DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim(s) 1-5, 10-12, 16-23, 25, 27-28, and 34 are pending.
Preliminary Amendments
Applicant’s preliminary amendment filed on 04/12/2024 is acknowledged. The claims were amended to (a) cancel 6-9, 13-15, 24, 26, 29-33, and 35-49, and (2) amend 3-5, 10, 18, 21-23, 25, and 27-28.
Applicant’s preliminary amendment filed on 06/30/2026 is acknowledged. Claim(s) 2-4 and 20-22 were amended.
Election/Restrictions
Applicant’s election without traverse of Group I in the reply filed on 06/30/2026 is acknowledged.
Claim(s) 27-28 and 34 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention of Group II, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 06/30/2026.
Applicant’s election without traverse of species of nucleic acid vector/circular DNA vector in the reply filed on 06/30/2026 is acknowledged. Applicant elected FLT3L, IL-12, and XCL1.
Claim(s) 1-5, 10-12, 16-23, and 25 are under consideration.
Priority
Acknowledgement is made that this application is a 371 of PCT/US2022/017575 filed 02/23/2022 and claims priority based on provisional application(s) filed as 63/152,575 and 63/152,540 on 02/23/2021.
All claims are given the priority date of 02/23/2021.
Information Disclosure Statement
Receipt of the information disclosure statement(s) on 08/22/2023 and 03/31/2025 are acknowledged. The signed and initialed PTO-1449 form(s) has/have been mailed with this action.
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 #1: This application contains sequence disclosures in accordance with the definitions for nucleotide and/or amino acid sequences set forth in 37 CFR 1.821(a)(1) and (a)(2). However, this application fails to comply with the requirements of 37 CFR 1.821 - 1.825.
Any SEQ ID NO: that is annotated with an “A”, e.g., SEQ ID NO: 1A, 9A, 11A, etc., is noncompliant because the corresponding sequence is not in the sequence listing. The following locations in the specification are not an exhaustive list of where “SEQ ID NO: XA”, X being any number corresponding to a sequence, is located: Pages 13-18, 30-32, 41, 44-45, and 82-98.
Required response – Applicant must provide:
A "Sequence Listing" part of the disclosure, as described above in item 1); as well as
An amendment specifically directing entry of the "Sequence Listing" part of the disclosure into the application in accordance with 1.825(b)(2);
A statement that the "Sequence Listing" includes no new matter in accordance with 1.825(b)(5); and
A statement that indicates support for the amendment in the application, as filed, as required by 37 CFR 1.825(b)(4).
If the "Sequence Listing" part of the disclosure is submitted according to item 1) a) or b) above, Applicant must also provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required incorporation-by-reference paragraph, 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;
If the "Sequence Listing" part of the disclosure is submitted according to item 1) b), c), or d) above, Applicant must also provide:
A replacement CRF in accordance with 1.825(b)(6); and
Statement according to item 2) a) or b) above.
Specification
Trademarks and/or Tradenames
The use of the following term(s), which is/are a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
QUANTI-Blue (p.8, line 27; p.9, line 31; p.103, lines 31 & 36; p.106, line 37);
Oligofectamine (p.58, lines 14 & 25);
Lipofectamine (p.103, line 22; p.106, line 27);
New England Biolabs (p. 102, lines 3 & 8);
Qiagen (p. 102, line 34);
P3000 (p. 103, line 22; p.106, line 27);
Triton-X (p.102, lines 32 & 34).
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.
Minor Informalities
The disclosure is objected to because of the following informalities: Any SEQ ID NO: that is annotated with an “A”, e.g., SEQ ID NO: 1A, 9A, 11A, etc., is not in the sequence listing. The following locations in the specification are not an exhaustive list of where “SEQ ID NO: XA”, X being any number corresponding to a sequence, is located: Pages 13-18, 30-32, 41, 44-45, and 82-98.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b) - Indefiniteness
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.
Claim 25 is 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 25 recites the limitation(s) ". . . the dendritic cell growth factor or activator-encoding gene, the lymphocyte signaling protein-encoding gene, and the dendritic cell chemoattractant gene" in lines 2-3. There is insufficient antecedent basis for this limitation in the claim. Claim 16 recites “. . . (ii) one or more heterologous protein encoding sequences. . .”. It would be remedial to amend claim 25 to depend from claim 19, where there is antecedent basis for the claimed items.
Claim Rejections - 35 USC § 102
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)(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.
Claim(s) 1-4 are rejected under 35 U.S.C. 102(2) as being anticipated by Xing et al (US 2023/0138756; published May 4th, 2023; filing date of May 27th, 2020).
Regarding claim(s) 1-4, Xing et al discloses, “. . . (a) a first nucleic acid sequence encoding a cell surface molecule that specifically recognizes a ligand or the cell surface molecule that specifically recognizes a ligand encoded thereby; (b) a second nucleic acid sequence encoding interleukin or interleukin encoded thereby; and (c) a third nucleic acid sequence encoding XCL1, XCL2, and/or Flt3L or XCL1, XCL2, and/or Flt3L protein encoded thereby. . . Preferably, the interleukin is IL-2, IL-7, IL-12, IL-15, IL-21, IL-17, IL-18, IL-23, or a subunit thereof, . . .”, (para [0026]).
Xing et al teaches, “In an embodiment, the above components (a), (b), and (c) can be introduced in sequence into the immune cell in any order. In another embodiment, the above components (a), (b), and (c) can be simultaneously introduced into the immune cell, e.g., cloning (a), (b), and (c) in one or more vectors.”, (para [0027]).
Xing et al teaches, “The advantages of the engineered immune cell of the present disclosure lie in that the co-expressed interleukin and Flt3L, XCL2, and/or XCL1 can effectively promote the differentiation or recruitment of DC cells at the tumor site, increase the number of DC cells, and increase the proliferation and survival time of engineered immune cell, thus, on one hand, reducing the inhibitory effect of the tumor microenvironment on the engineered immune cell, and improving the tumor killing ability of the engineered immune cell, and on the other hand, the increased DC cells can activate the adoptive immune recognition of the body's own T cells, which forms synergistic effect with the engineered immune cell, and eventually enhances the inhibition for tumor.”, (para [0032]).
Accordingly claim(s) 1-4 are anticipated by Xing et al.
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.
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.
Claim(s) 1-5 and 10-11 are rejected under 35 U.S.C. 103 as being unpatentable over Lu et al (US 2020/0171093 A1; Published June 4th, 2020; filing date of October 17th, 2018).
Regarding claim(s) 1-4 and 10, Lu et al teaches, “Provided for herein is an engineered cell comprising: a) a promoter; and b) an exogenous polynucleotide sequence comprising an expression cassette described in a formula, oriented from 5′ to 3′, comprising
S1-E1-L-S2-E2
wherein S1 comprises a polynucleotide sequence encoding a first signal peptide, E1 comprises a polynucleotide sequence encoding a first effector molecule, L comprises a linker polynucleotide sequence, S2 comprises a polynucleotide sequence encoding a second signal peptide, E2 comprises a polynucleotide sequence encoding a second effector molecule, and wherein the promoter is operably linked to the expression cassette, the first signal peptide is operably linked to the first effector molecule, and the second signal peptide is operably linked to the second effector molecule.”, ([0010]).
More specifically, Lu et al teaches, “In some aspects, the first effector molecule comprises interleukin 12 (IL12), for example, p35 and p40 as a dimer that is generally referred to in the art as IL-12p70.”, ([0027]).
“In some aspects, the second effector molecule comprises Flt3L.”, ([0030]).
“In some aspects, the expression cassette further comprises an E3 comprising a polynucleotide sequence encoding a third effector molecule. . . In some aspects, the third effector molecule comprises XCL1.”, ([0029]).
Regarding claim 5, Lu et al teaches, “In some aspects, the linker polynucleotide sequence encodes a second promoter, wherein the promoter is operably linked to the expression cassette such that a first polynucleotide comprising the formula S1-E1 is capable of being transcribed, wherein the second promoter is operably linked to the expression cassette such that a second polynucleotide comprising the formula S2-E2 is capable of being transcribed, and wherein the first and the second polynucleotide are separate polynucleotides. In some aspects, the promoter and the second promoter are identical. In some aspects, the promoter and the second promoter are different.”, ([0013]).
Moreover, “In general, a multicistronic system can use any number or combination of linkers, to express any number of genes or portions thereof (e.g., an exogenous sequence can encode a first, a second, and a third effector molecule, each separated by linkers such that separate polypeptides encoded by the first, second, and third effector molecules are produced). Exogenous sequences can use multiple promoters to express genes from multiple ORFs, i.e., more than one separate mRNA transcript can be produced from the exogenous sequence. For example, a first promoter can be operably linked to a polynucleotide sequence encoding a first effector molecule, and a second promoter can be operably linked to a polynucleotide sequence encoding a second effector molecule.”, ([0292] to [0293]).
Regarding claim 11, Lu et al teaches in figure 31, a circular DNA vector that the polynucleotides are cloned into.
Lu et al does not teach all three genes in one nucleic acid vector.
However, Lu et al teaches an IL12+Flt3L, IL12+XCL1, and a combination of IL12 + IL21 + Flt3L (see Figure 33).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Lu et al, i.e., a polynucleotide encoding IL12 and Flt3L, with the teachings of Lu et al, i.e., wherein the cassette further comprises XCL1 as a third effector molecule, to yield the predictable results of a nucleic acid vector with a dendritic cell chemoattractant (e.g., XCL1), a dendritic cell growth factor (e.g., Flt3L), and a lymphocyte-signaling protein encoding polynucleotide (e.g., IL-12). One would be motivated to do so because figure(s) 32 and 33 of Lu et al teaches different effector molecules alone or in combination for their efficacy of reducing tumor burden. XCL1 (figure 32) and Flt3L (figure 33) alone have a high expression of BLI, whereas when there are both combined with IL-12, their fold-change in expression is significantly reduced. One of skill in the art could look to the disclosure of Lu et al, identify a finite number of combinations such as (1) the first effector molecule comprises interleukin 12 (IL12); (2) the second effector molecule comprises Flt3L; and (3) the third effector molecule comprises XCL1, all taught by Lu et al, and arrive at the claimed nucleic acid vector with a high likelihood of success.
Further, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to substitute the nucleic acid vector as taught by the combination of the teachings of Lu et al, i.e., IL-12 – Flt3L – XCL1 nucleic acid vector, with the teachings of Lu et al, i.e., wherein each effector molecule is expressed by its own promoter, to yield the predictable results each effector molecule having its own promoter. Vectors wherein genes are regulated by one promoter versus vectors where genes are regulated by their own promoters have been known in the art.
One would be motivated to do the substitution because Lu et al teaches that the nucleic acid comprising IL-12, Flt3L, and XCL1 can be made up of individual polynucleotides containing their own promoter operably linked in the expression vector.
Accordingly, claim(s) 1-5 and 10-11 are unpatentable of Lu et al.
Claim 12 is rejected under 35 U.S.C. 103 as being unpatentable over Lu et al (supra) as applied to claim(s) 1-5 and 10-11 above, and in view of Schnepp et al (WO 2021/055760 A1; published March 25th, 2021; filing date of September 18th, 2019).
Lu et al teaches, “In some aspects, the exogenous polynucleotide sequence is encoded by a nucleic acid selected from the group consisting of: a DNA, a cDNA, an RNA, an mRNA, and a naked plasmid.”, ([0102]; see Figure 31).
Lu et al does not teach wherein the circular DNA vector lacks a bacterial origin of replication, a drug resistance gene, and a recombination sites.
Schnepp et al teaches, “. . . For example, traditional bacterial plasmid DNA vectors represent a versatile tool in gene delivery but can present limitations owing to their bacterial origin. Plasmid DNA vectors include bacterial genes, such as antibiotic resistance genes and origins of replication. Additionally, plasmid DNA vectors include bacterial signatures, such as CpG motifs. In addition, the use of bacterial expression systems for producing plasmid DNA vectors involves the risk of introducing contaminating impurities from the bacterial host, such as endotoxins or bacterial genomic DNA and RNA, which can lead to loss of gene expression in vivo, e.g., by transcriptional silencing.”, (p.1, lines 15-21)
Schnepp et al teaches, “In one aspect, the invention provides an isolated circular DNA vector including one or more heterologous genes encoding a therapeutic replacement protein, wherein the DNA vector lacks: (a) an origin of replication (e.g., a bacterial original of replication) and/or a drug resistance gene; and (b) a recombination site. For example, in some embodiments, the DNA vector lacks an origin of replication, a drug resistance gene, and a recombination site. The therapeutic replacement protein may be, e.g., an enzyme, a growth factor, a hormone, an interleukin, an interferon, a cytokine, an anti-apoptosis factor, an anti-diabetic factor, a coagulation factor, an anti-tumor factor, a liver-secreted protein, or a neuroprotective factor.”, (p. 2, lines 1-8).
Moreover, Schnepp et al teaches, “In another aspect, the invention provides an isolated circular DNA vector including one or more heterologous genes encoding an enzyme, a growth factor, a hormone, an interleukin, an interferon, a cytokine, an anti-apoptosis factor, an anti-diabetic factor, a coagulation factor, an anti-tumor factor, a liver-secreted protein, or a neuroprotective factor, wherein the DNA vector lacks: (a) an origin of replication (e.g., a bacterial original of replication) and/or a drug resistance gene; and (b) a recombination site.”, (p.2, lines 26-31). Further, “In some embodiments, the disorder is a cancer and the heterologous gene is CD40, CD40L, CD46, XCL1, MDA-7, IL-12, IL-24, or OPCML (opioid binding protein/cell adhesion molecule).”, (p.3, lines 15-17).
Therefore, it would have been obvious to one of skill in the art before the effective filing date of the claimed invention to modify the circular DNA vector taught by Lu et al in view of the teachings of Lu et al, i.e., a circular DNA vector with IL-2, Flt3L, and XCL1, with the teachings of Schnepp et al, i.e., a circular DNA vector including one or more heterologous genes wherein the DNA vector lacks: (a) an origin of replication (e.g., a bacterial original of replication) and/or a drug resistance gene; and (b) a recombination site, to yield the predictable results of a circular DNA vector comprising a dendritic cell chemo attractant, a dendritic cell growth factor, and a lymphocyte signaling protein encoding polynucleotide(s) lacking a bacterial origin of replication, a drug resistance gene, and a recombination site. One of skill in the art would be motivated to do so because Schnepp et al teaches that conventional plasmid DNA vectors risk introducing contaminating impurities from a bacterial host, e.g., endotoxins or bacterial genomic DNA or RNA, and that this can lead to loss of gene expression in vivo. Thus, one of skill could have looked to the teachings of Schnepp et al to modify the combined teachings of Lu et al in view of Lu et al, and arrived at the circular vector DNA lacking a bacterial origin of replication, a drug resistance gene, and a recombination site, with a high likelihood of success.
Accordingly, claim 12 is unpatentable over Lu et al in view of Schnepp et al.
Claim(s) 16-20 and 22-23 are rejected under 35 U.S.C. 103 as being unpatentable over Chikkanna-Gowda et al (Regression of mouse tumours and inhibition of metastases following administration of a Semliki Forest virus vector with enhanced expression of IL-12, Gene Therapy, vol 12, pages 1253-1263, published June 2nd, 2005) as evidence by Smerdou (Two-Helper RNA System for Production of Recombinant Semliki Forest Virus Particles, Journal of Virology, vol 73, issue 2, pages 1092-1098; published February 1st, 1999) in view of Schnepp et al (supra).
Chikkanna-Gowda et al teaches, “The Semliki Forest virus (SFV) vector is an RNA-based suicide expression vector that has been used experimentally for tumour therapy. Recently, a new enhanced vector pSFV10-E has been developed that expresses foreign genes at levels up to 10 times higher than the original vector. Interleukin-12 (IL-12), an immunomodulatory cytokine, plays a key role in the induction of T-helper1 responses. The two IL-12 gene subunits were cloned from mouse splenocytes and inserted into the pSFV10-E and pSFV10(nonenhanced) vectors. Both constructs expressed and secreted biologically active murine IL-12.”, (abstract).
Regarding claim(s) 16, 18, 19, and 22, Figure 1 of Chikkanna-Gowda et al teaches a circular vector, 5’ to 3’ (a) a promoter, i.e., SP6, (B) self-replicating RNA molecule encoding sequence comprising: (i) a replicase encoding sequences that transcribes RNA by self-replicating, i.e., NSP1-4, and (ii) a heterologous protein sequence, i.e., IL-12 (see below).
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While Chikkanna-Gowda et al does not explicitly recite a polyA sequence in the circular DNA vector, this is evidenced by Smerdou et al. Chikanna-Gowada cites the use of the constructs from Smerdou et al, which discloses a polyA tail in the vector in Figure 1.
Regarding claim 23, either of Chikkanna-Gowda et al’s circular DNA vectors in figure 1 are between 12571 and 12849 base pairs.
Chikkanna-Gowda et al does not explicitly teach wherein the circular DNA vector lacks a bacterial origin of replication and/or drug resistance.
Schnepp et al teaches, , “. . . For example, traditional bacterial plasmid DNA vectors represent a versatile tool in gene delivery but can present limitations owing to their bacterial origin. Plasmid DNA vectors include bacterial genes, such as antibiotic resistance genes and origins of replication. Additionally, plasmid DNA vectors include bacterial signatures, such as CpG motifs. In addition, the use of bacterial expression systems for producing plasmid DNA vectors involves the risk of introducing contaminating impurities from the bacterial host, such as endotoxins or bacterial genomic DNA and RNA, which can lead to loss of gene expression in vivo, e.g., by transcriptional silencing.”, (p.1, lines 15-21)
Regarding claim 16 and 17, Schnepp et al teaches, “In one aspect, the invention provides an isolated circular DNA vector including one or more heterologous genes encoding a therapeutic replacement protein, wherein the DNA vector lacks: (a) an origin of replication (e.g., a bacterial original of replication) and/or a drug resistance gene; and (b) a recombination site. For example, in some embodiments, the DNA vector lacks an origin of replication, a drug resistance gene, and a recombination site. The therapeutic replacement protein may be, e.g., an enzyme, a growth factor, a hormone, an interleukin, an interferon, a cytokine, an anti-apoptosis factor, an anti-diabetic factor, a coagulation factor, an anti-tumor factor, a liver-secreted protein, or a neuroprotective factor.”, (p. 2, lines 1-8).
Therefore, it would have been obvious to one of skill in the art before the effective filing date of the claimed invention to modify the circular DNA vector taught by Chikanna-Gowda et al as evidence by Smerdou et al, i.e., a circular DNA vector, 5’ to 3’ a promoter, recombinase genes, IL-12, and a polyA tail, with the teachings of Schnepp et al, i.e., a circular DNA vector including one or more heterologous genes wherein the DNA vector lacks: (a) an origin of replication (e.g., a bacterial original of replication) and/or a drug resistance gene; and (b) a recombination site, to yield the predictable results of a circular DNA vector lacking a bacterial origin of replication, a drug resistance gene, and a recombination site. One of skill in the art would be motivated to do so because Schnepp et al teaches that conventional plasmid DNA vectors risk introducing contaminating impurities from a bacterial host, e.g., endotoxins or bacterial genomic DNA or RNA, and that this can lead to loss of gene expression in vivo. Thus, one of skill could have looked to the teachings of Schnepp et al to modify the teachings of Chikanna-Gowda et al as evidence by Smerdou and arrived at the circular vector DNA lacking a bacterial origin of replication, a drug resistance gene, and a recombination site, with a high likelihood of success.
Regarding claim 20, Schnepp et al teaches, “In another aspect, the invention provides an isolated circular DNA vector including one or more heterologous genes encoding an enzyme, a growth factor, a hormone, an interleukin, an interferon, a cytokine, an anti-apoptosis factor, an anti-diabetic factor, a coagulation factor, an anti-tumor factor, a liver-secreted protein, or a neuroprotective factor, wherein the DNA vector lacks: (a) an origin of replication (e.g., a bacterial original of replication) and/or a drug resistance gene; and (b) a recombination site.”, (p.2, lines 26-31). Further, “In some embodiments, the disorder is a cancer and the heterologous gene is CD40, CD40L, CD46, XCL1, MDA-7, IL-12, IL-24, or OPCML (opioid binding protein/cell adhesion molecule).”, (p.3, lines 15-17).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to substitute IL-12 of the combined teachigns of Chikanna-Gowda et al as evidence by Smerdou in view of Schnepp, with XCL1 as taught by Schnepp et al. The substituted components i.e., the IL-12 (of Chikkanna-Gowda et al) and the XCL1 (of Schnepp et al) and their functions were known in the art. One of skill in the art could look to the teachings of Schnepp et al, e.g., “In some embodiments, the disorder is a cancer and the heterologous gene is CD40, CD40L, CD46, XCL1, MDA-7, IL-12, IL-24, or OPCML (opioid binding protein/cell adhesion molecule)”, and substituted any one of the listed heterologous genes for another. One would be motivated to do so because Schnepp et al teaches that those genes (listed above) are involved in cancer, and Chikkanna-Gowda et al teaches that the SFV vector been used experimentally for tumour therapy.
Accordingly, claim(s) 16-20 and 22-23 are unpatentable over Chikkanna-Gowda et al evidence by Smerdou in view of Schnepp et al.
Claim(s) 21 and 25 are rejected under 35 U.S.C. 103 as being unpatentable over Chikkanna-Gowda (supra) et al evidence by Smerdou (supra) in view of Schnepp et al (supra) as applied to claim(s) 16-20 and 22-23 above, and further in view of Lu et al (supra).
Of note: for claim 25, 5’ to 3’ of a circle vector is being interpreted as (A) dendritic cell growth factor or activator-encoding gene, the lymphocyte signaling protein-encoding gene, and the dendritic cell chemoattractant-encoding gene; (B) the lymphocyte signaling protein-encoding gene, the dendritic cell chemoattractant-encoding gene, and the dendritic cell growth factor or activator-encoding gene; and (C) the dendritic cell chemoattractant-encoding gene, the dendritic cell growth factor or activator-encoding gene, and the lymphocyte signaling protein-encoding gene.
Chikkanna-Gowda et al, Smerdou, and Schnepp et al do not teach Flt3L and a 5’ to 3’ orientation of a dendritic growth factor or activation-encoding gene, a lymphocyte signaling protein-encoding gene, and a dendritic cell chemoattractant-encoding gene.
Regarding claim 21, Lu et al teaches, “Provided for herein is an engineered cell comprising: a) a promoter; and b) an exogenous polynucleotide sequence comprising an expression cassette described in a formula, oriented from 5′ to 3′, comprising
S1-E1-L-S2-E2
wherein S1 comprises a polynucleotide sequence encoding a first signal peptide, E1 comprises a polynucleotide sequence encoding a first effector molecule, L comprises a linker polynucleotide sequence, S2 comprises a polynucleotide sequence encoding a second signal peptide, E2 comprises a polynucleotide sequence encoding a second effector molecule, and wherein the promoter is operably linked to the expression cassette, the first signal peptide is operably linked to the first effector molecule, and the second signal peptide is operably linked to the second effector molecule.”, ([0010]).
Lu et al teaches, “In some aspects, the first effector molecule comprises interleukin 12 (IL12), for example, p35 and p40 as a dimer that is generally referred to in the art as IL-12p70.”, ([0027]).
“In some aspects, the second effector molecule comprises Flt3L.”, ([0030]).
Lu et al teaches in figures 32 and 33 that combinations of effector molecules have a greater effect at reducing tumor burden than effectors alone, when paired with IL-12.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to substitute the IL-12 of the combined Chikkanna-Gowda et al as evidenced by Smerdou in view of Schnepp et al, i.e., a circular DNA vector with a promoter, self-replicating RNA encoding genes, IL-12, and a polyA (in that order 5’ to 3’) wherein the circular DNA vector lacks a bacterial origin of replication and/or drug resistance gene with Lu et al, i.e., a polynucleotide with IL-12 + IL21 +Flt3l. The substituted components i.e., the IL-12 (of Chikkanna-Gowda et al and Lu et al), and IL-12 + IL-21+Flt3l (of Lu et al) and their functions were known in the art. One of skill in the art could look to the teachings of Lu et al, e.g., that combinations of effector molecules have a greater effect at reducing tumor burden than effectors alone, when paired with IL-12, especially the combination of IL-12, IL21, and Flt3l, which has one of the highest efficacies for reducing tumor burden (higher than IL-12 alone) and make the substitution with a high likelihood of success.
Regarding claim 25, Lu et al teaches, “In some aspects, the expression cassette further comprises an E3 comprising a polynucleotide sequence encoding a third effector molecule. . . In some aspects, the third effector molecule comprises XCL1.”, ([0029]).”
Therefore, it would have been obvious to try to one of ordinary skill in the art before the effective filing date of the claimed invention to substitute the IL-21 of the combined teachings of Chikkanna-Gowda et al as evidenced by Smerdou in view of Schnepp et al in view of Lu et al, i.e., a circular DNA vector with a promoter, self-replicating RNA encoding genes, IL-12/IL21/FLT3L, and a polyA (in that order 5’ to 3’) wherein the circular DNA vector lacks a bacterial origin of replication and/or drug resistance, with XCL1 of the teachings of Lu et al, as the third effector molecule. One of skill in the art could have looked to the teachings of Lu et al e.g., (1) that the combination of IL-21 and XCL-1 has little to no efficacy in reducing tumor burden, and (2) that IL-12+IL21 has a lower efficacy than IL-12+XCL1, and arrive at the substitution of XCL1 for IL21 with a high likelihood of success.
Wherein the 5’ to 3’ of the one or more immunomodulatory protein-encoding sequences reads on (B) the lymphocyte signaling protein-encoding gene (IL-12), the dendritic cell chemoattractant-encoding gene (XCL1), and the dendritic cell growth factor or activator-encoding gene (Flt3L).
Accordingly, claim(s) 21 and 25 are unpatentable over Chikkanna-Gowda et al as evidenced by Smerdou in view of Schnepp et al in further view of Lu et al.
Conclusion
No claims allowed.
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/L.M.T./Examiner, Art Unit 1637
/Jennifer Dunston/Supervisory Patent Examiner, Art Unit 1637
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