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 .
Claims status
Applicants reply filed 4/29/2026 is acknowledged.
Claims 14-29 is/are currently pending and is/are under examination.
Withdrawn Objections
The objections presented herein represent the full set of objections currently pending in this application. Any objections not specifically reiterated are hereby withdrawn.
Drawings-Maintained, in part
The drawings remain objected to because:
(1) Figures 1D-F, 3C-D, 4C-F could not be evaluated because the conditions shown are indistinguishable. For example, in Figure 1D, %MNs with HOXC6, HOXC8 and HOXC9 is shown. However, since each of these cell markers is shown in the about the same tone of gray, these are effectively indistinguishable. Distinct gray tones or use of hatches/lines is recommended.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
In the reply filed 4/29/2026, Applicant state that “clearer” replacement drawing are filed to overcome the objection above (page 7, para 11). However, the issue with the drawings objected to is not that of clarity but that the conditions shows are each represented such that they cannot be distinguished. Thus, the objection is maintained. Use of distinct gray tones or use of hatches/lines was recommended.
Claim Suggestion
Claim 18, line 4 recites “D0 corresponding to the first day on which the hPSC are exposed to the Wnt signaling pathway activator”. Use of wherein to precede this clause is recommended such that the limitation reads: “wherein D0 corresponds to the first day on which the hPSC are exposed to the Wnt signaling pathway activator”.
Claim Objections – Maintained, New-necessitated by claim amendment
Claim 15 remains objected to because of the following informalities: It adds a step of obtaining axial progenitors from hPSCs but repeats the step of exposing the axial progenitors to the same compounds as claim 14 (“exposing the axial progenitors to the RA and the Hedgehog signaling pathway agonist, optionally combined with a FGFR agonist or a TGF/activin/nodal signaling pathway activator in the culture medium to obtain spinal motor neuron progenitors”). Removal of the repeated step is recommended.
Appropriate correction is required.
Claim 22 is objected to because of the following informalities: In line 10, the claim recites “adding RA to the culture medium of the RA”. This phrase is grammatically incorrect. Following language is recommended: “adding RA to the culture medium .
Appropriate correction is required.
In the reply filed 4/29/2026, Applicant state that “Claim 15 is hereby amended as suggested by Examiner” (page 8, para 6). However, the repeated step is not removed from the amended claim 15. Thus, the objection is maintained.
Claim Rejections - 35 USC § 112(b) – New, necessitated by claim amendments
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.
Previous rejection of Claims 14, 16-29 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 is withdrawn in light of claim amendments.
Claims 22, 23 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.
Claim 22 recites the limitations "hPSC", “Wnt signaling pathway activator” in the last two lines. There is insufficient antecedent basis for this limitation in the claim. For the purpose of compact prosecution, the claim(s) 22 is/are interpreted as depending from Claim 15 instead of claim 14.
Claim 23 recites the limitations "the FGFR agonist" in line 1. There is insufficient antecedent basis for this limitation in the claim. For the purpose of compact prosecution, the claim(s) 23 is/are interpreted as depending from Claim 15 instead of claim 14.
Claim Interpretation – New, to address claim amendments
Claim 14 is directed to a method “for obtaining human motor neuron subpopulations of specific rostro-caudal phenotype”. The claim does not recite or require obtention of human motor neuron subpopulations of any specific rostro-caudal phenotype such that the claim is interpreted to be directed to a method for obtaining human motor neuron subpopulations of any rostro-caudal phenotype. This interpretation is further supported by claim 22 that recites obtaining various human motor neuron subpopulations of different rostro-caudal phenotype such as brachial, anterior or caudal thoracic and lumbar.
The method comprises one active step of culturing axial progenitors in a medium comprising retinoic acid (RA) and a “hedgehog signaling pathway agonist” (See definition on page 20). The method recites that the resultant population is of spinal motor neuron progenitors of specific rostro-caudal phenotype (“to obtain”). Again, no specific phenotype is recited or required such that the claim is continued to be interpreted as directed to a method for obtaining spinal motor neuron progenitors subpopulations of human motor neuron of any rostro-caudal phenotype.
The method further recites the following wherein clauses:
“wherein said specific rostro-caudal phenotype is obtained by adjusting the moment at which retinoic acid is added to the culture medium” and,
“wherein the later the retinoic acid is added to the culture medium during the culture of said axial progenitors, the more motor neurons of caudal phenotype are obtained”
Regarding wherein clauses, See Griffin v. Bertina, 285 F.3d 1029, 1034, 62 USPQ2d 1431 (Fed. Cir. 2002) (finding that a "wherein" clause limited a process claim where the clause gave "meaning and purpose to the manipulative steps"). MPEP 2111.04.
However, in the instant case, the wherein clauses are not active steps nor do they further limit the active step (i.e. provide meaning or purpose). These wherein limitations do not require any specific rostro-caudal phenotype to be produced by the claimed active step. The wherein clause reciting “the later the retinoic acid is added [..] the more motor neurons of caudal phenotype are obtained” does not require addition of retinoic acid (RA) at any specific timepoint or for any specific duration. It recites a potential but not a required result of the claimed method wherein if RA is added “later” than some unrecited timepoint then more caudal motor neurons are obtained. See MPEP 2111.04(II) regarding contingent limitations that states “The broadest reasonable interpretation of a method (or process) claim having contingent limitations requires only those steps that must be performed and does not include steps that are not required to be performed because the condition(s) precedent are not met.” Not only the wherein clause with the contingent limitation not an active step, it is only recites a contingent intended result and not a required result.
The specification teaches motor neurons of rostro-caudal phenotype are produced when retinoic acid is added from D2 or D3 or D4 or D5 or D6 or D7 (i.e. 2-7 days after hPSC exposure to Wnt activator when axial progenitors are produced) (Figure 1D). Thus, claim 14 is interpreted as a method requiring exposing axial progenitors to RA and hedgehog signaling pathway agonist, thereby producing spinal motor neuron progenitors at least some of which have a rostro-caudal phenotype.
Claim 15 recites an optional active step of “optionally combined with a FGFR agonist […]” and also a wherein clause directed to this optional step (“wherein the concentration or duration of exposure to the FGFR agonist or […]). Since the said active step is optional, it is interpreted that the limitation recited in wherein clause directed to said optional active step is also optional.
Claim Rejections - 35 USC § 102 - Maintained
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(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) 14-18, 21-28 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Maury et al (Nature biotechnology, Vol. 33, Jan 2015; IDS 5/25/2023).
Regarding claims 14-15, 23, 24, 25 and 28, in view of the claim interpretation above, Maury teaches a method comprising exposing hPSC to Chir99021, a Wnt signaling pathway activator (as required by claims 15 and 28) to obtain axial progenitors, culturing the axial progenitors in the presence of RA and SAG, a hedgehog signaling pathway agonist at 500nM (as required by claims 24 and 25) (Figure 1C, 1D, 2A; Online Methods: Large-scale differentiation in 384-well plates; Supplementary Figure 4, 11; Supplementary Table 1).
Maury teaches RA exposure at D2 and D4 i.e. 2 or 4 days after start of culture (=claimed adjusting moment of RA addition, RA exposure at D4 which is later than D2 with regard to Wnt exposure would inherently result in more motor neurons of caudal phenotype being obtained as recited in claim 14 and 15; Figure 1C, 2A).
Maury also teaches inclusion of FGF2, a FGFR agonist (as required by claim 23 in view of the 112b interpretation above; Figure 1C).
Maury teaches that their method results in generation of spinal motor neuron progenitors, as identified by their Olig2+ marker expression (Figure 1, 2; page 90-col.1-para 2).
Since Maury’s method comprises a 2 day or a 4 day delay in RA exposure with regards to exposure to the Wnt signaling pathway activator, Maury’s method inherently produces caudal motor neurons wherein more caudal motor neurons are inherently produced in the condition with the 4 day delay in comparison to the condition with the 2 day delay.
Regarding claim 16, 26 and 27, Maury teaches exposing the spinal motor neuron progenitors to DAPT, a notch pathway inhibitor, at 10uM being the most potent (= at least 5uM; as required by claims 26 and 27; Figure 3; page 92-col. 1).
Regarding claim 17 and 18, Maury teaches exposing hPSC to Chir99021, a Wnt signaling pathway activator, in combination with dual SMAD inhibitors which are LDN-193189, a TGF/activin/nodal inhibitor, and SB-43152, a BMP signaling pathway inhibitor (Figure 1C, 2A; page90-col.1-para 2; Online Methods: Large-scale differentiation in 384-well plates). Maury teaches adding the dual SMAD inhibitors (i.e. TGF/activin/nodal inhibitor and a BMP signaling pathway inhibitor) along with Chir-99021, a Wnt signaling pathway activator, from D0-D4 (Figure 2A). Adding SAG, a hedgehog pathway agonist, from D2 to D16 or D4 to D16 or D7 to D16 (Figure 2A).
Regarding claim 21, Maury teaches adding RA to the culture medium for 2-11 days (Figure 1C, 2A).
Regarding claim 22, in view of 112b issues noted above, Maury teaches adding RA from D4-D9 to the culture medium and also teaches adding RA to the culture medium until D9. Thus Maury’s method results in obtention of at least brachial motor neurons and anterior thoracic motor neurons (Figure 1C, 2A).
Therefore, Maury anticipates the claimed invention.
Claim Rejections - 35 USC § 103 - Maintained
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) 19, 20, 22, 29 is/are rejected under 35 U.S.C. 103 as being unpatentable over Maury as applied to claims 14 and 15 above, and further in view of Lippmann et al (Stem Cell Reports, Vol. 4, pg. 632–644, April 14, 2015; ref of record).
The teachings of Maury as applied to claims 14 and 15 in the U.S.C. 102 rejection detailed above are relied upon for the instant rejection.
As noted above, Maury teaches the method to produce spinal motor neurons from hPSC -derived axial progenitors using Wnt, FGFR and hedgehog pathway activation along with RA.
Regarding concentration and duration of FGFR agonist, as required by claim 20, , Maury teaches FGF2 concentration from 0-50ng/ml – specifically teaching 15ng/ml – for a duration of at least 24 hours (Figure 1C, D).
Maury does not teach exposing axial progenitors to additional TGF/activin/nodal signaling pathway activator, as recited in claim 19, and thus does not teach a concentration or duration of exposure recited in claim 20 or GDF11 as recited in claim 29.
Regarding claim 19 and 29, Lippmann teaches the use of GDF11, a TGF/activin/nodal signaling pathway activator (as required by claim 29) to generate caudal spinal motor neurons from hPSCs in addition to RA and FGFR agonist (Figure 2, 3, 4).
Regarding claim 20, Lippmann teaches various GDF11 concentrations – from 0-50ng/ml (= at least 20ng/ml as claimed; Figure S3). Lippman uses 50ng/ml GDF11 and a 2 day exposure (= at least 24 hours as claimed) (Figure 3 and S3; Experimental Procedure: Induction and Propagation of NMPs and Differentiation to Neural Fates.).
Lippmann also teaches that a delay in RA exposure in relation to Chir (the Wnt activator), wherein the medium comprises FGFR agonist and GDF11 results in more caudal spinal motor neurons, with more delay resulting in more caudal phenotype, such as thoracic and lumbar motor neurons (as recited in claim 22; Figure 3B and 3D). To generate more caudal motor neurons such as lumbar motor neurons, Lippmann adds RA to the culture medium from D8 to D12 (= added between D5-D9 as claimed), and adds FGFR agonist at 200ng/ml from D1 to D8 (= added between D3-D5 as claimed) and GDF11, a TGF/activin/nodal signaling pathway activator, at 50ng/ml from D6-D8 (instead of D3-D5 as claimed) (as recited in claim 22; Figure 3 and S3; Experimental Procedure: Induction and Propagation of NMPs and Differentiation to Neural Fates.)
Referencing Maury, Lippman states that “a recent report demonstrated that manipulation of Wnt and RA concentrations could yield MNs possessing hindbrain or rostral spinal phenotypes but more caudal and further partitioning of regional HOX identity was not achieved (Maury et al., 2014)” (emphasis added; page 633-col.1-para 1). Lippman teaches the use of GDF11 and delayed RA addition to achieve more caudal identities.
Therefore, based on Lippmann’s teachings, it would be obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to include GDF11, a TGF/activin/nodal signaling pathway activator, in Maury’s method. An ordinary artisan would be motivated to include GDF11 in Maury’s method to achieve spinal motor neurons of more caudal identities, as taught by Lippmann. An ordinary artisan would reasonably expect to include to GDF11 in Maury’s method based on Lippmann’s teachings. Furthermore, an ordinary artisan would reasonably expect that inclusion of GDF11 in Maury’s method would increase caudal identities of the spinal motor neurons generated because Lippman teaches when generating spinal motor neurons from hPSCs, same as Maury, inclusion of GDF11 and delayed RA addition results in more caudal identities.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in
the art at the effective time of filing of the invention, especially in the absence of evidence to the
contrary.
Response to Arguments
Applicant's arguments filed 4/29/2026 regarding U.S.C. 102 rejection of claims as anticipated by Maury have been fully considered but they are not persuasive.
Applicant argue that Maury “does not teach a method to obtain motor neuron progenitors of a specific rostro-caudal phenotype by adjusting the time at which retinoic acid is added to the culture medium. This document even much less teaches adjusting the time at which retinoic acid is added so that the later retinoic acid is added to the culture medium during the culture of said axial progenitors, the more motor neurons of a caudal phenotype are obtained” (page 10, para 2). Further, Applicant allege “Maury does not allow for the specific generation of brachial, thoracic and lumbar MNs and in particular, among these MN subtypes, limb innervating MNs. Maury et al., identified spinal progenitors having putative characteristics of axial progenitors as
they were able to generate motor neurons. However, neither the competence of these progenitors nor the rostro-caudal identity of their progeny had been established” (page 10, para 3). Applicant allege without evidence that the instant Application discloses a method for “synchronous engineering with an unprecedented efficiency and precision of human MN subtypes with defined rostro-caudal identities” (page 10, para 4).
In response, Applicant have not identified what active steps recited in the instant claims are not taught by Maury. Each of the recited compounds and specifically recited duration of exposure in the claims is taught by Maury. Further, not only the claims do not require generation of any specific type of caudal motor neurons, it must be noted that any specific type of caudal motor neurons generated by the claimed method flows from the active steps of the method. Since Maury teaches the active steps, Maury’s method inherently results in the obtention of the caudal motor neurons. Identification of the specific identity of spinal motor neurons inherently generated by Maury’ method cannot overcome the anticipation rejection.
Applicant's arguments filed 4/29/2026 regarding U.S.C. 103 rejection of claims in view of Maury and Lippmann have been fully considered but they are not persuasive.
Applicant argue that Lippman does not remedy Maury’s deficiencies argued in the U.S.C. 102 rejection (page 11, para 2).
In response, Applicant’s arguments pertaining to Maury were not persuasive. Thus, Lippmann is not required to remedy those deficiency.
Regarding Lippmann, Applicant argue that Lippmann’s method “which relies on 2D adherent differentiation of hPSCs results in low percentage of MNs of mixed identities and often contamination with non-neuronal cells demonstrating a poor control over the differentiation process. This limitation precludes systematic studies of MN subtypes in health and even more in disease in which selective MN populations are affected.” (page 11, para 3)
In response, Lippman is relied for teachings pertaining to inclusion of GDF11 in Maury’s method and not for hPSC culture. Thus, relevance of this argument for the instant rejection is not established.
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 MATASHA DHAR whose telephone number is (571)272-1680. The examiner can normally be reached M-F 8am-4pm (EST).
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Peter Paras Jr. can be reached at (571)272-4517. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/MATASHA DHAR/Examiner, Art Unit 1632
/EMILY A CORDAS/Primary Examiner, Art Unit 1632
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