DETAILED ACTION
Applicant’s amendment and Arguments/Remarks received on 01 December 2025 have been entered. Claims 1-10, 12, and 14-23 were previously pending in the application. Claims 1-10, 12, and 14-23 are currently pending in the application. Claims 1 and 12 are independent claims. The following election of species remains in effect in the instant application:
Transcription factor overexpressed: c. Nfib,
Astrocyte biomarker: c. Vimentin (VIM).
Claim 3 remains withdrawn from consideration as being directed to a nonelected species, there being no allowable generic or linking claim.
Claims 1-2, 4-10, 12, and 14-23 are currently pending and under examination in the instant application. An action on the merits follows.
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA . The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Priority
The present application is a 35 U.S.C. 371 national stage filing of International Application No. PCT/EP2019/072065, filed 16 August 2019.
Thus, the earliest possible priority for the instant application is 16 August 2019.
Information Disclosure Statement
The information disclosure statement filed 01 December 2025 has been considered by the Examiner. Examiner notes the filing of IDS Size Fee assertions for the IDS filed 01 December 2025, as required under 37 CFR 1.98, indicating that no IDS size fee is required under 37 CFR 1.17(v) at this time.
37 CFR 1.121
The substitute specification filed 01 December 2025 has not been entered because it does not conform to 37 CFR 1.121(b) and (c) because: the marked up copy of the amended specification filed 01 December 2025 includes tracked changes, which is not an allowed amendment format. See MPEP 608.04(q), which states, “A marked-up copy of the substitute specification showing all the changes relative to the immediate prior version of the specification of record must also be submitted. The text of any added subject matter must be shown by underlining the added text. The text of any deleted matter must be shown by strike-through except that double brackets placed before and after the deleted characters may be used to show deletion of five or fewer consecutive characters. The text of any deleted subject matter must be shown by being placed within double brackets if strike-through cannot be easily perceived. Numbering the paragraphs of the specification of record is not considered a change that must be shown under 37 CFR 1.125(c). The paragraphs of any substitute specification, other than the claims, should be individually numbered in Arabic numerals (for example [0001]) so that any amendment to the specification may be made by replacement paragraph in accordance with 37 CFR 1.121(b)(1).”
37 CFR 1.821-1.825
The substitute specification filed 01 December 2025 has not been entered. Therefore, the specification still fails to comply with the requirements of 37 CFR 1.821 through 1.825 as addressed in the prior action:
This application contains sequence disclosures that are encompassed by the definitions for nucleotide and/or amino acid sequences set forth in 37 CFR 1.821(a)(1) and (a)(2), see for example paragraphs [47, 65, 80] (Tables 2, 5, 7, and 8) of the instant specification. However, this application fails to comply with the requirements of 37 CFR 1.821 through 1.825 for the reason(s) set forth below and on the Notice to Comply With Requirements For Patent Applications Containing Nucleotide Sequence And/Or Amino Acid Sequence Disclosures which is attached to this communication. Specifically, paragraphs [47, 65, 80] (Tables 2, 5, 7, and 8) disclose amino acid and/or nucleotide sequences but do not include any sequence identifiers. If the unidentified sequences of paragraphs [47, 65, 80] (Tables 2, 5, 7, and 8) of the instant specification are included in the submitted sequence listing, Applicant must amend the claims and specification and/or drawings to comply with the sequence identification requirements. Alternatively, if the unidentified sequences of paragraphs [47, 65, 80] (Tables 2, 5, 7, and 8) of the instant specification are not included in the presently submitted sequence listing, Applicant must submit an updated sequence listing in compliance with 37 CFR 1.821(c)-(d) and 37 CFR 1.825(b). See also the attached Notice to Comply.
APPLICANT IS GIVEN A THREE MONTH EXTENDABLE PERIOD WITHIN WHICH TO COMPLY WITH THE SEQUENCE RULES, 37 CFR 1.821-1.825. Failure to comply with these requirements will result in ABANDONMENT of this application under 37 CFR 1.821 (g). Extension of time may be obtained by filing a petition accompanied by the extension fee under the provisions of 37 CFR 1.136. In no case may an applicant extend the period for response beyond the six month statutory period. Applicant is requested to return a copy of the attached Notice to Comply with the response.
Specification
The objection to the specification of the disclosure for reciting trade names and/or marks used in commerce without the accompanying generic terminology and/or proper symbols is maintained in view of the amendment to the specification filed 01 December 2025 having not been entered.
Claim Objections
The objection to claims 14-16 for depending on a cancelled claim is withdrawn in view of the amendment to claim 14 such that claim 14 now recites “the population of cells of claim 1”.
The objection to claims 1, 7, and 16 for reciting abbreviations without first writing out the terms for which they are abbreviated, is withdrawn in view of the amendment to claims 1, 7 and 16 writing out the terms and/or deleting the abbreviations.
Claim Rejections - 35 USC § 112(b)
The rejection of amended and previously presented claims 1-2, 4-10, 12, and 14-23 under 35 U.S.C. 112(b) as failing to particularly point out and distinctly claim the subject matter which the inventor(s) regards as the invention for multiple issues of indefinite language is withdrawn over amended and previously presented claims 1-2, 4-10, 12, and 14-18, 20, 22-23 and maintained over previously presented claims 19 and 21 in view of Applicant’s amendments to the claims and arguments which address some, but not all, of the issues of indefiniteness as described below.
Applicant’s amendments overcome issues of indefiniteness described for language previously recited in amended and previously presented claims 8-10, 14-16, 20, and 22-23.
Additionally, applicant argued that the specification provides limiting definitions of the terms “functional” with regard to astrocytes and “overexpressed” in paragraphs [0019-0020]. Therefore, these issues of indefiniteness have been overcome.
However, Applicant neither amended to address nor argued the rejections of claims 19 and 21 for reciting the relative terms “increased” in claim 19 and “increase” in claim 20. Therefore, the metes and bounds of the claim still cannot be determined, Applicant’s amendments and arguments have not overcome a finding of indefiniteness for claims 19 and 21, and the rejection under 35 U.S.C. 112(b) is maintained.
**The following new rejection is necessitated by amendments to the claims.**
Amended and previously presented claims 14-16 are newly 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.
Amended claim 14 now recites the limitation "the population of cells of claim 1" in line 1, which has multiple issues of indefiniteness. Firstly, claim 1 is directed to a method and not a population of cells. Secondly, there is insufficient antecedent basis for this limitation in the claim. Amended claim 1 recites both a population of human pluripotent stem cells in line 3 and a population of induced functional astrocytes in lines 8-9.
Previously presented claims 15-16 are included in this rejection due to their dependence on amended claim 14.
As such, the metes and bounds of the claim cannot be determined.
Claim Rejections - 35 USC § 101
The rejection of amended and previously presented claims 12 and 17-23 under 35 U.S.C. 101 as being directed to a product of nature is withdrawn in view of Applicant’s amendments to the claims such that amended independent claim 1 now recites infecting the cells with expression vectors for conferring expression of Nfib or Nfib and Sox9.
Claim Rejections - 35 USC § 102
The rejection of amended and previously presented claims 1-2, 4-10, 12, and 17-23 under 35 U.S.C. 102(a)(1) as being anticipated by Canals et al. 2018, Nature Methods, 15, 693-696, published online 20 August 2019, IDS, is withdrawn in view of Applicant’s Declaration filed under 37 CFR 1.130(a) attesting that the disclosure was made by the inventors and that the additional co-authors did not contribute to the conceptual design of the invention.
Applicant argues that the co-inventors Henrik Ahlenius and Isaac Canals Montferrer (also known as Isaac Canals) were the sole inventors of the claimed invention, such that the additional co-authors who are not listed as inventors of the instant application, namely, Aurelie Ginisty, Ella Quist, Raissa Timmerman, Jonas Fritze, Giedre Miskinyte, Emanuela Monni, Marita G. Hansen, Isabel Hidalgo, David Bryder, and Johan Bengzon, are not inventors of the claimed subject matter, and thus the Canals et al. 2018 publication, published less than a year prior to the effective filing date of the instant application, does not qualify as prior art. Co-inventors and co-authors Issac Canals Monferrer and Henrick Ahlenius submitted Declarations under Affidavit-Rule 37 CFR 1.130(a) attesting to such inventorship, wherein only Issac Canals Monferrer and Henrick Ahlenius contributed to the conceptualization and design of all features of the instantly claimed invention.
Accordingly, the rejection of claims 1-2, 4-10, 12, and 17-23 under 35 U.S.C. 102(a)(1) over Canals is withdrawn.
The rejection of amended and previously presented claims 1-2 and 4-6 under 35 U.S.C. 102(a)(1) as being anticipated by Davila (US20190249147A1, published 15 August 2019), is maintained. Applicant's amendments to the claims and arguments have been fully considered but have not been found persuasive in overcoming the rejection for reasons of record as discussed in detail below.
Applicant amended independent claim 1 to recite “infecting… with one or more expression vectors suitable for conferring expression of one or more transcription factors selected from the group consisting of” Nfib and Nfib plus Sox9, “whereby the one or more transcription factors are overexpressed”. Claims 2 and 4-6 have not been amended. However, Davila anticipates these newly recited limitations.
Davila was cited for teaching astroglial cells/astrocytes can be generated from human pluripotent stem cells through directly reprogramming human pluripotent stem cells into the astroglial lineage using (e.g., delivering) transcriptions factors like NFIA, NFIB, SOX9, HES1, alone or in combination [0038, 0041, Figure 1, claims 9-10].
Davila further teaches that introduction of an expression vector encoding a polypeptide can be used to overexpress the encoded product [0116, 0126] and that increased gene expression may be achieved by delivering RNA or DNA that carry a reading frame of a specific gene to the cells using transfection methods or viral transduction (e.g., lentivirus, adeno-associated virus, sendai virus, or retrovirus) [0042].
Accordingly, by teaching all the limitations of amended and previously presented claims 1-2 and 4-6 Davila anticipates the instant invention as claimed.
Applicant argues that the present amendment incorporates non-rejected claim 7 into claim 1, thereby overcoming the rejection. However, this is not agreed. Note that non-rejected claim 7 previously recited the limitations now introduced into independent claim 1, but also recited wherein the cells are infected with one or more lentiviral vectors. Amended claim 1 does not require that the cells are infected with a lentiviral vector. Therefore, not all of the limitations of non-rejected claim 7 (as filed 15 February 2022) have been introduced into amended independent claim 1 (as filed 01 December 2025). Claim 7 was previously not included in the 35 U.S.C. 102(a)(1) rejection over Davila due specifically to the recitation of a lentiviral vector. Davila teaches Nfib as one of four transcription factors to deliver for the production of induced astrocytes from human pluripotent stem cells and lentiviral delivery of transcription factors as one of five delivery options (e.g., transfection, lentivirus, adeno-associated virus, sendai virus, or retrovirus) and so does not specifically anticipate the combination of Nfib delivered specifically via lentiviral transduction. However, by reciting “infecting” broadly, amended claim 1 only requires selecting from two delivery options taught by Davila (i.e., transfection or transduction/infection), which provides for a very limited number of combinations of transcription factor and delivery method.
Therefore, Applicants arguments do not overcome a finding of anticipation under 35 U.S.C. 102(a)(1) over Davila, and the rejection is maintained.
Claim Rejections - 35 USC § 103
The rejection of amended and previously presented claims 1-2, 4-10, 12, and 17-23 under 35 U.S.C. 103 as being unpatentable over Li et al. (2018, Stem Cell Reports, 11, 998-1008); in view of Tchieu et al. (2019, Nature Biotechnology, 37, 267-275, published online 25 February 2019); Davila (US20190249147A1, published 15 August 2019); Khakh & Sofroniew (2015, Nature Neuroscience, 18(17), 942-952); Bylicky et al. (2018, Oxidative Medicine and Cellular Longevity, 2018(6501031), 1-16); and van Kralingen et al. (2013, PLOS One, 8(12), e84269, 1-13), is maintained and newly applied to amended claims 14-16. Note that the expansion to include amended claims 14-16 is necessitated by amendment to claims 14-16 such that they now depend upon amended independent claim 1 and not on a cancelled claim. Applicant's amendments to the claims and arguments have been fully considered but have not been found persuasive in overcoming the rejection for reasons of record as discussed in detail below.
Applicant amended the claims to address issues of indefiniteness and to incorporate limitations previously recited in claim 7 into independent claim 1. However, the amendments do not introduce any new limitations which alter the scope of the claims sufficiently to overcome the obviousness rejection of record.
Regarding claims 14-16, Li teaches that hESC and hiPSC-derived induced astrocytes express the astrocyte marker vimentin [Table S1].
Therefore, Applicant’s amendments do not overcome a finding of obviousness under 35 U.S.C. 103 over Li, Tchieu, Davila , Khakh, Bylicky, and van Kralingen.
Applicant argues that:
Li does not teach or suggest all the limitations of amended independent claim 1;
Tchieu does not teach or suggest all the limitations of amended independent claim 1;
Davila does not teach or suggest all the limitations of amended independent claim 1;
None of Khakh, Bylicky, nor Kralingen alone or in combination teach or suggest all the limitations of amended independent claim 1.
In response to applicant’s arguments against the references individually, it is noted that the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981). One cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Further, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In addition, 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).
Specifically, regarding Applicant’s argument 1), note that no single reference was relied on for teaching every limitation of amended claim 1. Li was cited for teaching a method of converting human pluripotent cells into induced functional astrocytes (iAs) comprising contacting a population of human pluripotent stem cells with an effective dose of a reprogramming system comprising NFIA for a period of time sufficient to reprogram the pluripotent cells, wherein as a result of the method, a population of induced functional astrocytes is produced [abstract, column 3 ¶ 2], and was not relied on for teaching the motivation to substitute Nfia with Nfib.
Additionally, Li was cited for teaching that one way to accelerate the differentiation process is to force the expression of cell-type-specific transcription factors in stem cells, which has been demonstrated by fast generation of functional neurons from hESCs through virus-mediated expression of a pro-neural gene [column 2 ¶ 2]. Li was also cited for teaching that they created hESC and iPSC lines with doxycycline (DOX) inducible expression of gliometric transcription factors NFIA or NFIA + SOX9 via CRISPR/Cas9 (TRE3G-NFIA), such that utilizing inducible expression of NFIA or NFIA + SOX9, they developed a method for fast generation of homogenous functional and transplantable astrocytes from hESCs and iPSCs in 4-7 weeks [column 2 ¶ 2, Figure 1].
Regarding Applicant’s arguments 2)-3), neither Tchieu nor Davila were relied on for teaching every limitation of amended claim 1. Tchieu was cited for teaching the redundance of NFIA and NFIB in astrocyte differentiation and Davila was cited for teaching that either NFIA or NFIB can be used to directly differentiate human pluripotent stem cells into the astroglial lineage. Therefore, Tchieu and Davila teach the motivation to modify the method of Li for converting human pluripotent cells into induced functional astrocytes (iAs) by substituting NFIA with NFIB.
Tchieu was further cited for teaching that the hPSC-derived neural stem cells (NSCs) were infected with lentiviral vectors capable of conferring expression of NFIA, whereby NFIA is overexpressed [Supplemental Methods column 2 ¶ 1]. Additionally, Davila teaches that introduction of an expression vector encoding a polypeptide can be used to overexpress the encoded product [0116, 0126] and that increased gene expression may be achieved by delivering RNA or DNA that carry a reading frame of a specific gene to the cells using transfection methods or viral transduction (e.g., lentivirus, adeno-associated virus, sendai virus, or retrovirus) [0042].
Regarding Applicant’s argument 4), note that none of Khakh, Bylicky, nor von Kralingen were relied on for teaching all of the limitations of amended claim 1. Khakh, Bylicky, and von Kralingen were each cited for teaching limitations recited in dependent claims.
Therefore, Applicant’s arguments have not overcome a finding of obviousness for claims 1-2, 4-10, 12, and 14-23 under 35 U.S.C. 103 over Li, Tchieu, Davila , Khakh, Bylicky, and van Kralingen, and the rejection is maintained and newly applied to amended claims 14-16.
Conclusion
No claim is 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 Dr. KATIE L PENNINGTON whose telephone number is (703)756-4622. The examiner can normally be reached M-Th 8:30 am - 5:30 pm, Friday 8:30 am - 12:30 pm CT.
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DR. KATIE L. PENNINGTON
Examiner
Art Unit 1634
/KATIE L PENNINGTON/Examiner, Art Unit 1634
Dr. A.M.S. Wehbé
/ANNE MARIE S WEHBE/Primary Examiner, Art Unit 1634