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 of Group I, drawn to claims 1-5, in the reply filed on 06/03/2026 is acknowledged. Claims 6-18 are withdrawn from further consideration as being drawn to a non-elected invention.
Priority
The instant application claims benefit of US Provisional application 63/453,504 filed 03/21/2023.
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.
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 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 1-5 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.
Claim 1 recites the limitation “wherein the cell expresses a recombinant reporter capable of detecting compounds” (lines 2-3). The limitation “capable of detecting compounds” comprises latent and passive language. The claim does not require that the reporter detects compounds, but merely is capable of detecting compounds; the metes and bounds of what is encompassed by “capable of” is unclear. Furthermore, the limitation “detecting compounds” implies that the recombinant reporter actively detects compounds; however, a reporter does not detect compounds, but rather, responds to the presence of compounds and serves as a proxy for their readout. To overcome the rejection, the wherein clause in lines 2-3 should be rewritten in the active voice, and the language implying that the reporter detects compounds should be amended. For the purpose of examination, the limitation “wherein the cell expresses a recombinant reporter capable of detecting compounds” is interpreted as “wherein the cell expresses a recombinant reporter, wherein the recombinant reporter responds to a presence of compounds.”
Claims 2-5 are included in the rejection because they depend from claim 1.
Claim 3 recites the limitation “wherein the recombinant reporter construct is incorporated into a NOS3 gene locus” (lines 1-2). The term “gene locus” is not defined in the specification. The region encompassed by “NOS3 gene locus” is broader than “NOS3 gene,” and in fact comprises the ATG9B gene in addition to the NOS3 gene, as shown by NCBI’s gene report for NOS3 (p 1, “Genomic context”). Therefore, it is unclear which gene the recombinant reporter was inserted into. To overcome the rejection, the limitation should be amended to “wherein the recombinant reporter construct is incorporated into a NOS3 gene.”
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.
Claim(s) 1-3 and 5 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by US 2016/0244719 A1 (hereinafter Thomson).
Thomson teaches a method of culturing mesodermal cells (reads on arterial endothelial precursor cell of claim 1) to generate arterial endothelial cells (Abstract; para 6). Thomson teaches that the mesodermal cells are obtained by culturing human pluripotent stem cells, which can be human embryonic stem cells or human induced pluripotent stem cells (para 8, 44, 52-54, 63) (claim 3). Thomson teaches an in vitro method of screening test agents, wherein the method comprises contacting a test agent to arterial endothelial cells obtained according to a method provided therein, and detecting an effect of the agent on the contacted cells (para 11, 72).
Thomson teaches EFNB2-tdTomato/EPHB4-EGFP dual reporter H1 embryonic stem cells (claim 2), which were differentiated into mesoderm cells, which were in turn differentiated into endothelial cells (claim 1) (para 18-21, 23, 92-93). The dual reporter cell was made using CRISPR-Cas9 technology to target EFNB2 (ephrin B2) with tdTomato (reads on RFP of claim 5) and EPHB4 (ephrin type B receptor 4) with EGFP (para 92) (reads on genetically engineered with a recombinant reporter construct of claim 1). EFNB2 and EPHB4 are the most characterized embryonic arterial and venous endothelial cell markers, respectively (para 92) (claim 1).
Thomson teaches using the EFNB2-tdTomato/EPHB4-EGFP dual reporter cell line to investigate the effects of candidate factors, including growth factors, recombinant proteins, and small molecules on endothelial cell differentiation, by culturing the EFNB2-tdTomato/EPHB4-EGFP (para 92-99; Table 2). Compounds widely used in endothelial cell differentiation protocols, such as insulin, were added or removed from cell culture, to determine their effects on the number of EFNB2-tdTomatohigh/EPHB4-EGFPlow cells, which was used as a proxy for arterial differentiation (para 94-99; Table 2) (reads on a recombinant reporter capable of detecting compounds that promote arterial endothelial cell differentiation of claim 1).
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(s) 1- 5are rejected under 35 U.S.C. 103 as being unpatentable over US 2016/0244719 A1 (hereinafter Thomson), in view of Tousoulis (Current Vascular Pharmacology, 2012, 10(1): 4-18; Abstract only), as evidenced by GeneCards (NOS3 gene).
The teachings of Thomson are set forth above. Thomson anticipates claims 1-3 and 5.
Regarding claim 4: Thomson teaches an in vitro method of screening test agents, wherein the method comprises contacting a test agent to arterial endothelial cells obtained according to a method provided therein, and detecting an effect of the agent on the contacted cells (para 11, 72).
Thomson does not teach the reporter cell line of claim 1, wherein the recombinant reporter construct is incorporated into a NOS3 gene locus in the reporter cell line's genome.
Tousolis teaches that nitric oxide (NO) is a soluble gas continuously synthesized from the amino acid L-arginine in endothelial cells by the constitutive calcium-calmodulin-dependent enzyme nitric oxide synthase (NOS) (Abstract). Tousolis teaches that decreased production of NO is associated with diseases including hypertension, hypercholesterolemia, smoking, diabetes mellitus and heart failure (Abstract). Tousolis teaches that numerous therapies have been investigated to assess the possibility of reversing endothelial dysfunction by enhancing the release of nitric oxide from the endothelium (Abstract).
GeneCards shows that NOS3 encodes endothelial nitric oxide synthase, a constitutively expressed enzyme that generates nitric oxide (NO).
It would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to have modified the reporter cell line of Thomson by incorporating a recombinant reporter construct into the NOS3 gene locus. One of ordinary skill in the art would have been motivated to make this modification to create a reporter cell line to use in an in vitro method of screening test agents to identify agents that induce increased expression of NOS3, because Tousolis teaches that there is motivation to discover therapies to increase NO production. One of ordinary skill in the art would have had a reasonable expectation of making this modification because Thomson teaches that a reporter cell line can be made using CRISPR-Cas9 technology to target endogenous genes (para 92), and that cells obtained according to a method provided therein can be used in an in vitro method of screening test agents (para 11, 72).
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Risa Takenaka whose telephone number is (571)272-0149. The examiner can normally be reached M-F, 12-7 EST.
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/RISA TAKENAKA/Examiner, Art Unit 1632
/PETER PARAS JR/Supervisory Patent Examiner, Art Unit 1632
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