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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 4/8/2026 has been entered.
Claims 1-32 and 44 have been canceled, and claims 33-43 and 45 have been considered on the merits. All arguments have been considered.
Response to Amendment
The claim rejection under 35 USC 112 has been withdrawn due to the instant amendment. The instant amendment clarified that the term “directly” points out such that the composition is being injected directly to the tissue rather than the composition without modification.
As indicated during the telephonic interview held on 6/30/2026, it would be clearer if the term “directly” is placed in front of the term “into” of claim 33.
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.
(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) 33-34, 36, 38-40, 42 and 45 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Lee et al. (2019, Exp. Mol. Med.; IDS ref.) as evidenced by Yoon et al. (US2015/0307840; of record).
Lee et al. teach a method of administering/injecting a lentiviral vector or an adeno-associated viral (AAV) vector comprising a nucleic acid encoding ETV2 into the heart of mice having myocardial infarction (mouse model of myocardial infarction; i.e. ischemic disease), and the method resulted in enhanced ejection fraction and fractional shortening, and protected against massive fibrosis with increase in capillary density (Abstract). The mice of Lee et al. are the mouse model of myocardial infarction, and thus, the mice (subject) is considered in need of vascularization. In fact, the instant specification discloses myocardial infarction as an ischemic cardiovascular disease in need of new vascularization, i.e. revascularization.
The method step of Lee et al. injecting the nucleic acid encoding ETV2 into the heart of mice is understood as to meet the “directly” injecting the composition comprising the nucleic acid encoding ETV2 to a tissue of a subject as required by the limitation as the vector comprising nucleic acid encoding ETV2 is directly injected into the heart (intramyocardially) of the mice.
The lentiviral vector encoding ETV2 taught by Lee et al. is considered to meet the nucleic acid being RNA (claims 34 and 40) as the lentivirus is a RNA virus. Furthermore, the AAV is a DNA virus and thus, it meets the nucleic acid being DNA.
Regarding the limitation directed to generating blood vessels (claim 33) or wherein clause that the method providing revascularization (claim 39), these limitations are directed to the results of the method, and do not particularly provide patentable weight in determining patentability of the claimed methods. Furthermore, as the method steps of Lee et al. are identical to the claimed method steps, the results are expected the same. Regardless, Lee et al. teach the increased capillary density indicating enhanced blood vessel regeneration.
Regarding claim 38 directed to the composition comprising a nucleic acid or vector encoding ETV2 converting non-endothelial cells into endothelial cells or vessels, as the method steps of Lee et al. are identical to the claimed method steps, the results are expected the same.
Regarding the wherein clause directed to the method converting fibroblasts in the tissue into endothelial cells (claim 39), this limitation is directed to the results of the claimed method. As the method taught by Lee et al. is identical to the claimed method, the results obtainable from the Lee et al.’s method are expected the same as the claimed invention. Thus, the method of Lee et al. would inherently carry out the results as claimed. In support, Lee et al. teach the role of ETV2 in direct conversion of non-ECs (i.e. fibroblasts and skeletal muscle) into EC-like cells, suggesting the possibility that some proportion of newly formed vessels in MI hearts originated from non-EC through direct conversion upon lentiviral ETV2 injection (p.11, 2nd col.). Furthermore, Yoon et al. teach that fibroblasts can be converted into endothelial like cells when exposed to ETV2 (Abstract).
Thus, the reference anticipates the claimed invention.
Claim(s) 33-36, 38-42 and 45 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Kim (US2017/0130204) as evidenced by Yoon et al. (supra).
Kim teach a method of administering a direct transdifferentiation factor ETV2 protein or a nucleic acid molecule encoding the protein and a vector for expression the protein to a subject for treating ischemic vascular disease (p.8, claim 18). The ischemic vascular disease includes cerebrovascular disease, cardiovascular disease, limb ischemia, peripheral vascular disease or ischemic muscle necrosis (p.8, claim 19). Kim teach that the vector includes a viral vector such as a lentiviral vector or adeno-associated vector (AAV) (para. 31). The lentiviral vector encoding ETV2 taught by Kim is considered to meet the nucleic acid being RNA (claims 34 and 40) as the lentivirus is a RNA virus. Furthermore, the AAV is a DNA virus and thus, it meets the nucleic acid being DNA.
Regarding the limitation of “directly injecting the nucleic acid or vector encoding ETV2 or ETV2 protein or functional fragment thereof in a tissue of the subject” (claims 33 and 39), Kim teaches in claim 18 at page 8; “administering at least one protein selected from the group consisting of FLI1 (Friend leukemia virus integration 1) and ETV2 (ETS variant gene 2), a nucleic acid molecule encoding the protein, a vector comprising the nucleic acid molecule, or a combination thereof, or transplanting the vascular progenitor cell induced through direct transdifferentiation of claim 16, to a subject in need thereof.” Thus, this teaching would meet the step of directly injecting the ETV2 protein or nucleic acid/vector encoding thereof into a tissue of the subject without using a step of transducing cells and then administering the cells (indirect injection).
Regarding the wherein clause directed to the method converting fibroblasts in the tissue into endothelial cells (claim 39), this limitation is directed to the results of the claimed method. As the method taught by Kim is identical to the claimed method, the results obtainable from the Kim’s method are expected the same as the claimed invention. Thus, the method of Kim would inherently carry out the results as claimed. In support, Yoon et al. teach that fibroblasts can be converted into endothelial like cells when exposed to ETV2 (Abstract).
Regarding claims 34-35 and 40-41, Kim teach that the nucleic acid encoding ETV2 may be a DNA molecule or an RNA molecule (para. 29). While Kim does not teach the RNA molecule is mRNA, however, one skilled in the art would have at once envisaged that the RNA molecule encoding ETV2 would be mRNA.
Regarding the limitation directed to generating blood vessels (claim 33) or wherein clause that the method providing revascularization (claim 39), these limitations are directed to the results of the method, and do not particularly provide patentable weight in determining patentability of the claimed methods. Furthermore, as the method steps of Kim are identical to the claimed method steps, the results are expected the same.
Regarding claim 38 directed to the composition comprising a nucleic acid or vector encoding ETV2 converting non-endothelial cells into endothelial cells or vessels, as the method steps of Kim are identical to the claimed method steps, the results are expected the same.
Thus, the reference anticipates the claimed invention.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 35 and 41 is/are rejected under 35 U.S.C. 103 as being unpatentable over Lee et al. (supra) as applied to claims 33-34, 36, 38-40, 42 and 45 above, and further in view of Yoon et al. (supra)
Lee et al. teach the subject matter of claims 33-34, 36, 38-40, 42 and 45, and thus render them obvious (see above).
Regarding claims 35 and 41 directed to the nucleic acid being mRNA, Lee et al. do not particularly teach the limitation.
Yoon et al. teach that ETV2 mRNA can be delivered to the fibroblast by using electroporation or complexing the RNA with a cationic vehicle to facilitate uptake by endocytosis (para. 82).
It would have been obvious to a person skilled in the art to use the ETV2 mRNA for expression of the ETV2 protein in the fibroblast replacing the viral vector used in the method of Lee et al. with a reasonable expectation of success. A person of ordinary skilled in the art would have been motivated to do so because mRNA delivery is another known means to have a desired protein to be expressed in a cell and thus, can replace the viral delivery of a gene for the expression of gene product.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention.
Claim(s) 33-43 and 45 is/are rejected under 35 U.S.C. 103 as being unpatentable over Kim (US2017/0130204) in view of Van Pham et al. (2017, Cytotechnology; IDS ref.) and Rafii et al. (US2019/0352601) and as evidenced by Yim et al. (2016, BMB Rep.)
Kim teach the subject matter of claims 33-36, 38-42 and 45 and thus, render them obvious (see above).
Regarding the ETV2 protein being contained with an exosome (claims 37 and 43), Kim does not teach the limitation.
Van Pham et al. teach that ETV2 transfected fibroblasts produce extracellular vesicles (i.e. exosomes) and the EVs from ETV-2 positive fibroblast were injected in acute hind limb ischemic mice, and these EVs significantly stimulated endothelial cell proliferation and improved neovascularization in a murine model of hindlimb ischemia (Abstract; p.804, 2nd col.). Van Pham et al. teach that the EVs from ETV-2 positive fibroblasts were successfully isolated with the use of commercial kits, and these EVs contains both RNAs and proteins (p.809, 1st col.). Although they do not particularly teach that the EVs contain ETV-2 proteins, however, it is considered that overexpressed ETV-2 protein would inherently present in the EVs of ETV-2 positive fibroblasts of Van Pham et al. Furthermore, it is well known in the art that overexpression of a protein would be one way to load the EVs or exosomes with the overexpressed proteins (see Yim et al. 2016; Fig. 1).
Furthermore, Rafii et al. teach that ETV2 can be packaged in exosomes (para. 85).
It would have been obvious to a person skilled in the art to load ETV2 protein into exosomes by overexpression of ETV2 in fibroblasts as taught by Van Pham et al. or packaging ETV2 proteins into exosomes taught by Rafii et al. and administer them directly into the tissue (infarcted heart; ischemic tissue, etc.) of the subject for the method taught by Kim with a reasonable expectation of success.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention.
Response to Arguments
Applicant’s arguments with respect to the 112 rejections have been fully considered and are persuasive. The claim rejections under 112(b) and (d) have been withdrawn.
Applicant's arguments with regard to the 102 and 103 rejections have been fully considered but they are not persuasive.
Applicant has repeatedly alleged that Lee et al. do not teach “converting fibroblasts into endothelial cells” as they disclose activating pre-existing endothelial cells to increase angiogenesis. The claim rejection has acknowledged that Lee et al. do not teach the limitation. However, the claim rejections relied upon the claimed results are inherently produced by the claimed method. As the method steps of Lee et al. are identical to the claimed method using the same materials, i.e. nucleic acid or vector encoding ETV2, the same results are inherently expected.
As discussed during the applicant-initiated interview held on 6/30/2026, the basis of the Examiner’s argument is that the claimed injection of the composition comprising the nucleic acid encoding ETV2 or the ETV2 protein would affect the endogenously present fibroblasts in the tissue (i.e. heart tissue as taught by Lee et al.) as well as other cells present in the heart (e.g. cardiomyocytes, endothelial cells, etc.). Upon the injection of the composition into the heart, the nucleic acid would be inherently delivered to the resident cells including fibroblasts (i.e. in situ) in the heart, and the nucleic acid encoding ETV2 or the ETV2 protein would carry out its function on fibroblasts. As Yoon et al. teach such conversion of fibroblasts into endothelial cells via ETV2, it is expected that the same effect is anticipated.
Applicant asserted that Yoon et al. cannot be used in the 102 to show ETV2 in Lee inherently converts fibroblasts into endothelial cells in situ as they don’t teach or suggest converting fibroblasts into endothelial cells in situ by direct injection into a tissue of the subject in need of vascularization or revascularization. The Yoon reference is cited as an evidentiary reference to support the conclusion that fibroblasts in situ would be inherently converted to endothelial cells by ETV2, and thus, Yoon et al. do not need to show the claimed invention.
In fact, Lee et al. suggest that non-ECs can convert to ECs by ETV2 in vivo in MI hearts citing various studies in vitro showing the conversion of non-ECs to functional ECs (p.11, 2nd col.) consistent with Yoon et al. It is acknowledged that none of the cited references in Lee et al. as well as Yoon et al. provide evidence for the conversion of fibroblasts or non-ECs into endothelial cells by ETV2 in vivo, and the instant specification provides the evidence that some fibroblasts expressing FSP1 (i.e. TdTomato+ cells) are indeed co-stained with BSL1-lectin, suggesting direct reprogramming of fibroblasts into functional ECs in vivo (para. 104). However, the data provided in the instant specification merely confirm the inherent results occurring in vivo upon the injection of ETV2 into a tissue. The active step of the claimed method is the step of administering the claimed composition directly into a tissue of a subject in need of vascularization. As Lee et al. and Kim et al. teach the identical method, the results would be inherently produced by the method of Lee et al. or Kim et al.
M.P.E.P. §2112 states that “The discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer.” Atlas Powder Co. v. Ireco Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999). Thus the claiming of a new use, new function or unknown property which is inherently present in the prior art does not necessarily make the claim patentable. In re Best, 562 F.2d 1252, 1254, 195 USPQ 430, 433 (CCPA 1977). In In re Crish, 393 F.3d 1253, 1258, 73 USPQ2d 1364, 1368 (Fed. Cir. 2004), the court held that the claimed promoter sequence obtained by sequencing a prior art plasmid that was not previously sequenced was anticipated by the prior art plasmid which necessarily possessed the same DNA sequence as the claimed oligonucleotides. The court stated that “just as the discovery of properties of a known material does not make it novel, the identification and characterization of a prior art material also does not make it novel.”
Regarding the 102 rejection based on Kim, applicant argued that Kim et al. or Yoon et al. do not teach the converting fibroblasts into endothelial cells in situ. Applicant repeatedly asserted that Kim et al. teach the ex vivo transduced fibroblasts cells expressing ETV2 are injected intramuscularly into ischemic hindlimb mice. As discussed previously, this argument is incorrect as Kim clearly teaches a step of administering ETV2 protein or a nucleic acid molecule encoding ETV2 into a subject in need thereof (p.8, claim 18). Regarding the conversion of fibroblasts into endothelial cells in situ, the same analysis under the inherency as for Lee et al. above has been applied. Thus, it is the Examiner’s position that the method of Kim et al. is identical to the claimed method and the conversion of non-ECs including fibroblasts into ECs is inherently carried out by the method step of administering the composition,
Regarding the 103 rejections based on Lee et al., applicant stated that Lee teaches that ETV2 administration did not produce "any significant morphological changes of [cardiomyocytes] or [cardiac fibroblasts] into [endothelial cell]-like cells ... suggesting that transdifferentiation or direct conversion with ETV2 is unlikely to be a major contributor to augmented vascularization in [myocardial infarction] hearts." Lee at [p.]9. Based on this, applicant asserted that a person having ordinary skill in the art would have had no reasonable expectation of success that direct ETV2 injection would convert fibroblasts into endothelial cells, nor that such conversion would provide revascularization, as claimed.
It is noted that applicant’s argument is mainly based on the limitation directed to the “converts fibroblasts in the tissue into endothelial cells in situ”, and as if this is an active step of the claimed method. The Examiner does not consider this limitation as an active step to be carried out by the claimed invention. Rather, it is inherently carried out in situ upon the administering the claimed composition.
Based on the above discussion, it is the examiner’s position that the teachings of the cited references anticipate and render the claimed invention obvious.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to TAEYOON KIM whose telephone number is (571)272-9041. The examiner can normally be reached 9-5 EST Monday-Friday.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, JAMES SCHULTZ can be reached at 571-272-0763. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/TAEYOON KIM/Primary Examiner, Art Unit 1631
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