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 .
Applicant’s amendment and response filed on 10/17/2025 has been received and entered into the case.
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.
It is noted that claim 44 is indicated canceled using the status identifier (canceled). However, the text of the claim is listed in the instant amendment. Applicant should provide a correct amendment in the response to the instant OA.
Claim Rejections - withdrawn
The claim rejections under 35 USC 35 U.S.C. 112 have been withdrawn due to the instant amendment.
The claim rejection under 35 USC 102 based on Park et al. has been withdrawn due to the instant amendment.
The claim rejection under 35 USC 103 based on Park et al. has been withdrawn due to the instant amendment.
Claim Rejections - 35 USC § 112 (New Rejection)
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 33-43 and 45 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.
The instant amendment introduces new limitation that the nucleic acid or vector encoding ETV2 or ETV2 protein or functional fragment thereof is “directly” injected into “a tissue” of the subject. It is not clear if the term “directly injecting” of the materials is intended to point out to inject the materials into the tissue in need of the vascularization, i.e. directly into the tissue in need of vascularization; or the materials, i.e. nucleic acid, vector or protein/fragment, are injected without any modification (e.g. chemical modification or as a part of a composition comprising additional materials such as carriers, e.g. cells, or exosome as disclosed in claims 37 or 43). Clarification is required.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 37 and 43 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claims 37 and 43 disclose that the ETV2 protein or functional fragment thereof is contained within an exosome. These claims are dependent on claims 33 and 39, respectively, and claims 33 and 39 disclose that the ETV2 protein or functional fragment thereof is directly injected in a tissue of the subject. However, according to claims 37 and 43, the ETV2 protein or functional fragment thereof are first contained in an exosome, which is understood not a direct injection under the broadest reasonable interpretation of the term “directly injection”. The “directly injecting” would encompass that the material, in this case, ETV2 protein or functional fragment thereof is injected without modification into the tissue. However, when ETV2 protein or the fragment thereof is contained in an exosome, it cannot be considered as “directly” injecting the protein.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 102 (modified)
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 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 to a tissue of a subject as required by the newly added 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 claims 38 and 44 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, 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 claims 38 and 44 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 (Modified)
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
As indicated above, of the previous claim rejections under 35 U.S.C. 112, 102 and 103 based on Park et al. have been withdrawn based on the instant amendment.
However, the claim rejections based on Lee et al. or Kim are maintained and modified to address the newly added limitations.
Applicant 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 Examiner respectfully disagrees with this analysis. While Lee et al. do not particularly disclose that fibroblasts in the tissue of the subject convert into endothelial cells, however, 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. The discovery of a new use for an old structure based on unknown properties of the structure might be patentable to the discoverer as a process of using. In re Hack, 245 F.2d 246, 248, 114 USPQ 161, 163 (CCPA 1957). However, when the claim recites using an old composition or structure and the "use" is directed to a result or property of that composition or structure, then the claim is anticipated. In re May, 574 F.2d 1082, 1090, 197 USPQ 601, 607 (CCPA 1978) and In re Tomlinson, 363 F.2d 928, 150 USPQ 623 (CCPA 1966). See M.P.E.P. § 2112.02.
Furthermore, as Yoon et al. teach that fibroblasts can be converted into endothelial like cells when exposed to ETV2 (Abstract), the method of Lee et al. or Kim is expected to produce the same effect of converting fibroblasts into endothelial cells as it is shown by Yoon et al.
Regarding the 102 rejection based on Kim, applicant argued that Kim teaches making induced vascular progenitor cells by transducing fibroblasts cells to express ETV2, FLI1, or ETV2 and FLI1 and injecting the transduced induced vascular progenitor cells intramuscularly into ischemic hindlimb mice. Kim, paragraphs [0049] and [0062]. Kim does not disclose the claimed method of converting fibroblasts into endothelial cells by directly injecting a composition comprising a nucleic acid or vector encoding ETV2 or an ETV2 protein or a functional fragment thereof to a subject's tissue, as claimed herein. Rather, Kim discloses administering cells transduced to express ETV2. The Examiner respectfully disagrees with the applicant’s allegation.
As cited in the claim rejection, Kim teaches in claim 18 at page 8; “administering at least one protein selected from the group consisting of FLl1 (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.”
While Kim discloses one embodiment that requires the step of transducing vascular progenitor cells and transplanting the cells to a subject as pointed out by applicant, however, Kim clearly discloses another embodiment involving administration of ETV2 protein, nucleic acid or vector encoding ETV2 to a subject without using the cells. 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.
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.
While Lee et al. teach that at day 4-5 after transduction with ETV2, cardiac myocytes (CM) or cardiac fibroblast (CF) did not show any significant morphological changes into EC-like cells without showing any data. This is not sufficient to conclude that CM or CF did not convert to EC-like cells at all even with ETV2 expression. Particularly Yoon et al. teach the morphology change (cobblestone shape), a classic feature of ECs, appears day 16 (para. 85), suggesting that Lee et al. might not be able to detect morphological change in such an early stage. Therefore, without any further evidence supporting the Lee’s disclosure, it is the Examiner’s position that ETV2 would be able to convert fibroblasts to ECs by the method of Lee et al. based on the teaching of Yoon et al. Furthermore, if the teaching of Lee et al. is considered to show that there is no conversion from CM or CF into EC, then the teachings of Lee et al. would raise an enablement issue of the claimed invention. However, it is the examiner’s position that the conversion or transdifferentiation of fibroblasts into EC by ETV2 expression is well documented in the art and thus, the method of Lee et al. would inherently carry out such conversion in the absence of clear evidence to the contrary.
The claimed method comprises a step of administering the nucleic acid or vector encoding ETV2 into a tissue of a subject, and Lee et al. as well as Kim teach the identical step, and thus, even if the reference does not show the effect, however, the effect would be inherent as discussed in the claim rejection obvious.
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.
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 TAEYOON KIM whose telephone number is (571)272-9041. The examiner can normally be reached 9-5 EST Monday-Friday.
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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