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 preliminary claim amendments filed 5/25/2023 is acknowledged.
Claims 1-13 is/are cancelled and claims 14-29 is/are newly added and is/are under examination.
Information Disclosure Statement
The listing of references in the specification, such as pages 51-60, is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Drawings
The drawings are objected to because:
(1) Description for Figure 1A on page 33 refers to Fig. S1. No such figure is shown in Figure 1 or elsewhere in the specification.
(2) 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.
(3) The drawings are objected to under 37 CFR 1.83(a) because they fail to show Fig. S1 and S2 referenced on pages 33, 40, 41, 42, Fig S3 referenced on page 43, Fig. S4 referenced on page 44 as described in the specification. Any structural detail that is essential for a proper understanding of the disclosed invention should be shown in the drawing. MPEP § 608.02(d).
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.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code on pages 38 and 58. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
The use of the terms B27, Matrigel, Alexa Flour, SYBR, which are trade names or a marks used in commerce, has been noted in this application. The terms should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
The disclosure is objected to because of the following informalities:
(1) On page 3 line 2, incorrect abbreviation (GDG) for fibroblast growth factor is used.
(2) On page 4 line 18, incorrect abbreviation (TGB) for Transforming growth factor is used.
(3) Table S1 is repeatedly referenced on pages 11, 38, 41 and 45 but no such table is provided.
Appropriate correction is required.
Nucleotide and/or Amino Acid Sequence Disclosures
Summary of Requirements for Patent Applications Filed On Or After July 1, 2022, That Have Sequence Disclosures
37 CFR 1.831(a) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.831(b) must contain a “Sequence Listing XML”, as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.831-1.835. This “Sequence Listing XML” part of the disclosure may be submitted:
1. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter “Legal Framework”) in XML format, together with an incorporation by reference statement of the material in the XML file in a separate paragraph of the specification (an incorporation by reference paragraph) as required by 37 CFR 1.835(a)(2) or 1.835(b)(2) identifying:
a. the name of the XML file
b. the date of creation; and
c. the size of the XML file in bytes; or
2. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation by reference statement of the material in the XML format according to 37 CFR 1.52(e)(8) and 37 CFR 1.835(a)(2) or 1.835(b)(2) in a separate paragraph of the specification identifying:
a. the name of the XML file;
b. the date of creation; and
c. the size of the XML file in bytes.
SPECIFIC DEFICIENCIES AND THE REQUIRED RESPONSE TO THIS NOTICE ARE AS FOLLOWS:
Specific deficiency - Sequences appearing in the specification are not identified by sequence identifiers (i.e., “SEQ ID NO:X” or the like) in accordance with 37 CFR 1.831(c). See Table S4 on page 49.
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required sequence identifiers, consisting of:
• A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
• A copy of the amended specification without markings (clean version); and
• A statement that the substitute specification contains no new matter.
Claim Objections
Claim 15 is 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 (RA and hedgehog signaling pathway agonist along with the same optional compounds). Removal of the repeated step is recommended.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
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 14, 16-29 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 14 recites “delayed addition of the retinoic acid to the culture medium”. It is unclear in relation to what is the addition of the retinoic acid delayed? Claim 15 also recites “delaying” RA exposure to the axial progenitor and clearly recites that the delay is with regards to Wnt exposure. No Wnt exposure is recited in claim 14. The examples in the specification teach RA exposure in relation to Wnt exposure (See figures 1B, 3A and 4A). The embodiments described teach 2-3 day Wnt exposure is required to derive axial progenitors from hPSC (page 11-para 1; page 25-last para) and RA exposure starts “around” D3 to D5, wherein days are in relation to start of Wnt exposure (page 24-25). Taken together, it appears that the “delayed addition of the retinoic acid” is in relation to a step not recited in this claim.
Claim 18 recites adding various compounds at various timepoints during the culture (D0, D3 etc.). However, the claim does not clearly identify which timepoint is considered D0? For the purpose of compact prosecution, the claim(s) 18 is/are interpreted as wherein D0 is the day when hPSCs are exposed to Wnt signaling pathway activator. This interpretation is supported by the examples in the specification. See figures 1B, 3A and 4A, each of which designate D0 as the day of CHIR exposure (Wnt signaling pathway activator).
Claim 22 recites adding various compounds at various timepoints during the culture (D3, D4 etc.). However, the claim does not clearly identify which timepoint is considered D0 such that timepoint D3 etc. could be ascertained? This is further unclear because claim 22 depends from claim 14 that does not include exposing hPSCs to Wnt signaling pathway activator and as noted above D0 is previously interpreted, based on the specification, as the day when hPSCs are exposed to Wnt signaling pathway activator.
Claim 22 recites addition of RA to the culture medium “alone” (line 3, 8). It is unclear if the claim requires RA exposure without “hedgehog signaling pathway agonist” exposure or if the claim is merely emphasizing that RA exposure is performed without FGFR agonist and/or TGF/activin/nodal activator, as recited in the alternate.
Claim 22 recites limitations in the form of wherein clauses. No active step is recited. It is unclear if the claim requires, for example, that RA be added to the culture medium between “D4 to D9” in the culturing step of claim 14 such that brachial motor neurons are obtained. This is further unclear since the claim also recites other wherein clauses in which RA is added at different time points or require additional compounds. For example, in the first wherein clause RA is added to the culture medium from D4-D9 while in the second wherein clause, RA is added from D5-D9. Thus, it is interpreted that these wherein clauses are alternatives. Furthermore, although these alternatives are not recited as active steps, they are interpreted such that they limit the duration of exposure of the compounds of claim 14 (although see issue regarding use of D3, D4 etc. as timepoints noted above).
Claim 23 recites FGFR2 as FGFR agonist. FGFR2 is a receptor and not a ligand. Thus, it is unclear how FGFR2 is a FGFR agonist. The specification teaches FGF2 as a FGFR2 agonist. For the purpose of compact prosecution, the claim(s) 23 is/are interpreted as “FGF[[R]]2”.
Claim 16-29 is/are rejected due their dependence on claim 14 because they do not clarify the 112b issue noted with claim 14.
Claim Interpretation
Claim 14 is directed to a method “for controlling rostro-caudal identity of human neuron subpopulations”. 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), along with additional optional compounds (FGFR agonist and/or TGF/activin/nodal signaling pathway activator). The method recites that the resultant population is of spinal motor neuron progenitors (“thereby obtaining”).
The method further recites a wherein clause that states that “more and more caudal motor neurons identities are obtained by delayed addition of the retinoic acid in the culture medium, or by addition of the retinoic acid in combination with the FGFR agonist or the TGF/activin/nodal signaling pathway activator” (emphasis added). See, e.g., 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 clause is not an active step nor does it further limits an active step (i.e. provide meaning or purpose). This wherein limitation does not require any specific amount of caudal motor neurons to be produced by the claimed active step or that retinoic acid (RA) must be added in a “delayed manner” for any specified duration and/or at any specified time. As noted in the U.S.C 112b rejection above, the phrase “delayed addition of the retinoic acid” is indefinite.
The specification teaches caudal motor neurons are produced when retinoic acid is added at D2 (i.e. 2 days after hPSC exposure to Wnt activator when axial progenitors are produced) and also when retinoic acid is added at D7 (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 are caudal motor neuron progenitors.
Claim Rejections - 35 USC § 102
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 112b issues noted 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 (=“delayed” with regards to exposure to the Wnt signaling pathway activator as required by claim 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
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).
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, 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.
Conclusion
No claim is allowed.
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