DETAILED ACTION
Applicant’s response filed March 11, 2025 has been received and entered into the application file. Applicant’s arguments and amendments to the claims have been fully considered.
Claims 1, 2, 6, 7, 19, 24-29, 31-33, 36-42, 44, and 59-68 from the claim set filed March 11, 2025 are pending. Examiner acknowledges claims 3-5, 8-18, 20-23, 30, 34-35, 43, and 45-58, are canceled. Claims 6, 7, 19, 25-29, 37, and 39-41 are withdrawn. Thus, claims 1, 2, 24, 31-33, 36, 38, 42, 44, and 59-68 are being examined on the merits herein.
Examiner notes claims 1 and 64-66 have been amended. Claims 67 and 68 are newly added.
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 .
Priority
A claim for benefit of a prior-filed application under 35 U.S.C. 119(a)-(f) or under 35
U.S.C. 120, 121, 365(a)-(c), 386 (a) or 386(c) has been made. The effective filing date of the
present application is November 14, 2018.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 3/11/2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Objection(s)/Rejection(s) Withdrawn
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
RE: Claim 30 is rejected under 35 U.S.C. 112(b), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
Applicant cancelled claim 30 thus making the rejection of said claim moot.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
RE: Claim 64 is rejected under 35 U.S.C. 112(a) as failing to comply with the written description requirement. The claims contain subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, at the time the application was filed, had possession of the claimed invention.
Applicant amended claim 64 to remove the term “derivative thereof, or any combination thereof.” Thus, the previously filed rejection is withdrawn.
Claim Rejections - 35 USC § 102(a)(1) and 102(a)(2)
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
RE: Claims 1, 24, 30, 31, 32, 44, 59, 60, 63, and 65 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Heffner (US 20150216903 A1, published August 6, 2015; PTO 892).
Applicant amended claim 1 to now state: “a) a lipid bilayer comprising a re-targeted fusogen, wherein the re-targeted fusogen comprises a targeting moiety that binds to a target cell, and wherein the target cell is a hematopoietic stem cell (HSC).”
Heffner does not teach of a re-targeted fusogen comprising a targeting moiety that binds to a target cell, and wherein the target cell is a hematopoietic stem cell. As such, the previously filed rejections are withdrawn. Examiner notes claim 30 has been cancelled, making the rejection of said claim moot.
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 2, 36, and 38 are rejected under 35 U.S.C. 103 as being unpatentable over Heffner in view of Kingsman (WO 2008071959, published June 19, 2008; IDS filed January 19, 2022).
RE: Claims 33 and 42 are rejected under 35 U.S.C. 103 as being unpatentable over Heffner in view of Lieber (US 7094398 B1, published August 22, 2006; PTO 892).
RE: Claims 61 and 62 are rejected under 35 U.S.C. 103 as being unpatentable over Heffner in view of Zhang (US 20180312824, published November 1, 2018; PTO 892).
RE: Claims 64 and 66 are rejected under 35 U.S.C. 103 as being unpatentable over Heffner in view of Wertz (US 20030072773 A1, published April 17, 2003; PTO 892).
For the reasons discussed above, the anticipation rejection over Heffner is withdrawn, and thus the obviousness rejections that are based on the same basis are likewise withdrawn. However, Applicant amendment has necessitated new grounds of rejection as set forth below.
New Ground(s) of Rejections, Necessitated by 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.
Claims 1, 24, 31, 32, 44, 59, 60, 63, and 65 are rejected under 35 U.S.C. 103 as being unpatentable over Verhoeyen (Verhoeyen et al., Methods in Molecular Biology (2008) 434(2) p99-112; PTO 892) in view of Heffner (previously cited).
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.
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).
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].
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).
Thus, Heffner teaches of point (b).
As both Heffner and Verhoeyen teach of HIV1 fusosomes for gene transfer/gene delivery to HSCs and additionally both Heffner 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 Verhoeyen 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 due to both Heffner and Verhoeyen teaching of gene transfer/gene delivery through the use of fusosomes to HSCs.
Thus, the claim is obvious and 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, Verhoeyen and Heffner 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, Verhoeyen and Heffner 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, Verhoeyen and Heffner 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 44, Verhoeyen and Heffner 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, Verhoeyen and Heffner 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, Verhoeyen and Heffner 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, Verhoeyen and Heffner 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.
Claims 2, 36 and 38 are rejected under 35 U.S.C. 103 as being unpatentable over Verhoeyen in view of Heffner and further in view of Kingsman.
In regards to claim 2, Verhoeyen and Heffner teach the fusosome of claim 1. Neither Verhoeyen 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, one of ordinary skill in the art would have been motivated to combine the teachings of Kingsman, Verhoeyen, 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, Heffner and Kingsman render the invention obvious.
In regards to claim 36, Verhoeyen, Heffner and Kingsman teach the fusosome of claim 2. 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, Verhoeyen, Heffner and Kingsman 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.
Claims 33 and 42 are rejected under 35 U.S.C. 103 as being unpatentable over Verhoeyen, in view of Heffner and further in view of Lieber.
In regards to claim 33, Verhoeyen and Heffner teaches the fusosome of claim 32. Neither Verhoeyen nor Heffner 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.
In regards to claim 42, Verhoeyen, Heffner and Lieber teach the fusosome of claim 33. Further, Verhoeyen teaches of a lentiviral vector particle (Fig 1).
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 Heffner and further in view of Zhang.
In regards to claim 61, Verhoeyen and Heffner 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 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 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, Verhoeyen, Heffner and Zhang teach the fusosome of claim 61. Further, Zhang 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 Heffner and further in view of Wertz.
In regards to claim 64, Verhoeyen and Heffner 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. 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, Verhoeyen and Heffner teaches 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 Heffner and Wertz, and further in view of Fejoz (US 2019/0144885, published 5/16/2019, priority April 21, 2016; PTO 892)
In regards to claim 68, Verhoeyen, Heffner and Wertz 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).
Thus, one is left with the question of why use Nipah virus G glycoprotein fused to TPO or SCF, rather than influenza heamaglutinin glycoprotein or murine leukemia virus (MLV) glycoprotein.
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 and Fejoz. A POSITA would have been so motivated due to both Verhoeyen 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 Heffner, Wertz, and Fejoz and further in view of Maltzahn (US 2020/0060980 A1, published Feb 27, 2020, priority to May 8, 2017; PTO 892).
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 Remarks/Amendment
RE: Indefiniteness
Examiner notes Applicant remarks regarding the indefiniteness of “wherein the fusogen is re-targeted for delivery to the hematopoietic stem cell” has been found persuasive. As such, Examiner has addressed said limitation in the newly amended claim 1 which incorporates said claim language.
RE: Rejections under 102
Examiner withdrew said rejections, thus making Applicant remarks moot.
Conclusion
No claims are allowable.
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).
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