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 .
1. Claims 1 – 22 are pending.
Election/Restrictions
2. Applicant’s election without traverse of Group I (claims 1 – 20) in the reply filed on 10/06/2025 is acknowledged.
3. Claims 21 – 22 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 10/06/2025.
4. Claims 1 – 20 are under consideration.
Priority
5. This application is the U.S. national stage entry of PCT/US2021/040178 filed 07/01/2021, which claims priority to U.S. provisional patent application No. 63/047697 filed 07/02/2020.
Information Disclosure Statement
6. The information disclosure statement (IDS) submitted on 10/09/2025, 10/15/2024, and 04/14/2023 are acknowledged. The submissions are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Drawings
7. The drawings are objected to because of the following informalities: there is description of color in the Specification of Figure 5M on page 5 para. 00014 and Figure 7 on page 5, para. 00016, and the various colors cannot be distinguished from each other since the figures are in black and white.
Color photographs and color drawings are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted. Any such petition must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via the USPTO patent electronic filing system or three sets of color drawings or color photographs, as appropriate, if not submitted via the via USPTO patent electronic filing system, and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification:
The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2).
Specification
8. The specification filed on 12/29/2022 is acknowledged.
Claim Objections
9. Claim 1 is objected to because of the following informalities: in line 1, “spinal dI4 progenitor cells” should read “spinal dorsal interneuron domain 4 (dI4) progenitor cells” as disclosed in Applicant’s specification at para. 0002. Appropriate correction is required.
10. Claim 1 is objected to because of the following informalities: in line 10 and 12, “spinal dl4 progenitor cells” should read “spinal dI4 progenitor cells” where the letter after “d” and preceding “4” should be an “I” that stands for “interneurons”. Appropriate correction is required.
11. Claim 18 is objected to because of the following informalities: in line 2, “spinal dl4 progenitor cells” should read “spinal dI4 progenitor cells” where the letter after “d” and preceding “4” should be an “I” that stands for “interneurons”. Appropriate correction is required.
12. Claim 19 is objected to because of the following informalities: in line 2, “spinal dl4 progenitor cells” should read “spinal dI4 progenitor cells” where the letter after “d” and preceding “4” should be an “I” that stands for “interneurons”. Appropriate correction is required.
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.
13. Claims 1 – 12 and 16 – 20 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.
14. Claim 1 recites “a medium additionally comprising” in lines 8 – 9. It is unclear if “a medium” refers to the same medium of step (a) “additionally comprising” a RA signaling agonist and a SHH signaling inhibitor or if a different medium. For the purpose of applying prior art, “a medium” of step (b) is interpreted as comprising a Wnt signaling pathway inhibitor, a BMP signaling pathway inhibitor, a TGFβ signaling pathway inhibitor, a RA signaling agonist and a SHH signaling inhibitor based on Applicant’s specification at page 27 – 28, para. 00073 – 00074 and Figure 2B. Claims 2 – 12 and 16 – 20 are also rejected as they depend from claim 1 and do not clarify the grounds of rejection.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
15. Claim 18 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 18 does not further limit claim 1 because claim 1 requires that the spinal dI4 progenitor cells express PTF1A, PAX7, and ASCL1, while claim 18 requires the cells express at least one of PTF1A, PAX7, and ASCL1. Thus, claim 18 broadens claim 1 by only requiring the cells express at least one of the recited markers.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Interpretation
16. For the purpose of applying prior art, “a medium” of step (b) is interpreted as comprising a Wnt signaling pathway inhibitor, a BMP signaling pathway inhibitor, a TGFβ signaling pathway inhibitor, a RA signaling agonist and a SHH signaling inhibitor based on Applicant’s specification at page 27 – 28, para. 00073 – 00074 and Figure 2B.
17. For the purpose of applying prior art, “human stem cells are obtained from a human embryo” of claim 4 is interpreted as the human stem cells of claim 1 are human embryonic stem cells because Example 1 of Applicant’s specification cultures hESCs (page 25, para. 00072).
18. For the purpose of applying prior art, claim 19 is interpreted as a portion of the spinal dI4 progenitor cells of step (b) further differentiate into spinal GABA interneurons by culturing in any culture medium because the claim does not recite any active method steps or any requirements for a culture medium for differentiating spinal dI4 progenitors into spinal GABA interneurons.
Claim Rejections - 35 USC § 102
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 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.
19. Claim(s) 1 – 3, 5 – 9, 11 – 13, and 16 – 20 are is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Chen (CN-109554342-A; Filed 10/23/2018; Published 04/02/2019), hereinafter Chen as evidenced by Xu (Xu J, et. al. Front Mol Neurosci. 2022 Apr 8;15:845875), hereinafter Xu. A machine translation of CN1095543342A is provided. The translation was performed on 12/09/2025 of pages 2 – 6 of the original document.
Claim 1 is drawn to a method of generating a population of spinal dl4 progenitor cells from
human stem cells, the method comprising: (a) culturing the human stem cells in a culture medium comprising a Wnt signaling pathway agonist, a BMP signaling pathway inhibitor, and a TGFP signaling
pathway inhibitor, to generate a population of cells comprising spinal neuroepithelia progenitors, wherein at least 95% of the population of cells generated are Sox1 +/Hoxa3+ spinal neuroepithelia progenitors; and (b) culturing the spinal neuroepithelia progenitors of step (a) in a medium
additionally comprising a retinoic acid (RA) signaling agonist and a SHH signaling inhibitor,
to generate a population of cells comprising spinal dl4 progenitor cells, wherein at least 90% of the population of cells generated are PTF1A+/PAX7+/ ASCL1+ spinal dl4 progenitor cells.
Regarding step (a) of claim 1 – 3 and claims 5 – 7 and 11 – 12, Chen teaches a method comprising a first step of culturing human induced pluripotent stem cells (“human stem cells” of claim 1; claim 2; “human induced pluripotent stem cells” of claim 3) in a medium comprising CHIR99021, SB431542, and DMH for 7 days (“step (a)” of claim 1; “CHIR99021” of claim 5; “DMH-1” of claim 6; “SB431542” of claim 7; “7 days” of claims 11 – 12) to form neuronal epithelial cells wherein the resulting cells express Sox1 and Hoxa3 (“at least 95% of the population of cells generated are Sox1+/Hoxa3+ spinal neuroepithelia progenitors”) (page 3, para. 2 – 3; page 3, last para.; page 4, para. 8; page 5, para. 2 and last para.; Figure 1, 2a, and 2b of the original document).
Regarding step (b) of claim 1 and claims 8 – 9, 13, and 16 – 18, Chen teaches the method further comprises a second step of adding cyclopamine and retinoic acid to the medium for continuous induction of differentiation for an additional 7 days (“step (b)” of claim 1; “retinoic acid” of claim 8; “cyclopamine” of claim 9; claim 13; “7 days” of claims 16 – 17) to form spinal cord interneuron precursor cells (page 3, para. 2 – 4; page 4, para. 1 and para. 7 – 8; page 5, para. 2 – 5; page 6, para. 1; Figure 1, 2a and 2b of the original document). As Chen anticipates the recited step (a) and step (b) of claim 1, the product of Chen after step (b) inherently meets the limitation of “at least 90% of the population of cells generated are PTF1A+/PAX7+/ASCL1+ spinal dI4 progenitor cells” of claim 1 and “the spinal dI4 progenitor cells of step (b) express at least one gene selected from PTF1A, PAX7, and ASCL1” of claim 18 as evidenced by Xu, which is a post-filing publication of Chen where the method of Chen produces dI4 progenitors that express Ascl1, Ptf1a, and Pax2 (Figure 2 and 3A – D; page 6, left col., sub-paragraphs 6 – 10 and right col. sub-paragraphs 11 – 14).
Regarding claim 19, Chen teaches further differentiating the cells after day 14 to form GABAergic spinal interneurons (page 3, para. 5; page 5, para. 6 – 11; page 6, para. 2 – 3; Figure 1 and 4 of the original document).
Regarding claim 20, as Chen anticipates the recited step (a) and step (b) of claim 1 and differentiation of the cells at step (b) to GABAergic spinal interneurons, the GABAergic spinal interneurons inherently meet the limitation of “the spinal GABA interneurons express at least one gene selected from PAX2 and LHX1/5 or a combination thereof” as evidenced by Xu, which is a post-filing publication of Chen where the method of Chen produces dI4 progenitors that express Pax2 and Lhx1/5 (Figure 3B – F; page 6, right col. sub-paragraphs 15 – 18; page 7, left col.).
Therefore, Chen anticipates claims 1 – 3, 5 – 9, 11 – 13, and 16 – 20.
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 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.
20. Claim(s) 1 – 20 is/are rejected under 35 U.S.C. 103 as being unpatentable over by Chen (CN-109554342-A; Filed 10/23/2018; Published 04/02/2019), hereinafter Chen as evidenced by Xu (Xu J, et. al. Front Mol Neurosci. 2022 Apr 8;15:845875), hereinafter Xu in view of Du (Du, Zhong-Wei, et al. Nature communications 6.1 (2015): 6626), which is cited on the IDS filed 04/14/2023. A machine translation of CN1095543342A is provided. The translation was performed on 12/09/2025 of pages 2 – 6 of the original document.
Chen anticipates claim 1 as set forth above.
Regarding claim 4, Chen teaches human pluripotent stem cells (page 3, last para.) but does not teach human embryonic stem cells.
Regarding claim 10, Chen teaches the molar concentration ratio of the CHIR99021, SB431542, and DMH1 is 3:2:2 (page 3, para. 7) but does not teach “µM”.
Regarding claim 14 and 15, Chen teaches the molar concentration ratio of the CHIR99021, SB431542, and DMH1 is 3:2:2 and the molar concentration ratio of the cyclopamine to retinoic acid is 5:1 (page 3, para. 7) but does not teach “µM”.
Chen teaches spinal cord injury is a common traumatic disease that causes a range of motor and psychological problems where nearly 40% to 50% of patients have neuropathic pain in 1 year and that later becomes chronic pain, affecting the recovery of patients (page 2, para. 1 of Background technique). Chen teaches new treatment methods are needed for the clinical treatment of pain (page 2, last para.). Chen teaches the spinal GABAergic interneurons can be used for treating pain (page 3, para. 11 – 12). Chen teaches the high-purity spinal GABAergic interneurons can be obtained quickly and efficiently by the method (page 6, last para.).
Regarding claims 4 and 10, Du teaches a method of generating neuroepithelial progenitors (NEPs) that are SOX1+/HOXA3+ from human embryonic stem cells (hESCs) (claim 4) by culturing hESCs with 2 µM SB431542, 2 µM DMH1, and 3 µM CHIR99021 (claim 10) (page 2, right col. para. 1; Figure 1a – b; page 7, right col. para. 3).
Regarding claims 14 – 15, Du teaches culturing the NEPs with 2 µM SB431542, 2 µM DMH1, and 3 µM CHIR99021, 0.5 µM cyclopamine, and 0.1 µM retinoic acid where GABA neurons are produced (Supplementary Figure 3; page 5, left col.; page 7, right col. para. 3 – 4). Du teaches degeneration of spinal motor neurons is implicated in a number of devastating diseases (page 2, left col. para. 2). Du teaches while pluripotent stem cells have been generated from patients and attempts have been made to identify disease-related phenotypes and to dissect out the underlying mechanisms before embarking on drug discovery, such efforts are hindered by the inability to produce pure of highly enriched spinal motor neurons with consistent quality (page 2, left col. para. 2). Du teaches there is a critical need to develop new methods that enable generation of highly pure and functionally mature spinal motor neurons with consistent quality in a short time (page 2, left col. para. 2). Du teaches the method enables the generation of large quantities of spinal motor neurons with consistency and high purity, providing a basis for modeling motor neuron diseases in vitro and for drug discovery.
It would have been obvious prior to the effective filing date of the invention as claimed for the person of ordinary skill in the art to combine the teachings of Chen regarding a method of differentiating human pluripotent stem cells to GABAergic spinal neurons where the molar concentration ratio of the CHIR99021, SB431542, and DMH1 is 3:2:2 and the molar concentration ratio of the cyclopamine to retinoic acid is 5:1 with the teachings of Du regarding a method of differentiating hESCs to NEPs with 2 µM SB431542, 2 µM DMH1, and 3 µM CHIR99021 followed by differentiating NEPs to GABA neurons with 2 µM SB431542, 2 µM DMH1, and 3 µM CHIR99021, 0.1 µM cyclopamine, and 0.5 µM retinoic acid to arrive at the claimed method where the human pluripotent stem cells are hESCs and the concentration of CHIR99021, DMH1, SB431542, RA, and cyclopamine are 3, 2, 2, 0.5, and 0.1 µM, respectively. One would have been motivated to combine the teachings of Chen and Du in a method to produce spinal dI4 progenitor cells and GABA interneurons for discovering drugs to treat motor neuron diseases as Chen teaches spinal cord injury causes a range of motor and psychological problems where nearly 40% to 50% of patients have neuropathic pain in 1 year and that later becomes chronic pain, affecting the recovery of patients and new treatment methods are needed for the clinical treatment of pain and Du teaches there is a critical need to develop new methods that enable generation of highly pure and functionally mature spinal motor neurons with consistent quality in a short time. One would have a reasonable expectation of success in combining the teachings as Chen teaches the molar ratio of the molar concentration ratio of the CHIR99021, SB431542, and DMH1 is 3:2:2 and the molar concentration ratio of the cyclopamine to retinoic acid is 5:1 used in the method that produces GABA interneurons and Du teaches the same molar ratio in the method that produces GABA neurons and Chen teaches the high-purity spinal GABAergic interneurons can be obtained quickly and efficiently by the method and Du teaches the method enables the generation of large quantities of spinal motor neurons with consistency and high purity, providing a basis for modeling motor neuron diseases in vitro and for drug discovery.
Conclusion
No claims allowed.
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/Z.M.B./Examiner, Art Unit 1632
/MARCIA S NOBLE/Primary Examiner, Art Unit 1632