DETAILED ACTION
Claims 1-3, 6-7, 11-13, 15-19, and 22-23 from the claim set filed September 9, 2025 are pending. Examiner acknowledges the cancellation of claims 4-5, 8-10, 14, 20-21, and 24-76. Claims 15-19 and 22 are withdrawn. Claims 1-3, 6-7, 11-13, and 23 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 .
Election/Restrictions
Applicant's election of Group I, claims 1-3, 6-7, 11-13, 15-19, and 22-23 and claims 12-13 in regards to the species election in the reply filed on September 9, 2025 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Upon further examination, Examiner has noted claims 18-19 and 22 are directed to fibroblasts transfected with an immune stimulatory gene. As such, said claims read on species 2, i.e., “wherein said fibroblasts are transfected with one or more immune stimulatory genes”. Thus, species 2 from the Election/Restriction requirement filed May 9, 2025 encompasses claims 15-19 and 22.
Thus, claims 15-19 and 22 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention (i.e., a nonelected species), there being no allowable generic or linking claim. Claims 1-3, 6-7, 11-13, and 23 will be examined on the merits herein.
Priority
A claim for benefit of a prior-filed application under 35 U.S.C. 119(a)-(f) or under 35
U.S.C. 120, 121, 365(a)-(c), 386 (a) or 386(c) has been made. The effective filing date of the
present application is May 6, 2021.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 2/20/2023, 10/3/2023, and 8/18/2022 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892 or listed on the submitted IDS(s), they have not been considered.
Claim Objections
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”.
Appropriate correction is required.
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.
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.
Claim 1 is directed to a method of inducing cell death of tumor cells in an individual, comprising the step of administering to the individual a therapeutically effective amount of a plurality of modified fibroblasts, wherein:
(I) the fibroblasts express recombinant:
(a) one or more endothelial-inducing genes and/or one or more vascular channel-inducing genes; and
(b) one or more suicide or death-inducing genes, and/or
(II) the fibroblasts are cultured in endothelial progenitor cell conditioned media.
Issues:
Claim 1 encompasses fibroblasts expressing one or more of ANY endothelial inducing gene(s) AND/OR one or more of ANY vascular channel inducing gene(s) and one or more of ANY suicide genes. Additionally, said claim encompasses fibroblasts not expressing any endothelial inducing genes, vascular channel inducing genes and suicide genes. Examiner thus notes that due to the language of claim 1, multiple embodiments are encompassed due to the use of “one or more” as well as “and/or”, as well as points (I) and (II) not both being required limitations.
Claim 1 does not define any actual genes to be expressed but rather uses generic categories of genes to be expressed.
In regards to point (II), claim 1 incorporates endothelial progenitor cell conditioned media that encompasses ANY amount being used for culturing for ANY amount of time in ANY concentration. Thus, the claim encompasses culturing the fibroblasts for one second, or for one year, in an undefined concentration, in an undefined amount.
Claim 1 is a method for inducing cell death in a tumor yet claim 1 does not state how a POSITA would arrive at inducing cell death in tumor cells due to there being no active step of tumors being required for claim 1.
The method of claim 1 does not appear to comprise properties of the fibroblasts causing targeting of tumor cells.
The individual being administered the composition of claim 1 is not required to actively have tumor cells. Said individual could be cancer free and thus not having tumor cells to kill.
The claim does not state how the fibroblasts are modified/recombinant as the claim reads on both fibroblasts not expressing any of the types of genes listed in claim 1 as well as the claim reading on genes naturally expressed in fibroblasts.
A review of the specification shows that Applicants have not provided sufficient description of the invention to support they were in possession of the claimed method. Possession of an invention may be shown in a variety of ways including description of an actual reduction to practice, or by showing that the invention was "ready for patenting" such as by the disclosure of drawings or structural chemical formulas that show that the invention was complete, or by describing distinguishing identifying characteristics sufficient to show that the applicant was in possession of the claimed invention. See, e.g., Pfaff v. Wells Elecs., Inc., 525 U.S. 55, 68, 119 S.Ct. 304, 312, 48 USPQ2d 1641, 1647 (1998).
In the instant case, the specification provides zero actual data or experiments regarding the claimed method but rather states what has been shown in the prior art. Thus, the specification in view of the prior art, appears to support (1) a method differentiating fibroblasts into endothelial progenitor cells via transfection of said fibroblasts with ETV2, FOXC2, and FLI1, (2) transfection of the fibroblasts of point 1 with anti-tumor agents, (3) culturing the transfected fibroblasts of point 2 in a defined endothelial progenitor cell conditioned media, and (4) a method of inducing cell death of tumor cells via administering to an individual in need thereof, a therapeutically effective amount of the above discussed transfected fibroblasts.
Thus, a review of the specification shows that Applicants have not provided sufficient description of the invention to support they were in possession of the claimed method.
Thus, the claims are properly rejected.
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.
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.
In regards to claim 1, Examiner notes the metes and bounds of the claim cannot be determined due to multiple issues found within the claim.
Issues:
Claim 1 encompasses fibroblasts expressing one or more of ANY endothelial inducing gene(s) AND/OR one or more of ANY vascular channel inducing gene(s) and one or more of ANY suicide genes. Additionally, said claim encompasses fibroblasts not expressing any endothelial inducing genes, vascular channel inducing genes and suicide genes. Examiner thus notes that due to the language of claim 1, multiple embodiments are encompassed due to the use of “one or more” as well as “and/or”, as well as points (I) and (II) not both being required limitations.
Claim 1 does not define any actual genes to be expressed but rather uses generic categories of genes to be expressed.
In regards to point (II), claim 1 incorporates endothelial progenitor cell conditioned media that encompasses ANY amount being used for culturing for ANY amount of time in ANY concentration. Thus, the claim encompasses culturing the fibroblasts for one second, or for one year, in an undefined concentration, in an undefined amount.
Claim 1 is a method for inducing cell death in a tumor yet claim 1 does not state how a POSITA would arrive at inducing cell death in tumor cells due to there being no active step of tumors being required for claim 1.
The method of claim 1 does not appear to comprise properties of the fibroblasts causing targeting of tumor cells.
The individual being administered the composition of claim 1 is not required to actively have tumor cells. Said individual could be cancer free and thus not having tumor cells to kill.
The claim does not state how the fibroblasts are modified/recombinant as the claim reads on both fibroblasts not expressing any of the types of genes listed in claim 1 as well as the claim reading on genes naturally expressed in fibroblasts.
Thus, the claim is considered indefinite because there is a question or doubt as to what exactly the claim entails within the scope of the invention.
Thus, the claims are properly rejected.
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.
In regards to claim 6, the wording of said claim is unclear. It is not clear if the fibroblasts, i.e., the modified endothelial progenitor cells, from claim 1 are produced, i.e., generated, from pluripotent stem cells, i.e., said stem cells have differentiated into endothelial progenitor cells.
In the interest of compact prosecution, Examiner believes the claim is meant to state the modified endothelial progenitor cells are generated from pluripotent stem cells. However, the wording of said claim is not clear. Thus, the claim is considered indefinite because there is a question or doubt as to what exactly the claim entails within the scope of the invention.
Despite the above interpretation, such treatment does not relieve Applicant of the responsibility of responding to this rejection. If the actual interpretation of the claim is different than that posited by the Examiner, additional rejections and art may be readily applied in a subsequent final Office action.
Thus, the claims are properly rejected.
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.
In regards to claim 12, Examiner notes the metes and bounds of the claim cannot be determined due to multiple issues found within the claim. Claim 12 uses a generic term when defining the genes to be transfected. The claim does not define nor identify which genes are to be used in said transfection. The use of the generic term “thrombosis associated genes” is unclear as to what exactly the scope of the invention entails. Are said genes, genes which cause an increase in blood clots? Further, the claim does not require the active step of hypoxia but requires the gene to be upregulated in response to hypoxia.
Thus, the claims are considered indefinite because there is a question or doubt as to what exactly the claims entail within the scope of the invention.
Therefore, the claims are properly rejected.
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 1-3 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).
Claims 1-3:
In regards to claim 1 and a search of the prior art, Examiner notes the claim language as currently written is generic and unclear. Please see the above 112b. The claim relates to fibroblasts expressing a number of undefined and alternative genes, for the purpose of cancer treatment. Based upon the specification, Examiner believes the invention requires the conversion of fibroblasts into epithelial cells or at the minimum for said fibroblasts to behave more endothelial cell-like in activity. However, the language of claim 1 does not require such epithelial cells/endothelial cell-like activity. In regards to searching the prior art, Examiner has relied upon the dependent claims to narrow the search in the interest of compact prosecution and has looked for art regarding the conversion of fibroblasts into epithelial cells for the treatment of cancer or inducing cell death of tumor cells.
Cornell teaches of the conversion of non-vascular cells into epithelial 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/recombinant [0013] (claims 2 and 3, instant application). As a POSITA will appreciate and as is well known in the art, ETV2, FLI1, and ERG are endothelial-inducing genes, as well as vascular channel inducing genes. Cornell teaches in some embodiments, the non-vascular cells are selected from the group consisting of …, fibroblasts [0018]. Cornell further teaches in some embodiments, this disclosure provides a method for treating a tumor in a human subject, comprising administering to the subject, i.e., an individual, 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, wherein the ECs are engineered to deliver an anti-tumor agent, and upon administration, said ECs form vessels into said tumor [0022]. This reads on inducing cell death of tumor cells. In regards to said anti-tumor agent, Cornell teaches the cells can be engineered such that they also express a protein having anti-tumor activity [0051]. This reads on said cells have one or more suicide or death-inducing genes.
Thus, Cornell teaches claim 1, points (I)(a) and (b).
In regards to claim 1, point (II), 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] (claim 3, instant application).
Thus, Cornell teaches point (II).
The above teachings also teach of claims 2-3, as noted supra.
Thus, claims 1-3 are anticipated and are properly rejected.
In regards to claims 6 and 7, Examiner notes the wording of claim 6 is unclear. Please see the above 112b. Examiner believes the claim is meant to imply the modified endothelial progenitor cells are generated from pluripotent stem cells. However, the wording of said claim is not clear.
Cornell teaches the non-vascular cells are selected from the group consisting of amniotic cells, embryonic stem cells, induced pluripotent stem cells, mesenchymal stem cells, fibroblasts, etc (claim 22). Thus, Cornell teaches the modified endothelial progenitor cells may be generated from pluripotent stem cells. Examiner believes this reads on the limitations of claim 6.
In regards to claim 7, as noted supra, Cornell teaches of embryonic stem cells.
Thus, the claims are anticipated and are properly rejected.
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.
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).
In regards to claim 11, 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/recombinant [0013]. Cornell teaches the non-vascular cells are selected from the group consisting of amniotic cells, embryonic stem cells, induced pluripotent stem cells, mesenchymal stem cells, fibroblasts, etc (claim 22). Cornell additionally teaches introduction of a nucleic acid encoding said transcription factors can be achieved using such methods as …, transfection, [0075].
Thus, Cornell teaches wherein said pluripotent stem cells are differentiated into endothelial progenitor cells (i.e., rECs) by transfection of ETV2, FLI1, and ERG. Cornell does not teach of FOXC2.
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).
As a POSITA will appreciate and as is well known in the art, ETV2, FLI1, and ERG (as taught by Cornell) are endothelial-inducing genes, as well as vascular channel inducing genes. As a POSITA will further appreciate, FOXC2 is an endothelial-inducing gene, as well as vascular channel inducing gene. Moreover, Examiner notes both Cornell and G-P teach of using said endothelial-inducing genes/vascular channel inducing genes to induce fibroblasts into epithelial cells.
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 epithelial 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 claim is obvious and is properly rejected.
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).
In regards to claims 12 and 13, Cornell does not teach wherein said fibroblasts are transfected with one or more thrombosis associated genes.
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).
In regards to the phrase “wherein said gene is upregulated in response to hypoxia”, Examiner notes said phrase is simply reciting an inherent feature of a thrombosis associated gene such as TF. As a POSITA will appreciate, hypoxia naturally leads to the upregulation of genes such as TF due to hypoxia triggering changes in gene expression that create a more prothrombotic, i.e., clot forming, state. As a POSITA will appreciate, and as is well known, hypoxia increases the expression of pro-thrombotic, i.e., blood coagulation genes.
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 and Berdel, in order to have epithelial cells expressing both vascular channel inducing genes, i.e., ETV2, FLI1, and ERG, (as taught by Cornel) and blood coagulation genes, i.e., TF, (as taught be Berdel) for a treatment of inducing cell death of tumors. A POSITA would have been so motivated to combine said teachings due to both Cornell and Berdel teaching the use of epithelial cells for antivascular tumor therapy. A POSITA would have had a reasonable expectation of success in combining said teachings due to all working in the field of antivascular tumor therapy.
Thus, the claims are obvious and are properly rejected.
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).
In regards to claim 23, Cornell does 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).
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 Yu. A POSITA would have been motivated to select for fibroblasts expressing CD73 (as taught by Yu) in order to ensure said fibroblasts were cancer targeting and thus able to target the induced endothelial cells generated by Cornell to cause tumor cell death. A POSITA would have had a reasonable expectation of success in combining said teachings do to all studying fibroblasts and cancer.
Thus, the claim is obvious and is properly rejected.
Conclusion
No claims are allowable.
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/KATHERINE R SMALL/Examiner, Art Unit 1633
/EVELYN Y PYLA/Primary Examiner, Art Unit 1633