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 .
This office action is in response to the paper filed on 1/09/2026. Claims 1-20 were previous presented. No new claims are presented.
Election/Restriction
Applicant’s election of inventions of Group I (Claims 1-18), in the reply filed on 1/09/2026, is acknowledged.
Applicant elects the invention of Group I (Claims 1-18) and the following species: (I) Ef1a promoter for the promoter of claim 6, (II) Cre recombinase for the recombinase of claim 7, (III) ICasp9 as the pro-death protein of claim 9, (IV) Icasp9 and pro-death agent AP20187 as the pro-death and pro-death agent combination of claim 10, (V) BiTE blinatumomab as the payload protein of claim 15, and tumor-associated macrophage (TAM) as the macrophage of claim 18.
Applicant argues that election of species for a single macrophage of claim 18 is improper as examiner fails to show a search burden and that claim 18 appears to constitute a reasonable number of species. In addition, applicant argues that at least M1 and M2 macrophages should be encompassed by Tumor Associated Macrophages as TAMs exist as both types. In addition, the use of RAW264.7 macrophages in the instant application is capable of polarizing into M1-like and M2-like macrophage.
Applicant’s arguments regarding M1 and M2 macrophages in relation to the elected TAM are found persuasive. Hence, the restriction requirement among M1, M2, and TAM is hereby withdrawn, and the three specie will be considered/examined on the merits in the instant application.
Claims 19 and 20 withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Applicant is reminded that upon the cancelation of claim to a non-elected invention, the inventorship must be corrected in compliance with 37 CFR 1.48(a) if one or more of the currently named inventors is no longer an inventor of at least one claim remaining in the application. A request to correct inventorship under 37 CFR 1.48(a) must be accompanied by an application data sheet in accordance with 37 CFR 1.76 that identifies each inventor by his or her legal name and by the processing fee required under 37 CFR 1.17(i).
Application Status
This action is written in response to applicant’s correspondence received on 1/09/2026. Claims 1-20 are currently pending in the instant application. Claims 1-18 are currently under examination on the merits.
Priority
This application claims priority to provisional application 63/251,847 filed on October 4, 2021.
Drawings
Color photographs and color drawings are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted. Any such petition must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via the USPTO patent electronic filing system or three sets of color drawings or color photographs, as appropriate, if not submitted via the via USPTO patent electronic filing system, and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification:
The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee. In the case of the instant application, the supplemental drawings filed on 10/03/2022 contain colored figures.
Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2).
Claim Objections
Claims 6, 9, and 10are objected to because of the following informalities: Claim 9 recites improper Markush-type claim language for the pro-death proteins of claim 9 should be “the pro-death protein selected from the group consisting of”, instead of the recited claim language of comprising. In addition, the word “or” in line 8 should be “and”. Claims 6 and 15 both recite improper Markush-type claim language as described for claim 9.
Appropriate correction is required.
Claim Rejections - Improper Markush Groups
Claims 9, 10, and 15 are rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
The Markush grouping of claims 9, 10, and 15 is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons:
Regarding claim 9, the pro-death gene encoding a pro-death protein have no shared structural similarities. Applicant claims a group of genes and proteins capable of inducing cellular death, however, genes and proteins are off different classes altogether. Applicant claims a deaminase, ICasp9, Cas9, a kinase, toxins, and a nucleoside phosphorylase. Though this is only a portion of the genes and proteins claimed, there is clear evidence they do not share any single structural similarities.
Regarding claim 10, applicant claims a default gene, wherein the default gene is a pro—death gene encoding a pro-death protein that is capable of halting cell growth and/or inducing cell death. The combinations of pro-death gene and pro-agent share no single structural similarity as applicant claims ICasp9, a kinase, a deaminase, a nucleoside phosphorylase, a carboxypeptidase, a carboxylesterase, just to list a few. These are all different classes of enzymes with no single shared structural similarity.
Regarding claim 15, applicant claims wherein the population of macrophages, wherein the payload transcript can generate a payload protein, wherein the protein is or comprises: a protein that can be a Cre recombinase, a T cell engager, a cytokine, a growth factor, a chemokine, an antibody, just to list a few. Based off the claim language, “is” indicates that the payload protein can be a single protein chosen from the listed proteins of the claim. Therefore, the proteins listed share no single structural similarity as a recombinase is not the same as a cytokine, a growth factor, chemokine, or antibody.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
Claim Interpretation
Regarding claim 1 of the instant application, applicant claims a population of heat-inducible macrophages comprising of two sets of promoters and polynucleotides. A population of heat-inducible macrophages is disclosed as “one or more of said heat-inducible macrophages comprise”, indicating that a population can be a single macrophage (see paragraph 0006 of the specification, instant application). The first promoter and polynucleotide pair expresses a recombinase protein. The second polynucleotide comprises of a payload gene. For the claim interpretation of claim 1, the recombinase gene can be any recombinase gene. The payload gene can be any payload gene, where inducing transcription generates a payload transcript. Based off the specification of the instant application, a payload protein comprises a constitutive signal peptide for protein degradation, a nuclear localization signal (NLS), or a nuclear export signal (NES). In other embodiments, a payload protein can comprise a dosage indicator protein, comprising of green fluorescent protein (GFP) (see paragraph 0038 of the specification, instant application).
Regarding the default gene of claim 8, the default gene can be interpreted as any gene capable of generating a protein that is encoded by any ‘third’ polynucleotide. The claim also does not specify whether a gene encoded by a second polynucleotide and a gene encoded by a third polynucleotide has to be expressed simultaneously, only that the promoter remains constant.
Regarding a population of heat-inducible macrophages applicable to all claims, applicant does not specify the method of induction in the claims. Based off the specification of the instant application, applicant notes that, in some embodiments, methods and compositions employing thermally actuated control elements to solve the aforementioned problems in the art, exploiting the ability for temperature to elevated at arbitrary depth with high spatial precision using noninvasive methods such as focused ultrasound (FUS) (see paragraph 0082). For the purpose of examination, the use of ultrasound to elevate temperature within a cell is considered a viable method of heat induction.
Claim Rejections - 35 USC § 102
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 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.
Claims 1, 2, 5, 6, 7, 8, 9, 11, 12, 13, 15, 16, and 17 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by US Patent Application Publication US2020/0108145 A1, (Publication Date 4/9/2020), or Wang et al., herein referred to as Wang.
Regarding claim 1, Wang teaches a method for remotely-controlling and non-invasively manipulating a nucleic acid expression in a cell, or an immune cell, wherein the immune cell can be a macrophage (see paragraph 0008).
Furthermore, Wang teaches a mammalian or human promoter or transcriptional activator activated by increased temperature, where in a recombinase gene can be controlled. Fig. 18A-C of Wang schematically illustrates that Cre recombinase is under control of the HSP promoter (see paragraph 0122). Fig. 18A shows that upon heat stimulation, heat-activated Cre will act on the two Lox sites to cause recombination, leading to the removal of the stop codon and constitutive expression of the reporter gene (see paragraph 0223).
Regarding claim 2, Wang teaches where upon heat stimulation, Cre will act on the two Lox sites, leading to the removal of the stop codon. This reads where Lox are recombinase are target sites for the recombinase, which flanks a sequence (stop codon) (paragraph 0223).
Regarding claim 5, Wang teaches where in Fig 18A (see paragraph 0223), the target reporter gene is downstream of two lox sites flanking a stop codon. Figure 18A illustrates the genetic orientation as PGK promoter-LoxP-STOP-LoxP-Reporter gene. This reads on where there is a stop cassette (stop codon) situate between the second promoter (PGK) and the payload gene (reporter gene).
Regarding claim 6, Wang teaches where the promoter is a heat shock protein, optionally a 70B HSP (see claim 1). The instant application claims heat shock 70 kDa which is a general heat shock protein family and HSP 70B is a more specific member of this family.
Regarding claim 7, Wang discloses that to convert transient expression of target genes to a permanent one, Cre-Lox recombination system was used (see paragraph 0222). This reads on claim 7 where the chosen recombinase is Cre.
Regarding claim 8, Wang teaches that Fig. 12C graphically illustrates the representative flow cytometry data of Jurkat cells expressing the eGFP tagged anti-CD19 CAR driven by the HSP promoter (see paragraph 0190). This reads on claim 8 wherein the second polynucleotide, eGFP, and the third polynucleotide, anti-CD19 CAR, are driven by the same promoter, HSP. The specification of the instant application discloses where the second promoter comprises a ubiquitous promoter, optionally selected from a group including heat shock 70 kDa proteins.
Regarding claim 9, Wang teaches that in alternative embodiment, provided are compositions and methods for stimulating or inhibiting ligand-receptor interactions, including any surface molecular interaction, including but not limiting to inhibitory CTLA-4 and apoptotic Fas (see paragraph 0127). Claim 9 of the instant application recites Shiga-like toxin Fas as a pro-death protein.
Regarding claim 11, Wang teaches that the nucleic acid or target gene is linked to a promoter activated by increase temperature, optionally linked to a heat shock protein (HSP), optionally a 70B HSP, which can be activated at 43°C. This anticipates the activating temperature of 43°C recited in claim 11 of the instant application.
Regarding claim 12, Wang teaches the HSP promoter driven eGFP in Jurkat lymphocytes, wherein the percentage of cells expressing eGFP increased from 0.8% to 30.6% 13 hours after heat shock as compared to the control (see paragraph 0186).
Regarding claim 13, Wang discloses wherein the gene of interest is linked to a mammalian or human promoter, activated by increase temperature, optionally operably linked to a heat shock protein (HSP) (see claim 1).
Regarding claim 15, Wang teaches Fig. 18A-C which illustrates Cre recombinase is under the control of the HSP promoter, while the target reporter gene is downstream of two Lox sites flanking a stop codon under the control of a constitutive promoter. Upon heat stimulation, the heat-activated Cre will act on the two Lox sites to cause recombination, leading to the removal of the stop codon and the constitutive expression of the reporter gene, e.g., CD19CAR (see paragraph 0223-0225). CD19CAR read on a “chimeric antigen receptor (CAR)” of claim 15.
Regarding claim 16, Wang teaches an engineered cell, or immune cell, or plurality of cells or immune cells, as engineered for the use as a medicament in remotely-controlled and non-invasive manipulation of physiologic and/or a genetic process in a cell, or immune cell, or for the addition of a function or a target specificity to the cell, or immune cell, or plurality of cells or immune cells, or for the manipulation or correction of a pathological process, optionally, for eradicating a tumor or cancer in an individual in vivo (see claim 9). The eradication of a tumor or cancer in an individual indicates where in the engineered cell is capable of expressing a payload protein that is capable of remodeling a tumor microenvironment.
Regarding claim 17, Wang teaches where Fig. 5 shows proof-of-concept that Gene Transducing Module or GTMs (which comprise of a nucleic acid linked to a promoter, activated by heat, and a thermos-responsive protein-expression nucleic acid linked to an inducible or constitutive promoter) (see paragraph 0033), can be engineered and integrated into the endogenous molecular network for the sensing of ultrasound stimulation to guide gene activations (see paragraph 0152). GTMs are vectors that are engineered into a cell. The cells having the GTMs are not described to comprise a “targeting moiety” binding to a target site of a subject.
Thus, Wang clearly anticipates claims 1, 2, 5, 6, 7, 8, 9, 11, 12, 15, 16, and 17 of the instant application.
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.
Claims 1, 2, 3, 4, 5, 6, 7, 8, 9, 11, 12, 15, 16, and 17 are rejected under 35 U.S.C. 103 as being unpatentable over Wang et al. (US 2020/0108145 A1, 2020) in view of Xu et al (A rapid in vitro method to flip back the double-floxed inverted open reading frame in a plasmid, BMC Biotechnology, 2018).
Regarding claims 1, 2, 5, 6, 7, 8, 9, 11, 12, 15, 16, and 17 are taught by Wang as described above.
Regarding claims 3 and 4, the population of claim 1 is taught by Wang, as described above.
Regarding claim 3, the instant application claims wherein the second polynucleotide is flanked by recombinase target sites. The instant application also specifies that the first polynucleotide comprises a recombinase gene to generate a recombinase upon thermal stimulation and a second polynucleotide with the payload gene (see paragraph 0057 of the instant application).
Wang teaches where the Cre recombinase is under the control of the HSP promoter, while the target reporter gene is under the control of the HSP promoter, while the target reporter gene is downstream of two Lox sites flanking a stop codon under the control of a constitutive promoter (see paragraph 0122).
Wang does not teach where the second polynucleotide, the payload protein, is flanked by recombinase target sites, or in this case, Lox sites. Wang also does not teach where the second polynucleotide comprising a payload gene is inverted.
Regarding claim 4, Xu teaches a FLEx plasmid. In Fig. 1 of Xu, the plasmid comprises of an inverted or “reverse” gene of interest (ORF) flanked by WT LoxP sites. Fig. 1A shows Cre-mediated recombination where Cre enzyme can induce ORF inversion with two LoxP sites or two Lox2272 sites.
It would have been obvious to one with ordinary skill in the art, before the effective filing date, to combine the heat inducible-macrophages taught in Wang with the Cre-lox recombinase system taught by Xu in order to have a system of controlled, Cre-mediated expression of a payload gene.
One would have been motivated to do so because the design of the FLEx system taught in Xu allows two pairs of mismatched LoxP sites to first invert and turn on the switch, and a subsequent excision event to eliminate one of the LoxP partners to prevent re-inversion (see background). This method greatly reduces leaky expression in the absence of Cre recombinase, making the FLEx switch the preferred method to turn on genes in mammalian cells (see background). By implementing the FLEx system of Cre-recombination as oppose to the removal of a stop codon seen in Lox-STOP-Lox system of Cre recombination, one would expect to see a reduction of leaky expression which can result in off target effects. As a result, this combination will allow for tumor associated macrophages to deliver a therapeutic payload with greater reliability and accuracy.
In view of the foregoing, claims 1, 2, 3, 4, 5, 6, 7, 8, 9, 11, 12, 15, 16, and 17 would have been prima facie obvious before the effective filing date.
Claim 6 is rejected under 35 U.S.C. 103 as being unpatentable over Wang et al (US 2020/0108145 A1, 2020) in view of Allen et al (WO 2021/062155 A1, 04/01/2021) and Qin et al (Systematic Comparison of Constitutive Promoters and the Doxycycline-Inducible Promoter, PLoS One, 2010).
Regarding claim 6, Wang teaches the population of heat-inducible macrophages of claim 1, as described above. Wang also discloses a cell comprising eGFP operably linked to “a constitutive promoter”, which is a PGK promoter (see Fig. 18a and paragraph 0223). Wang teaches that the promoter linked to the “protein-expression nucleic acid” is either “an inducible or constitutive promoter” (see claim 18).
Wang does not teach where the second promoter is elongation factor 1-alpha (EF1-α).
Allen teaches Jurkat cells comprising a construct comprising eGFP flanked by two LoxP sites, wherein the eGFP is operably linked to an EF1a promoter (See Fig. 19a).
Qin teaches where PGK is a weaker constitutive promoter compared to EF1a which is consistently strong in all cell types, specifically mammalian cells (see results and discussion).
It would have been obvious to one with ordinary skill in the art, before the effective filing date, to combine the population of heat-inducible macrophage of Wang with the constitutive promoter EF1-alpha taught by Allen. It is well known in the art that PGK is a weaker constitutive promoter compared to EF1a which is consistently strong in all cell types, specifically mammalian cells as described by Allen and Qin. By using the EF1a promoter taught by Allen with the engineered cells of Wang, one could use the EF1a promoter to drive higher levels of expression, which is suitable for stronger production of the payload protein.
Claims 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 and 17 are rejected under 35 U.S.C. 103 as being unpatentable over Wang et al (US 2020/0108145 A1, 2020) in view of Abedi et al (US 2021/0324389 A1, filed on 04/15/2021).
Regarding claims 1, 2, 5, 6, 7, 8, 9, 11, 12, 13, 15, 16, and 17, Wang teaches these embodiments as described above.
Regarding claim 14, Wang teaches an immune cell that includes a macrophage comprising a Cre recombinase gene operably linked to an HSP promoter that is induced by heat (See Fig. 18a).
Wang does not teach specifically where the first promoter comprises a nucleotide sequence that is at least 80% identical to any one of SEQ ID NOs: 1-14.
Abedi teaches a first inducible promoter comprising a nucleic acid selected from the group consisting of SEQ ID NOs: 1-14 capable of inducing transcription of the payload gene to generate a payload transcript upon thermal stimulation (see claim 1). All SEQ ID NOs: 1-14 of Abedi have 100% identity to SEQ ID NOs: 1-14 of the instant application in corresponding order).
Abedi also teaches a nucleic acid composition where a first inducible promoter is operably linked to a first polynucleotide comprising a payload gene, wherein the first inducible promoter is capable of inducing transcription of the payload gene to generate a payload transcript upon thermal stimulation (see paragraph 0007). Other embodiments include a first inducible promoter operably linked to a first polynucleotide comprising a recombinase gene, where the first inducible promoter is capable of inducing transcription of the recombinase gene to generate a recombinase transcript upon thermal stimulation (see paragraph 0014), and where in some embodiments, the second polynucleotide is flanked by recombinase target sites and prior to the recombination event, the payload gene is inverted relative to the promotor (see paragraph 0015).
Further embodiments include a nucleic acid composition wherein at least one stop cassette is configured to prevent transcription of the payload gene (see claim 18). Abedi further discloses where the ubiquitous promoter can be EF1a (see paragraph 0015), the use of a payload protein which can be an inducer of cell death (e.g. a bacterial pore-forming toxin) (see paragraph 0146) and where in some embodiments, the payload protein can comprise a CRE recombinase, GCaMP, a cell therapy component, a knock-down gene therapy component, a cell-surface exposed epitope, or any combination thereof (see paragraph 0146).
It would have been obvious to one with ordinary skill in the art, before the effective filing date, to use the heat shock protein promoter of SEQ ID NO: 1-14 presented in Abedi for the composition of an immune cell in Wang.
One would be motivated to do so because SEQ ID NO: 1-14 of Abedi encode for art recognized HSP promoters operably linked to Cre. This induces transgene expression (originally inverted) upon heat treatment, which allows for expression of a payload protein (See Fig. 4E of Abedi). Furthermore, Wang was explicit about using HSP promoters linked to CRE.
In view of the foregoing, claims 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 and 17 would have been prima facie obvious before the effective filing date.
Claim 14 is rejected under 35 U.S.C. 103 as being unpatentable over Wang et al (US 2020/0108145 A1, 2020) in view of Tsang et al. (US 2005/0164961 A1, 06/28/2005).
Wang teaches a HSP 70B promoter, which is taught to be “activated by heat shock, at optionally above 43 degrees Celsius (see paragraph 0022).
Tsang teaches hyperthermic inducible expression vectors for gene therapy using heat shock promoters. Tsang teaches HSP 70B promoter that is at least 80% identical to SEQ ID NO: 1 of the instant application.
It would have been obvious to one with ordinary skill in the art, before the effective filing date, to use the heat shock protein promoter HSP presented in Tsang for the composition of an immune cell in Wang as Tsang’s promoter of SEQ ID NO: 1 was known in the art as an effective HSP for vector expression and because Tsang’s HSP 70B promoter sequence qualifies as the sequence of the HSP 70B promoter taught by Wang.
In view of the foregoing, claim 14 would have been prima facie obvious before the effective filing date.
Claim 15 is rejected under 35 U.S.C. 103 as being unpatentable over Wang et al (US 2020/0108145 A1, 2020) in view of Naddafi et al (The Epigenetic Regulation of Blinatumomab Gene Expression: Tumor Cell-dependent T cell Response against Lymphoma Cells and Cytotoxic Activity, Int. J. Mol. Cell. Med., 05/25/2019)
Regarding claim 15, Wang teaches the population of heat-inducible macrophages as described above.
Wang does not teach where the payload transcript is capable of being translated to generate a payload protein, wherein the payload protein is a bispecific T cell engager (BiTE), specifically blinatumomab.
Naddafi teaches where BiTEs antibodies (BsAb), specifically Blinatumomab, can form a transient cytolytic synapse between T cells and the tumor target cells (see introduction). BsAbs leads to a discharge of T cells contents and induces tumor cell death. Blinatumomab can redirect T cells toward malignant B cells, and induce cancer cell lysis (see introduction). Naddafi further teaches a FC550A-1 plasmid that expresses a Bispecific antibody (Blinatumomab) with an EF1a promoter (See Fig. 1).
It would have been obvious, before the effective filing date of the invention, to combine the population of heat-inducible macrophages of Wang with a vector, similar to that of Naddafi, which encodes for a BiTE, specifically Blinatumomab.
One would have a reasonable chance of success as Naddaffi shows this expression vector can induce BsAb protein production in cells (see discussion) and that BsAb induced cytotoxicity of T-cells against CD19+ cell line, in vitro (see discussion).
One would have been motivated to combine these inventions in order to create a population of heat-inducible macrophages capable of expressing Blinatumomab, in order to produce Blinatumomab as a payload protein within a cell.
In view of the foregoing, claim 15 would have been prima facie obvious, before the effective filing date.
Claims 9, 10 and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Wang et al (US 2020/0108145 A1, 2020), in view of Mantovani et al (Tumor-associated macrophages as treatment targets in oncology, Nature Reviews Clinical Oncology, Issue 14, Pg. 399-416, 2017), in further view of Lipus et al (Targeted Integration of Inducible Caspase-9 in Human iPSCs Allows Efficient in vitro Clearance of iPSCs and iPSC-Macrophages, Int J Mol Sci, Issue 21, 2020).
With regards to claim 9, 10, and 18, the heat inducible of claim 1 is taught by Wang as described above. Furthermore, Wang discloses that the compositions provided are for remotely-controlled and non-invasive manipulation of physiologic or genetic processes and/or protein expression in live cells in vivo (see paragraph 0126) or in vitro (see paragraph 0230).
Wang does not teach wherein the default gene of the third polynucleotide encodes for a pro-death gene encoding a pro-death protein, wherein the pro-death protein is ICasp9 (claims 9 and 10) or where the heat inducible macrophages are tumor-associated macrophages (claim 18).
Regarding claims 9 and 10, Lipus teaches where induced pluripotent stem cells (iPSCs) can be used to derive macrophages (see abstract) which allowed them to study the effects of iCasp9 on said macrophages. Lipus teaches the expression of iCasp9 from a EF1alpha promoter was previously reported for human iPSCs with >95% killing efficiency (see discussion). Lipus also provides evidence that the introduction of the iCasp9 suicide gene into the AAVS1 locus enables the effective clearance of human iPSCs and thereof derived macrophages. Lipus also teaches the in vivo administration of the CID may be performed directly into the lung or via the intravenous route. Notably, intravenous and intraperitoneal delivery of the dimerizer has been well studied and described to effectively induce iCasp9-mediated cell death in teratomas and tumors thereby limiting their growth in murine models (see discussion).
Lipus teaches that iCasp9 is a viable suicide gene as it is non-immunogenic and has a significantly faster cell killing rate compared to common suicide gene methods such as the Herpes Simplex Virus thymidine kinase (HSV-TK) (see introduction)
Lipus teaches that iCasp9 dimerizing drug AP20187 was applied to iPSCs cultured on MED feeder cells at concentration ranging from 0.01nM to 10nM (see section 2.2). It was concluded that in both iCasp9-mono and iCasp9-bi-allelic clones, concentrations of 0.1 nM AP20187 was sufficient to induce apoptosis in more than 90% of iPSCs and their progeny macrophages (see abstract).
Mantovani teaches that tumor associated macrophages (TAMs) contribute to tumor progression at different levels and are crucial drivers of tumor-promoting inflammation (see abstract).
While Mantovani does not teach iCasp9 as a way to target TAMs, Mantovani does teach that macrophage-centered therapeutic approaches are viable in TAMs including blockade of the tumor-promoting activities of TAMs, and the exploitation of macrophage antitumor effector functions (see conclusions).
It would have been obvious to one with ordinary skill in the art, before the effective filing date, to use the heat-inducible macrophage presented in Wang with iCasp9 and AP20187 taught by Lipus in order to express a pro-death gene, in this case, iCasp9.
One would have seen a reasonable chance of success as Lipus already shows that iCasp9 can induce cell killing by more than 90% in iPSCs that develop into macrophages (see discussion) with the addition of AP20187.
One would have been motivated to do so because the iCasp9 allows one to create a “safety-switch” (see discussion of Lipus) when using a heat-inducible macrophage to deliver a therapeutic payload. It is noted in Lipus that one reason for such cautious employment of iPSC-based cell products in patients are concerns about their pluripotent and possible tumor-initiating origin. Any residual pluripotent cells in a therapeutic product or a compromised functionality and stability of iPSC-derived cells in vivo may cause severe adverse effects (see introduction). By implementing iCasp9 and AP20187, one would be able to effectively kill tumor associated macrophages in order to prevent unwanted adverse effects.
In view of the foregoing, claims 9, 10, and 18 would have been prima facie obvious before the effective filing date.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
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Claims 1-18 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 and 3-18 of U.S. Patent No. 12,359,208 B2 in view of Belteki et al (Conditional and inducible transgene expression in mice through the combinatorial use of Cre-mediated recombination and tetracycline induction, Nucleic Acids Res., 03/22/2005), Lipus et al (Targeted Integration of Inducible Caspase-9 in Human iPSCs Allows Efficient in vitro Clearance of iPSCs and iPSC-Macrophages, Int J Mol Sci, Issue 21, 2020) and Mantovani et al. (Tumor-associated macrophages as treatment targets in oncology, Nature Reviews Clinical Oncology, Issue 14, Pg. 399-416, 2017).
US Patent 12,359,208 B2 and the instant application claim a first inducible promoter selected from a group consisting of SEQ ID NOs: 1-14. Both the instant application and the US Patent have 100% identity between SEQ ID NOs: 1-14. Furthermore, both claim that the first polynucleotide is operably linked to the first promoter. Both also claim a second promoter linked to a second polynucleotide comprising of a payload gene encoding a payload protein comprising of a chimeric antigen receptor (CAR), T-cell receptor (TCR), or a cytokine. Both also claim that upon thermal stimulation, transcription is increased by at least 1.1-fold and that both the nucleic acid composition and the population of heat-inducible macrophages are capable of remodeling the tumor microenvironment.
Belteki teaches both Cre-recombinase and tetracycline-inducible transgenic systems (tetracycline transactivator and reverse tetracycline transactivator) as methods for transgenic expression (see introduction). Cre recombinase transgene provides spatial control, however, once Cre expression has been switched on and recombination has occurred, the resultant change in gene expression is, in most cases, irreversible. Tetracycline transactivator systems allow for reversible temporal regulation of transgene expression (see introduction).
Lipus teaches the generation of iCasp9-iPSCs were done through inserting the transgene into the human AAVS1 site, and employing TALENs as an efficient tool for genome editing (see section 2.1). Lipus teaches that the generation of macrophage capable of expressing a transgene was done through viral vectors, which is embodied by a nucleic acid composition.
Mantovani teaches that tumor associated macrophages (TAMs) contribute to tumor progression at different levels and are crucial drivers of tumor-promoting inflammation (see abstract).
It would have been obvious to modify the claims of US Patent 12,359,208 B2 to arrive at the claims of the instant application. Belteki shows that both Cre-recombination and tetracycline transactivator systems are useful in transgene expression, where one may opt to use transactivators for reversible gene expression. Lipus shows that the method of creating iSPC-macrophages capable of expressing a “payload” gene comes from inserting the transgene into cells using an AAV, which is a nucleic acid composition. Mantovani shows that tumor associated macrophages (TAMs) contribute to tumor progression at different levels and are crucial drivers of tumor-promoting inflammation (see abstract) and that macrophage-centered therapeutic approaches are viable in TAMs including blockade of the tumor-promoting activities of TAMs, and the exploitation of macrophage antitumor effector functions (see conclusions).
Therefore, one would have modified with a reasonable expectation of success the transactivator promoter of US Patent 12,359,208 B2 with a Cre recombinase promoter and expect successful transgene expression in a macrophage. One would be motivated to specifically to insert a nucleic acid composition into a tumor-associated macrophage because claim 17 of US Patent 12,359,208 B2 recites where the expression of said nucleic acid composition is capable of remodeling a tumor microenvironment. As shown by Mantovani, tumor-associated macrophages are key actors in the tumor microenvironment and tumor progression.
Claims 1-18 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1, 4, 13, 15, 16, 17, 18, 19, 35, 36, 45, 53, 54, and 55 of copending Application No. 19/235,417 in view of Belteki et al (Conditional and inducible transgene expression in mice through the combinatorial use of Cre-mediated recombination and tetracycline induction, Nucleic Acids Res., 03/22/2005), Lipus et al (Targeted Integration of Inducible Caspase-9 in Human iPSCs Allows Efficient in vitro Clearance of iPSCs and iPSC-Macrophages, Int J Mol Sci, Issue 21, 2020) and Mantovani et al. (Tumor-associated macrophages as treatment targets in oncology, Nature Reviews Clinical Oncology, Issue 14, Pg. 399-416, 2017).
Although the claims at issue are not identical, they are not patentably distinct from each other because they both claim that the first polynucleotide is operably linked to the first promoter. Both also claim a second promoter linked to a second polynucleotide comprising of a payload gene encoding a payload protein comprising of a chimeric antigen receptor (CAR), T-cell receptor (TCR), or a cytokine. Both also claim that upon thermal stimulation, transcription is increased by at least 1.1-fold and that both the nucleic acid composition and the population of heat-inducible macrophages are capable of remodeling the tumor microenvironment.
Belteki teaches both Cre-recombinase and tetracycline-inducible transgenic systems (tetracycline transactivator and reverse tetracycline transactivator) as methods for transgenic expression (see introduction). Cre recombinase transgene provides spatial control, however, once Cre expression has been switched on and recombination has occurred, the resultant change in gene expression is, in most cases, irreversible. Tetracycline transactivator systems allow for reversible temporal regulation of transgene expression (see introduction).
Lipus teaches the generation of iCasp9-iPSCs were done through inserting the transgene into the human AAVS1 site, and employing TALENs as an efficient tool for genome editing (see section 2.1). Lipus teaches that the generation of macrophage capable of expressing a transgene was done through viral vectors, which is embodied by a nucleic acid composition.
Mantovani teaches that tumor associated macrophages (TAMs) contribute to tumor progression at different levels and are crucial drivers of tumor-promoting inflammation (see abstract).
It would have been obvious to modify the claims of the copending application No. 19/235,417 to arrive at the claims of the instant application. Belteki shows that both Cre-recombination and tetracycline transactivator systems are useful in transgene expression, where one may opt to use transactivators for reversible gene expression. Lipus shows that the method of creating iSPC-macrophages capable of expressing a “payload” gene comes from inserting the transgene into cells using an AAV, which is a nucleic acid composition. Mantovani shows that tumor associated macrophages (TAMs) contribute to tumor progression at different levels and are crucial drivers of tumor-promoting inflammation (see abstract) and that macrophage-centered therapeutic approaches are viable in TAMs including blockade of the tumor-promoting activities of TAMs, and the exploitation of macrophage antitumor effector functions (see conclusions).
Therefore, one would have modified, with a reasonable expectation of success, the transactivator promoter of copending application No. 19/235,417 with a Cre recombinase promoter and expect successful transgene expression in a macrophage. One would be motivated to specifically to insert a nucleic acid composition into a tumor-associated macrophage because claim 54 of copeding application No. 19/235,417 recites where the expression of said nucleic acid composition and payload protein (of claims 1-53) is capable of remodeling a tumor microenvironment. As shown by Mantovani, tumor-associated macrophages are key actors in the tumor microenvironment and tumor progression.
This is a provisional nonstatutory double patenting rejection.
Conclusion
No claims are allowed.
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/D.T.Y./Examiner, Art Unit 1635
/DANA H SHIN/Primary Examiner, Art Unit 1635