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/US2021/012003, filing date 01/01/2021, which claims the benefit of the prior-filed United States Provisional Patent Application No. 62/967,767, filing date 01/30/2020.
Status of Application/Claims
The preliminary amendment, filed 07/22/2022, in which claims 1-25 were modified, is acknowledged. Claims 5, 8, 16, and 23 were canceled. Claims 1-4, 6-7, 9-12, 15, 19,and 21-22 were amended. Claims 1-4, 6-7, 9-15, 17-22, and 24-25 are currently pending and are examined on the merits herein.
Information Disclosure Statements
The information disclosure statements (IDSs) submitted on 07/22/2022, 08/23/2024, 12/16/2024, and 08/13/2025 have been fully considered by the examiner.
Specification
The use of the terms Mediatech, Gibco, Manassas, Invitrogen, Millipore, R&D Systems, Panomics, Lipofectamine, Selleckchem, Promega, Glomax, Biolegend, Corning, Invivogen, Addgene, Qiagen, Xenogen, and VisualSonics, which are a trade names or a 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.
The disclosure is objected to because of the following informalities:
p.33, [0099]: The term “RnD systems” should be corrected to “R&D Systems” (with proper trademark/trade name designation).
p.33, [0100]: The term “IFN□-Luc” appears to have a font substitution issue. For further examination, this term is interpreted to mean “IFNγ-Luc.”
Appropriate correction is required.
Claim Objections
Claims 17 and 24 are objected to because of the following informalities: Claims 17 and 24 recite “…targeting the EG…” which should be corrected to “…targeting the EGFR…”. 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 10, 14, and 21 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 10 recites the following: “The composition of matter of claim 1, further comprising a polymer, wherein said polymer comprises a reverse nuclear localization signal (rNLS), rNLSd, a polycyclooctene polymer with pendant tetralysine and a rNLS oligopeptide having a sequence of VKAKKKP (SEQ ID NO: 4).” The format of claim renders it unclear if “rNLSd is a type of rNLS and is being defined as a polycyclooctene polymer with pendant tetralysine and rNLS or if the polymer comprises separate elements that are 1) rNLS, 2) rNLSd, 3) a polycyclooctene polymer with pendant tetralysine, and 4) a rNLS oligopeptide having a sequence of VKAKKKP. For further interpretation, the claim is interpreted to mean that the polymer comprises rNLSd, which IS a polycyclooctene polymer with a pendant rNLS that comprises a tetralysine (see disclosure drawings, Fig.2A).
Claims 14 and 21 recite the following: “…wherein said cytokine is selected from the group consisting of interleukin-27 (IL-27) and related cytokines including IL27p28 (IL-30) or EBI3 monomers, IL-23, IL-18, of IL17…”. The phrase “related cytokines including” renders the claim indefinite because the intended scope of the claim is unclear. It is not clear whether “related cytokines” in addition to IL-27 are limited to the cytokines listed or if other cytokines not specifically named are encompassed by the claims.
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 and 6-7 are rejected under 35 U.S.C. 103 as being unpatentable over Pflanz, et al. IL-27, a heterodimeric cytokine composed of EBI3 and p28 protein, induces proliferation of naïve CD4+T Cells. Immunity (2002), 16, p.779-790 (herein referred to as Pflanz), and further in view of Ellis, et al. Imaging cytokine targeting to the tumor/bone microenvironment in vivo. Human Gene Therapy Clinical Development (2014), 25, p.200-201 (herein referred to as Ellis).
Pflanz teaches heterodimeric cytokine IL-27 that consists of EBI3, an IL-12p40-related protein, and p28, an IL-12p35-related polypeptide; and, that IL-27 is an early product of activated antigen-presenting cells that drives rapid clonal expansion of naïve T cells, triggers IFNγ production of naïve CD4+ T cells, and mediates its biologic effects through the orphan cytokine receptor WSX-1/TCCR (title; abstract); and, teaches that EBI3 is a member of the IL-6/IL-12 subgroup of class I cytokine receptors (p.779, col.2, para.3). Pflanz teaches that p28 binds EBI3 to form the heterodimeric cytokine (p.779, col.2, para.4; Fig.2C). Pflanz teaches construction of engineered vectors harboring one-chain EBI3/p28 fusions (i.e., a plurality of genes) generated from mouse EBI3 and mouse p28; and, from human EBI3 and human p28; and, wherein the EBI3 subunit is connected to the p28 subunit by the synthetic linker GSGSGGSGGSGSGKL (p.788, col.2, para.2).
Pflanz does not teach that the vector comprises a targeting polypeptide (instant claim 1); that the targeting polypeptide comprises S7 or ‘pepL’ targeting the IL-6 receptor alpha subunit or pepB1 targeting BMPR1b (instant claim 6); that the targeting polypeptide sequence is SEQ ID NO: 1 (LSLITRL) or SEQ ID NO: 10 (AISMLYLDENEKVVL) (instant claim 7); or, that the linker is SEQ ID NO: 2 (GGGGS; instant claim 9).
Ellis teaches that a hurdle of systemic cytokine therapies is achieving therapeutic levels within the affected tissue, especially in the case of bone metastatic cancer; and that there remains a lack of therapeutics that can simultaneously and effectively treat the prostate tumor while restoring affected bone tissue (p.201, col.1, para.1). Ellis teaches an ultrasound-mediated intramuscular sonodelivery (i.e., sonication delivery) model for localization of plasmids expressing Gaussia luciferase (GLuc) and targeting peptides to intratibial prostate tumors in mice (Fig.1A-D and legend). Ellis teaches a strategy of C-terminal modification of these secreted molecules, using (GLuc), for enabling their targeting and accumulation at metastatic sites; and that the secreted molecules were modified at the C-terminus by addition of peptide sequences that could specifically bind receptor upregulated in tumor or remodeling bone but not in other tissues (p201, col.1, para.4). Ellis teaches that the receptor-binding peptide sequences used were “pepTu” LSLITRL (i.e., instant SEQ ID NO: 1) for IL6-Rα binding and “pepB” AISMLYLDENEKVVL (i.e., instant SEQ ID NO: 10) for BMPR1b binding, which are relevant for targeting therapeutic cytokines for tumor/bone retention (p.201, col.1, para.4; Fig.1A). As evidenced by the instant specification, the “pepTu” targeting polypeptide taught by Ellis has the identical amino acid structure of instant specification “S7/pepL/SEQ ID NO: 1 (i.e., LSLITRL; instant specification, p.3, [0008]). Ellis teaches that computational design was used to identify an optimal linker (Gly4Ser; i.e., GGGGS) for joining the GLuc and the targeting peptide to enhance the likelihood of native peptide folding (p.201, col.1, para.1 – col.2, para.1). Ellis teaches that the peptide-targeting GLuc retained functional activity and was able to localize and accumulate GLuc at intratibial tumors following sonodelivery at levels up to 123-fold higher than controls (p.201, col.2, para.1; Fig.1E).
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 Pflanz with the teachings of Ellis by modifying the vector containing the single-chain IL-27 harboring the EIB3 and p28 subunits (as taught by Pflanz) to also have a C-terminal tumor/bone-specific targeting peptide of LSLITRL or AISMLYLDENEKVVL for specifically targeting the IL-6 receptor alpha subunit or BMPR1b to activate immune cells at tumor/bone remodeling sites, respectively, to arrive at the instantly claimed invention . One of ordinary skill in the art would have a reasonable expectation of success because Ellis teaches sequences for targeting peptides that can be used for tumor/bone-specific targeting of secreted molecules including cytokines and Pflanz teaches that IL-27 is a cytokine and EBI3 is a member of the IL-6 family of cytokine receptors important for immune cell activation .
Claim 4 is rejected under 35 U.S.C. 103 as being unpatentable over Pflanz and Ellis, as applied to claims 1-2 above; and further in view of UniProt. Q14213 IL27B_Human (2004)[Wingdings font/0xE0] UniProt/Swiss-Prot Q14213: Variant p.Val201Ile (2019), Internet – Wayback Machine, p.1-11 (herein referred to as UP-IL27B); and, further in view of UniProt. Q8NEV9 IL27A_Human (2008)[Wingdings font/0xE0] dbSNP. rs17855750 (2019), Internet – Wayback Machine, p.1-12 (herein referred to as UP-IL27A).
The combination of Pflanz and Ellis teaches an engineered plasmid vector comprising a targeting peptide and human IL-27 cytokine subunits EIB3 and p28 joined via a linker.
The combination of Pflanz and Ellis does not teach that the IL-27 cytokine IL27B (EBI3) and IL27A (IL27p28) subunits are encoded by human instant SEQ ID NO: 6 (instant claim 4).
Instant SEQ ID NO: 6 is an amino acid sequence that encodes a human IL27B/EBI3 subunit linked to a human IL27A/IL27p28 subunit. UP-IL27B teaches a human IL-27B/EBI3 amino acid sequence wherein the primary sequence varies from instant SEQ ID NO: 6 IL-27B subunit by a single V[Wingdings font/0xE0]I amino acid substitution at position 201 (UP-IL27B, p.8; see alignment below – black arrow); and, UP-IL27A teaches a human IL-27A/IL27p28 amino acid sequence wherein the primary sequence varies from instant SEQ ID NO: 6 IL-27A subunit by a single S[Wingdings font/0xE0]A amino acid substitution at position 59 (UP-IL27A, p.6; see alignment below – white arrow). UP-IL27B also teaches that the aforementioned amino acid V201I substitution is a known single nucleotide polymorphism (SNP; i.e., rs4740) that has similar physico-chemical properties and that V and I amino acids are both medium sized and hydrophobic (UP-IL27B, p.10-11). UP-IL27A teaches that the aforementioned amino acid S59A substitution is also a known benign SNP variation (i.e., rs17855750) that exists in the human population (UP-IL27A, p.9 and 13) (see sequence alignments below):
[AltContent: textbox ([img-media_image1.png])]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 further combine the teachings of Pflanz and Ellis with the teachings of UP-IL27B and UP-IL27A by using the SNP IL-27B variant (taught by UP-IL27B) and the SNP IL-27A variant (taught by UP-IL27A) amino acid sequences to produce the engineered plasmid vector harboring a therapeutic human IL-27 EBI3/IL27p28 fusion protein (as taught by Pflanz and Ellis), to arrive at SEQ ID NO: 6 of the instantly claimed invention because this would be a simple substitution of one known IL-27 EBI3 variant for another and would be a simple substitution of one known IL-27 IL27p28 variant for another to obtain a predictable result. One of ordinary skill in the art would have a reasonable expectation of success because UP-IL27B and UP-IL27A teach the V206I and S59A SNP variants of instant SEQ ID NO: 6 exist in the human population and that the sequences are expected to provide for functional similarity to the V206 and S59 amino acids of the major alleles of the human population.
Claim 9 is rejected under 35 U.S.C. 103 as being unpatentable over Pflanz and Ellis, as applied to claim 1 above; and, further in view of Chen, et al. Fusion protein linkers: Property, design and functionality. Adv. Drug Deliv. Rev. (2013), 65:10, p.1357-1369 (herein referred to as Chen).
The combination of Pflanz and Ellis teaches an engineered plasmid vector comprising a targeting peptide and IL-27 cytokine subunits EIB3 and p28 joined via the GSGSGGSGGSGSGKL linker.
The combination of Pflanz and Ellis does not teach that the linker is GGGGS (i.e., SEQ ID NO: 2; instant claim 9).
Chen teaches fusion protein linker properties, design, and functionality, including flexible linkers, rigid linkers, and cleavable linkers (title; abstract, p.4, para.2).Chen teaches that flexible linkers are generally composed of small, non-polar or polar amino acids (p.4, para.3). Chen teaches that the most commonly used flexible linkers have sequences consisting primarily of stretches of Gly and Ser residues (“GS” linker); and, that an example of the most widely used flexible linker has the sequence of (Gly-Gly-Gly-Gly-Ser)n (i.e., instant linker SEQ ID NO: 2). Chen also teaches that besides the GS linkers, many other flexible linkers have been designed for recombinant fusion proteins, such as flexible linkers that are rich in small or polar amino acids such as Gly and
Ser, but can contain additional amino acids such as Thr and Ala to maintain flexibility, as well as polar amino acids such as Lys and Glu to improve solubility (p.4, para.4).
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 Pflanz and Ellis with the teachings of Chen by substituting the GSGSGGSGGSGSGKL linker (taught by Pflanz) with another flexible linker such as GGGGS/SEQ ID NO: 2 (as taught by Chen) to arrive at the instantly claimed invention because this would be a simple substitution of one known element (i.e., a flexible linker) for another to obtain a predictable result. One of ordinary skill in the art would have a reasonable expectation of success because Chen teaches that flexible linkers can be used to produce fusion proteins and Pflanz teaches joining EIB3 and p28 subunits with a flexible linker to produce an IL-27 fusion protein.
Claims 10, 12-14, and 17 are rejected under 35 U.S.C. 103 as being unpatentable over Pflanz and Ellis, as applied to claim 1 above; and, further in view of Parelkar, et al. Polymer-based delivery platforms: effect of oligopeptide orientation on polymer-based DNA delivery. Biomacromolecules (2014), 15:4, p.1328-1336 (herein referred to as Parelkar).
The combination of Pflanz and Ellis teaches an engineered plasmid vector comprising a targeting peptide and human or mouse IL-27 cytokine subunits EIB3 and p28 joined via a linker, wherein the targeting peptide has a sequence of LSLITRL (i.e., instant SEQ ID NO: 1) or AISMLYLDENEKVVL (i.e., instant SEQ ID NO: 10) as described in detail above.
The combination of Pflanz and Ellis does not teach that the composition further comprises a polymer rNLSd, a polycyclooctene polymer with pendant tetralysine and a rNLS oligopeptide having a sequence of VKRKKKP (instant SEQ ID NO: 2).
Parelkar teaches polymer-peptide delivery platforms for polymer-based DNA delivery (title). Parelkar teaches that synthetic cationic polymers are appealing alternatives to natural viral vectors that threaten immunogenicity and carcinogenicity stemming from insertional mutagenesis into the chromosomes of infected cells; and that synthetic polymers offer excellent structural and chemical versatility, high therapeutic capacity, and long shelf-life (p.2, para.1). Parelkar teaches that cationic polymers complex to DNA non-covalently to form nanoscale ‘polyplexes’ that can enter cells, translocate to the nucleus, and release their nucleotide cargo for transcription and therapeutic protein production. Parelkar teaches linear, graft (comb), branched, and dendritic cationic polymers (p.2, para.2). Parelkar further teaches graft copolymers with pendent oligopeptide nuclear localization signal (NLS) groups; as well as reverse NLS (rNLS). Additionally, Parelkar teaches the specific NLS oligopeptide PKKKRKV wherein the Pro is the site of attachment to the polymer; and, rNLS oligopeptide VKRKKKP wherein the Val is the site of attachment to the polymer (p.2, para.3; p.5, para.3; p.15, Fig.1). Parelkar teaches preparation of poly(cyclooctene-graft-oligopeptide) comb polymers and their use in complexation of DNA and transfection of SKOV3 (human ovarian adenocarcinoma) and SKVLB1 (multidrug resistant human ovarian adenocarcinoma cells, and intramuscular gene delivery in vivo; wherein higher transfection levels were achieved with the rNLS comb structures (p.2, para.4; p.9, para.1). Parelkar teaches synthesis of the VKRKKKP peptide using solid phase peptide synthesis (SPSS; p.4, paras.1-2 – p.5, paras.1-3). Parelkar teaches synthesis of NLS-containing homopolymers homopolymerization of macromonomers bearing the rNLS sequence using ring-opening metasynthesis polymerization (ROMP) in a mixture to produce rNLSa-e (i.e., including “rNLSd”; p.9, para.2; Table S1; Fig.S1). Parelkar shows that rNLSd provides higher transfection efficiency and cytotoxicity in SKVLB1 cancer cells (Fig.S7).
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 further combine the teachings of Pflanz and Ellis with the teachings of Parelkar by modifying the engineered IL-27/targeting peptide vector (taught by Pflanz and Ellis) by combining rNLSd polymer complex in a mixture (taught by Parelkar) to arrive at the claimed invention, in order to receive the expected benefit of higher transfection efficiency (taught by Parelkar). One of ordinary skill in the art would have a reasonable expectation of success because Parelkar teaches that the reverse orientation of the NLS in the rNLSd polymer-peptide platform affords higher transfection than the NLS peptide.
Claim 11 is rejected under 35 U.S.C. 103 as being unpatentable over Pflanz and Ellis, as applied to claim 1 above; and, further in view of Meka, et al. Peptide-directed liposomal delivery improves the therapeutic index of an immunomodulatory cytokine in controlling autoimmune arthritis. J. Control Release (2018), 286, p.279-288 (herein referred to as Meka).
The combination of Pflanz and Ellis teaches an engineered plasmid vector comprising a targeting peptide and IL-27 cytokine subunits EIB3 and p28 joined via a linker.
The combination of Pflanz and Ellis does not teach a method for treating an immune disease of a subject comprising administering the composition of claim 1 with a carrier (instant claim 11).
Meka teaches peptide-directed liposomal delivery (i.e., a carrier) of IL-27 for treatment of autoimmune arthritis (title; abstract). Meka teaches that anti-arthritic drugs are currently given systemically and, thus, are distributed widely to other organs that are not the intended therapeutic target; and, that there is a need for improved methods of drug delivery in order to target the drug to sites of inflammation (abstract).
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 Pflanz and Ellis with the teachings of Meka by modifying the method of treating autoimmune arthritis (i.e., immune disease; as taught by Meka) by administering the IL-27 EIB3 and p28 subunits-containing vector harboring a targeting polypeptide (as taught by Pflanz and Ellis) to arrive at the instantly claimed invention, in order to improve IL-27 delivery (as taught by Meka) by using a targeting polypeptide (as taught by Ellis). One of ordinary skill in the art would have a reasonable expectation of success because Meka teaches IL-27 administration for the treatment of immune disease.
Claim 15 is rejected under 35 U.S.C. 103 as being unpatentable over Pflanz, Ellis, and Parelkar, as applied to claim 12 above; and further in view of UP-IL27B; and, further in view of UP-IL27A.
The combination of Pflanz, Ellis, and Parelkar teaches a method of sonocation-mediated intramuscular ultrasound delivery of an engineered plasmid vector comprising a targeting peptide and human IL-27 cytokine subunits EIB3 and p28 joined via a linker in a mixture with the rNLSd-polycyclooctene polymer containing SEQ ID NO: 4.
The combination of Pflanz, Ellis, and Parelkar does not teach that the IL-27 cytokine IL27B (EBI3) and IL27A (IL27p28) subunits are encoded by human instant SEQ ID NO: 6 (instant claim 15).
The combination of UP-IL27B and UP-IL27A, respectively teach the IL27B/EBI3 and IL27A/IL27p28 human IL-27 subunit variants that are comprised within instant human SEQ ID NO: 6, which is described in detail above.
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 further combine the teachings of Pflanz, Ellis, and Parelkar with the teachings of UP-IL27B and UP-IL27A by using the SNP IL-27B variant (taught by UP-IL27B) and the SNP IL-27A variant (taught by UP-IL27A) amino acid sequences to produce the engineered plasmid vector harboring a therapeutic human IL-27 EBI3/IL27p28 fusion protein in a mixture with the rNLSd/polycyclooctene polymer (as taught by Pflanz, Ellis, and Parelkar), to arrive at a mixture (as taught by Parelkar) that comprises a fusion IL-27 cytokine of SEQ ID NO: 6 (as taught by UP-IL27B and UP-IL27A) of the instantly claimed invention because this would be a simple substitution of one known IL-27 EBI3 variant for another and would be a simple substitution of one known IL-27 IL27p28 variant for another to obtain a predictable result. One of ordinary skill in the art would have a reasonable expectation of success because UP-IL27B and UP-IL27A teach the V206I and S59A SNP variants of instant SEQ ID NO: 6 exist in the human population and that the sequences are expected to provide for functional similarity to the V206 and S59 amino acids of the major alleles of the human population.
Claim 18 is rejected under 35 U.S.C. 103 as being unpatentable over Pflanz, Ellis, and Parelkar, as applied to claim 12 above; and, further in view of Chen.
The combination of Pflanz, Ellis, and Parelkar teaches sonocation-mediated intramuscular ultrasound delivery of an engineered plasmid vector comprising a targeting peptide and IL-27 cytokine subunits EIB3 and p28 joined via the GSGSGGSGGSGSGKL linker and comprising a targeting peptide in a mixture with the rNLSd-polycyclooctene polymer containing SEQ ID NO: 4.
The combination of Pflanz, Ellis, and Parelkar does not teach that the linker is GGGGS (i.e., SEQ ID NO: 2; instant claim 9).
Chen teaches fusion protein linker properties, design, and functionality, including flexible linkers, rigid linkers, and cleavable linkers (title; abstract, p.4, para.2).Chen teaches that flexible linkers are generally composed of small, non-polar or polar amino acids (p.4, para.3). Chen teaches that the most commonly used flexible linkers have sequences consisting primarily of stretches of Gly and Ser residues (“GS” linker); and, that an example of the most widely used flexible linker has the sequence of (Gly-Gly-Gly-Gly-Ser)n (i.e., instant linker SEQ ID NO: 2). Chen also teaches that besides the GS linkers, many other flexible linkers have been designed for recombinant fusion proteins, such as flexible linkers that are rich in small or polar amino acids such as Gly and
Ser, but can contain additional amino acids such as Thr and Ala to maintain flexibility, as well as polar amino acids such as Lys and Glu to improve solubility (p.4, para.4).
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 Pflanz, Ellis, and Parelkar with the teachings of Chen by substituting the GSGSGGSGGSGSGKL linker (taught by Pflanz) with another flexible linker such as GGGGS/SEQ ID NO: 2 (as taught by Chen) for the composition comprising a mixture of an IL-27 fusion polypeptide/targeting polypeptide and rNLSd/polycyclooctene polymer (as taught by Pflanz, Ellis, and Parelkar) to arrive at the instantly claimed invention because this would be a simple substitution of one known element (i.e., a flexible linker) for another to obtain a predictable result. One of ordinary skill in the art would have a reasonable expectation of success because Chen teaches that flexible linkers can be used to produce fusion proteins and Pflanz teaches joining EIB3 and p28 subunits with a flexible linker to produce an IL-27 fusion protein.
Claims 19-21, and 24 are rejected under 35 U.S.C. 103 as being unpatentable over Pflanz, Ellis, and Parelkar; and, further in view of Meka.
The combination of Pflanz, Ellis, and Parelkar teaches sonocation-mediated intramuscular ultrasound delivery of an engineered plasmid vector comprising a targeting peptide of instant SEQ ID NO: 1 (LSLITRL) or instant SEQ ID NO: 10 (AISMLYLDENEKVVL) and IL-27 cytokine subunits EIB3 and p28 joined via the GSGSGGSGGSGSGKL linker and comprising a targeting peptide in a mixture with the rNLSd-polycyclooctene polymer containing SEQ ID NO: 4, as described in detail above.
The combination of Pflanz, Ellis, and Parelkar does not teach a method for treating an immune disease of a subject comprising administering the composition of claim 1 with a carrier (instant claims 19-21).
Meka teaches peptide-directed liposomal delivery (i.e., a carrier) of IL-27 for treatment of autoimmune arthritis as described above (title; abstract). Meka teaches that anti-arthritic drugs are currently given systemically and, thus, are distributed widely to other organs that are not the intended therapeutic target; and, that there is a need for improved methods of drug delivery in order to target the drug to sites of inflammation (abstract).
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 Pflanz, Ellis, and Parelkar with the teachings of Meka by modifying the method of treating autoimmune arthritis (i.e., immune disease; as taught by Meka) by administering a composition comprising a mixture of an IL-27 fusion polypeptide/targeting polypeptide and rNLSd/polycyclooctene polymer (as taught by Pflanz, Ellis, and Parelkar) to arrive at the instantly claimed invention, in order to improve IL-27 delivery (as taught by Meka) by using a targeting polypeptide (as taught by Ellis). One of ordinary skill in the art would have a reasonable expectation of success because Meka teaches IL-27 administration for the treatment of immune disease.
Claim 22 is rejected under 35 U.S.C. 103 as being unpatentable over Pflanz, Ellis, Parelkar, and Meka, as applied to claim 19 above; and further in view of UP-IL27B; and, further in view of UP-IL27A.
The combination of Pflanz, Ellis, Parelkar, and Meka teaches a method of treating immune disease comprising administering an engineered plasmid vector comprising a targeting peptide of instant SEQ ID NO: 1 (LSLITRL) or instant SEQ ID NO: 10 (AISMLYLDENEKVVL) and IL-27 cytokine subunits EIB3 and p28 joined via the GSGSGGSGGSGSGKL linker and comprising a targeting peptide in a mixture with the rNLSd-polycyclooctene polymer containing SEQ ID NO: 4, as described in detail above.
The combination of Pflanz, Ellis, Parelkar, and Meka does not teach that the therapeutic protein comprises a sequence of human instant SEQ ID NO: 6 (instant claim 22).
The combination of UP-IL27B and UP-IL27A, respectively teach the IL27B/EBI3 and IL27A/IL27p28 human IL-27 subunit variants that are comprised within instant human SEQ ID NO: 6, which is described in detail above.
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 further combine the teachings of Pflanz, Ellis, Parelkar, and Meka with the teachings of UP-IL27B and UP-IL27A by modifying the method of treating immune disease (taught by Meka) to use the SNP IL-27B variant (taught by UP-IL27B) and the SNP IL-27A variant (taught by UP-IL27A) amino acid sequences to produce the engineered plasmid vector harboring a therapeutic human IL-27 EBI3/IL27p28 fusion protein in a mixture with the rNLSd/polycyclooctene polymer (as taught by Pflanz, Ellis, and Parelkar), to arrive at a mixture (as taught by Parelkar) that comprises a fusion IL-27 cytokine of SEQ ID NO: 6 (as taught by UP-IL27B and UP-IL27A) of the instantly claimed invention because this would be a simple substitution of one known IL-27 EBI3 variant for another and would be a simple substitution of one known IL-27 IL27p28 variant for another to obtain a predictable result. One of ordinary skill in the art would have a reasonable expectation of success because UP-IL27B and UP-IL27A teach the V206I and S59A SNP variants of instant SEQ ID NO: 6 exist in the human population and that the sequences are expected to provide for functional similarity to the V206 and S59 amino acids of the major alleles of the human population.
Claim 25 is rejected under 35 U.S.C. 103 as being unpatentable over Pflanz, Ellis, Parelkar, and Meka, as applied to claim 19 above; and, further in view of Chen.
The combination of Pflanz, Ellis, Parelkar, and Meka teaches a method of treating immune disease comprising administering an engineered plasmid vector comprising a targeting peptide and IL-27 cytokine subunits EIB3 and p28 joined via the GSGSGGSGGSGSGKL linker and comprising a targeting peptide in a mixture with the rNLSd-polycyclooctene polymer containing SEQ ID NO: 4.
The combination of Pflanz, Ellis, Parelkar, and Meka does not teach that the linker is GGGGS (i.e., SEQ ID NO: 2; instant claim 25).
Chen teaches fusion protein linker properties, design, and functionality, including flexible linkers, rigid linkers, and cleavable linkers (title; abstract, p.4, para.2).Chen teaches that flexible linkers are generally composed of small, non-polar or polar amino acids (p.4, para.3). Chen teaches that the most commonly used flexible linkers have sequences consisting primarily of stretches of Gly and Ser residues (“GS” linker); and, that an example of the most widely used flexible linker has the sequence of (Gly-Gly-Gly-Gly-Ser)n (i.e., instant linker SEQ ID NO: 2). Chen also teaches that besides the GS linkers, many other flexible linkers have been designed for recombinant fusion proteins, such as flexible linkers that are rich in small or polar amino acids such as Gly and
Ser, but can contain additional amino acids such as Thr and Ala to maintain flexibility, as well as polar amino acids such as Lys and Glu to improve solubility (p.4, para.4).
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 Pflanz, Ellis, Parelkar, and Meka with the teachings of Chen by substituting the GSGSGGSGGSGSGKL linker (taught by Pflanz) with another flexible linker such as GGGGS/SEQ ID NO: 2 (as taught by Chen) for the composition comprising a mixture of an IL-27 fusion polypeptide/targeting polypeptide and rNLSd/polycyclooctene polymer (as taught by Pflanz, Ellis, and Parelkar) for the treatment of immune disease (taught by Meka) to arrive at the instantly claimed invention because this would be a simple substitution of one known element (i.e., a flexible linker) for another to obtain a predictable result. One of ordinary skill in the art would have a reasonable expectation of success because Chen teaches that flexible linkers can be used to produce fusion proteins and Pflanz teaches joining EIB3 and p28 subunits with a flexible linker to produce an IL-27 fusion protein.
Conclusion
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/JAMI MICHELLE GURLEY/Examiner, Art Unit 1647
/JOANNE HAMA/Supervisory Patent Examiner, Art Unit 1647