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 .
Claim Status
Applicant’s election without traverse of claims 1 – 4, 6 – 15, 17 – 36, 38 and 47 in the reply filed on December 12, 2025, is acknowledged.
Additionally, Applicants’ election of the following species is acknowledged.
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Claims 40 – 43, 46, 48, 49 and 52 – 54 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on December 12, 2025. The requirement for restriction between Groups I-IV is maintained for reasons of record, and hereby made FINAL.
Therefore, claims 1 – 4, 6 – 15, 17 – 36, 38 and 47 are currently under examination to which the following grounds of rejection are applicable. Claims 1, 13, 26, 27 are independent claims.
Priority
The present application is a 35 U.S.C. 371 national stage filing of International Application No. PCT/US2021/031878, filed May 11, 2021
This application is claiming the benefit under 35 U.S.C. 119(e) of prior-filed provisional applications 63/023, 191 filing date 05/11/2020 and 63/133,224 filing date 12/31/2020.
Thus, the earliest possible priority for the instant application is May 11, 2020.
Claim Objections
Claim 12 is objected to because of the following informalities:
In claim 12, line 4, “has-miR486-5p” should read “hsa-miR486-5p”
Appropriate correction is required.
Claim Rejections - 35 USC § 112
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 3, 4, 13, 27, 28, 29, 34 and 36, 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.
Claims 3, 13, 27, 28, 34 and 36, recite the term “optionally”. These claims are indefinite because it is unclear if the “optionally” recited item is intended to be recited in the alternative or as an addition to the non-optional item. For the purposes of examination, the claims are interpreted as excluding for claims 3, 13, 27 and 28; interpreted as including for claims 34 and 36.
Claim 4 recites the term “and/or” in line 13. Markush groups using the conjunction “or” and “and” is confusing. The metes and bounds of the claim are indefinite.
Regarding claim 29, the phrase "for example or e.g." , in line 6 of the claim renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d). It is noted that the applicant did elect the single chain variable fragment species for the claim.
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)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1 – 4, 6 – 11, 27 – 29, 30, 32, 34, 35 and 38 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Morgan et al. (U.S. Patent Application Publication No. 2019/0388528 A1; cited on IDS, hereinafter Morgan) as evidenced by Blot et al. (The conserved dileucine- and tyrosine-based motifs in MLV and MPMV envelope glycoproteins are both important to regulate a common Env intracellular trafficking. Retrovirology. 2006 Sep 15;3:62; cited on IDS, hereinafter Blot).
Regarding claim 1, Morgan discloses an expression vector comprising: a polynucleotide comprising a polynucleotide-of-interest encoding a chimeric antigen receptor (CAR) and one or more additional polynucleotides-of-interest including but not limited to an inhibitory nucleic acid sequence including, but not limited to an miRNA (para. [0222]). The expression vector may comprise 1, 3, 4, 5, 6, 7, 8, 9 or 10 polynucleotides-of-interest (para. [0221]).
Regarding claims 2 and 8, Morgan discloses (para. [0253]) the recombinant vector of claim 1 can comprise a suicide gene such as: caspase-9, caspase-8, or cytosine deaminase. Cytotoxic polypeptides that convert a prodrug to a cytotoxic drugs are selected from the group consisting of a polypeptide having cytosine deaminase activity.
Regarding claims 3 and 4, Morgan discloses the recombinant vector of claim 1, wherein (a) comprises a CAR comprising (para. [0007]) a murine anti-BCMA (B cell maturation antigen) antibody or antigen binding fragment (single chain variable fragment) that binds one or more epitopes of a human BCMA polypeptide; a transmembrane domain, one or more intracellular co-stimulatory signaling domains, and a primary signaling domain.
Regarding claim 6, Morgan discloses the recombinant vector of claim 3, wherein the transmembrane domain is (para. [0016]) from a polypeptide selected from the group consisting of: alpha, beta or zeta chain of the T-cell receptor, CD3ԑ, CD3ζ, CD8 and etc.
Regarding claim 7, Morgan discloses an ITAM motif that encodes an intracellular signaling domain (para. [0176]) selected from a group that includes CD3ζ.
Regarding claim 9, Morgan discloses that in some embodiments the recombinant vector is an integrating viral vector (para. [0288]).
Regarding claim 10, Morgan discloses that in some embodiments the recombinant vector is a retroviral vector (para. [0262]).
Regarding claim 11, Morgan discloses the use of replication defective viruses (para. [0263]) such as the Moloney murine leukemia (para. [0260]), which is a non-replicating gammaretrovirus.
Regarding claim 27, Morgan discloses a retroviral vector (paras. [0262]), in some embodiments that comprises: a polynucleotide comprising a polynucleotide-of-interest encoding a chimeric antigen receptor (CAR) and one or more additional polynucleotides-of-interest including but not limited to an inhibitory nucleic acid sequence including, but not limited to an miRNA (para. [0222]). The expression vector may comprise 1, 3, 4, 5, 6, 7, 8, 9 or 10 polynucleotides-of-interest (para. [0221]). Furthermore, Morgan discloses the pharmaceutically acceptable carrier (para. [0432]) for delivery into an animal or human.
Regarding claim 28, Morgan discloses the composition of claim 27, wherein the construct comprises a CAR comprising (para. [0007]) a murine anti-BCMA (B cell maturation antigen) antibody or antigen binding fragment that binds one or more epitopes of a human BCMA polypeptide; a transmembrane domain, one or more intracellular co-stimulatory signaling domains, and a primary signaling domain.
Regarding claims 29 and 38, Morgan discloses the composition of claim 27, wherein the construct comprises a CAR comprising (para. [0007]) a murine anti-BCMA (B cell maturation antigen) (and/or CD19 (para. [0502])) antibody or antigen binding fragment that binds one or more epitopes of a human BCMA polypeptide. Morgan (para. [0482]) discloses that a CAR is an artificial molecule comprised of an antigen reactive single chain variable fragment fused to T cell signaling domains via a transmembrane region.
Regarding claim 30, Blot discloses (p. 2, Background, 1st para.) that retroviruses are surrounded by a lipid envelope acquired by the virus from cellular membranes through a budding process.
Regarding claim 32, Morgan discloses a nucleic acid cassette (para. [0220]) that contains a gene of interest, e.g., a CAR.
Regarding claims 34 and 35, Morgan discloses a suicide gene (para [0253]) that can be cytosine deaminase.
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 12 is rejected under 35 U.S.C. 103 as being unpatentable over Morgan in view of Pass et al. (U.S. Patent Application Publication No. 2011/0071215 A1; cited on IDS, hereinafter Pass).
Regarding claim 12, Morgan teaches all of the elements of the current invention as stated above but does not explicitly disclose a group consisting of the miRNAs of instant claim 12.
However, Pass teaches a miRNA targeting sequence for hsa-miR-223 (para. [0045], SEQ ID NO:21), which is the precursor form of hsa-miR-223p. The “3p” refers to a 3’-phosphate group that is primed and ready to bind target mRNAs for gene expression regulation.
The motivation would be to use various functional inhibitory RNAs in combination with a chimeric nucleic acid for the purpose of manipulating gene expression more effectively in a target cell or tissue.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the optimized miRNA of Pass with the expression vector of Morgan. Doing so would incorporate a biologically active “ready-to-use” mature miRNA in the expression vector of Morgan.
Claims 13 – 15, 17 – 26, 31 and 47 are rejected under 35 U.S.C. 103 as being unpatentable over Morgan and Pass as applied to claim 12 above, and further in view of Aguilar-Cordova (U.S. Patent Application Publication No. 2006/0057553 A1), Morgan et al. (U.S. Patent Application Publication No. 2019/0388526 A1; cited on IDS, hereinafter Morgan 2), and Park et al. (Gamma-retroviral vector design for the co-expression of artificial microRNAs and therapeutic proteins. Nucleic Acid Ther. (2014) Oct;24(5):356-63; hereinafter Park) as evidenced by Hansen et al. (U.S. Patent Application Publication No. 2005/0118710 A1) and Chang (U.S. Patent No. 5,693,508).
Regarding claims 13 – 15, Morgan teaches (para. [0295]) a recombinant viral particle comprising: a gag, a pol, an env, and a retroviral polynucleotide contained in a viral capsid or particle (para. [0268]). Morgan discloses that short hairpin RNA constructs (para. [0225]), expressed as human miRNA primary transcripts, adds a Drosha processing site, which translates into greater siRNA/miRNA production and greater potency for expressed hairpins. Furthermore, Aguilar-Cordova teaches (p. 25, paragraph above [0215]) in an embodiment of chimeric viral vectors, a chimeric nucleic acid vector comprising adenoviral inverted terminal repeat flanking sequence, the retroviral long terminal repeat (R) sequence comprises SEQ ID NO: 2, which a 100% match to SEQ ID NO: 25 of instant claim 14, from nucleotide 1 to about nucleotide 145. In an additional specific embodiment a gag nucleic acid sequence. A pol nucleic acid sequence and a env nucleic acid sequence. However, neither suggests wherein the retroviral polynucleotide comprises from 5’ to 3’: (R-U5 domain)-(optional signal peptide coding sequence domain)-(Binding domain coding sequence domain)-(optional hinge/linker coding sequence domain)-(transmembrane coding sequence domain)-(miRNA target domain(s))-(U3-R domain).
Morgan 2 suggests (para. [0482]; Fig. 1; Table 3-list of vector components) a retroviral polynucleotide contained wherein the retroviral polynucleotide comprises from 5’ to 3’: (R-U5 domain)-(optional signal peptide coding sequence domain)-(Binding domain coding sequence domain)-(optional hinge/linker coding sequence domain)-(transmembrane (TM) coding sequence domain)-(U3-R domain).
Although, Morgan 2 does teach about miRNA function (para. [0227]), an miRNA target domain is not explicitly disclosed in the vector.
Park teaches gammaretroviral vector design principles for coexpression of an RNAi inducing moiety along with a model of anti-tumor antigen receptor, which includes CARs (p. 356, Introduction). Furthermore, Park discloses an artificial microRNA-truncated CD34 vector design (Fig. 1).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the vector of Morgan 2 with the R-U5 domain of Aguilar-Cordova and the miRNA target domain of Park, under the motivation of Morgan’s teachings on the advantages of miRNA (para. [0225]) constructs compared to conventional shRNA designs.
Regarding claims 17 and 19, Morgan discloses (para. [0253]) the recombinant vector of claim 1 can comprise a suicide gene such as: caspase-9, caspase-8, or cytosine deaminase. Cytotoxic polypeptides that convert a prodrug to a cytotoxic drugs are selected from the group consisting of a polypeptide having cytosine deaminase activity.
Regarding claim 18, Morgan discloses (para. [0203]) in one embodiment, where the expression of two or more polypeptides is desired, the polynucleotide sequences encoding them can be separated by an IRES sequence.
Regarding claims 20 and 21, Morgan discloses (para. [0221]) a polynucleotide comprising a polynucleotide-of-interest encoding a chimeric antigen receptor (CAR) and one or more additional polynucleotides-of-interest including but not limited to an inhibitory nucleic acid sequence including, but not limited to an miRNA (para. [0222]). The expression vector may comprise 1, 3, 4, 5, 6, 7, 8, 9 or 10 polynucleotides-of-interest (para. [0221]).
Regarding claim 22, Pass discloses (para. [200]) that multiple miRNAs may regulate the same mRNA target by recognizing the same or multiple sites.
Regarding claim 23, Pass discloses (para. [202]) that there may be variability in the 5’ and 3’ ends of any pair of miRNA and miRNA*. This implies that the miRNA targeting sequences can be different.
Regarding claim 24, Hansen discloses a Moloney murine leukemia virus (M-MuLV) long terminal repeat that is 100% identical to SEQ ID NO: 25 from nucleotide 5537 to 6051.
Regarding claim 25, Morgan 2 (para. [0160]) discloses small spacer (linkers) sequences of about 1 – 20 nucleotides.
Regarding claim 26, Morgan discloses the pharmaceutically acceptable carrier (para. [0432]) for delivery into an animal or human.
Regarding claim 31, Aguilar-Cordova discloses an amphotrophic envelope (para. [0032]).
Regarding claim 47, Chang discloses (col. 19, lines 40 – 42) an amphotrophic M-MuLV-based vector, pLNL6 [SEQ ID NO:1], which is a 100% match to SEQ ID NO:25 of the instant application.
Claim 33 is rejected under 35 U.S.C. 103 as being unpatentable over Morgan in view of Navon et al. (Novel rank-based statistical methods reveal microRNAs with differential expression in multiple cancer types. PLoS One. 2009 Nov 25;4(11); cited on IDS, hereinafter Navon).
Regarding claim 33, Morgan teaches all of the elements of the current invention as stated above except an miR targeting sequence for miRNA that are expressed in off-target cells. As stated above, Morgan discloses a polynucleotide that can have multiple miRNAs encoded. However, Navon discloses a rank-based statistical method for miRNAs that are under-expressed (miR-486-5p, from the original group in claim 12) and over-expressed in cancer (p. 8, left-hand column, 2nd paragraph and right-hand column, 1st paragraph), thereby allowing one to select a target sequence for miRNA(s) that are expressed in off-target cells and not the target cells.
It would have been prima facie obvious to one of ordinary skill to modify the composition of Morgan to include one or more targeting sequences for miRNA(s) that are expressed in off-target transduced cells. The motivation for doing so would be to limit viral replication and/or expression of vector-containing coding sequences in the off-target transduced cells. The miRNAs expressed in off-target cells can bind to such miRNA target sequences and suppress expression of the viral polynucleotide.
Claim 36 is rejected under 35 U.S.C. 103 as being unpatentable over Morgan and Park and in further view Philip et al. (A highly compact epitope-based marker/suicide gene for easier and safer T-cell therapy. Blood 2014; 124 (8): 1277–1287; hereinafter Philip).
Regarding claim 36, Morgan and Park teach all of the elements of the current invention as stated above except a composition that explicitly comprises: a polynucleotide comprising from 5’ to 3’: R-U5-(antigen binding receptor coding sequence)-(miR targeting sequence or cassette)-(optional suicide gene)-U3-R. Morgan teaches the limitations of claim 27 and Park discloses the microRNA target domain. However, Philip discloses a SFG (3rd generation Moloney murine leukemia virus-derived) gammaretroviral vector (Fig. 4A) that encodes for the suicide gene RQR8 upstream of an Anti-GD2 CAR, further enhanced by a scaffold attachment region.
It would have been prima facie obvious to one of ordinary skill to modify the constructs of Morgan and Philip to fit the limitations of instant claim 36 and add the miR target sequence of Park under the motivation to enable selective destruction of T cells in case of toxicity in adoptive cell therapies.
Claims 1 – 4, 6 – 15, 17 – 36, 38 and 47 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to WALTER JACKSON III whose telephone number is (571)272-0247. The examiner can normally be reached M-F 9:00A - 5:00P.
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/WALTER JACKSON III/Examiner, Art Unit 1638
/MARIA G LEAVITT/Supervisory Patent Examiner, Art Unit 1634
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