DETAILED ACTION
Applicant’s response filed 5/1/2026 has been received and entered into the application file. Applicant’s arguments and amendments to the claims have been fully considered.
Claims 1, 3, 6-7, 11-12, 15-19, 22-23, and 77 from the claim set filed 5/1/2026 are pending. Examiner acknowledges the cancellation of claims 2, 4-5, 8-10, 13-14, 20-21, and 24-76. Claims 15-19 and 22 are withdrawn. Claims 1, 3, 6-7, 11-12, 23, and 77 are being examined on the merits herein.
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 .
Objection(s)/Rejection(s) Withdrawn
Claim Objections
RE: Claim 6 is objected to because of the following informalities: Examiner believes there is a typographical error. The language of claim 6 states: “endothelial cell progenitor cell conditioned media”. Claim 1, from which claim 6 depends, states “endothelial progenitor cell conditioned media”. Examiner believes claim 6 should thus state “endothelial progenitor cell conditioned media”.
Applicant amended claim 6 to state “endothelial progenitor cell conditioned media”. As such the previously filed objection is withdrawn.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
RE: Claims 1-3, 6-7, 11-13 and 23 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claims contain subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, at the time the application was filed, had possession of the claimed invention. Claims 2-3, 6-7, 11-13 and 23 are rejected by virtue of their dependency to claim 1 and for not remedying the issue at hand.
Applicant amendment cancelled claims 2 and 13 thus making the rejection of said claims moot.
Applicant amended claim 1 to correct for the issues discussed in the previously filed OA. Amended claim 1 now states:
“A method of inducing cell death of tumor cells in an individual having tumor cells, comprising the step of administering to the individual a therapeutically effective amount of a plurality of modified fibroblasts, wherein:
the modified fibroblasts are fibroblasts modified to express recombinant:
(a) ETV2, FOXC2, and FLI1; and
(b) one or more suicide or death-inducing genes, wherein the one or more death- inducing genes are TNF alpha, TNF beta, FAS ligand, and/or TRAIL.”
As such, the previously filed rejections are withdrawn.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
RE: Claims 1-3, 6-7, 11-13, and 23 are rejected under 35 U.S.C. 112(b), 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 2-3, 6-7, 11-13 and 23 are rejected by virtue of their dependency on claim 1 and for not remedying the issue at hand.
Applicant amendment cancelled claims 2 and 13 thus making the rejection of said claims moot.
Applicant amended claim 1 to correct for the issues discussed in the previously filed OA. Amended claim 1 now states:
“A method of inducing cell death of tumor cells in an individual having tumor cells, comprising the step of administering to the individual a therapeutically effective amount of a plurality of modified fibroblasts, wherein:
the modified fibroblasts are fibroblasts modified to express recombinant:
(a) ETV2, FOXC2, and FLI1; and
(b) one or more suicide or death-inducing genes, wherein the one or more death- inducing genes are TNF alpha, TNF beta, FAS ligand, and/or TRAIL.”
As such, the previously filed rejections are withdrawn.
RE: Claims 6 and 7 are rejected under 35 U.S.C. 112(b), 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 7 is rejected by virtue of its dependency on claim 6 and for not remedying the issue at hand.
Applicant amended claim 6 to state “wherein said endothelial progenitor cell conditioned media is generated from endothelial progenitor cells that were differentiated from pluripotent stem cells”, thus overcoming the previously filed rejections. As such, said rejections are withdrawn.
RE: Claims12-13 are rejected under 35 U.S.C. 112(b), 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 13 is rejected by virtue of its dependency on claim 12 and for not remedying the issue at hand.
Applicant amendment cancelled claim 13 thus making the rejection of said claim moot.
Applicant amended claim 12 to state “wherein said fibroblasts are transfected with tissue factor and/or an inhibitor of Protein C”, thus overcoming the previously filed rejection. As such, said rejection is withdrawn.
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.
RE: Claims 1-3 and 6-7 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Cornell Univ (US2019/0352601 A1, published Nov 21, 2019; IDS filed 8/18/2022).
Applicant amended claim 1 to now state:
“A method of inducing cell death of tumor cells in an individual having tumor cells, comprising the step of administering to the individual a therapeutically effective amount of a plurality of modified fibroblasts, wherein:
the modified fibroblasts are fibroblasts modified to express recombinant:
(a) ETV2, FOXC2, and FLI1; and
(b) one or more suicide or death-inducing genes, wherein the one or more death- inducing genes are TNF alpha, TNF beta, FAS ligand, and/or TRAIL.”
Cornell does not teach of FOXC2, nor does Cornell teach of “one or more suicide or death-inducing genes, wherein the one or more death- inducing genes are TNF alpha, TNF beta, FAS ligand, and/or TRAIL.” As such, the previously filed rejections are withdrawn. However, Applicant amendment has necessitated new grounds of rejection, as set forth below.
Applicant amendment cancelled claim 2 thus making the rejection of said claim moot.
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.
RE: Claim 11 is rejected under 35 U.S.C. 103 as being unpatentable over Cornell in view of Gallego-Perez, henceforth G-P (US 2020/0115425 A1, published April 16, 2020; IDS filed 10/3/2025).
RE: Claims 12-13 are rejected under 35 U.S.C. 103 as being unpatentable over Cornell in view of Berdel (WO 2005021593 A1, published 3/10/2005; English Translation provided PTO 892).
RE: Claim 23 is rejected under 35 U.S.C. 103 as being unpatentable over Cornell in view of Yu (Yu, et al., Nature Communications (2020) 11: 1-17; PTO 892).
For the reasons discussed above, the anticipation rejection over Cornell is withdrawn, and thus the obviousness rejections that are based on the same basis are likewise withdrawn. However, Applicant amendment has necessitated new grounds of rejection as set forth below.
Applicant amendment cancelled claim 13 thus making the rejection of said claim moot.
New Ground(s) of Rejection, Necessitated by Amendment
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.
Claims 1 and 3 are rejected under 35 U.S.C. 103 as being unpatentable over Cornell in view of Gallego-Perez, henceforth G-P, and Deng (Deng, et al., Oncol Lett. (2018) 15(4): 5004-5012; PTO 892).
In regards to claim 1, Cornell teaches of the conversion of non-vascular cells into endothelial cells (ECs) [0006]. Cornell teaches of reprogramming-derived endothelial cells (rECs) [0010]. Cornell teaches in some embodiments, the rECs are derived from non-vascular cells by a process comprising expressing transcription factors ETV2 and FLI1, as well as ERG, from exogenous nucleic acids in the non-vascular cells, i.e., said non-vascular cells are modified to express recombinant ETV2 and FLI1 [0013]. Cornell teaches in some embodiments, the non-vascular cells are selected from the group consisting of …, fibroblasts [0018].
Thus, Cornell teaches of the conversion of fibroblasts (i.e., non-vascular cells) into endothelial cells (ECs) and further teaches of reprogramming-derived endothelial cells. Cornell teaches the reprogrammed-derived endothelial cells are derived from fibroblasts by a process comprising expressing recombinant ETV2 and FLI1 from exogenous nucleic acids in the fibroblasts. Therefore, Cornell teaches of modified fibroblasts, modified to express recombinant ETV2 and FLI1.
Cornell further teaches in some embodiments, the disclosure provides a method for treating a tumor in a human subject, comprising administering to the subject (i.e., an individual having tumor cells) a composition (i.e., in a therapeutically effective amount) comprising a substantially pure population of non-vascular cell-derived ECs (i.e., a plurality of modified fibroblasts) disclosed herein (i.e., modified to express recombinant ETV2 and FLI1), wherein the ECs are engineered to deliver an anti-tumor agent, and upon administration, said ECs form vessels into said tumor ([0022], claim 8, claim 11, claim 22, claim 28). Cornell teaches said fibroblasts are used to treat tumors [0046] and further teaches because tumors frequently stimulate the in-growth of new blood vessels into the tumor (stimulate tumor angiogenesis), endothelial cells (i.e., the modified fibroblasts expressing recombinant ETV2 and FLI1) delivered to a subject can contribute to the new tumor vasculature. Thus, the modified fibroblasts can be used to deliver agents directly to a tumor site. Examples of agents that can be targeted to tumors using said endothelial cells, i.e., modified fibroblasts, include, but are not limited to, cytotoxic drugs, other toxins, radionuclides, and gene expression products [0051].
Thus, a POSITA would be motivated, based upon the teachings of Cornell, to utilize modified fibroblasts, engineered to express ETV2 and FLI1, to stimulate the in-growth of new blood vessels into the tumor and further to use said fibroblasts to deliver anti-cancer agents, which Cornell teaches as a method of treating a tumor in a human subject.
Examiner therefore respectfully notes, the method of Cornell thus reads on a method of inducing cell death of tumor cells in an individual having tumor cells, comprising administering to the individual a therapeutically effective amount of a plurality of modified fibroblasts, wherein the modified fibroblasts are fibroblasts modified to express recombinant ETV2 and FLI1; and an anti-tumor agent such as gene expression products.
Cornell does not teach of FOXC2 nor does Cornell teach of one or more suicide or death-inducing genes, wherein the one or more death-inducing genes are TNF alpha, TNF beta, FAS ligand and/or TRAIL.
G-P teaches a method for reprogramming somatic cells into vasculogenic and/or endothelial cells that involves delivering intracellularly into the somatic cells a polynucleotide comprising two or more nucleic acid sequences encoding proteins selected from the group consisting of ETV2, FOXC2, and FLI1 [0008]. G-P teaches said somatic cells can be any stromal/support cells from connective or epithelial tissues, including skin fibroblasts, muscle fibroblasts, … ([0120], Example 1).
Thus, G-P teaches a method for reprogramming fibroblasts into endothelial cells via modifying said fibroblasts to express recombinant ETV2, FOXC2, and FLI1.
As noted supra, Cornell teaches reprogramming fibroblasts into endothelial cells via modifying said fibroblasts to express recombinant ETV2, FLI1 and ERG [0013].
Thus, as a POSITA will appreciate and as is taught by Cornell, ETV2, FLI1, and ERG are endothelial-inducing genes. As a POSITA will further appreciate, and as is taught by G-P, ETV2, FLI1, and FOXC2 are endothelial-inducing genes. Thus, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to do a simple substitution of one known element for another to obtain predictable results. It would have been obvious to substitute FOXC2 in the place of ERG for inducing endothelial cells.
The skilled artisan would have had a reasonable expectation of said substitution being successful. Substitution of one element for another known in the field is considered to be obvious, absent a showing that the result of the substitution yields more than predictable results. See KSR International Co. v Teleflex Inc 82 USPQ2d 1385 (US 2007) at page 1395.
Thus, the combination of Cornell and G-P teaches of modified fibroblasts, modified to express recombinant ETV2, FOXC2, and FLI1.
In regards to said modified fibroblasts expressing one or more suicide or death inducing genes, wherein the one or more death-inducing genes are TNF alpha, TNF beta, FAS ligand and/or TRAIL, Examiner offers the teachings of Deng.
Deng teaches glioma is one of the most common aggressive neuroepithelial malignant tumors in the central nervous system. It has a high recurrence rate and poor prognosis, primarily due to the fact that novel therapeutic agents cannot penetrate the blood-brain barrier (BBB). Endothelial progenitor cells (EPCs) have been reported to move across the BBB and access the tumor site (Abstract). Deng teaches EPCs can self-proliferate and differentiate into endothelial cells and further have the capability of vasculogenesis and are involved in tumor vessel neogenesis. Deng teaches of endothelial progenitor cells as a vector for tumor treatment (p5011, 1st column, Discussion 2nd paragraph).
Deng teaches TRAIL induces apoptosis, i.e., is a death-inducing gene. Further, Deng teaches of TRAIL-expressing EPCs. Deng teaches EPCs were transfected and stably expressed with TRAIL through lentiviral infection (i.e., Deng teaches of EPCs modified to express recombinant TRAIL). Deng teaches of the pro-apoptotic effect of these TRAIL-expressing EPCs on a glioma cells line. Said TRAIL-expressing EPCs could navigate to the glioma cells and induce apoptosis. Deng teaches the TRAIL-expressing EPCs as a useful strategy for tumor treatment (Abstract).
As noted supra, Cornell and G-P teach a method for treating a tumor in a human subject, via the use of reprogramming-derived endothelial cells (i.e., modified fibroblasts, modified to express recombinant ETV2, FLI1, and FOXC2). Further, Cornell teaches wherein the endothelial cells are engineered to deliver an anti-tumor agent, and upon administration, said endothelial cells form vessels into said tumor. Cornell teaches said cells are used to treat tumors and further teaches because tumors frequently stimulate the in-growth of new blood vessels into the tumor (stimulate tumor angiogenesis), endothelial cells (i.e., the modified fibroblasts expressing recombinant ETV2, FOXC2 and FLI1) delivered to a subject can contribute to the new tumor vasculature. Thus, the modified fibroblasts can be used to deliver agents directly to a tumor site. Examples of agents that can be targeted to tumors using said endothelial cells include, but are not limited to, cytotoxic drugs, other toxins, radionuclides, and gene expression products.
Thus, a POSITA would be motivated, based upon the teachings of Cornell and G-P, to utilize endothelial cells (i.e., modified fibroblasts), engineered to express ETV2, FOXC2, and FLI1, to stimulate the in-growth of new blood vessels into the tumor and further to use said cells to deliver anti-cancer agents, which Cornell teaches as a method of treating a tumor in a human subject.
Thus, it would have been obvious to a POSITA, before the effective filing date of the claimed invention, to combine the teachings of Cornell and G-P with the teachings of Deng in order to have the modified fibroblasts, i.e., endothelial cells, of Cornell and G-P expressing recombinant TRAIL as the anti-tumor agent, as taught by Deng. A POSITA would have been so motivated due to Deng teaching of endothelial cells expressing TRAIL being able to infiltrate tumors and to induce apoptosis in said tumors. As Cornell teaches of endothelial cells expressing anti-cancer agents (i.e., of which TRAIL is an example of), it thus would have been obvious and a POSITA would have been so motivated to combine said teachings. A POSITA further would have had a reasonable expectation of success in combining said teachings due to all working in the field of cancer treatment.
Therefore, Examiner respectfully notes, the teachings of Cornell, G-P, and Deng teach the limitations of claim 1 as currently written.
Thus, the claim is obvious and is properly rejected.
In regards to claim 3, the above cited references teach claim 1. Further, Cornell teaches cells undergoing conversion (i.e., the recombinant fibroblasts) were grown in EC media, i.e., endothelial progenitor cell conditioned media, supplemented with VEGF [0099].
Thus, the claim is obvious and is properly rejected.
Claim 12 is rejected under 35 U.S.C. 103 as being unpatentable over Cornell in view of Gallego-Perez, henceforth G-P, and Deng, and further in view of Berdel.
In regards to claim 12, the above cited references do not teach wherein said fibroblasts are transfected with tissue factor and/or an inhibitor of Protein C.
Berdel teaches of fusion polypeptides and uses thereof in antivascular tumor therapy (Title). Berdel teaches a fusion polypeptide composed of at least 2 peptides, a peptide which enables selective binding of the fusion polypeptide to endothelial cells in tumor vessels and the other peptide which consists of tissue factor (TF), wherein the TF is characterized in that it can activate blood coagulation when binding to endothelial cells in tumor vessels (p1, 1st paragraph).
Berdel teaches adequate neovascularization is a prerequisite for progressive tumor growth. Berdel teaches anti-angiogenic therapy strategies which intervene in the complex process of growth and differentiation of the blood vessels. Berdel teaches antivascular therapy strategies have been developed in the prior art for combating tumors. Said strategies are aimed at destroying the blood vessels and the tumor associated therewith (p1, 2nd- 3rd paragraph). Berdel teaches the present invention relates to medicaments to be used for the treatment of tumors, and in particular relates to antivascular tumor therapy (p2, 3rd full paragraph).
Thus, Berdel teaches of targeting endothelial cells in tumor vessels and teaches the use of TF targeted to said cells to activate blood coagulation and to thus kill tumor cells.
Thus, it would have been obvious to a POSITA, before the effective filing date of the claimed invention, to combine the teachings of Cornell, G-P, Deng and Berdel, in order to have epithelial cells expressing both vascular channel inducing genes, i.e., ETV2, FLI1, and FOXC2, (as taught by Cornel and G-P), a suicide gene (as taught by Deng) and a blood coagulation gene, i.e., TF, (as taught by Berdel) for a treatment of inducing cell death of tumors. A POSITA would have been so motivated to combine said teachings due to all teaching the use of epithelial cells for tumor treatment. A POSITA would have had a reasonable expectation of success in combining said teachings due to all working in the field of tumor treatment.
Thus, the claim is obvious and is properly rejected.
Claim 23 is rejected under 35 U.S.C. 103 as being unpatentable over Cornell in view of Gallego-Perez, henceforth G-P, and Deng, and further in view of Yu.
In regards to claim 23, the above cited references do not teach wherein said fibroblasts are selected for expression of one or more of CXCR4, CD73, CD206 and interleukin 3 receptor.
Yu teaches CD73 is elevated in tumor tissues. Yu additionally teaches of cancer-associated fibroblasts that express CD73 (Abstract). Yu teaches of targeting CD73 on fibroblasts in order to neutralize CD73 (i.e., a known immunosuppressive) and restore the immune system’s ability to attack cancer. Yu teaches said method will be vital to improve therapies that induce massive cell death, to alleviate the cancer associated fibroblast-CD73-mediated immune checkpoint for ultimate and durable tumor control (p14, 1st column, 2nd paragraph; Abstract).
Thus, it would have been obvious to a POSITA, before the effective filing date of the claimed invention, to combine the teachings of Cornell, G-P, and Deng with the teachings of Yu. A POSITA would have been motivated to select for fibroblasts expressing CD73 (as taught by Yu) in order to neutralize CD73 and its immunosuppressive behavior. A POSITA would have been so motivated due to Yu teaching said method will be vital to improve therapies that induce massive cell death (such as the teachings of Cornell, G-P, and Deng), to alleviate the cancer associated fibroblast-CD73-mediated immune checkpoint for ultimate and durable tumor control. A POSITA would have had a reasonable expectation of success in combining said teachings due to all studying cancer.
Thus, the claim is obvious and is properly rejected.
Claim 77 is rejected under 35 U.S.C. 103 as being unpatentable over Cornell in view of Gallego-Perez, henceforth G-P, and Deng, and further in view of Kong (Kong, et al., Stem Cell Research and Therapy (Jan 8, 2021) 12:47; PTO 892).
In regards to claim 77, the above cited references do not teach wherein the fibroblasts are cultured in endothelial progenitor cell conditioned media.
Kong teaches of neovascularization and teaches endothelial progenitor cells contribute to neovascularization through differentiation into mature endothelial cells and paracrine manners to trigger angiogenic events. Kong teaches of EPC conditioned media for vascularization. Kong teaches of substantial biological factors derived from EPCs including angiogenic mRNAs, microRNAs, proteins, and chemical molecules in the conditioned media. Kong teaches, of note, endogenous nitric oxide (NO), as a paracrine pro-angiogenic signaling molecule is primarily synthesized by endothelial nitric oxide synthase and released from EPCs or mature endothelial cells during neovascularization. Kong teaches it is well known that NO could improve EPCs’ and endothelial cells’ migration and angiogenesis, and therefore, NO release contributes to the paracrine properties of EPCs during neovascularization (p2, 1st column). Kong teaches of culturing EPCs or HUVECs in EPC conditioned media (p3, Cell Proliferation Assay; p5, 2nd column, 2nd paragraph).
Thus, it would have been obvious to a POSITA, before the effective filing date of the claimed invention, to combine the teachings of Cornell, G-P, and Deng with the teachings of Kong. As Cornell, G-P, and Deng teach of converting fibroblasts to endothelial cells for vascularization of tumors and Kong teaches of the beneficial effect of endothelial progenitor cell conditioned media in regards to neovascularization, a POSITA would thus have been motivated to culture the fibroblasts of Cornell, G-P, and Deng in the endothelial progenitor cell conditioned media of Kong in order to ensure the best culture conditions for the fibroblasts to be converted into endothelial cells for neovascularization of tumors. A POSITA would have had a reasonable expectation of success in combining said teachings due to all studying vascularization.
Thus, the claim is obvious and is properly rejected.
Claims 6, 7, and 11 are rejected under 35 U.S.C. 103 as being unpatentable over Cornell in view of Gallego-Perez, henceforth G-P, Deng, and Kong, and further in view of Williams (Williams et al., Arterioscler Thromb Vasc Biol (2019) 39(7); PTO 892).
In regards to claims 6 and 7, the above cited references do not teach wherein said endothelial progenitor cell conditioned media is generated from endothelial progenitor cells that were differentiated from pluripotent stem cells. Kong teaches endothelial progenitor cell conditioned media which is generated from human peripheral blood-derived EPCs (p2, 2nd column, 3rd full paragraph).
Williams teaches human pluripotent stem cells (hPSCs) are capable of unlimited self-renewal and subsequent differentiation into any adult somatic cell type. As such, hPSCs are an attractive cellular source for generating endothelial cells (ECs) (and thus endothelial progenitor cells). Williams teaches the majority of hPSCs-derived ECs have been generated from either human embryonic stem cells (hESCS) or human induced pluripotent stem cells (hiPSCs) (i.e., claim 7). Williams additionally teaches hiPSCs are especially valuable because they can be derived from easily accessible cell sources and they allow for the generation of patient-specific hPSCs (p2, 2nd full paragraph).
Thus, it would have been obvious to a POSITA, before the effective filing date of the claimed invention, to do a simple substitution of one known element for another to obtain predictable results. It would have been obvious to substitute the human peripheral blood-derived EPCs of Kong for the hiPSC-derived EPCs of Williams in order to have an easily accessible cell source capable of unlimited self-renewal and subsequent differentiation. The skilled artisan would have had a reasonable expectation of successfully substituting said cells. Substitution of one element for another known in the field is considered to be obvious, absent a showing that the result of the substitution yields more than predictable results. See KSR International Co. v Teleflex Inc 82 USPQ2d 1385 (US 2007) at page 1395.
Thus, the above cited references teach wherein said endothelial progenitor cell conditioned media is generated from endothelial progenitor cells that were differentiated from hiPSCs.
Thus, the claims are obvious and are properly rejected.
In regards to claim 11, as discussed supra, Cornell, G-P, and Deng teach of fibroblasts engineered to express ETV2, FOXC2, and FLI1. As is also discussed supra, Kong and Williams teach of endothelial progenitor cell conditioned media generated from iPSCs.
Further, Examiner notes Cornell teaches the engineered fibroblasts (i.e., the engineered EPCs) may be derived from induced pluripotent stem cells [0075] and teaches transfection of said cells with the exogenous nucleic acids.
Thus, it is conceivable that it would have been obvious to a POSITA and a POSITA would have been so motivated, before the effective filing date of the claimed invention, to transfect iPSCs with ETV2, FOXC2 and FLI1 (as taught by Cornell and G-P) to generate endothelial progenitor cells expressing ETV2, FOXC2, and FLI1 for the endothelial progenitor cell conditioned media in which the endothelial progenitor cells were differentiated from pluripotent stem cells expressing the desired nucleic acids of the claimed invention. A POSITA would have had a reasonable expectation of success in combining said teachings due to all working in the field endothelial cells.
Thus, the claim is obvious and is properly rejected.
Response To Applicant Remarks
RE: 35 USC 103
In regards to Applicant remarks addressing claim 11 (p8), and specifically to the remarks stating “both Cornell and G-P are directed to methods of vasculature repair and creating, objectives that are fundamentally at odds with the present claims” as well as in regards to Applicant remarks stating “the instant claims are directed to modified fibroblasts that cause vasculature destabilization” and “given that both references are squarely focused on promoting vascular growth and stability, one of ordinary skill in the art would have had no motivation to combine fibroblasts expressing ETV2, FOXC2, and FLI1 with a death inducing gene for the purpose of destabilizing vasculature and inducing tumor cell death” , Examiner respectfully points Applicant to the updated rejection of claim 1 in which Examiner explained the obviousness and the motivation in combining fibroblasts expressing ETV2, FOXC2, and FLI1 with a death inducing gene for the purpose of inducing tumor cell death.
In regards to “destabilizing vasculature”, Examiner respectfully notes that claim 1, as currently written, does not include said limitation.
Conclusion
No claims are allowable.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KATHERINE R SMALL whose telephone number is (703)756-4783. The examiner can normally be reached Monday - Friday 8:30am-4pm.
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/KATHERINE R SMALL/Examiner, Art Unit 1633
/EVELYN Y PYLA/Primary Examiner, Art Unit 1633
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