DETAILED ACTION
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 without traverse in the reply filed on 10/14/2025 is acknowledged.
Election of the following species on the reply filed on 10/14/2025 is acknowledged: Sox-17.
Claims 1-19, 21, 23, and 26 are pending.
Claims 14-15 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected species, there being no allowable generic or linking claim.
Claims 1-13, 16-19, 21, 23, and 26 are examined on the merits.
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.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 13, 16-19 and 21 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 13, and 16-19 recite the limitation "SOXF RNA". The claims are dependent on claim 1, and there is insufficient antecedent basis for this limitation in the claim. The parent claim does not recite RNA.
For purposes of compact prosecution claims 13, 16 and 17 are interpreted as dependent on claim 10.
Claim 18 recites the limitation “the SOXF transcription factor RNA”. The claim is dependent on claim 17 and there is insufficient antecedent basis for this limitation in the claim. The parent claim does not recite “SOXF transcription factor RNA”.
Appropriate correction is required.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claim 23 is rejected under 35 U.S.C. 101 because the claimed inventions are directed to a judicial exception (specifically a natural product) without significantly more.
The claims have been analyzed for eligibility in accordance with their broadest reasonable interpretation.
Regarding claim 23: Claim 23 is drawn to a product (in this case the hemogenic endothelial progenitor cells are considered a product).
Step 1: Is claim directed to a statutory category of invention?
Yes, the claim is drawn to a product (hemogenic endothelial progenitor cells), which is a statutory category of invention (Step 1: YES).
Step 2A, Prong 1: Does the claim recite a product of nature judicial exception (JE)?
Claim 23 discloses an enriched preparation of hemogenic endothelial progenitor cells. The naturally occurring counter part of the claimed product is hemogenic endothelial progenitor cells existing in nature. Wu et al (Stem Cells (2007)25:11;1-16) teach hemogenic endothelial progenitor cells can be isolated from human umbilical cord blood (title, abstract).
The claimed hemogenic endothelial progenitor cells are not markedly different from the naturally occurring hemogenic endothelial progenitor cells because there is no evidence that the claimed product is different from the naturally occurring counterpart and no indication in the specification that the claimed cells possess any characteristics significantly different from those in nature.
Thus there is no marked difference between the claimed product and product of nature.
Thus the claim does recite a product of nature judicial exception (Step 2A, Prong 1: YES).
Step 2A, Prong 2: Does the claim recite additional elements that integrate the JE into a practical application?
Claim 23 does not integrate the product into a practical application because the claim is to the population of hemogenic endothelial progenitor cells, per se, not a method of use.
(Step 2A, Prong 2: NO).
Step 2B: Are there additional elements that add significantly more to the ‘product of nature judicial exception’?
The claim does not recite any elements in addition to the active steps of the method, so there are no additional elements that add significantly more to the judicial exception (Step 2B: NO).
The claim is patent ineligible.
Claim Interpretation
The claims in this application are given their broadest reasonable interpretation using the plain meaning of the claim language in light of the specification as it would be understood by one of ordinary skill in the art.
The claims recite “hemogenic endothelial progenitor cells” and the instant specification is silent on an explicit definition of the term. The broadest reasonable interpretation of the progenitor cells is progenitor cells which can generate hemogenic endothelium and progenitor cells that arise from hemogenic endothelium.
The claims recite the term “enriched” and the instant specification is silent on an explicit definition of this term. The Merriam-Webster dictionary defines the term “enrich” as “to process so as to add or increase the proportion of a desirable ingredient” (https://www.merriam-webster.com/dictionary/enrich). Thus the broadest reasonable interpretation of the claim limitation is a preparation of cells which contains more hemogenic endothelial cells as compared to a different population of cells.
The claims are examined with the interpretation as stated.
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)(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.
Claims 1-4, 8-9 and 23 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Clarke et al (Nature Cell Biology (2013) 15:5;502-516).
Regarding claims 1, 8, 23: Clarke teach a method of generating hemogenic endothelium from pluripotent stem cells (mouse embryonic stem cells) (abstract). This reads on “providing a population of pluripotent stem cells” of the instant claim 1.
Clarke further teach differentiation of mESCs which comprise the SoxF transcription factor construct Sox17-mCherry (p511 ¶5). Figure 1 teach the expression of Sox17 identifies the emergence of hemogenic endothelial and hematopoietic progenitors in vitro (p503). Figure 1a teaches a differentiation protocol for the ESCs to generate hemogenic endothelial progenitors (p503). This reads on inducing expression of a SOXF transcription factor and culturing the population of pluripotent cells expressing the SoxF transcription factor.
Regarding “the enriched preparation of hemogenic endothelial progenitor cells is produced as a result of said culturing”, as Clarke teach the culturing step, the method of Clarke would inherently produce the enriched preparation of hemogenic endothelial progenitor cells.
Regarding claim 2: Regarding the expression of VE-cadherin (VEC) and CD34 by the hemogenic endothelial progenitor cells; Clarke teach the culturing step, thus it would inherently produce the enriched preparation of hemogenic endothelial progenitor cells which co-express VE-cadherin (VEC) and CD34.
Regarding claim 3: Clarke teach cultures of enriched hemogenic endothelial progenitor cells (Fig 1c D5.25) which do not express CD31 (Sox17 expressing cells which are negative for expression of CD31) (Fig 1c).
Regarding claim 4: Regarding the expression of VE-cadherin (VEC) and CD34 by at least 60% of the hemogenic endothelial progenitor cells; Clarke teach the culturing step, thus the method of Clarke would inherently produce the enriched preparation of hemogenic endothelial progenitor cells with expression of VE-cadherin (VEC) and CD34 by at least 60% of the cells.
Regarding claims 9: Clarke teach an mESC cell line carrying a Sox17-mCherry fusion DNA (p502 col2 ¶2, p511 col1 ¶5). Generating an mESC line carrying a Sox17-mCherry fusion requires the introduction of a nucleic acid molecule encoding the SOXF transcription factor into cells of the pluripotent stem cell population.
Thus the teachings of Clarke anticipates the invention as claimed.
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.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1-9 and 23 are rejected under 35 U.S.C. 103 as being unpatentable over Clarke et al (Nature Cell Biology (2013) 15:5;502-516) in view of Choi et al (Cell Reports (2012)2;553-567).
Clarke et al anticipate the invention of claims 1-4, 8-9 and 23 and thus render them obvious (see above).
Regarding claims 5, 6 and 7: The teachings of Clarke are discussed supra. Clarke teach the stem cells are mouse pluripotent stem cells. Clarke do not teach the stem cells are human induced pluripotent stem cells or human embryonic stem cells, or that the hemogenic endothelial progenitor cells are human hemogenic endothelial progenitor cells.
Choi teach human hematopoietic progenitor cells can be generated from human pluripotent stem cells (p554 col1 ¶2). Choi further teach the pluripotent stem cells can be induced pluripotent stem cells or human embryonic stem cells (p563 col2 ¶4l p564 col2 ¶4). Choi also teach a system for generation of hematopoietic stem cells from human pluripotent stem cells would provide an opportunity to study human HSC development and provide a novel source of therapeutic cells for blood disease (p553 col1 ¶1).
It would have been obvious to one of ordinary skill in the art to adapt the methods of Clarke drawn to producing hemogenic endothelial progenitor cells by using human induced pluripotent stem cells or human embryonic stem cells as taught by Choi to generate human endothelial progenitor cells.
One of ordinary skill in the art would have been motivated to modify the method of Clarke to use human iPSCs or human ESCs to generate human hemogenic endothelial progenitor cells as taught by Choi to for the purposes of developing a system to study human HSC development and to provide a novel source of therapeutic cells for blood disease.
One would have had a reasonable expectation of success because the inventions of both Clarke and Choi are drawn to the development of hemogenic endothelial progenitor cells.
Thus the invention as claimed is rendered obvious by the teachings of Clarke and Choi.
Claims 10 and 16 are rejected under 35 U.S.C. 103 as being unpatentable over Clarke et al (Nature Cell Biology (2013) 15:5;502-516) as applied to claims 1-9 and 23 above, and further in view of Nakajima-Takagi et al (Blood (2013) 121:3;1-12).
Clarke et al teach the subject matter of claims 1-9 and 23 (see above).
Regarding claims 10 and 16: As discussed surpa, for purposes of compact prosecution claim 16 is interpreted as dependent on claim 10.
Clarke teach an mESC cell line carrying a targeted Sox17-mCherry fusion DNA (p502 col2 ¶2, p511 col1 ¶5). Clarke do not teach introducing a nucleic acid molecule encoding a SOXF transcription factor RNA into the pluripotent stem cells.
Nakajima-Takagi teach over expression of Sox17 promotes cell growth and expansion of cells expressing hemogenic endothelial markers (abstract). Nakajima-Takagi further teach cells transduced with a vector comprising Sox17 (p2 col1 ¶3). Nakajima-Takagi teach the transcription factor is subcloned into the MIG retrovirus vector (p2 col2 ¶3). The MIG retrovirus vector is an RNA virus, and thus Sox17 cloned into the MIG retrovirus and transduced into cells reads on introducing a nucleic acid molecule encoding the SOXF transcription factor wherein the SOXF transcription factor is a SoxF transcription factor RNA. A viral vector reads on a delivery vehicle as required by claim 16.
Nakajima-Takagi further teach Sox17 promotes the expansion of hemogenic endothelial-like cells (p2 col1 ¶2).
It would have been obvious to one of ordinary skill in the art to adapt the methods of Clarke drawn to producing hemogenic endothelial progenitor cells by introducing a nucleic acid molecule encoding the SOX17 RNA as taught by Nakajima-Takagi, to generate human endothelial progenitor cells.
One of ordinary skill in the art would have been motivated to modify the method of Clarke to introduce a nucleic acid molecule encoding the SOX17 RNA as taught by Nakajima-Takagi to generate human hemogenic endothelial progenitor cells because Nakajima-Takagi teach Sox17 promotes expansion of hemogenic endothelial-like cells.
One would have had a reasonable expectation of success because the inventions of both Clarke and Nakajima-Takagi are drawn to the development of hemogenic endothelial progenitor cells.
Thus the invention as claimed is rendered obvious by the teachings of Clarke and Nakajima-Takagi.
Claim 13 is rejected under 35 U.S.C. 103 as being unpatentable over Clarke et al (Nature Cell Biology (2013) 15:5;502-516) as applied to claims 1-9 and 23 above, and further in view of Nakajima-Takagi et al (Blood (2013) 121:3;1-12) and Iwama et al (JP2012050357A).
Regarding claim 13: The claim is interpreted as dependent on claim 10, as discussed supra.
The teachings of Clarke are discussed supra. Clarke do not teach introducing a human Sox17 RNA.
Nakajima-Takagi teach introducing Sox17 RNA, as discussed surpa. Nakajima-Takagi do not teach the Sox17 RNA is a human Sox17 RNA.
Iwama teach a method to amplify hematopoietic precursor cells by expression of a gene encoding the transcription factor Sox17 (abstract). Iwama further teach it is preferable to express a gene encoding human Sox17 when human hematopoietic progenitor cells are used (p5 ¶11).
It would have been obvious to one of ordinary skill in the art to adapt the methods of Clarke drawn to producing hemogenic endothelial progenitor cells by introducing a nucleic acid molecule encoding human SOX17 RNA as taught by Nakajima-Takagi and Iwama, to generate human endothelial progenitor cells.
One of ordinary skill in the art would have been motivated to modify the method of Clarke to introduce a nucleic acid molecule encoding the human SOX17 RNA as taught by Nakajima-Takagi and Iwama to generate human hemogenic endothelial progenitor cells because Iwama teach it is preferable to express a gene encoding human Sox17 when human hematopoietic progenitor cells are used.
One would have had a reasonable expectation of success because the inventions demonstrate successful differentiation of pluripotent stem cells for generation of hemogenic endothelial progenitor cells.
Thus the invention as claimed is rendered obvious by the teachings of Clarke , Nakajima-Takagi and Iwama.
Claims 17-19 are rejected under 35 U.S.C. 103 as being unpatentable over Clarke et al (Nature Cell Biology (2013) 15:5;502-516) as applied to claims 1-9 and 23 above, and further in view of and Randolph et al (Scientific Reports (2017)7:1549;1-8).
Regarding claims 17-19: Claim 17 is interpreted as dependent on claim 10, as discussed supra.
The teachings of Clarke are discussed supra. Clarke do not teach the SOXF RNA is contained in a plasmid expression vector operatively coupled to an inducible promoter.
Randolph teach drug-inducible gene expression systems to achieve versatile inducible gene expression in human pluripotent stem cells (Abstract). Randolph teach the vector comprises elements of the PiggyBac transposase system and a Tet-On drug-inducible gene expression system (abstract). Randolph further teach plasmids using a constitutive promoter to express a gene of interest are not suitable for human stem cell differentiation applications where temporal control of gene expression is crucial, and that inducible plasmid constructs are more effective for stem cell differentiation applications due to increased user control of the gene expression (p2 ¶1). Randolph teach an inducible gene expression system comprising a plasmid that provides tight use control of temporal and tunable gene expression for pluripotent stem cells (p2 ¶3).
Randolph teach addition of the drug doxycycline induces protein expression of the inducible vector (Fig 2, p4). This reads on administering an effective amount of the drug to mediate expression from the expression vector.
It would have been obvious to one of ordinary skill in the art to adapt the methods of Clarke drawn to producing hemogenic endothelial progenitor cells by introducing a plasmid expression vector with SOX17-mC operatively coupled to a drug inducible promoter as taught by Randolph, to generate human endothelial progenitor cells.
One of ordinary skill in the art would have been motivated to modify the method of Clarke to introduce plasmid expression vector with a transgene operatively coupled to a drug inducible promoter as taught by Randolph to generate human hemogenic endothelial progenitor cells because Randolph teach an inducible gene expression system comprising a plasmid that provides tight use control of temporal and tunable gene expression is preferable for gene expression in pluripotent stem cells intended for differentiation.
One would have had a reasonable expectation of success because the inventions demonstrate successful differentiation of pluripotent stem cells for generation of hemogenic endothelial progenitor cells and one of ordinary skill in the art would understand that drug inducible gene expression systems are well known in the art and are part of standard molecular biology techniques.
Thus the invention as claimed is rendered obvious by the teachings of Clarke, and Randolph.
Claim 21 is rejected under 35 U.S.C. 103 as being unpatentable over Clarke et al (Nature Cell Biology (2013) 15:5;502-516) in view of Randolph et al (Scientific Reports (2017)7:1549;1-8) as applied to claims 1-9, 17-19 and 23 above, and further in view of Addgene (PiggyBac-ing Through the Genome Editing Field [online] (2016). Addgene corporation [retrieved on 01/29/2026]. Retrieved from the Internet: <URL: https://blog.addgene.org/piggybac-ing-through-the-genome-editing-field).
Regarding claim 21: The teachings of Clarke are discussed supra. Clarke do not teach the removing the expression vector from the hemogenic endothelial progenitor cells.
The teachings of Randolph are discussed supra. Randolph also teach plasmid systems using transposon technology (such as the disclosed system) allows reversible insertion and removal from the genome of the cell of interest (p2 ¶2).
Clarke in view of Randolph do not explicitly teach removing the expression vector from the cells after culturing.
Addgene teach the piggyBac transposon system (used in the vector disclosed by Randolph) can be used for generating transgenic cell lines, such as those disclosed in the instant application (p2 ¶2). Addgene teach the donor cassette can be removed to result in footprint-free integration of the gene of interest, and that the donor plasmid can be removed by using a negative selection marker to kill off any cells that contain the donor plasmid (p4 ¶1). Addgene teach removal of the donor cassette prevents reintegration of the donor, and killing cells that comprise the donor after excision of the donor cassette results in a cell population with only the gene edit that is footprint free (p2¶1).
It would have been obvious to one of ordinary skill in the art to adapt the methods of Clarke drawn to producing hemogenic endothelial progenitor cells by introducing a plasmid expression vector with a transgene operatively coupled to a drug inducible promoter as taught by Randolph and Addgene, to generate human endothelial progenitor cells.
One of ordinary skill in the art would have been motivated to modify the method of Clarke to introduce plasmid expression vector by removing the expression vector from the hemogenic endothelial progenitor cells as taught by Randolph and Addgene to generate human hemogenic endothelial progenitor cells because Addgene teach removal of the donor cassette prevents reintegration of the donor, and killing cells that comprise the donor after excision of the donor cassette results in a cell population with only the gene edited cells that are footprint free.
One would have had a reasonable expectation of success because the invention of Randolph teach a gene expression system comprising components of a footprint-free gene editing and Randolph teach successful gene editing of pluripotent stem cells.
Thus the invention as claimed is rendered obvious by the teachings of Clarke, Randolph and Addgene.
Claim 26 is rejected under 35 U.S.C. 103 as being unpatentable over Clarke et al (Nature Cell Biology (2013) 15:5;502-516) as applied to claims 1-9 and 23 above, and further in view of Choi et al (Cell Reports (2012)2;553-567) and Bazinet et al (Current Oncology (2019) 26:3;187-191).
Regarding claim 26: The teachings of Clarke are discussed supra. Clarke do not teach the method of treating a condition mediated by a loss of hematopoietic stem cells by administering an enriched preparation of hemogenic endothelial progenitor cells.
Choi teach hemogenic endothelium is a source of hematopoietic stem cells and could provide a novel source of therapeutic cells for blood disease (abstract, p553 col1 ¶1).
Bazinet teach hematopoietic stem-cell transplantation (HSCT) is a medical procedure that consist of infusing (administering) stem cells after a course of chemotherapy and/or radiotherapy (abstract). This reads on administering cells to a subject. Bazinet further teach conditioning a patient for the transplant comprises ablating the recipient’s own bone marrow (p188 col2 ¶3). This reads on a subject having a condition mediated by a loss of hematopoietic stem cells.
It would have been obvious to one of ordinary skill in the art to use the enriched preparation of hemogenic endothelial progenitor cells taught by Clarke for administering the cells to a subject, as taught by Bazinet.
One of ordinary skill in the art would have been motivated to modify the method as taught by Clarke to administer the population of cells to a subject, as taught by Bazinet, because Choi teach hemogenic endothelium is a source of hematopoietic stem cells and could provide a novel source of therapeutic cells for blood disease (abstract, p553 col1 ¶1).
One would have been motivated to administer the cells of Clarke to a subject having a condition mediated by a loss of hematopoietic stem cells, as taught by Bazinet, because Choi teach hemogenic endothelium is a source of hematopoietic stem cells and provide a novel source of therapeutic cells for blood disease.
One would have had a reasonable expectation of success because Bazinet teach more than 50,000 HSCT procedures are performed annually for a variety of diseases, and one of ordinary skill in the art would understand a widely used procedure has a reasonable expectation of success.
Thus the invention as claimed is rendered obvious by the teachings of Clarke, Choi and Bazinet.
Conclusion
No claims are allowed.
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/ANDREA LYNNE MORRIS SPENCER/Examiner, Art Unit 1631
/TAEYOON KIM/Primary Examiner, Art Unit 1631