Abstract). Zhang specifically teaches of Cas9 (Title). Zhang teaches of the use of microvesicles and liposomes to deliver Cas9 [0485] as well as the use of viral vectors [0490] and specifically of lentivirus vectors [0521]. Zhang further teaches of the use of target-specific promoters, and specifically mentions hematopoietic cell promoters [0509]. Zhang teaches of a polynucleotide encoding a Cas9 and further teaches of a vector comprising the polynucleotide operably linked to a suitable promoter [0033].
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to do a simple substitution of one known element for another to obtain predictable results. It would have been obvious to substitute the therapeutic gene of interest (i.e., exogenous agent) as taught by Heffner for the Cas9 polynucleotide (i.e., exogenous agent comprising a site-specific nuclease) as taught by Zhang ‘2824 in order to have a vector expressing a site-specific nuclease in HSCs.
The skilled artisan would have had a reasonable expectation of successfully substituting said exogenous agents. Substitution of one element for another known in the field is considered to be obvious, absent a showing that the result of the substitution yields more than predictable results. See KSR International Co. v Teleflex Inc 82 USPQ2d 1385 (US 2007) at page 1395.
Thus, the claim is obvious and is properly rejected.
In regards to claim 62, the above cited references teach the fusosome of claim 61. Further, Zhang ‘2824 teaches wherein the site-specific nuclease is a Cas9 (Title).
Thus, the claim is obvious and is properly rejected.
Claims 64 and 66 are rejected under 35 U.S.C. 103 as being unpatentable over Verhoeyen, in view of Zhang, Ziegler, Heffner, and Kingsman, and further in view of Wertz.
In regards to claim 64, the above cited references teach the fusosome of claim 1. Further, Heffner teaches envelope proteins (i.e., fusogens) for pseudotyping a virus may include such viruses as Paramyxoviridae such as Hendra virus and Nipah virus [0156]. Heffner does not teach of Nipah virus F and G proteins nor of Hendra virus F and G proteins.
Wertz teaches of surface glycoproteins (i.e., fusogens) and further teaches of heterologous proteins that mediate cell infection and targeting include, but are not limited to, the F protein of HPV I, F protein of HPV III, HN protein of HPV I, HN protein of HPV III, HA protein of influenza, NA protein of influenza, Ebola GP protein, Flavivirus E protein, Nipah virus F protein, Hendra virus F proteins, Measles virus F protein and Measles virus H protein [0075]. Additionally, Wertz teaches of the use of viral vectors that can infect a cell but cannot spread beyond said cell (claim 6) by employing specific proteins such as Nipah virus F protein and Hendra virus F proteins (claim 13).
Thus, one of ordinary skill in the art, would have been motivated to combine the teachings of Verhoeyen, Heffner and Wertz in order to have a fusosome with a fusogen comprising a sequence of Nipah virus F protein or Hendra virus F protein for specific cell infection and targeting. The skilled artisan would have had a reasonable expectation of success in combining said teachings due to Heffner teaching a fusosome (i.e., a vector) comprising an envelope protein for pseudotyping a virus (i.e., a fusogen comprising a sequence), with such examples of an envelope protein being given such as Hendra and Nipah virus (i.e., paramyxoviral proteins). Further, the skilled artisan would have had a reasonable expectation of success in combining said teachings because of Wertz taking said teachings one step further by teaching of cell targeting and infection through the use of viral vectors containing the surface glycoproteins (i.e., envelope proteins) Nipah virus F protein and Hendra virus F protein.
Thus, the claim is obvious and is properly rejected.
In regards to claim 66, the above cited references teach the fusosome of claim 1. Further, Heffner teaches envelope proteins (i.e., fusogens) for pseudotyping a virus may include such viruses as Paramyxoviridae such as Hendra virus and Nipah virus [0156]. Heffner does not teach of paramyxovirus F and G proteins.
Wertz teaches of surface glycoproteins (i.e., fusogens) and further teaches of heterologous proteins that mediate cell infection and targeting include, but are not limited to, the F protein of HPV I, F protein of HPV III, HN protein of HPV I, HN protein of HPV III, HA protein of influenza, NA protein of influenza, Ebola GP protein, Flavivirus E protein, Nipah virus F protein, Hendra virus F proteins, Measles virus F protein and Measles virus H protein. Further, Wertz teaches virtually any individual or combination of transmembrane proteins providing attachment/entry function can be used [0075]. As one of ordinary skill in the art will appreciate, both Nipah virus and Measles virus are paramyxoviruses. Thus, Wertz teaches of wherein the paramyxovirus fusogen comprises paramyxovirus F (i.e., Nipah virus F protein) and H (i.e., Measles virus H protein) proteins. Additionally, Wertz teaches of the use of viral vectors that can infect a cell but cannot spread beyond said cell (claim 6) by employing specific proteins such as Nipah virus F protein and Measles virus H protein (claim 13) (i.e., paramyxovirus F and H proteins).
Thus, one of ordinary skill in the art, would have been motivated to combine the teachings of Verhoeyen, Heffner and Wertz in order to have a fusosome with a paramyxovirus fusogen comprising paramyxovirus F protein and Measles virus H protein for specific cell infection and targeting. The skilled artisan would have had a reasonable expectation of success in combining said teachings due to Heffner teaching a fusosome (i.e., a vector) comprising an envelope protein for pseudotyping a virus (i.e., a fusogen comprising a sequence), with such examples of an envelope protein being given such as paramyxovirus proteins. Further, the skilled artisan would have had a reasonable expectation of success in combining said teachings because of Wertz taking said teachings one step further by teaching of cell targeting and infection through the use of viral vectors containing the surface glycoproteins (i.e., envelope proteins) Nipah virus F protein and Measles virus H protein.
Thus, the claim is obvious and is properly rejected.
Claim 68 is rejected under 35 U.S.C. 103 as being unpatentable over Verhoeyen, in view of Zhang, Ziegler, Heffner, and Kingsman, and further in view of Fejoz.
In regards to claim 68, the above cited references teach the fusosome of claim 64. Further, Verhoeyen teaches thrombopoietin (TPO) was inserted N-terminally of the surface subunit HA1 from the influenza heamaglutinin glycoprotein. Verhoeyen further teaches stem cell factor (SCF) was inserted N-terminally of the surface subunit SU from the murine leukemia virus (MLV) glycoprotein. The schematic of said glycoproteins is shown below:
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As discussed supra in regards to claim 1, Verhoeyen teaches the recombinant glycoproteins displaying SCF or TPO can specifically target the lentiviral particles to hematopoietic stem cells (Figure 1). Further, Heffner teaches envelope proteins (i.e., fusogens) for pseudotyping a virus may include such viruses as Paramyxoviridae such as Hendra virus and Nipah virus [0156]. Thus, the combination of Verhoeyen and Heffner teach of paramyxoviral fusogens displaying SCF or TPO.
Thus, one is left with the question of why use Nipah virus G glycoprotein fused to TPO or SCF.
Fejoz teaches of pseudotyped retrovirus-like particles or retroviral vectors comprising both engineered envelope glycoproteins derived from a virus of the Paramyxoviridae family fused to a cell targeting domain and fused to a functional domain. Fejoz teaches these pseudotyped retrovirus-like particles or retroviral vectors are particularly useful for gene therapy, immune therapy, and/or vaccination (Abstract). As can be seen in Fig 8, Fejoz teaches of the Nipah virus G glycoprotein (NiV-G) fused to CD8-scFv. Thus, Fejoz teaches of a Nipah virus G protein linked to a targeting moiety. As can be further see in Fig 8, Fejoz also teaches of the Nipah virus F protein (NiV-F). Thus, Fejoz teaches of “wherein the re-targeted fusogen comprises: (i) Nipah virus F protein; and (ii) a Nipah virus G protein linked to the targeting moiety.
Fig 8 Fejoz
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Additionally, Fejoz teaches the targeting domain of the re-targeted fusogen may be selected from the group consisting of a DARPin, a scFv, targeting peptide and their combinations and / or said functional domain may be selected from the group consisting of a cytokine, growth factor, hormone, neurotransmitter, apoptosis ligand and their combinations [0026]. Fejos further teaches target cells may be selected from the group consisting of …, hematopoietic stem cells [0027]. Fejos teaches in a preferred embodiment, the retrovirus is a lentivirus, more preferably HIV, such as HIV-1 or HIV-2 [0055].
Thus, it would have been obvious, before the effective filing date of the claimed invention, to combine the teachings of Verhoeyen, Heffner and Fejoz. A POSITA would have been so motivated due to both Verhoeyen, Heffner and Fejoz teaching of pseudotyping lentiviral vectors. Further, Fejoz teaches the pseudotyping of the claimed invention is particularly useful for gene therapy and additionally teaches the target cells may be HSCs and the targeting domain of the re-targeted fusogen may be a cytokine, such as is taught by Verhoeyen. Verhoeyen teaches the re-targeting domain of TPO or SCF (both “early-acting-cytokines”) specifically targets the vector particles to HSCs.
The person of ordinary skill in the art would have been motivated to combine the teachings of Verhoeyen, Heffner, and Wertz with Fejoz to arrive at the claimed invention by attaching the targeting moieties taught by Verhoeyen (i.e., TPO or SCF) with the glycoprotein (i.e., NiV-G) as taught by Fejoz, for the predictable result of pseudotyping the lentiviral vectors to the HSCs, thus meeting the limitations of claim 68.
The skilled artisan would have had a reasonable expectation of success in combining said teachings because each of these teachings are directed at pseudotyping lentiviral vectors.
Thus, the claim is obvious and is properly rejected.
Claim 67 is rejected under 35 U.S.C. 103 as being unpatentable over Verhoeyen, in view of Zhang, Ziegler, Heffner, and Kingsman, and further in view of Maltzahn.
In regards to claim 67, Examiner notes the only difference between claims 67 and 68 is where the targeting moiety is linked. Claim 67 has the targeting moiety linked to Nipah virus F protein, whereas claim 68 has the targeting moiety linked to Nipah virus G protein. As discussed supra, in regards to claim 68, it is obvious to link the targeting moiety to Nipah Virus G protein. In regards to linking to the Nipah virus F protein, Maltzahn teaches of a re-targeted fusogen comprising a sequence chosen from a Nipah virus protein F [0449]. Thus, Maltzahn teaches of Nipah Virus F protein linked to a targeting moiety.
As it has been established in the rejection of claim 68 supra, that it is obvious to have a fusosome wherein the re-targeted fusogen comprises Nipah virus G protein linked to the targeting moiety, it would thus be obvious before the effective filing date of the claimed invention, to do a simple substitution of one known element for another. It would be obvious to substitute the Nipah virus protein linked to the re-targeting domain. One would have a reasonable expectation of success in substituting the Nipah virus G protein linked to the targeting domain (as taught by Fejoz) for the Nipah virus F protein linked to the targeting domain (as taught my Maltzahn) as both Fejoz and Maltzah teach of Nipah virus proteins F and G being linked to targeting domains.
Examiner additionally notes Maltzahn also teaches of a re-targeted fusogen comprising a sequence chosen from a Nipah virus protein G [0452].
Thus, the claim is obvious and is properly rejected.
RESPONSE TO APPLICANT’S REMARKS
RE: 103 Rejections
Applicant remarks state: “Applicant respectfully submits that amended claim 1 requires at least three modes of targeting to provide specificity to HSC – (i) the re-targeted paramyxoviral fusogen comprising a targeting moiety to HSC; (ii) the positive HSC-specific regulatory element; and (iii) the non-target cell-specific regulatory element (NTCSRE) that is a non-HSC-specific regulatory element.”
Examiner respectfully notes the language of claim 1 does not per se require three modes of targeting to provide specificity to HSC. Rather, the language of claim 1, as currently written, provides one mode of targeting to provide specificity to HSC and further provides two modes of regulation over the payload gene. One mode of regulation being a positive HSC-specific regulatory element, i.e., point (b)(ii), and one mode being a non-target cell-specific regulatory element (NTCSRE).
Applicant’s remarks state: “In contrast to the three targeting modes in claim 1, Verhoeyen, Zhang, and Ziegler only describe providing cell specificity via a protein at the surface of a viral particle. In particular, Verhoeyen states that “our targeting strategy for gene transfer consists of an interaction of a ligand displayed on the surface of the vector with its specific receptor,” and “as a consequence of the specific stimulation, gene transfer into the target cell is significantly enhanced”. Zhang relates to “pseudotyping lentiviral particles with Sindbis virus envelop (Env) proteins modified with an immunoglobulin Fc-binding domain”. Ziegler relates to “the production of lentiviruses enveloped with both anti-CD20 antibody and the candidate fusogenic molecule”. A person of ordinary skill in the art, reading Verhoeyen, Zhang, and Ziegler, would reasonably conclude that these publications have effectively targeted a viral particle to an HSC using the methods described therein. The skilled artisan, reading Verhoeyen, Zhang, and Ziegler, would have no reason to assume that further means of targeting the particle to an HSC would be necessary or beneficial.”
Examiner respectfully notes Verhoeyen, Zhang and Ziegler are not used to teach further means of targeting the particle to an HSC. Rather, said references are used to teach claim 1(a) (minus the newly amended requirement of the paramyxoviral fusogen). Thus, said references are used to teach ONE mode of targeting.
Applicant’s remarks state: “Similarly, Heffner discloses that an “expression control sequence may be a stem cell specific expression control sequence that directs stem cell specific expression of the polynucleotide-of-interest in… a hematopoietic stem cell.” The skilled artisan, reading Heffner, would reasonably conclude that Heffner also effectively targeted a viral particle to an HSC using the method it describes. And Heffner likewise does not provide the skilled artisan with reason to assume that further means of targeting the particle to an HSC outside that disclosed by Heffner would be necessary or beneficial.”
“Thus, the skilled artisan would view Verhoeyen, Zhang, Ziegler, and Heffner, at most, as disclosing a series of alternative means to providing specificity for targeting HSCs, when any single one appeared to be more than sufficient to achieve HSC targeting. The skilled artisan would accordingly have no motivation to combine any two of these references. Thus, the alleged motivation is a solution without a problem.”
Examiner respectfully notes Heffner is not solely relied upon to teach an additional mode of targeting but rather is used to teach a method of regulating payload gene expression in an HSC and further for teaching paramyxoviral fusogens. Please see the above rejection of claim 1 for more details.
Applicant’s remarks state: “Further, even if the skilled artisan were motivated to combine the references to reach a fusosome comprising two modes of target cell specificity, which Applicant does not concede, there would still be no motivation to further add a third mode of target cell specificity, as required by amended claim 1. Instead, at best, the skilled artisan would have viewed Kingsman as merely disclosing yet another alternative mode for target cell specificity.
Examiner respectfully notes Kingsman is not used to teach an additional mode of targeting but rather is used to teach a method of regulating payload gene expression. Please see the above rejection of claim 1 for more details.
Applicant’s remarks state: “In summary, each of the cited references relates to only one mode of target cell specificity, and there is no teaching or suggestion in any of the references that additional modes of specificity would be necessary or even desirable. The skilled artisan would accordingly have recognized no need or desire to combine the five cited references to arrive at the claimed subject matter.
Examiner respectfully reiterates, the language of claim 1 does not per se require three modes of targeting to provide specificity to HSC. Rather, the language of claim 1, as currently written, provides one mode of targeting to provide specificity to HSC and further provides two modes of regulation over the payload gene. One mode of regulation being a positive HSC-specific regulatory element, i.e., point (b)(ii), and one mode being a non-target cell-specific regulatory element (NTCSRE).
Applicant’s remarks state: “To combine the cited references in this manner, absent some factual basis for combining them, therefore amounts to impermissible hindsight reconstruction.”
In response to Applicant's argument that the Examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). In this case, the rejection of record clearly takes into account the disclosures of the above cited references, disclosed at the time the claimed invention was made, and does not include knowledge gleaned only from the Applicant's disclosure. The previously filed rejection of record points to specific disclosures in the cited prior art that describe the limitations of Applicant’s claimed method.
It is noted that the test for obviousness is what the combined teachings of references would have suggested to one of ordinary skill in the art. See In re Keller, 642 F.2d 413, 425 (CCPA 1981) (citing cases). Applicant is reminded that “[a] person of ordinary skill in the art is also a person of ordinary creativity, not an automaton.” KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385, 1397 (2007). “[I]n many cases a person of ordinary skill will be able to fit the teachings of multiple patents together like pieces of a puzzle.” Id. Office personnel may also take into account “the inferences and creative steps that a person of ordinary skill in the art would employ.” Id., 82 USPQ2d at 1396 (see MPEP § 2141.03).
Conclusion
No claims are allowable. No claims are free of the prior art.
Applicant's amendment necessitated the updated ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any extension fee 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 date of this final action.
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/KATHERINE R SMALL/Examiner, Art Unit 1633
/EVELYN Y PYLA/Primary Examiner, Art Unit 1633
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