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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 1/30/2026 has been entered.
Claims 1, 3, 5, 10, 14, 22, 25, 55, 64, and 100-106, of record 1/30/2026, are pending and subject to prosecution. Claim 106 is newly added.
Status of Prior Rejections/Response to Arguments
RE: Rejection of claims 1, 3, 5, 10, 14, 22, 25, 55, 64, 100-102, and 105 under 35 U.S.C. 103 over Yoder et al. (US 20190211304 A1), evidenced by Melero-Martin (Cold Spring Harbor Perspectives in Medicine, 2022), in view of Qiu et al. (Biomaterials, 2015), evidenced by Beamish et al. (Journal of Biomedical Materials Research, 2009), and Wimmer et al. (Nature, 2019):
The applicant asserts that:
The citation of eight different references to support the Examiner’s finding of obviousness is itself evidence that the invention is not obvious (Applicant Remarks, page 9).
None of the prior art references teach the specific method for producing meso-VPCs using the specific combination of steps and specific combination of growth factors and/or agents, under the specific conditions for the specific time that the claims require (Applicant Remarks, page 9-12).
The prior art fails to provide sufficient motivation for combining teachings with any reasonable expectation of success (Applicant Remarks, page 9-10).
Unlike the claimed method, the process of Yoder et al. requires selection steps for mesoderm and endothelial progenitor cells, which yields cells that differ from those resulting from the claimed method (Applicant Remarks, page 11).
One of ordinary skill would not have been motivated to include a TGFβ inhibitor in the method of Yoder et al. because it is explicitly taught that exogenous TGFβ inhibition is not required (Applicant Remarks, page 11-13).
Hindsight reasoning is relied upon for combining elements of the prior art teachings, including the use of microwell arrays for endothelial differentiation by Qiu et al. with the method of Yoder et al. (Applicant Remarks, page 13-14).
The claimed invention exhibits superior and unexpected results in the form of advantageous vascular progenitor properties and therapeutic efficacy (Applicant Remarks, page 14-15).
The applicant’s arguments have been fully considered but are not found persuasive. As an initial matter, reliance on a large number of references in a rejection does not, without more, weigh against the obviousness of the claimed invention. See In re Gorman, 933 F.2d 982, 18 USPQ2d 1885 (Fed. Cir. 1991). Further, the prior art references, when combined, do not need to teach or suggest all of the claim limitations in a finding of obviousness. See MPEP 2141(III).
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Previous Office actions have pointed out that Yoder et al. teach a method for generating mesoderm cells from PSCs with further endothelial lineage differentiation that comprises every limitation of independent claim 1 but two: culturing the PSC-derived mesoderm cells in the presence of a TGFβ inhibitor and in non-adherent or low adherent conditions.
Regarding the use of a TGFβ inhibitor in conjunction with the method of Yoder et al., Yoder et al. do not teach that a TGFβ inhibitor cannot or should not be added, only that it need not be added (“The method disclosed herein… does not require exogenous TGF-β inhibition.” See ¶0113 and 0126). This does not amount to a teaching away but rather suggests that the addition of an exogenous TGFβ inhibitor would represent an alternative method. Indeed, Yoder et al. disclose an embodiment wherein the endothelial inducing step is carried out in the absence of one or more of: co-culture cells, embryoid body formation, and exogenous TGFβ inhibition (See ¶0015), which implies embodiments wherein a TGFβ inhibitor could be used as an option. Because there is no explicit prohibition, one of ordinary skill would understand that, should motivation exist for the use of a TGFβ inhibitor, such an addition would be permissible with the method of Yoder et al.
It was known in the art that inhibition of TGFβ was beneficial in the in vitro production of endothelial cells from pluripotent cells. Aside from the teachings of Wimmer et al., cited in the rejection of the instant claims, James et al. (Nature Biotechnology, 2010) teach that addition of a TGFβ inhibitor to a hESC-derived mesodermal intermediate increased the expansion of vascular lineage cells (See Abstract; page 162, col. 1, ¶1-2; and fig. 2), and Watanabe et al. (Journal of Cell Biology, 2003) teach that a TGFβ inhibitor enhances the growth and integrity of ESC-derived endothelial cells and suggest that TGFβ inhibits the proliferation of differentiating vascular progenitor cells (See Abstract; page 1305, col. 2, full ¶1-2; and fig. 4). The addition of a TGFβ inhibitor to the method of Yoder et al. would therefore not necessarily be the product of impermissible hindsight reconstruction.
Regarding the argument directed toward Qiu et al., a reference may be relied upon as prior art for all that it contains and would have reasonably suggested to one of ordinary skill in the art. See MPEP2123(I). The prior art also need not address the same problem as the applicant but only be reasonably pertinent to the applicant’s endeavors. See MPEP 2141(a)(I). Because Qiu et al. indicate that endothelial differentiation efficiency is increased through culturing undifferentiated MSCs in non-adherent or low adherent microwells (See Abstract; page 606, col. 1, full ¶1 and col. 2, ¶1; and fig. 4 and 6), one of ordinary skill would be sufficiently motivated to apply the teachings of Qiu et al. to the method of endothelial differentiation taught by Yoder et al.
The applicant alleges that the cells resulting from the method of Yoder et al. differ from those of the instant invention. However, the instant claims are directed to a method of producing mesoderm-derived vascular progenitor cells from PSCs. There is no requirement that Yoder et al. generate exactly the same cells as those alleged by the applicant. The claims also feature the transitional phrase “comprising”, which is open-ended or inclusive and does not exclude additional, unrecited steps. See MPEP 2113.03(I). Yoder et al., in combination with secondary references, render obvious a method of producing mesoderm-derived vascular progenitor cells from PSCs that encompasses the claimed method; nothing further is required to reject the instant claims.
With respect to the assertion of unexpected results, a showing of unexpected results must be fully commensurate with the claims in order to overcome a finding of obviousness. See MPEP 716.02(d). The instant claims are considerably broader than the conditions used to achieve the results in examples 7, 9, 12-13, and 15, depicted in in fig. 5-7 and 15-16. Further, these examples would not lead one of ordinary skill in the art to reasonably expect every method encompassed by the claims to yield superior results compared to other methods of producing vascular progenitor cells. Disclosure of just two experimental protocols (which differ only by the presence or absence of 2 µM forskolin) in the examples that comprise the claimed limitations does not provide sufficient support for any sort of trend in results that could be expected to be observable over the full scope of the claims. See MPEP 2145.
The rejection is maintained in modified form to include newly added claim 106.
RE: Rejection of claims 1, 3, 5, 10, 14, 22, 25, 55, 64, and 100-105 under 35 U.S.C. 103 over Yoder et al. (US 20190211304 A1), evidenced by Melero-Martin (Cold Spring Harbor Perspectives in Medicine, 2022), in view of Qiu et al. (Biomaterials, 2015), evidenced by Beamish et al. (Journal of Biomedical Materials Research, 2009), and Wimmer et al. (Nature, 2019), further in view of Patsch et al. (Nature Cell Biology, 2015):
The arguments directed toward the combination of Yoder et al., Melero-Martin, Qiu et al., Beamish et al., and Wimmer et al. are addressed above. The rejection is maintained.
New/Maintained Rejections
Claim Rejections - 35 USC § 112
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.
Claim 106 is 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 106 contains the trademark/trade name Matrigel. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe a basement membrane preparation and, accordingly, the identification/description is indefinite.
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.
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.
Claims 1, 3, 5, 10, 14, 22, 25, 55, 64, 100-102, and 105-106 are rejected under 35 U.S.C. 103 as being unpatentable over Yoder et al. (US 20190211304 A1), of record, evidenced by Melero-Martin (Cold Spring Harbor Perspectives in Medicine, 2022), of record, in view of Qiu et al. (Biomaterials, 2015), of record, evidenced by Beamish et al. (Journal of Biomedical Materials Research, 2009), of record, and Wimmer et al. (Nature, 2019), of record.
Regarding claims 1, 3, 5, 10, 14, 25, 100, 102, and 105-106: Yoder et al. teach methods for generating mesoderm and endothelial colony-forming cells from pluripotent stem cells (See Abstract). Pluripotent cells such as hESCs and hiPSCs were maintained on Matrigel (which reads on “an extracellular matrix surface”) at 5% CO2 for about two days (See ¶0103). The cells were treated with 10 ng/ml activin A (which reads on “about 5-15 ng/mL Activin-A” and “about 10 ng/mL Activin-A”), 10 ng/ml FGF2 (which reads on “about 5-25 ng/mL FGF” and “about 10 ng/mL FGF-2), 20 ng/ml BMP4 (which reads on “about 5-50 ng/mL BMP4” and “about 25 ng/mL BMP4”), and 10 ng/ml VEGF165 (which reads on “about 5-25 ng/mL VEGF” and “about 10 ng/mL VEGF165”) for four days (which reads on “for about 3 days to about 5 days”) (See fig. 1A). The activin A was present only for the first day (which reads on “removing Activin-A from the mesoderm differentiation medium after about 24 hours of culturing”) (See ¶0107-0108 and fig. 1A). Mesoderm cells were harvested after day 4 of differentiation (which reads on “culturing… to produce mesoderm cells”) (See ¶0116). The isolated mesoderm cells can be further induced to undergo endothelial differentiation by culturing in a medium comprising VEGF, FGF2 (which reads on “FGF”), and BMP4 for about 6-8 days (which reads on “about 3 days to about 7 days”) to yield endothelial colony forming cell-like cells (See ¶0013). Melero-Martin teaches that endothelial colony-forming cells are progenitor cells that can give rise to vascular endothelial cells (which reads on “vascular progenitor cells”) (See Abstract). Yoder et al. do not teach culturing the mesoderm cells in low adherence conditions or the inclusion of a small molecule TGF-β inhibitor in the vascular differentiation medium.
Qiu et al. teach the endothelial differentiation of stem cells using a 3D microwell culture system (See Abstract). Aggregates of MSCs were formed using polyethylene glycol dimethacrylate microwells, and endothelial differentiation was induced (See page 601, col. 2, full ¶3 and fig. 1). Qiu et al. teach that endothelial differentiation efficiency increased significantly in 3D culture versus monolayer culture (See page 606, col. 2, ¶1).
Beamish et al. teaches that polyethylene glycol dimethacrylate does not support cell attachment (which reads on “non-adherent or low adherent conditions” and “ultra-low attachment surface”) (See page 441, col. 2, ¶1 and page 442, col. 2, full ¶1).
Wimmer et al. teach the generation of blood vessel organoids from pluripotent stem cells (See Abstract). Wimmer et al. teach that the use of 10 µM SB421542 (which reads on “small molecule inhibitor of transforming growth factor-beta… type I receptor” and “about 5-20 µM”) in the endothelial differentiation medium increases the yield of endothelial cells as mesoderm cells undergo vascular lineage promotion (See page 511, col. 1, ¶3 and fig. 1a).
It would have been obvious to one having ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method of Yoder et al. to comprise the culture of mesodermal cell aggregates in microwells and differentiation of the aggregates to the endothelial lineage (which would inherently yield “mesoderm-derived vascular progenitor cells” and “a vasculonoid” during the process). One would be motivated to make this modification because Qiu et al. teach that efficiency of endothelial differentiation increases in 3D cell aggregates versus 2D monolayer culture (See page 606, col. 2, ¶1). There would be a reasonable expectation of success in doing so because the isolated mesoderm cells of Yoder et al. could be readily seeded in the microwell plates taught by Qiu et al. for endothelial differentiation and because Qiu et al. demonstrate that the seeding and differentiation of multipotent (but not pluripotent) cells can be carried out successfully and efficiently in such a culture system.
It also would have been obvious to modify the endothelial differentiation medium of Yoder et al. to comprise SB421542, as taught by Wimmer et al. One would be motivated to make this modification because Wimmer et al. teach that the inclusion of SB421542 during the promotion of the vascular lineage from mesoderm increases the yield of endothelial cells in blood vessel organoids (See page 511, col. 1, ¶3 and fig. 1a). There would be a reasonable expectation of success in making this modification because SB421542 could be readily added to the differentiation medium and because the results of Wimmer et al. suggest that 10 µM SB421542 is an appropriate concentration, particularly in a differentiation medium comprising VEGF and FGF2 (page 511, col. 1, ¶3 and fig. 1), like that of Yoder et al. While Yoder et al. teach that their method does not require an exogenous TGF-β inhibitor, they do not expressly prohibit its presence and therefore do not teach away from its inclusion (See ¶0015, 0113, and 0126).
Regarding claim 22: Following the discussion of claims 1, 3, 5, 10, 14, 25, 100, 102, and 105-106, Yoder et al. do not expressly teach the culture of mesoderm cells under normoxia conditions. However, Yoder et al. teach culturing the pluripotent stem cells in 5% CO2 (See ¶0103 and 0158) and do not expressly teach the culture of mesodermal cells under hypoxic or hyperoxic conditions, therefore it would be obvious to one of ordinary skill to continue culturing the mesoderm cells at 5% CO2 (which reads on “a normoxia condition of 5% CO2 and 20% O2”).
Regarding claim 55: Following the discussion of claims 1, 3, 5, 10, 14, 25, 100, 102, and 105-106, Yoder et al. teach that the cells resulting from endothelial differentiation are characterized by expression of CD31 and KDR (See ¶0013-0014).
Regarding claim 64: Following the discussion of claims 1, 3, 5, 10, 14, 25, 100, 102, and 105-106, Yoder et al. teach that the differentiated cells can form blood vessels (which reads on “producing a vascular endothelial cell” (See fig. 1G).
Regarding claim 101: Following the discussion of claims 1, 3, 5, 10, 14, 25, 100, 102, and 105, Yoder et al., evidenced by Melero-Martin, in view of Qiu et al., evidenced by Beamish et al., and Wimmer et al., render obvious the endothelial differentiation of mesoderm cells in a medium comprising 10 ng/ml FGF2, 20 ng/ml BMP4, 10 ng/ml VEGF165, and 10 µM SB421542 but do not expressly teach higher concentrations of FGF2, BMP4, and VEGF. However, Yoder et al. teach that the endothelial differentiation medium comprises the same medium as the mesoderm differentiation medium and that the mesoderm differentiation medium can comprise about 5-50 ng/ml VEGF (which reads on “about 50 ng/mL VEGF”), about 5-25 ng/ml BMP4 (which reads on “about 25 ng/ml BMP4”), and about 5-25 ng/ml FGF2 (See ¶0110-0112 and 0159-0160 and fig. 1). Yoder et al. do not expressly teach the inclusion of about 50 ng/ml FGF2, however, such an increase in concentration would lie within the reach of routine optimization, particularly if one desired to maintain the same ratio of FGF2 to VEGF in the medium. Differences in concentration will not support the patentability of subject matter encompassed by the prior art unless there is evidence of criticality. See MPEP 2144.05(II)(A).
Claims 1, 3, 5, 10, 14, 22, 25, 55, 64, and 100-106 are rejected under 35 U.S.C. 103 as being unpatentable over Yoder et al. (US 20190211304 A1), evidenced by Melero-Martin (Cold Spring Harbor Perspectives in Medicine, 2022), in view of Qiu et al. (Biomaterials, 2015), evidenced by Beamish et al. (Journal of Biomedical Materials Research, 2009), and Wimmer et al. (Nature, 2019), further in view of Patsch et al. (Nature Cell Biology, 2015).
The teachings of Yoder et al., Melero-Martin, Qiu et al., Beamish et al., and Wimmer et al. are set forth in the rejection above and are incorporated herein in their entirety.
Regarding claims 103-104: Following the discussion of claims 1, 3, 5, 10, 14, 22, 25, 55, 64, 100-102, and 105-106, Yoder et al., evidenced by Melero-Martin, modified by Qiu et al., evidenced by Beamish et al., and Wimmer et al., render obvious a method of producing vascular progenitor cells from mesoderm cells but do not teach the inclusion of forskolin in the medium.
Patsch et al. teach the generation of vascular endothelial cells from pluripotent stem cells (See Abstract). Patsch et al. teach that the addition of 2 µM forskolin to mesoderm cells leads to an increase in vascular development through PKA activation (See page 995, col. 2, full ¶2 and fig. 2).
It would have been obvious to one having ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method of Yoder et al., evidenced by Melero-Martin, modified by Qiu et al., evidenced by Beamish et al., and Wimmer et al., to include 2 µM forskolin in the endothelial differentiation medium, as taught by Patsch et al. One would be motivated to make this modification because Patsch et al. teach that it increases vascular development (See page 995, col. 2, full ¶2). There would be a reasonable expectation of success in doing so because forskolin could be readily added to culture media and because Patsch et al. teach that 2 µM forskolin is appropriate for the endothelial differentiation of mesoderm cells (See fig. 2).
Conclusion
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 JENNIFER S SPENCE, whose telephone number is 571-272-8590. The examiner can normally be reached M-F 8:30-5:30.
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/JENNIFER S SPENCE/Examiner, Art Unit 1633
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