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 .
DETAILED ACTION
The action is in response to papers filed on April 24, 2026. Pursuant to the amendments filed on November 15, 2025, claims 1-13 are currently pending as per claims filed on 11/15/2023. Applicants’ election with traverse of Group I, e.g. claims 1-7 in response to restriction requirement filed on April 24, 2026 is acknowledged.
Response to Election/Restrictions
The traversal is on the ground(s) that “An international application which complies with those unity of invention requirements must then be accepted by all of the designated and elected offices, including the USPTO, since Article 27(1) of the Patent Cooperation Treaty does not permit any national law or national office to require compliance with different regulations relating to the contents of the international application. Thus, the U.S. application must be examined for unity of invention consistent with the Patent Cooperation Treaty, not just by giving verbal assent to the unity of invention standard but in actual application of the standard. See Caterpillar Tractor Co. v. Commissioner of Patents and Trademarks, 23 l USPQ 590 (E.D. VA. 1986)” and as such Applicants request that the restriction requirement be withdrawn in its entirety and that all the claims be examined in this application” Applicants’ arguments have been respectfully considered but have not been found persuasive.
With regard to Applicant’s assertion that the claims possess unity of invention according to the Written Opinion, and that the Written Opinion concedes many of the present claims are novel over the prior art, e.g., 1-13 (see page 3 of untranslated Japanese Incoming Written description), the Examiner is not persuaded. On the international level, all written opinions are nonbinding and a patent does not issue; what does issue is an international preliminary examination report (IPER), which is nonbinding on the Elected States. See M.P.E.P. § 1878.01, Item V. Note also that according to the untranslated Japanese Written Opinion filed on 11/15/2023 claims 1-5 and 8-13 are found obvious over the prior art (page 3).
Moreover, Applicant did not explicitly establish that the claimed invention provides a contribution over the cited prior art Qian et al (US Pub 2017/0283772) as set forth at pages 3-4 of the Restriction Requirement mailed on February 25, 2026.
Therefore, claims 8-13 are withdrawn from consideration pursuant to 37 CFR 1.142(b), as being drawn to non-elected invention, there being no allowable generic or linking claim. The requirement for restriction between Groups I-V is maintained for reasons of record and the foregoing commentary, and hereby made FINAL.
Applicant is reminded of the right to petition under 37 CFR 1.144, if applicant disagrees with the requirements for restriction filed on 02-19-2010. Note that after a final requirement for restriction, the Applicants, in addition to making any response due on the remainder of the action, may petition the Commissioner to review the requirement. Petition may be deferred until after final action on or allowance of claims to the invention elected, but must be filed not later than appeal. A petition will not be considered if reconsideration of the requirement was not requested. (See § 1.181.).
Therefore, claims 1-7 are currently under examination to which the following grounds of rejection are applicable.
Priority
The instant application is a 35 U.S.C. 371 national stage filing of International Application PCT/JP2022/020827 filed May 19, 2022. The International Application claims priority to Japanese Application 2021-085121 filed May 20, 2021. Filing of a certified untranslated copy of the Japanese Application 2021-085121, filed November 15, 2023 is acknowledged.
Should applicant desire to obtain the benefit of foreign priority under 35 U.S.C. 119(a)-(d) prior to declaration of an interference, a certified English translation of the foreign application must be submitted in reply to this action. 37 CFR 41.154(b) and 41.202(e).
Failure to provide a certified translation may result in no benefit being accorded for the non-English application.
Thus, the earliest possible priority for the instant application is May 20, 2021.
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.
Claims 1-7 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.
Regarding claim 1, it is indefinite in its recitation of the term, “endothelial-like” as the metes and bounds of what constitutes something to be “endothelial-like” is unclear. The term " endothelial-like " is not defined by the claim, the specification does not provide a definition of “endothelial-like”, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Appropriate action is required.
Moreover, the claim 1 is absent of any criteria for determining whether a cell falls within the scope of the claim. In other words, it is unclear how the single step of culturing vascular endothelial progenitor cells results in the production of brain microvascular endothelial-like cells. As such the metes and bounds of the claim are indefinite.
Moreover, claim 1 is indefinite in its recitation of the term “by using” as it does not specify the manner in which Lamnin511 fragment, fibronectin and collagen type IV are used.
Further, claim 1 is indefinite in its recitation of the term “Laminin511 fragment” in line 2, as it is unclear which fragment or class of fragments is encompassed by the claim. The term “Laminin511 fragment " is not defined by the claim, the specification does not provide a definition of “Laminin511 fragment”, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Appropriate action is required. As such, the metes and bounds of this claim are indefinite.
Claim 2 is indefinite due to the use of parentheticals. It is not clear whether the parenthetical is used to indicate a limitation, a preferred embodiment, or synonym, etc. Accordingly, the metes and bounds of the claim are not clear.
Regarding claim 2, it is rendered indefinite because of the notation “registered trademark” in line 3. The use of trademarks in claims is improper because the product to which it is drawn to does not have a definite or fixed meaning. Applicant is required to replace the trademark with the generic terminology for the material to delete the trademark notation.
Claims 5 and 7 are indefinite in their recitation of “using vascular endothelial growth factor” and “using an A 83-01-containing medium”, respectively. These claims are indefinite since the claim does not set forth any steps involved in the method/process, it is unclear what method/process applicant is intending to encompass. Additionally, because the claims do not to set forth any steps involved in the process, it results in an improper definition of a process, i.e., results in a claim which is not a proper process claim.
Regarding claim 7, it is indefinite in its recitation of the phrase “the brain pericytes are cells differentiated, using an A 83-01-containing medium, from pluripotent stem cells”, as it is unclear if the A83-01-containing medium is used to differentiate pluripotent stem cells, the brain pericytes, or both. Appropriate correction is required.
Claims 3-4 and 6 are indefinite insofar that they depend on claim 1.
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.
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) 1 and 3-6 are rejected under 35 U.S.C. 103 as being unpatentable over Aoki et al. (Publidhed: 2020. Cited in IDS Cite No. 7 filed on 11/15/2023. Fluids and Barriers of the CNS, 2020, Vol. 17, No. 25, pp.1-11) in view of Farkas et al. (Published 2020.” Frontiers in Cell and Developmental Biology, vol. 8).
The applied Aoki et al. reference has a common assignee with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(1). The publication dated for Aoki et al. is March 30, 2020. The earliest effective filing date of the instant application is May 20, 2021.
Therefore rejection under 35 U.S.C. 103 CANNOT be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C.102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B); or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement. See generally MPEP § 717.02. Because the reference qualifies as prior art under 102(a)(1), the provisions of MPEP 717.02 do not apply.
Regarding claim 1, Aoki teaches a method for producing brain microvascular endothelial-like cells (pp. 1, Abstract "iBMELCs were differentiated from human iPS cells on several matrices."), and a culturing step using Laminin511, fibronectin, and collagen type IV (pp. 1 Abstract, "MELCs differentiated on laminin 221 fragment (LN221F-iBMELCs) had higher TEER values and lower permeability of LY and FD4 as compared with iBMELCs differentiated on Matrigel (Matrigel-iBMELCs)"; pp. 4 col 2 bottom to pp. 5 col 1 top, "The cells were centrifuged at 100×g, resuspended, seeded on a transwell culture insert or into the wells of a multiwell plate coated with a mixture of FBN (100 μg/mL) and collagen type IV, and LN221F at a density of 3.0 × 105 cells/well, and cultured in HE-SFM-based medium supplemented with 10 μM RA and 20 ng/mL of FGF2. On day 9, the medium was switched to HE-SFM-based medium without 10 μM RA and 20 ng/mL of FGF2; pp. 3 col 2 "Briefly, iPS cells were seeded into the wells of a 6-well plate coated with Matrigel GFR, FBN, VTN-N, LN221F, LN411F, or LN511F and cultured with StemSure hPSC medium supplemented with 35 ng/mL of FGF2 for 3 or 4 days." ).
However, Aoki fails to teach that brain-microvascular endothelial-like cells were cultured from culturing vascular endothelial progenitor cells.
Farkas teaches that human pluripotent stem cells are a source for autologous endothelial progenitor cells Farkas (pp. 1, Abstract "Human pluripotent stem cells (hPSCs) are a promising source of autologous endothelial progenitor cells (EPCs) that can be used for the treatment of vascular diseases. However, this kind of treatment requires a large amount of EPCs.”; Abstract, “Our protocol follows the proper physiological pathway by differentiating EPCs from hPSCs in three phases that mimic in vivo embryonic vascular development. Specifically, hPSCs are differentiated into (i) primitive streak, which is subsequently turned into (ii) mesoderm, which finally differentiates into (iii) EPCs.”)
A person with ordinary skill in the art would have modified the method of culturing brain microvascular endothelial-like cells (BMELCs) taught by Aoki to select endothelial progenitor cells (EPCs) as an alternative source of pluripotent cells , as they were known in the art to be endothelial-lineage precursors capable of differentiating into specialized endothelial phenotypes. Moreover, a person with ordinary skill in the art would have had reason to use vascular endothelial progenitors as the starting population as the cells are already driven towards an endothelial lineage.
Regarding claim 3, the combined teachings of Aoki and Farkas render obvious the claimed methodology of claim 1. Moreover, both Aoki and Farkas teaches that the vascular endothelial progenitor cells are cells differentiated from pluripotent stem cells (Aoki et al. pp. 1, Abstract "iBMELCs were differentiated from human iPS cells on several matrices."; Farkas pp. 1, Abstract "Human pluripotent stem cells (hPSCs) are a promising source of autologous endothelial progenitor cells (EPCs) that can be used for the treatment of vascular diseases.”).
Regarding claim 4, the combined teachings of Aoki and Farkas render obvious the claimed methodology of claim 1. Moreover, both Aoki and Farkas teaches that the vascular endothelial progenitor cells are cells differentiated from human induced pluripotent stem cells (Aoki et al. pp. 1, Abstract "iBMELCs were differentiated from human iPS cells on several matrices."; Farkas pp. 1, Abstract "Human pluripotent stem cells (hPSCs) are a promising source of autologous endothelial progenitor cells (EPCs) that can be used for the treatment of vascular diseases.”).
Regarding claim 5, the combined teachings of Aoki and Farkas render obvious the claimed methodology of claim 1. Moreover, Farkas teaches wherein the vascular endothelial progenitor cells are cells differentiated using vascular endothelial growth factor (FIG 1, see Attached).
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Note however that the recitation of “wherein the vascular endothelial progenitor cells are cells differentiated from pluripotent stem cells” (claim 3), “wherein the vascular endothelial progenitor cells are cells differentiated from human induced pluripotent stem cells” (claim 4) and “ wherein the vascular endothelial progenitor cells are cells differentiated using vascular endothelial growth factor” (claim 5), does not provide an active step, and do not add any structural differences to the claimed vascular endothelial progenitor cells in the method claim. The structure implied by the process steps should be considered when assessing the patentability of product-by-process claims over the prior art, especially where the product can only be defined by the process steps by which the product is made, or where the manufacturing process steps would be expected to impart distinctive structural characteristics to the final product. See, e.g., In re Garnero, 412 F.2d 276, 279, 162 USPQ 221, 223 (CCPA 1979)
Regarding claim 6, the combined teachings of Aoki and Farkas render obvious the claimed methodology of claim 1. Moreover, Aoki teaches that the culturing step comprises co- culturing the vascular endothelial progenitor cells with brain pericytes (pp. 10, col 1, " To enhance barrier integrity, iBMELCs are often co-cultured with BBB components, such as brain pericytes, astrocytes, and neurons”).
***
Claim(s) 1, 2, 7 is/are rejected under 35 U.S.C. 103 as being unpatentable over Aoki et al. (Published: 2020. Cited in IDS Cite No. 7 filed on 11/15/2023. Fluids and Barriers of the CNS, 2020, Vol. 17, No. 25, pp.1-11) in view of Farkas et al. (Published 2020. Frontiers in Cell and Developmental Biology, vol. 8) and in further view of Daly et al. (Published: 2019. US Patent Pub No. US20190316094A1) and Neal et al. (Published: 2019. Stem cell reports vol. 12,6 (2019): 1380-1388).
With regard to claim 1, the combined teachings of Aoki and Farkas render obvious the claimed methodology, as iterated above in the 103 rejection the content of which is incorporated in claim 1. Moreover, Aoki teaches that the cells were cultured in Fibroblast Growth-Factor 2 (pp. 4 col 2 bottom to pp. 5 col 1 top, "The cells were centrifuged at 100×g, resuspended, seeded on a transwell culture insert or into the wells of a multiwell plate coated with a mixture of FBN (100 μg/mL) and collagen type IV, and LN221F at a density of 3.0 × 105 cells/well, and cultured in HE-SFM-based medium supplemented with 10 μM RA and 20 ng/mL of FGF2. On day 9, the medium was switched to HE-SFM-based medium without 10 μM RA and 20 ng/mL of FGF2.").
However, neither Farkas or Aoki teach that the culturing step uses a medium containing B27 or A 83-01.
Neal teaches that the inclusion of B27 supplement improves brain microvascular endothelial cells (BMEC) barrier function and were essential to successful BMEC differentiation (pp. 1382 col 2, “Collectively, these results indicate that replacement of serum with B27 during differentiation produces BMECs with robust passive barrier properties, with the added benefit of eliminating reliance on an undefined material with substantial lot-to-lot variability.”; pp. 1383 col 2 “To further simplify the differentiation scheme, we sought to identify specific components of B27 that were essential to a successful BMEC differentiation”).
A skilled artisan would have been motivated to include B27 supplement into Aoki’s culturing step in order to improve barrier properties and have a more accurate representation of the blood brain barrier (BBB). Moreover, a skilled artisan would have been motivated to implement B27 into Aoki’s BMEC culture as it is “essential to a successful BMEC differentiation”(pp. 1383, col 2.). There would have been reasonable expectations of success in combining these teachings as one of ordinary skill in the art would recognize to combine known elements in the art to give predictable results.
However, neither Farkas or Aoki teach that the culturing step uses a medium containing A 83-01.
Daly teaches that the medium contains A 83-01 (para [0036], “Suitable concentrations of transferrin, insulin, FGF2, VEGF-A (165), and the TGFβ1 inhibitor in the second chemically defined medium are sufficient to differentiate the cells into discrete CD34+/CD34− (CD31+/CD31−) cell populations… In one specific embodiment, the concentration of TGFβ1 inhibitor is about 5 μM. TGFβ1 inhibitor are known in the art and include, but are not limited to, for example, SB431542, A83-01, Ki26894, LDN-193189, and Galunisertib (LY2157299). Suitable concentrations within these ranges are able to be determined by one of ordinary skill in the art.”). Moreover, Daly teaches that the methods are
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used to differentiate cells into either pericyte progenitors or endothelial progenitors (para 0020, “The methods described can be used to differentiate both endothelial cells and pericytes from iPSCs in the same workflow, as depicted in FIG. 1A. The Examples below demonstrated that pericytes have been differentiated in vitro from multiple ESC and iPSC cell lines. Media formulations and material substrates have been optimized to increase the expression of pericyte markers and to prolong their ability to expand in culture.”; FIG 1A, see above. ).
A skilled artisan would have been motivated to modify the culture method of Farkas, Aoki and Neil to incorporate A83-01 into a medium according to Daly to support differentiation of human induced pluripotent stem cells into endothelial progenitor cells. There would have been reasonable expectations of success in combining these teachings as one of ordinary skill in the art would recognize to combine known elements in the art to give predictable results.
Conclusion
No claims allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Katriel B Kasayan whose telephone number is (571)272-1402. The examiner can normally be reached 10-4p.
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, Maria G Leavitt can be reached at (571) 272-1085. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/KATRIEL BARCELLANO KASAYAN/Examiner, Art Unit 1634
/MARIA G LEAVITT/Supervisory Patent Examiner, Art Unit 1634
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