DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
The instant application is claiming the benefit as a 35 U.S.C. 371 national phase application from, and claims priority to, International Application No. PCT/US2022/030012, filing date 05/19/2022, which claims the benefit of the prior-filed United States Provisional Patent Application No. 63/191,031, filing date 05/20/2021.
Status of Application/Claims
The preliminary amendment, filed 11/22/2024, is acknowledged. Claims 2, 5-11, 13-15, 18, 22-26, 28, 31-34, 40, 45-52, 54-56, and 58-137 are canceled. Claims 3-4, 12, 17, 19, 21, 27, 30, 36-38, 44, and 57 are currently amended. Claims 1, 3-4, 12, 16-17, 19-21, 27, 29-30, 35, 39, 41-44, 53, and 57 are currently pending and are examined on the merits herein.
Information Disclosure Statements
The information disclosure statements (IDSs) submitted on 01/26/2024, 10/04/2024, 11/19/2024, and 04/30/2025 have been fully considered by the examiner.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the specification are not identified by sequence identifiers in accordance with 37 CFR 1.821(d).
There are 3 instances where the peptide amino acid sequence “EGSRNQDWL” is recited, but not identified by an associated SEQ ID NO. These recitations are found on p.73, [00272], line 3; and, p.77, [00300], lines 3 and 4.
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Specification
The use of the terms Sigma, Corning, Gibco, Life Technologies, Hampton, qNano, Abcam, Sigma Aldrich, Thermo Fisher Scientific, ProteinSimple, BioLegend, Cell Signaling, Research Products International, and Ethicon, which are trade names or marks used in commerce, have been noted in this application. The terms should be in all caps wherever they appear or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the terms.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Objections
Claims 4, 21, 30, 44, and 53 are objected to because of the following informalities:
Claim 4 and 53 each recite the following limitations twice each: “CD80,” “CD86,” and “CD48”.
Claim 21 recites the term “VSV-G” which should be corrected to “VSVG” for consistency.
Claim 30 recites “…wherein when the fusion protein is expressed on the surface of the multivalent particle, the oligomerization domain is outside of the multivalent particle, outside of the multivalent particle and adjacent to a signal peptide, inside of the multivalent particle, or inside of the multivalent particle and adjacent to the transmembrane domain” which should be corrected to, “…wherein when the fusion protein is expressed on the surface of the multivalent particle, the oligomerization domain is (a) outside of the multivalent particle, (b) outside of the multivalent particle and adjacent to a signal peptide, (c) inside of the multivalent particle, or (d) inside of the multivalent particle and adjacent to the transmembrane domain”.
Claim 44 recites “(b) comprises a viral-like a particle” which should be corrected to “(b) comprises a viral-like particle”.
Appropriate correction is required.
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.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 17 and 35- -are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 17 recites the limitation “the VSVG” in lines 1-2. There is insufficient antecedent basis for this limitation in the claim.
Claim 35 requires both an oligomerization domain and a cytosolic domain. However, claim 35 is dependent on claim 19 which only requires an oligomerization domain or a cytosolic domain (i.e., an alternative). Claim 35 recites the limitation "the following orders" in 3. There is insufficient antecedent basis for this limitation in the claim. Further, regarding proper antecedent basis, the term “domain” is used in claim 35 but only applies to the “oligomerization domain” and “cytosolic domain,” rather than the “signal peptide” and “mammalian immune checkpoint polypeptide”. The examiner suggests the following claim descriptions for claims 19 and 35 as example revisions; and, for further examination, the examiner interprets the claims as follows:
Claim 19: “The multivalent particle of claim 1, wherein the fusion protein further comprises an oligomerization domain and/or a cytosolic domain.”
Claim 35: “The multivalent particle of claim 19, wherein the fusion protein comprises an oligomerization domain and a cytosolic domain; wherein the fusion protein further comprises a signal peptide; and, wherein the fusion protein comprises an N-terminus to C-terminus arrangement selected from the following: (a)…; (b)…; or, (c).”
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1, 3-4, 12, 16, 39, and 41-44- are rejected under 35 U.S.C. 103 as being unpatentable over Bellier, et al.—US20200347363A1. Virus-like particles which can be used in the treatment of autoimmune disease (publication date: 11/05/2020; effective filing date: 10/26/2018; herein referred to as Bellier); as evidenced by Nooraei, et al. Virus-like particles: preparation, immunogenicity and their roles as nanovaccines and drug nanocarriers. J.Nanobiotechnol, published 02/25/2021, 19:59, p.1-27 (herein referred to as Nooraei); and, further in view of Venter, et al. Multivalent display of proteins on viral nanoparticles using molecular recognition and chemical ligation strategies. Biomacromolecues 2011, 12, p.2293-2301 (herein referred to as Venter)..
Bellier teaches virus-like particles (VLPs) comprising immunoregulatory molecules exposed on its surface for the purpose of treating autoimmune disease by modifying, regulating, or suppressing an immune response (title; abstract; [0001]). Bellier teaches that VLPs can block the activation of antigen presenting cells to modulate immune responses or induce specific immune tolerance ([0006]); and, that VLPs are used for anti-infectious or anti-tumor vaccination ([0005]). Bellier teaches that the immunoregulatory molecule can function as a regulatory and/or suppressive molecule toward antigen presenting cells and promote recruitment of regulatory T cells [0023]; and, that the immunoregulatory molecule can be an immune-checkpoint receptor comprising an extracellular domain of an immune-checkpoint inhibitor including CTLA-4, OX40, PD-1, Tim3, LAG-3, or TIGIT [0023]). Bellier teaches that the VLPs can be obtained from double-stranded DNA viruses such as herpes virus, adenovirus, parvovirus, single-stranded DNA viruses, double-stranded RNA viruses such as reoviruses, positive polarity single-stranded RNA viruses, negative polarity single-stranded RNA viruses, retroviruses; and, that the VLPs are obtained from the assembly of structural proteins of AAV, adenoviruses, VSV, herpes viruses [0047]); and, that the VLPs are unable to replicate ([0046]). Bellier teaches VLPs that are synthetic retroviral particles comprising a structural proteins, including an envelope derived from VSV that preferably comprises VSV-G glycoprotein transmembrane polypeptide that ([0049]), wherein the approach is to select an envelope that has tropism form mammalian cells, particularly human cells (0050]). Bellier teaches pharmaceutical compositions comprising the virus-like particle or plasmids capable of producing VLPs ([0030], [0032]). Bellier teaches the VLPs are formed by self-assembly of at least one structural protein of viral origin such as the capsid protein or envelope protein; and, that the VLPs mimic the structure and antigenic properties of the native virion but are unable to replicate ([0046]) because, as evidenced by Nooraei, VLP do not contain genetic material (abstract). Bellier teaches that their VLP invention preferably comprises envelope derived from VSV; and that some viruses are surrounded by a lipid bilayer envelope containing glycoproteins that helps modulate tropism and immunogenicity ((0049]). Bellier teaches a VLP that is a synthetic retroviral particle that comprises an envelope protein synthesized from an “env gene” wherein the envelopes used can additionally be from the following viruses: 4070A, RD114, 10A1, VSV, LCMV, HIV, rabies virus, or GALV (0050]).
[AltContent: textbox (Bellier CTLA-4 extracellular domain SEQ ID NO: 3 vs instant CTLA-4 amino acid SEQ ID NO: 3
[img-media_image1.png])]Bellier teaches that the VLPs can include modified viral proteins wherein the viral proteins can be covalently or non-covalently bound to the immunoregulatory molecule by genetic modification or by chemical binding ([0052]). Bellier teaches that, in order to be exposed to the surface of the VLP, the immunoregulatory molecule is preferably fused to the transmembrane domain or anchoring domain protein that is preferably from a glycoprotein coat protein ([0067]), and specifically VSV-G [0068]). Bellier specifically teaches VLPs that comprise the immunoregulatory molecule CTLA-4 on the surface of the particle ([0007], [0022], Figs.1-2), and teaches SEQ ID NO: 3 which comprises instant CTLA-4 amino acid SEQ ID NO: 3 at 100% identity (see alignment 1 below; [0094]).
While Bellier teaches VLP genetic modification to mimic the structure and antigenic properties of the native virion, Bellier does not teach the valency for VLP envelope proteins. That is, Bellier does not teach that VLP fusion protein comprises a valency of at least about 10 copies on the surface of the VLP (instant claim 1); that the valency is at least about 50 copies (instant claim 39); that the valency is at least about 100 copies (instant claim 41); that the valency is at least about 150 copies (instant claim 42); or, that the valency is at least about 200 copies (instant claim 43).
Venter discloses a multivalent display of heterologous proteins on viral nanoparticles known to form the basis for numerous applications in nantotechnology, including vaccine development, targeted therapeutic delivery, and tissue-specific bioimaging (abstract). Venter teaches strategies for attachment of a variety of proteins on viral particles using covalent and noncovalent principles, including using domain 4 of anthrax protective antigen and its receptor to display multiple copies of a target protein on virus-like particles (VLPs; abstract). Venter highlights the use of viruses and VLPs in nanotechnology and nanomedicine due to their ability to serve as effective scaffolds for multivalent presentation of a wide variety of functional ligands; and, that whole proteins or protein domains can be presented on the exterior surface of the particle (p.2293, col.1, para.1). Venter further teaches that VLPs have a highly ordered array of protein display due to the underlying icosahedral or helical symmetry of the particle; and, that such ordered arrays are known to induce potent antibody responses because they effectively and reliably cross-link B cell receptors (p.2293, col.1, para.2). Venter teaches that genetic insertion of a protein antigen of interest directly into the structural proteins of the particle can be used to achieve this goal (p.2293, col.2, para.1). Regarding copy numbers for the protein of interest, Venter teaches examples of particles engineered to multivalently display 180 copies of target protein on chimeric MVP particles that permit display of fusion proteins (p.2296, col.2, para.6; p.2294, para.3; i.e., MVPs with the protein of interest expressed at a valency of at least about 10 copies/50 copies/100 copies/150 copies/200 copies on a surface of the MVP).
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Bellier with the teachings of Venter by modifying a virus-derived vesicle comprising a VSV-G transmembrane domain for transferring a protein that is an immune checkpoint inhibitor protein to human and/or non-human mammalian target cells for anti-infectious or anti-tumor treatment (as taught by Bellier) by modifying the vesicle/particle to express the target protein of interest as a fusion protein that is displayed in a highly ordered array of about 180 copies to elicit immune responses (taught by Venter) to arrive at the instantly claimed invention, because the combination of prior art elements according to known methods results in a predictable result of producing a VLP that displays a VSV-G linked immune checkpoint inhibitor fusion protein in an ordered array with at least about 10 copies, at least about 50 copies, at least about 100 copies, at least about 150 copies, or at least about 200 copies. One of ordinary skill in the art would have a reasonable expectation of success because Bellier teaches the use of virus-derived particles comprising immune checkpoint inhibitors to target immune checkpoint proteins for tumor treatment and Venter teaches strategies for target protein display on virus-derived particles in order to effectively display target proteins on the particle and elicit effective immune responses.
Claims 17 is rejected under 35 U.S.C. 103 as being unpatentable over Bellier (as evidenced by Nooraei) and Venter, as applied to claims 1 and 16 above; and further in view of Kim, et al.—WO2019066535A1. Novel recombinant plasma membrane-based vesicle, for treating cancer (publication date: 04/04/2019; herein referred to as Kim).
The combination of Bellier and Venter teaches the VLP comprising a fusion protein comprising the VSV-G transmembrane glycoprotein and an immune checkpoint inhibitor that is CTLA-4 encoded by SEQ ID NO: 3 (see above), wherein the valency of the fusion protein is expressed at a valency of at least about 10 copies on a surface of the multivalent particle, as applied to claims 1 and 16 above.
The combination of Bellier and Venter does not teach that the VSV-G is full length VSV-G (instant claim 17).
Kim teaches a recombinant plasma membrane-based vesicle (i.e., exosome, extracellular vesicle, microvesicle; p.2, paras.6-7; p.4, paras. 3, 5-9) comprising a VSV-G transmembrane protein/polypeptide (abstract) for the treatment of cancer (title) in human or non-human mammals (p.8, para.9); and, wherein the vesicle is multivalent (see Figure.1). Kim teaches that VSV-G is a transmembrane protein/polypeptide that has been proposed to transfer various proteins to target cells (p.3, para.2). Kim’s invention includes pharmaceutical compositions comprising, as an active ingredient, a recombinant plasma membrane-based vesicle into which a virus-derived membrane fusion protein is introduced into a membrane (p.6, para.8); and, wherein the virus-derived membrane fusion protein can be selected from the group consisting of VSV-G protein, a Gibraltar virus, influenza virus hemagglutinin, a respiratory syncytial virus F protein, a human immunodeficiency virus gp120 or gp41, flavivirus E protein, alphavirus E1 protein, baculovirus gp64, hepatitis C virus gp31 or gp70, measles virus H protein or F protein, Ebola virus gp1 or gp2; and, wherein the VSV-G protein can be wild type full-length or a pH-sensitive mutant (p.6, para.9). Further, Kim teaches that the composition may further comprise anti-cancer compounds including immunogenic cell death inducers or immune checkpoint inhibitors; and, that these anticancer compounds can be simply administered in combination with the recombinant plasmid membrane-based endoplasmic reticulum of the present invention based on the membrane surface of the recombinant plasmid-based vesicle. When the antibody, the functional fragment of the antibody or the single chain-based antibody analog is presented on the membrane surface of the recombinant plasma membrane-based vesicle, the immune checkpoint inhibitor according to an embodiment of the present invention can be used as a recombinant plasmid-based vesicle produced by transfecting a host cell with a gene encoding the viral envelope using the recombinant technology in the same manner as the viral membrane fusion protein of the present invention and expressing it on the membrane surface of the host cell (i.e., expression of an immune checkpoint inhibitor/viral membrane fusion protein; p.6, para.10—p.7, para.2).
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Bellier and Venter with the teachings of Kim by modifying VLP comprising a fusion protein comprising the VSV-G transmembrane glycoprotein and an immune checkpoint inhibitor that is CTLA-4 wherein the valency of the fusion protein is expressed at a valency of at least about 10 copies on a surface of the multivalent particle (as taught by the combination of Bellier and Venter) to use a full-length VSV-G for producing the virus-derived vesicle nanoparticle comprising a VSV-G transmembrane domain for transferring a protein that is an immune checkpoint inhibitor protein to human and/or non-human mammalian target cells for cancer treatment (as taught by Kim) to arrive at the instantly claimed invention, because the combination of prior art elements according to known methods results in a predictable result of producing a VLP that displays a full-length VSV-G linked immune checkpoint inhibitor fusion protein in an ordered array with at least about 10 copies, at least about 50 copies, at least about 100 copies, at least about 150 copies, or at least about 200 copies. One of ordinary skill in the art would have a reasonable expectation of success because Kim teaches the use of virus-derived particles for cancer treatment and Venter teaches strategies for target protein display on virus-derived particles in order to effectively display target proteins on the particle and elicit effective immune responses.
Claims 19 and 27 are rejected under 35 U.S.C. 103 as being unpatentable over Bellier, Venter, and Kim as applied to claims 1, 16, and 17 above; further in view of Arber and Shapira—US20190153409A1. Compositions comprising particles and methods for treating cancer (publication date 05/23/2019; effective filing date: 11/17/2017; herein referred to as Arber); and, as evidenced by Ci, et al. Vesicular stomatitis virus G protein transmembrane region is crucial for the hemi-fusion to full fusion transition. Sci. Reports 2018, 8:10669, p.1-11 (herein referred to as Ci) and Meyer, et al. Pseudotyping exosomes for enhanced protein delivery in mammalian cells. International J. of Nanomedicine 2017, 12, p.3153-3170 (herein referred to as Meyer).
The combination of Bellier/Venter/Kim teaches the VLP comprising a fusion protein comprising a full-length VSV-G transmembrane glycoprotein and an immune checkpoint inhibitor that is CTLA-4 encoded by SEQ ID NO: 3 (see above), wherein the valency of the fusion protein is expressed at a valency of at least about 10 copies on a surface of the multivalent particle, as applied to claims 1 and 16-17 above.
The combination of Bellier/Venter/Kim does not explicitly teach that the fusion protein comprises an oligomerization domain and/or a cytosolic domain (instant claim 19); or, teach that the transmembrane polypeptide comprises an amino acid sequence with at least 90% identity to instant SEQ ID NO: 63 (instant claim 27).
Arber teaches cell-free particles for treating cancer (title; abstract); wherein the particles comprise retrovirus envelope glycoprotein VSV-G ([0031], [0033]); and, wherein the VSV-G is encoded by SEQ ID NO: 58, which aligns 100% with instant SEQ ID NO: 63 (see alignment below). As evidenced by Meyer, the full-length VSV-G comprises, from N- to C-terminus, a large N-terminal ectodomain, a stem domain, a transmembrane domain, and a cytoplasmic/cytosolic domain (p.3153, Fig.1A); and, as evidenced by Ci, the transmembrane domain is encoded by the boxed sequence below (Fig.2A).
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Bellier/ Venter/ with the teachings of Arber by modifying the virus-derived vesicle comprising a full-length VSV-G transmembrane protein/polypeptide (as taught by Bellier/Venter/Kim) by using wild-type full-length VSV-G amino acid sequence SEQ ID NO: 58 (taught by Arber), to arrive at the instantly claimed invention, because the combination of prior art elements according to known methods results in a predictable result of producing a VLP that displays a fusion protein comprising full-length VSV-G molecule that comprises a transmembrane domain (as evidenced by Ci; boxed sequence) and a cytosolic/ cytoplasmic domain (evidenced by Meyers); wherein the fusion protein also comprises an immune checkpoint inhibitor protein in an ordered array with at least about 10 copies. One of ordinary skill in the art would have a reasonable expectation of success because Bellier, Kim, and Arber all teach the use of virus-derived particles comprising VSV-G; Kim teaches that full-length VSV-G can be used; Arber teaches the full-length VSV-G amino acid sequence; Bellier and Kim teach fusion proteins of VSV-G and immune checkpoint inhibitors to target immune checkpoint proteins for tumor treatment; and, Venter teaches strategies for target protein display on virus-derived particles in order to effectively display target proteins on the particle and elicit effective immune responses.
[AltContent: textbox (Arbor SEQ ID NO: 58 vs. instant SEQ ID NO: 63
[img-media_image2.png])]
Claims 19-21, 29-30, 35, 53, and 57 are rejected under 35 U.S.C. 103 as being unpatentable over Bellier, Venter, Kim, and Arber as applied to claims 1, 16-17, and 19 above; as evidenced by Ci and Meyer; and, further in view of Roche, et al. Crystal structure of the low-pH form of the vesicular stomatitis virus glycoprotein G. Science 2006, 313, p.187-192 (herein referred to as Roche).
The combination of teachings by Bellier/Venter/Kim/Arber teaches the VLP comprising a fusion protein comprising a full-length VSV-G transmembrane glycoprotein encoded by SEQ ID NO: 63 and an immune checkpoint inhibitor that is CTLA-4 encoded by SEQ ID NO: 3 (see above), wherein the valency of the fusion protein is expressed at a valency of at least about 10 copies on a surface of the multivalent particle, as applied to claims 1, 16-17, and 19 above.
The combination of Bellier/Venter/Kim/Arbor does not teach an oligomerization domain (OD; instant claim 19); that the OD comprises a trimerization domain (instant claim 20); that the OD comprises a D4 post-fusion trimerization domain of VSV-G (instant claim 21); that the OD comprises an amino acid sequence that has at least 95% sequence identity to one of SEQ ID NOs: 65-78 (instant claim 29); that the oligomerization domain is outside of the multivalent particle (instant claim 30); or, that domains of the fusion protein are arranged in the following order, from N- to C-terminus: the signal peptide, the mammalian immune checkpoint polypeptide, the oligomerization domain, the transmembrane polypeptide, and the cytosolic domain (instant claim 35).
Roche teaches the crystal structure and polypeptide domain arrangements for VSV-G (abstract; Fig.1). Roche teaches that the transmembrane VSV-G protein forms trimers that form the spikes that protrude from the viral surface; and that most of the protein constitutes the N-terminal ectodomain (p.187). Roche teaches the overall VSV-G linear domain structure, from N- to C-terminus, as well as the three-dimensional trimeric inverted cone structure (Fig.1), which includes trimerization domain IV (i.e., the D4 domain; i.e., an oligomerization domain; p.188, col.1, para.1; Fig.1), transmembrane domain, and cytosolic domain (Fig.1D). Thus, the full-length VSV-G instant SEQ ID NO: 63 taught by Arber comprises instant SEQ ID NO: 65 which encodes for the oligomerization domain (see underlined sequence in alignment above). As the oligomerization domain is arranged N-terminally to the transmembrane domain (see Roche, Fig.1D), the inherent orientation of the oligomerization domain is “outside of the multivalent particle” as evidenced by Meyer’s “ectodomain” (see Meyer’s, Fig.1A).
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Bellier/Venter/Kim/Arber with the teachings of Roche by producing a MVP expressing a fusion protein of a surface-exposed immune checkpoint inhibitor and a full-length VSV-G domain (taught by Bellier/Venter/Kim) wherein the oligomerization domain of VSV-G is a trimerization D4 domain (taught by Roche) that is N-terminal to the transmembrane domain (taught by the combination of Roche and Meyer) by using the amino acid sequence of Arber to produce a multivalent particle comprising a fusion protein wherein the oligomerization domain is located outside of the VLP particle. One of ordinary skill would have a reasonable expectation of success because the combination of prior art teachings teaches that the domain structure is well characterized for VSV-G (as per Meyer and Roche), and the amino acid sequences for the domains are known (as per Arber and Roche).
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Jami M Gurley whose telephone number is (571)272-0117. The examiner can normally be reached Monday - Friday, 8am - 4pm.
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/JAMI MICHELLE GURLEY/Examiner, Art Unit 1647
/JOANNE HAMA/Supervisory Patent Examiner, Art Unit 1647
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