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, 8, 10, 11, 13 – 15, 20, 21, 24, 25, 31, 33, 38, 47, 48, 51, 52, 54, 57, 61 – 66, and 75 – 79 are pending. Claims 1, 8, 10, 11, 13 – 15, 20, 21, 24, 25, 31, 33, 47, 48, 51, 52, 54, 57, 61 – 66, and 75 – 79 are under consideration.
Information Disclosure Statement
2. The information disclosure statement (IDS) submitted on 05/29/2026 is acknowledged. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
3. The information disclosure statement filed 05/29/2026 provides a copy of the C14 non-patent literature on page 4 of the IDS filed 07/24/2023. Therefore, this non-patent literature document has been considered.
Withdrawn Specification Objection
4. The objection to the specification is withdrawn in view of Applicant’s amendment to the specification
Withdrawn Claim Objections
5. The objection to claim 19 is rendered moot in view of Applicant’s cancellation of the claim.
6. The objections to claim 24 is withdrawn in view of Applicant’s amendment to the claim.
7. The objections to claim 33 is withdrawn in view of Applicant’s amendment to the claim.
8. The objection to claim 67 is rendered moot in view of Applicant’s cancellation of the claim.
9. The objection to claim 73 is rendered moot in view of Applicant’s cancellation of the claim.
10. The objection to claim 74 is rendered moot in view of Applicant’s cancellation of the claim.
Withdrawn Claim Rejections
11. The rejection of claims 24 and 25 under 35 U.S.C. 112(b) are withdrawn in view of Applicant’s amendment to claim 1 to recite ROCK inhibitor.
12. The rejection of claim 74 under 35 U.S.C. 112(b) is rendered moot in view of Applicant’s cancellation of the claim.
13. The rejection of claims 19, 62, and 67 – 74 under 35 U.S.C. 102(a)(1) as being anticipated by Neely is rendered moot in view of Applicant’s cancellation of these claims.
14. The rejection of claims 1, 8, 13, 14, 20, 21, 24, 31, 33, 47, 61 – 65, and 75 under 35 U.S.C. 102(a)(1) as being anticipated by Neely is withdrawn in view of Applicant’s amendment to claim 1 to exclude SB431542 and LDN193189.
15. The rejection of claims 28, 35, 36, 50, 67 – 71, 73, and 74 under 35 U.S.C. 102(a)(1) as being anticipated by Arshad is rendered moot in view of Applicant’s cancellation of these claims.
16. The rejection of claims 1, 8, 10, 13, 14, 31, 33, and 63 – 66, under 35 U.S.C. 102(a)(1) as being anticipated by Arshad is withdrawn in view of Applicant’s amendment to claim 1 to delete A8301.
17. The rejection of claims 67 – 71, 73, and 74 under 35 U.S.C. 102(a)(1) as being anticipated by Muguruma is rendered moot in view of Applicant’s cancellation of these claims.
18. The rejection of claims 1, 8, 10, 13, 19, 20, 21, 24, 31, 49, and 63 – 66, under 35 U.S.C. 102(a)(1) as being anticipated by Muguruma is withdrawn in view of Applicant’s amendment to claim 1 to exclude SB431542 and LDN193189.
19. The rejection of claims 28, 35, 36, and 67 – 74 under 35 U.S.C. 102(a)(1) as being anticipated by Gonzalez is rendered moot in view of Applicant’s cancellation of these claims.
20. The rejection of claims 1, 8, 10, 13, 31, 33, 47, and 61 – 65, under 35 U.S.C. 102(a)(1) as being anticipated by Gonzalez is withdrawn in view of Applicant’s amendment to claim 1 to require a ROCK inhibitor.
21. The rejection of claim 28 under 35 U.S.C. 102(a)(1) as being anticipated by Petersen is rendered moot in view of Applicant’s cancellation of the claim.
22. The rejection of claims 1, 14, 31, 33, 47, and 63 – 65 under 35 U.S.C. 102(a)(1) as being anticipated by Petersen is withdrawn in view of Applicant’s amendment to claim 1 to require a ROCK inhibitor.
23. The rejection of claims 19, 28, 35, 36, 50, 53, 55, 56, 58 – 60, 62, and 67 – 74 under 35 U.S.C. 103 is rendered moot in view of Applicant’s cancellation of these claims. All other claim rejections under 35 U.S.C. 103 are withdrawn in view of Applicant’s amendment to claim 1.
24. The rejection of claims 19, 28, 35, 36, 50, 53, 55, 56, 58 – 60, 62, and 67 – 74 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1, 2, 9, 11, 16, 19, 29, 30, 33, 34, 38, 42, 51, 54, 55, 62, 67, 69 of copending Application No. 18855867 is rendered moot in view of Applicant’s cancellation of these claims.
25. The rejection of claim 33 under 35 U.S.C. 112(b) is withdrawn in view of Applicant’s amendment to the claim.
Maintained and New Claim Objections Necessitated by Amendment
26. Claim 1 remains objected to because of the following informalities: in lines 6 and 7, “the cells” should read “the stem or progenitor cells” to clarify that it is the stem or progenitor cells (and not the neural cells) that are contacted with a ROCK inhibitor and not contacted with LDN193189 and SB431542. Appropriate correction is required.
27. Claim 21 is objected to because of the following informalities: in line 1, “the cells” should read “the stem or progenitor cells” to clarify that it is the stem or progenitor cells that are contacted with a ROCK inhibitor. Appropriate correction is required.
28. Claim 63 is objected to because of the following informalities: in line 2, “the cells” should read “the stem or progenitor cells” to clarify that it is the stem or progenitor cells that are not contacted with a SMAD inhibitor. Appropriate correction is required.
29. Claim 64 is objected to because of the following informalities: in line 2, “the cells” should read “the stem or progenitor cells” to clarify that it is the stem or progenitor cells that are not contacted with a BMP4 inhibitor. Appropriate correction is required.
30. Claim 65 is objected to because of the following informalities: in line 2, “the cells” should read “the stem or progenitor cells” to clarify that it is the stem or progenitor cells that are not contacted with a SMAD inhibitor and a BMP4 inhibitor. Appropriate correction is required.
31. Claim 66 is objected to because of the following informalities: in line 2, “the cells” should read “the stem or progenitor cells” to clarify that it is the stem or progenitor cells that are not contacted with a), b), c). Appropriate correction is required.
Claim Rejections Necessitated by Amendment
Claim Rejections - 35 USC § 112(a) – New Matter
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
32. Claims 78 and 79 are rejected under 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. 37 CFR 1.118 (a) states that “No amendment shall introduce new matter into the disclosure of an application after the filing date of the application”.
Claim 78 is drawn to the method of claim 77, wherein the ventral midbrain cells express Otx-2, Lmx1a, FoxA2, and Msx-1.
Claim 79 is drawn to the method of claim 78, wherein the ventral midbrain cells comprise cells that are Pax6-
The specification provides no implicit or explicit support for ventral midbrain cells expressing Otx-2, Lmx1a, FoxA2, and Msx-1 of claim 78 or Otx-2, Lmx1a, FoxA2, Msx-1 and Pax6- of claim 79. The specification has only provided support for measuring by qRT-PCR at day 8 for the markers Otx-2, Lmx1a, FoxA2, and Msx-1 at para. 0085, where Msx-1 and FoxA2 were not detected (Figure 6). Applicant’s specification discloses evaluating the cells for expression of a cell marker such as Pax6, Otx2, FoxA2, Lmx1a, and Msx1 at para. 0050 but does not disclose ventral midbrain cells that express Otx2, Lmx1a, FoxA2 and Msx1 and do not express Pax6. Applicants are reminded that it is their burden to show where the specification supports any amendments to the claims. See 37 CFR 1.121 (b)(2)(iii), the MPEP 714.02, 3rd paragraph, last sentence and also the MPEP 2163.07, last sentence.
MPEP 2163.06 notes “If new matter is added to the claims, the examiner should reject the claims under 35 U.S.C. 112, first paragraph - written description requirement. In re Rasmussen, 650 F.2d 1212, 211 USPQ 323 (CCPA 1981).” MPEP 2163.02 teaches that “Whenever the issue arises, the fundamental factual inquiry is whether a claim defines an invention that is clearly conveyed to those skilled in the art at the time the application was filed...If a claim is amended to include subject matter, limitations, or terminology not present in the application as filed, involving a departure from, addition to, or deletion from the disclosure of the application as filed, the examiner should conclude that the claimed subject matter is not described in that application. MPEP 2163.06 further notes “When an amendment is filed in reply to an objection or rejection based on 35 U.S.C. 112, first paragraph, a study of the entire application is often necessary to determine whether or not “new matter” is involved. Applicant should therefore specifically point out the support for any amendments made to the disclosure [or point to case law supporting incorporation of such a limitation as in the instant case]” (emphasis added).
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.
33. Claims 63 – 66 remain 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.
34. Regarding claim 63, it is unclear how to exclude a SMAD inhibitor when claim 1 requires selecting one of the recited compounds, all of which can be a SMAD inhibitor. For example, Hao (Hao, Jijun, et al. ACS chemical biology 5.2 (2010): 245-253; previously cited), which is cited on the IDS filed 07/23/2024 teaches DMH1 is a BMP4 inhibitor in Figure 4b and blocks Smad 1/5/8 phosphorylation but not Smad2 in Figure 4c and d. It is unclear if claim 63 is meant to further limit the required selection of one or more of DMH1, DMH2, or K02288.
Additionally, it is unclear if the claim is referring to a second unrecited step of further contacting the stem or progenitor cells or contacting the neural cells because the claim recites “further compound” but claim 1 does not recite any additional steps.
35. Regarding claim 64, it is unclear how to exclude a BMP4 inhibitor when claim 1 requires selecting one of the recited compounds, all of which can inhibit BMP4 signaling. For example, Hao (Hao, Jijun, et al. ACS chemical biology 5.2 (2010): 245-253; previously cited), which is cited on the IDS filed 07/23/2024 teaches DMH1 is a BMP4 inhibitor in Figure 4b and blocks Smad 1/5/8 phosphorylation but not Smad2 in Figure 4c and d. It is unclear if claim 64 is meant to further limit the required selection of one or more of DMH1, DMH2, or K02288.
Additionally, it is unclear if the claim is referring to a second unrecited step of further contacting the stem or progenitor cells or contacting the neural cells because the claim recites “further compound” but claim 1 does not recite any additional steps.
36. Regarding claim 65, it is unclear how to exclude a SMAD inhibitor and a BMP4 inhibitor when claim 1 requires selecting one of the recited compounds, all of which are either a BMP4 inhibitor or a SMAD inhibitor, or both. For example, Hao (Hao, Jijun, et al. ACS chemical biology 5.2 (2010): 245-253.), which is cited on the IDS filed 07/23/2024 teaches DMH1 is a BMP4 inhibitor in Figure 4b and blocks Smad 1/5/8 phosphorylation but not Smad2 in Figure 4c and d. Santivale (Sanvitale, Caroline E., et al. PloS one 8.4 (2013): e62721; previously cited), which is cited on the IDS filed 07/24/2023 teaches K02288 inhibits BMP signaling in Figure 4a as K02288 decreases BMP4 induced Smad 1/5/8 phosphorylation. Claim 1 requires selecting one or more of DMH1, DMH2, K02288, or A8301 as “the compound”. It is unclear if claim 65 is meant to further limit the required selection of one or more of DMH1, DMH2, or K02288.
Additionally, it is unclear if the claim is referring to a second unrecited step of further contacting the stem or progenitor cells or contacting the neural cells because the claim recites “further compound” but claim 1 does not recite any additional steps.
37. Regarding claim 66, it is unclear if the claim requires “the compound” satisfy a, b, and c or only one of a, b, or c. It is unclear if claim 66 is meant to further limit the required selection of one or more of DMH1, DMH2, or K02288.
Additionally, it is unclear if the claim is referring to a second unrecited step of further contacting the stem or progenitor cells or contacting the neural cells because the claim recites “further compound” but claim 1 does not recite any additional steps.
Claim Rejections - 35 USC § 112(d)
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.
38. Claims 63 – 66 and 75 are 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. [2]. 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.
39. Regarding claim 63, recitation of “a SMAD inhibitor” does not further limit claim 1 because claim 1 recites “wherein the method excludes contacting the cells with LDN193189 and SB431542”, and therefore, claim 63 broadens claim 1 to any SMAD inhibitor.
40. Regarding claim 64, recitation of “a BMP4 inhibitor” does not further limit claim 1 because claim 1 recites “wherein the method excludes contacting the cells with LDN193189 and SB431542”, and therefore, claim 64 broadens claim 1 to any BMP4 inhibitor.
41. Regarding claim 65, recitation of “a SMAD and BMP4 inhibitor” does not further limit claim 1 because claim 1 recites “wherein the method excludes contacting the cells with LDN193189 and SB431542”, and therefore, claim 64 broadens claim 1 to any SMAD inhibitor and any BMP4 inhibitor.
42. Regarding claim 66, recitation of “Noggin modulator”, “an activator or repressor of Noggin”, and “activator thereof” does not further limit claim 1 because claim 1 recites “wherein the method excludes contacting the cells with LDN193189 and SB431542”, and therefore, claim 66 broadens claim 1 to any “modulator”, “activator or repressor” or “activator” because Applicant’s specification discloses that Noggin and Chordin are BMP inhibitors and LDN193189 is a BMP inhibitor at para. 0006 and 0071.
43. Regarding claim 75, recitation of “comprise induced pluripotent stem cells (iPS cells)” fails to further limit claim 8 because claim 8 recites “comprise induced pluripotent stem cells (iPSCs)”. Should Applicant amend claim 75 to replace “comprise” with “are”, the rejection may be overcome upon further consideration.
Duplicate Claims Warning
44. Applicant is advised that should claim 8 be found allowable, claim 75 will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
Claim Interpretation
45. For the purpose of applying prior art, “a compound selected from DMH1, DMH2, K02288, or combinations thereof” of claim 1 is interpreted as a Markush group but the claim does not limit the method only to contacting the cells with one or more of the recited compounds as the claim recites “the method comprising”.
46. For the purpose of applying prior art, “early neural cells” of claim 76 is interpreted as cells that express nestin, Sox1, and/or Pax6 based on Applicant’s specification at para. 0028 and 0083.
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.
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.
47. Claims 1, 8, 10, 13, 14, 20, 21, 24, 25, 31, 33, 47, 61, 63 – 66, and 75 – 79 are rejected under 35 U.S.C. 103 as being unpatentable over Gonzalez (US9926529-B2; Filed 04/23/2013; Published 03/27/2018; previously cited), hereinafter Gonzalez which is cited on the IDS filed 07/24/2023 as evidenced by Bahrami (Bahrami N, et. al. Mol Neurobiol. 2017 Sep;54(7):5668-5675), hereinafter Bahrami and Yeap (Yeap YJ, et. al. Int J Mol Sci. 2023 Jan 28;24(3):2523), hereinafter Yeap in view of Stover (Stover AE, et. al. J Neurosci Res. 2013 Oct;91(10):1247-62), hereinafter Stover.
Regarding claims 1, 8, 10, 13, 14, 31, 33, 47, 61, 63 – 66, 76, and 77, Gonzalez teaches a method of contacting human embryonic stem (hES) cells (“stem or progenitor cells” of claim 1; “(ES) cells” of claim 8; “human ES cells” of claim 10) with 1 µM DMH1 (“DMH1” of claim 1; “0.01 – 5 µM compound” of claim 14; claim 47) in N2B27 medium (“N-2 supplement” of claim 33) for 7 days (claim 13) to form neural stem cells (hPSC-NSCs) that express Pax6 (“neural cells” of claim 1; “early neural cells” of claim 76) and are ventral midbrain neuroectodermal cells (claim 76, 77) which are precursors to dopaminergic neurons (claim 61) (col. 2, lines 53 – 57; col. 17, lines 20 – 67; Figure 3). Gonzalez teaches further differentiation of the hPSC-NSCs to dopamine precursors (“dopaminergic precursor cells” of claim 61) and then to dopamine neuron cells (“dopaminergic neurons” of claim 31) that express Foxa2 and Lmx1a (“wherein the neural cells express one or more neural cell markers wherein the one or more neural cell markers include one or more of Otx-2, Lmx1a, and FoxA2” of claim 1) by culturing the hPSC-NSCs with FGF8 and purmorphamine for 7 days followed by culturing with guggulsterone which is a naturally occurring steroid (col. 18, lines 35 – 67; col. 19, lines 1 – 13; Figure 6). Gonzalez does not teach the method of Example 1 and 4 include contacting the hPSC or hPSC-NSCs with LDN193189 and SB431542 (“wherein the method excludes contacting the cells with LDN193189 and SB431542” of claim 1) or a SMAD inhibitor (claim 63, 65) or a BMP4 inhibitor (claim 64, 65) or a Noggin protein, modulator, activator or repressor, or a chordin (claim 66) (col. 17, lines 20 – 67; col. 18, lines 35 – 67; col. 19, lines 1 – 13). Gonzalez does not teach contacting the hPSCs with a ROCK inhibitor of claim 1.
Regarding claim 75, Gonzalez teaches the hPSCs comprise iPSCs (col. 2, lines 44 – 47).
Regarding claim 78, Gonzalez teaches the hPSC-NSCs express FoxA2, Lmx1a, Otx2 (col. 2, lines 48 – 52; col. 3, lines 23 – 27 and 65 – 67; col. 4, lines 1 – 2; Figure 3; col. 5, lines 7 – 9; col. 10, lines 15 – 20). Gonzalez does not teach the hPSC-NSCs express “Msx-1”. However, Gonzalez teaches neural stem cells can be identified by increased expression of Mash1, Otx2, Lmx1a and FoxA2 (col. 9, lines 38 – 48). Gonzalez teaches the dopamine precursors were produced by culturing hPSC-NSC with FGF8 and purmorphamine (col. 18, lines 40 – 45), where purmorphamine is a small molecule that mimics Shh protein as evidenced by Bahrami (page 5671, right col. para. 2). Lmx1a induces the expression of Msx1 and together they activate Mash1 to drive dopamine neuron neurogenesis, and FoxA2 converges on Ngn2/Mash1 via the Msx1-Lmx1a pathway, and the Shh-FoxA2 pathway converges on Msx1 as evidenced by Yeap (Figure 1; page 4, para. 1). Therefore, as Gonzalez teaches the hPSC-NSCs express FoxA2, Mash1, and Lmx1a, the hPSC-NSCs would also express Msx1.
Regarding claim 79, the hPSC-NSCs were 95% positive for PAX6 and therefore comprise cells that do not express PAX6 (col. 17, lines 36 – 39).
Gonzalez does not teach contacting the hPSCs with a ROCK inhibitor of claim 1 or the ROCK inhibitor comprises Y27632 of claim 20 or 5 – 15 µM ROCK inhibitor of claim 21 or the stem 24 or the cells are contacted with the ROCK inhibitor for a time period of 1 – 48 hours of claim 25. However, Gonzalez teaches Parkinson’s disease (PD) is a neurological disorder caused by a progressive degeneration of midbrain dopamine neurons and there is currently no cure for PD (col. 1, lines 50 – 67; col. 13, lines 4 – 11). Gonzalez teaches the localized nature of the loss of dopamine neurons makes cell replacement therapy an attractive approach to treating PD patients (col. 1, lines 65 – 67; col. 2, line 1). Gonzalez teaches implantation of neuronal cells such as neural stem cells and dopamine neurons have already been shown to improve the motor symptoms in PD animal models (col. 2, lines 1 – 5). Gonzalez teaches it is critical to be able to generate a homogenous population of NSCs which will in turn generate a homogenous population of dopamine neurons (col. 2, lines 1 – 10).
Regarding contacting the hPSCs with a ROCK inhibitor of claim 1 and the ROCK inhibitor comprises Y27632 of claim 20 and 5 – 15 µM ROCK inhibitor of claim 21, Stover teaches a method of producing NSCs from iPSCs by contacting the iPSCs with DMH1 and the ROCK inhibitor Y27632 (claim 1 and 20) at 10 µM (claim 21) (page 6, para. 1; page 10, last para.; page 11, para. 1 – 2). Stover teaches that ROCK inhibition at the time of passage can further enhance rosette formation and neural induction (page 11, para. 2).
Regarding claim 24, Stover teaches passaging iPSCs with ROCK inhibitor Y27632 (10 µm) prior to NSC differentiation (page 5, para. 3 – 4). Stover teaches the ROCK inhibitor was added to aid recovery of the cells and help prevent aneuploidies (page 5, para. 3; page 8, para. 4).
Regarding claim 25, Stover teaches passaged PSCs were allowed to reach confluence and then cultured for an additional 24 hours prior to NSC differentiation (page 5, last para.). Stover teaches cell density plating following passaging affects growth and differentiation with low density seeding displaying more uncontrolled differentiation and higher rates of apoptosis than high density seeding (page 8, para. 4). Stover teaches one confluent well of a six-well plate generates on average 2.6± 0.6 106 cells by 5 days after plating at a 1:6 splitting at a seeding density of 4 x 104 to 1 x 105 cells/cm2 but there is some variability in the rate of expansion between cell lines, so this rate should be determined for each specific line to facilitate scale up (page 5, para. 3; page 8, para. 4). Therefore, it would be obvious to adjust the time period the cells are contacted with the ROCK inhibitor, since it is a result-effective variable dependent on the number of cells.
Stover teaches robust strategies for developing patient-specific, human iPSC-based therapies of the brain require an ability to derive large numbers of highly defined neural cells (Abstract). Stover teaches for these strategies to be truly successful, it is first necessary to devise protocols that allow generation of large numbers of specific cell types for transplantation or disease modeling (page 2, para. 2). Stover teaches to increase the success of patient-specific therapies based on iPSC technologies, it is important to develop well-defined production methods in which the production process is characterized in great detail (page 2, last para.). Stover teaches the NSCs produced by contacting PSCs with DMH1 could be further differentiated into mature neurons and astrocytes (page 12, para. 3 – 4; page 13, para. 1).
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 Gonzalez regarding a method of differentiating hPSCs to NSCs and dopamine neurons by contacting hPSCs with DMH1 with the teachings of Stover regarding a method of differentiating iPSCs to NSCs by contacting iPSCs with DMH1 and a ROCK inhibitor to arrive at the claimed method for differentiating stem or progenitor cells into neural
cells or for producing neural cells from stem or progenitor cells, the method comprising contacting the stem or progenitor cells with a compound selected from DMH1, DMH2, or K02288 ,or combinations thereof, wherein the neural cells express one or more neural cell markers wherein the one or more neural cell markers include one or more of Otx-2, Lmx1a and FoxA2, and the method further comprises contacting the cells with a Rho Kinase (ROCK) inhibitor and further wherein the method excludes contacting the cells with LDN193189 and SB431542, to thereby provide said neural cells. One would have been motivated to combine the teachings of Gonzalez and Stover in a method to produce large numbers of NSCs and dopamine neurons for treating Parkinson’s disease as Gonzalez teaches Parkinson’s disease is a neurological disorder caused by a progressive degeneration of midbrain dopamine neurons and there is currently no cure for PD and cell replacement therapy is an attractive approach to treating Parkinson’s disease patients and Gonzalez teaches it is critical to be able to generate a homogenous population of NSCs which will in turn generate a homogenous population of dopamine neurons and Stover teaches robust strategies for developing patient-specific, human iPSC-based therapies of the brain require an ability to derive large numbers of highly defined neural cells and Stover teaches for these strategies to be truly successful, it is first necessary to devise protocols that allow generation of large numbers of specific cell types for transplantation or disease modeling. One would have a reasonable expectation of success in combining these teachings as Gonzalez teaches NSCs and dopamine neurons can be derived from hPSCs by contacting with DMH1 and Stover teaches that ROCK inhibition at the time of passage can further enhance rosette formation and neural induction by DMH1.
48. Claim 11 is/are rejected under 35 U.S.C. 103 as being unpatentable over Gonzalez (US9926529-B2; Filed 04/23/2013; Published 03/27/2018; previously cited), hereinafter Gonzalez which is cited on the IDS filed 07/24/2023 as evidenced by Bahrami (Bahrami N, et. al. Mol Neurobiol. 2017 Sep;54(7):5668-5675), hereinafter Bahrami and Yeap (Yeap YJ, et. al. Int J Mol Sci. 2023 Jan 28;24(3):2523), hereinafter Yeap in view of Stover (Stover AE, et. al. J Neurosci Res. 2013 Oct;91(10):1247-62), hereinafter Stover as applied to claims 1, 8, 10, 13, 14, 20, 21, 24, 25, 31, 33, 47, 61, 63 – 66, and 75 – 79 above, and further in view of Rodin (Rodin, Sergey, et al Nature biotechnology 28.6 (2010): 611; previously cited), hereinafter Rodin.
Gonzalez in view of Stover makes obvious the limitations of claim 1 as set forth above. Gonzalez teaches contacting human embryonic stem cell (hESC) line WA-09 with DMH1 (col. 17, lines 20 – 67) but does not teach HS420 cells of claim 11. However, Gonzalez teaches the hESCs was grown on Matrigel when contacted with DMH1 (col. 17, lines 20 – 36). Gonzalez teaches a potential application of stem cells is making cells and tissues for medical therapies and stem cells offer the possibility of a renewable source of replacement cells and tissues to treat a myriad of diseases, conditions, and disabilities including Parkinson’s disease, which is a neurological disorder caused by a progressive degeneration of midbrain dopamine neurons (col. 1, lines 47 – 59). Gonzalez teaches there is currently no cure for Parkinson’s disease and the localized nature of the loss of dopamine neurons makes cell replacement therapy an attractive approach (col. 1, lines 62 – 67). Gonzalez teaches implantation of neuronal cells such as neural stem cells and dopamine neurons have already been shown to improve the motor symptoms in Parkinson’s disease animal models (col. 2, lines 1 – 4). Gonzalez teaches it is critical to be able to generate a homogenous population of NSCs which will in turn generate functional dopamine neurons either in situ or in vitro, depending on whether the terminal differentiation occurs in the patient’s brain or in culture (col. 2, lines 5 – 10). Gonzalez teaches the method provides for the generation of neural stem cells from hPSCs that can be further differentiated into mature neurons for cell therapies or drug discovery (col. 6, lines 52 – 55).
Stover does not teach HS420 cells of claim 11. However, Stover teaches contacting 2 different hESCs with DMH1 and ROCK inhibitor to form NSCs that could be further differentiated to form mature neurons and astrocytes (page 3, para. 3; page 4, last para.; page 5, last para.; page 6, para. 1; page 8, last para.; page 9, para. 1; page 12 para. 3 – 4). Stover teaches it is necessary to devise protocols that allow generation of large numbers of specific cell types for transplantation or disease modeling (page 2, para. 2). Stover teaches the NSCs produced by contacting PSCs with DMH1 could be further differentiated into mature neurons and astrocytes (page 12, para. 3 – 4; page 13, para. 1).
Regarding claim 11, Rodin teaches HS420 cells can be cultured for at least 4 months in a chemically defined medium and the cells self-renewed with normal karyotype and were capable of differentiation (Abstract; page 611, right col. last para.; page 612, left col. para. 1 and right col. para. 2 – 3; page 616, left col. para. 1; page 10, last para.; page 11, para. 1 – 2). Rodin teaches there is a great need for chemically defined, xeno-free, feeder-free culture systems for hES cells and the human laminin coating may have considerable advantages for the standardization of stable hES cell cultures (page 614, right col. para. 2). Rodin teaches when plated on laminin-511, hES cells spread out in a monolayer, which provides more controllable conditions for the design of differentiation methods (Abstract). Rodin teaches this xeno-free and feeder-free system may be useful for the development of cell lineages for therapeutic purposes (Abstract). Rodin teaches the composition of Matrigel varies from batch to batch (page 611, right col. para. 2). Rodin teaches hES cells grown on laminin-511 had a higher average contact area compared to Matrigel and proliferated at a stable rate similar to that of cells grown on Matrigel (page 612, left col. para. 2 and right col. para. 2).
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 Gonzalez regarding a method of differentiating hPSCs to NSCs and dopamine neurons by contacting hPSCs with DMH1 with the teachings of Stover regarding a method of differentiating iPSCs to NSCs by contacting iPSCs with DMH1 and a ROCK inhibitor with the teachings of Rodin regarding HS420 hES cells plated on laminin-511 spread out in a monolayer, which provides more controllable conditions for the design of differentiation methods to arrive at the claimed method where the cells comprise HS420 cells. One would have been motivated to combine the teachings of Gonzalez, Stover, and Rodin in a chemically-defined method to produce large numbers of NSCs and dopamine neurons for treating Parkinson’s disease as Gonzalez teaches Parkinson’s disease is a neurological disorder caused by a progressive degeneration of midbrain dopamine neurons and there is currently no cure for PD and cell replacement therapy an attractive approach to treating Parkinson’s disease patients and Gonzalez teaches it is critical to be able to generate a homogenous population of NSCs which will in turn generate a homogenous population of dopamine neurons and Stover teaches it is first necessary to devise protocols that allow generation of large numbers of specific cell types for transplantation or disease modeling and Rodin teaches there is a great need for chemically defined, xeno-free, feeder-free culture systems for hES cells and the human laminin coating may have considerable advantages for the standardization of stable hES cell cultures and Rodin teaches the composition of Matrigel varies from batch to batch. One would have a reasonable expectation of success in combining these teachings as Gonzalez teaches NSCs and dopamine neurons can be derived from hESCs plated on Matrigel by contacting with DMH1 and Stover teaches that multiple hES cell lines can form hNSCs by contacting with a ROCK inhibitor and DMH1 and the hNSCs can be further differentiated to mature neurons and Rodin teaches hES cells grown on laminin-511 had a higher average contact area compared to Matrigel and proliferated at a stable rate similar to that of cells grown on Matrigel.
49. Claim 15 is/are rejected under 35 U.S.C. 103 as being unpatentable over Gonzalez (US9926529-B2; Filed 04/23/2013; Published 03/27/2018; previously cited), hereinafter Gonzalez which is cited on the IDS filed 07/24/2023 as evidenced by Bahrami (Bahrami N, et. al. Mol Neurobiol. 2017 Sep;54(7):5668-5675), hereinafter Bahrami and Yeap (Yeap YJ, et. al. Int J Mol Sci. 2023 Jan 28;24(3):2523), hereinafter Yeap in view of Stover (Stover AE, et. al. J Neurosci Res. 2013 Oct;91(10):1247-62), hereinafter Stover as applied to claims 1, 8, 10, 13, 14, 20, 21, 24, 25, 31, 33, 47, 61, 63 – 66, and 75 – 79 above, and further in view of Hao (Hao, Jijun, et al. ACS chemical biology 5.2 (2010): 245-253; previously cited), hereinafter Hao which is cited on the IDS filed 07/24/2023.
Gonzalez in view of Stover makes obvious the limitations of claim 1 as set forth above. Gonzalez teaches contacting with 1 µM DMH1 (col. 17, lines 20 – 35) but does not teach 0.2 µM DMH1. However, Gonzalez teaches DMH1 is a BMP inhibitor (col. 2, lines 64 – 65). Gonzalez teaches there is currently no cure for Parkinson’s disease and the localized nature of the loss of dopamine neurons makes cell replacement therapy an attractive approach (col. 1, lines 62 – 67). Gonzalez teaches implantation of neuronal cells such as neural stem cells and dopamine neurons have already been shown to improve the motor symptoms in Parkinson’s disease animal models (col. 2, lines 1 – 4). Gonzalez teaches it is critical to be able to generate a homogenous population of NSCs which will in turn generate functional dopamine neurons either in situ or in vitro, depending on whether the terminal differentiation occurs in the patient’s brain or in culture (col. 2, lines 5 – 10).
Stover teaches contacting hPSCs with 2 µM DMH1 (page 6, para. 1) but does not teach 0.2 µM DMH1. However, Stover teaches DMH1 could effectively substitute for Noggin used in many standard neural differentiation protocols (page 10, last para.; page 11, para. 1 – 2). Stover teaches reducing the Noggin concentration 5 times and using a simple medium allowed for production of a culture of nearly 100% Pax-6 positive neuroepithelial cells while allowing for a significant reduction in the cost of the neural differentiation procedure (page 10, para. 3). Stover teaches it is necessary to devise protocols that allow generation of large numbers of specific cell types for transplantation or disease modeling (page 2, para. 2). Stover teaches the NSCs produced by contacting PSCs with DMH1 could be further differentiated into mature neurons and astrocytes (page 12, para. 3 – 4; page 13, para. 1).
Hao teaches in Figure 4b DMH1 inhibited BMP signaling in a dose-dependent manner with inhibition at 0.2 µM only slightly less than at 0.5 µM. Hao teaches the IC50 for inhibition of BMP signaling by DMH1 is approximately 100 nM (page 4, para. 4).
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 Gonzalez regarding a method of differentiating hPSCs to NSCs and dopamine neurons by contacting hPSCs with 1 µM DMH1 with the teachings of Stover regarding a method of differentiating iPSCs to NSCs by contacting iPSCs with 2 µM DMH1 and a ROCK inhibitor, where DMH1 can substitute effectively for Noggin, and a cost-effective method of neural differentiation by reducing the concentration of Noggin by 5 times with the teachings of Hao regarding the IC50 for inhibition of BMP signaling by DMH1 is approximately 100 nM and DMH1 inhibited BMP signaling at 0.2 µM to arrive at the claimed method where the cells are contacted with 0.2 µM DMH1. One would have been motivated to combine the teachings of Gonzalez, Stover, and Hao in a cost-effective method of producing dopamine neurons as Gonzalez teaches there is currently no cure for Parkinson’s disease and the localized nature of the loss of dopamine neurons makes cell replacement therapy an attractive approach and Stover teaches it is necessary to devise protocols that allow generation of large numbers of specific cell types for transplantation or disease modeling. One would have a reasonable expectation of success in combining the teachings as Hao teaches DMH1 inhibited BMP signaling in a dose-dependent manner with inhibition at 0.2 µM only slightly less than at 0.5 µM and Hao teaches the IC50 for inhibition of BMP signaling by DMH1 is approximately 100 nM and Stover teaches DMH1 is an effective substitute for Noggin in neural differentiation and Noggin concentration can be reduced 5 times in a simple media and still induce neural differentiation.
50. Claim 48 is/are rejected under 35 U.S.C. 103 as being unpatentable over Gonzalez (US9926529-B2; Filed 04/23/2013; Published 03/27/2018; previously cited), hereinafter Gonzalez which is cited on the IDS filed 07/24/2023 as evidenced by Bahrami (Bahrami N, et. al. Mol Neurobiol. 2017 Sep;54(7):5668-5675), hereinafter Bahrami and Yeap (Yeap YJ, et. al. Int J Mol Sci. 2023 Jan 28;24(3):2523), hereinafter Yeap in view of Stover (Stover AE, et. al. J Neurosci Res. 2013 Oct;91(10):1247-62), hereinafter Stover as applied to claims 1, 8, 10, 13, 14, 20, 21, 24, 25, 31, 33, 47, 61, 63 – 66, and 75 – 79 above, and further in view of Hao (Hao, Jijun, et al. ACS chemical biology 5.2 (2010): 245-253; previously cited), hereinafter Hao which is cited on the IDS filed 07/24/2023.
Gonzalez in view of Stover makes obvious the limitations of claim 1 as set forth above. Gonzalez teaches contacting hES cells with DMH1 (col. 2, lines 53 – 57; col. 17, lines 20 – 67; Figure 3) but does not teach DMH2 of claim 48. However, Gonzalez teaches DMH1 is a BMP inhibitor (col. 2, lines 64 – 65). Gonzalez teaches there is currently no cure for Parkinson’s disease and the localized nature of the loss of dopamine neurons makes cell replacement therapy an attractive approach (col. 1, lines 62 – 67). Gonzalez teaches implantation of neuronal cells such as neural stem cells and dopamine neurons have already been shown to improve the motor symptoms in Parkinson’s disease animal models (col. 2, lines 1 – 4). Gonzalez teaches it is critical to be able to generate a homogenous population of NSCs which will in turn generate functional dopamine neurons either in situ or in vitro, depending on whether the terminal differentiation occurs in the patient’s brain or in culture (col. 2, lines 5 – 10).
Stover teaches contacting hPSCs with DMH1 (page 6, para. 1) but does not teach DMH2 of claim 48. However, Stover teaches DMH1 could effectively substitute for Noggin used in many standard neural differentiation protocols (page 10, last para.; page 11, para. 1 – 2). Stover teaches reducing the Noggin concentration 5 times and using a simple medium allowed for production of a culture of nearly 100% Pax-6 positive neuroepithelial cells while allowing for a significant reduction in the cost of the neural differentiation procedure (page 10, para. 3). Stover teaches it is necessary to devise protocols that allow generation of large numbers of specific cell types for transplantation or disease modeling (page 2, para. 2). Stover teaches the NSCs produced by contacting PSCs with DMH1 could be further differentiated into mature neurons and astrocytes (page 12, para. 3 – 4; page 13, para. 1).
Regarding DMH2 of claim 48, Hao teaches DMH2 is BMP inhibitor that inhibits ALK2 with an IC50 of approximately 43 nM, which is lower than that of DMH1 (~108 nM) (Table 2). Hao teaches the structural similarity of DMH1 and DMH2 in Figure 3.
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 substitute DMH1 of Gonzalez and Stover with DMH2 of Hao to arrive at the claimed method where the compound is DMH2. One would have been motivated to make such a substitution in a cost-effective method of producing dopamine neurons for treating Parkinson’s disease by lowering the amount of compound used in the method as Gonzalez teaches there is currently no cure for Parkinson’s disease and the localized nature of the loss of dopamine neurons makes cell replacement therapy an attractive approach and Hao teaches both DMH1 and DMH2 are BMP inhibitors that are structurally similar and DMH2 has an IC50 that is lower than DMH1 for ALK2 inhibition. One would have a reasonable expectation of success in carrying out the substitution as Hao teaches both DMH1 and DMH2 are structurally similar BMP inhibitors and Stover teaches DMH1 is an effective substitute for Noggin in neural differentiation and Noggin concentration can be reduced 5 times in a simple media and still induce neural differentiation.
51. Claim 49 is/are rejected under 35 U.S.C. 103 as being unpatentable over Gonzalez (US9926529-B2; Filed 04/23/2013; Published 03/27/2018; previously cited), hereinafter Gonzalez which is cited on the IDS filed 07/24/2023 as evidenced by Bahrami (Bahrami N, et. al. Mol Neurobiol. 2017 Sep;54(7):5668-5675), hereinafter Bahrami and Yeap (Yeap YJ, et. al. Int J Mol Sci. 2023 Jan 28;24(3):2523), hereinafter Yeap in view of Stover (Stover AE, et. al. J Neurosci Res. 2013 Oct;91(10):1247-62), hereinafter Stover as applied to claims 1, 8, 10, 13, 14, 20, 21, 24, 25, 31, 33, 47, 61, 63 – 66, and 75 – 79 above, and further in view of Mohedas (Mohedas, Agustin H., et al. ACS chemical biology 8.6 (2013): 1291-1302.), hereinafter Mohedas.
Gonzalez in view of Stover makes obvious the limitations of claim 1 as set forth above. Gonzalez teaches contacting hES cells with DMH1 (col. 2, lines 53 – 57; col. 17, lines 20 – 67; Figure 3) but does not teach K02288 of claim 49. However, Gonzalez teaches DMH1 is a BMP inhibitor (col. 2, lines 64 – 65). Gonzalez teaches there is currently no cure for Parkinson’s disease and the localized nature of the loss of dopamine neurons makes cell replacement therapy an attractive approach (col. 1, lines 62 – 67). Gonzalez teaches implantation of neuronal cells such as neural stem cells and dopamine neurons have already been shown to improve the motor symptoms in Parkinson’s disease animal models (col. 2, lines 1 – 4). Gonzalez teaches it is critical to be able to generate a homogenous population of NSCs which will in turn generate functional dopamine neurons either in situ or in vitro, depending on whether the terminal differentiation occurs in the patient’s brain or in culture (col. 2, lines 5 – 10).
Stover teaches contacting hPSCs with DMH1 (page 6, para. 1) but does not teach K02288 of claim 49. However, Stover teaches DMH1 could effectively substitute for Noggin used in many standard neural differentiation protocols (page 10, last para.; page 11, para. 1 – 2). Stover teaches reducing the Noggin concentration 5 times and using a simple medium allowed for production of a culture of nearly 100% Pax-6 positive neuroepithelial cells while allowing for a significant reduction in the cost of the neural differentiation procedure (page 10, para. 3). Stover teaches it is necessary to devise protocols that allow generation of large numbers of specific cell types for transplantation or disease modeling (page 2, para. 2). Stover teaches the NSCs produced by contacting PSCs with DMH1 could be further differentiated into mature neurons and astrocytes (page 12, para. 3 – 4; page 13, para. 1).
Regarding K02288 of claim 49, Mohedas teaches K02288 is a BMP inhibitor that inhibits ALK2 with an IC50 of approximately 1.2 nM, which is approximately 10 times lower than that of DMH1 (page 1294, left col. last para. and right col. para. 1; Figure 2b, 2d).
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 substitute DMH1 of Gonzalez and Stover with K02288 of Mohedas to arrive at the claimed method where the compound is K02288. One would have been motivated to make such a substitution in a cost-effective method of producing dopamine neurons for treating Parkinson’s disease by lowering the amount of compound used in the method as Gonzalez teaches there is currently no cure for Parkinson’s disease and the localized nature of the loss of dopamine neurons makes cell replacement therapy an attractive approach and Mohedas teaches both DMH1 and K02288 are BMP inhibitors and K02288 has an IC50 that is 10 times lower than DMH1 for ALK2 inhibition. One would have a reasonable expectation of success in carrying out the substitution as Mohedas teaches both DMH1 and K02288 are BMP inhibitors and Stover teaches DMH1 is an effective substitute for Noggin in neural differentiation and Noggin concentration can be reduced 5 times in a simple media and still induce neural differentiation.
52. Claims 1, 8, 10, 13, 14, 21, 31, 33, 51, 61, 63 – 66, and 76 – 79 are rejected under 35 U.S.C. 103 as being unpatentable over Cosset-2019 (Cosset, Erika, et al. JoVE (Journal of Visualized Experiments) 148 (2019): e59682.), hereinafter Cosset-2019 which is cited on the IDS filed 09/17/2025 in view of Hao (Hao, Jijun, et al. ACS chemical biology 5.2 (2010): 245-253; previously cited), hereinafter Hao which is cited on the IDS filed 07/24/2023 in view of Gonzalez (US9926529-B2; Filed 04/23/2013; Published 03/27/2018; previously cited), hereinafter Gonzalez which is cited on the IDS filed 07/24/2023 as evidenced by Bahrami (Bahrami N, et. al. Mol Neurobiol. 2017 Sep;54(7):5668-5675), hereinafter Bahrami and Yeap (Yeap YJ, et. al. Int J Mol Sci. 2023 Jan 28;24(3):2523), hereinafter Yeap.
Regarding claim 1, 8, 10, 21, and 31, Cosset-2019 teaches a method of forming dopaminergic organoids (“neural cells” of claim 1; “dopaminergic neurons” of claim 31) by contacting hESCs (“stem or progenitor cells of claim 1; claim 8, 10) with 10 µM ROCK inhibitor (“contacting the cells with a Rho Kinase (ROCK) inhibitor” of claim 1; claim 21), a BMP inhibitor, and a TGFβ/Activin/Nodal inhibitor (page 3, 4. hESC-derived dopaminergic organoids for PD studies, steps 1 – 4; Figure 3A). Cosset-2019 does not teach Cosset-2019 does not teach that the BMP inhibitor and/or TGFβ inhibitor are LDN193189 or SB431542 (“wherein the method excludes contacting the cells with LDN193189 and SB431542”) of claim 1. Cosset-2019 does not teach that the BMP inhibitor and/or TGFβ/Activin/Nodal inhibitor are DMH1, DMH2, or K0228 or the neural cells express one or more of Otx-2, Lmx1a, and FoxA2 of claim 1.
Regarding claim 13, Cosset-2019 teaches at day 8, most of the cells should be positive for Nestin and day 8 is the start of the neural maturation (page 3, 4. hESC-derived dopaminergic organoids for PD studies, step 4 – 5; Figure 3A).
Regarding claim 14, Cosset-2019 teaches 0.5 µM BMP inhibitor (page 3, 4. hESC-derived dopaminergic organoids for PD studies, step 2).
Regarding claim 33, Cosset-2019 teaches DMEM-F12 (page 3, 4. hESC-derived dopaminergic organoids for PD studies, step 2, sub-step 1).
Regarding claim 61, Cosset-2019 teaches the method forms neural progenitors that are dopamine progenitors (page 3 4. hESC-derived dopaminergic organoids for PD studies, step 4 – 5).
Regarding claim 66, Cosset-2019 does not teach the method comprises a Noggin protein or modulator or Chordin (page 3 4. hESC-derived dopaminergic organoids for PD studies).
Regarding claim 76, Cosset-2019 teaches the method produces neural progenitors that are positive for Nestin (page 3 4. hESC-derived dopaminergic organoids for PD studies, step 4 – 5).
Regarding claim 77, Cosset-2019 teaches the cells have ventral midbrain identity (page 3 4. hESC-derived dopaminergic organoids for PD studies, step 2 and 4).
Cosset-2019 does not teach that the BMP inhibitor and/or TGFβ/Activin/Nodal inhibitor are DMH1, DMH2, or K0228 or the neural cells express one or more of Otx-2, Lmx1a, and FoxA2 of claim 1 or the compound comprises DMH1 and DMH2 of claim 51 or that the method excludes contacting the cells with a further compound not comprising a SMAD inhibitor and BMP4 inhibitor of claims 63 – 65 or “the ventral midbrain cells express Otx-2, Lmx1a, FoxA2 and Msx-1”of claim 78 or “the ventral midbrain cells comprise cells that are Pax6-“ of claim 79. However, Cosset-2019 teaches the cells express neural markers Nurr1 and TH (Figure 3; page 3, last para.). Cosset-2019 teaches the lack of relevant in vitro models is an important obstacle on medical progress for neuropathologies (Abstract). Cosset-2019 teaches establishment of relevant cellular models is crucial both to better understand the pathological mechanism of these diseases and identify new therapeutic targets and strategies (Abstract). Cosset-2019 teaches such a model would not only allow screening of therapeutic molecules but also can be used to optimize neural protocol differentiation for example in the context of transplantation in Parkinson’s disease (Abstract). Cosset-2019 teaches the dopamine organoid not only represents a suitable source of dopamine neurons for cell therapy in Parkinson’s disease but also can be used for drug testing (Abstract). Cosset-2019 teaches Parkisonian symptoms are associated with the bilateral degeneration of dopaminergic neurons leading to the disappearance of dopaminergic axons (page 1, last para.; page 2, para. 1). Cosset-2019 teaches early loss of tyrosine hydroxylase (TH) activity followed by a decline in TH protein expression is a hallmark of Parkinson’s disease (page 2, para. 1).
Regarding DMH1 and DMH2 of claims 1 and 51, Hao teaches DMH1 is a BMP inhibitor that exclusively targets BMP and DMH2 is a TGFβ type I receptor like kinase 5 inhibitor (Abstract; page 2, last para.; Figure 4; Table 2). Hao teaches the IC50s for DMH1 and DMH2 in a BMP-responsive reporter assay is approximately 100 nM and 20 nM, respectively (page 4, para. 4). Hao does not teach the neural cells express one or more of Otx-2, Lmx1a, and FoxA2 of claim 1 or that the method excludes contacting the cells with a further compound not comprising a SMAD inhibitor and BMP4 inhibitor of claims 63 – 65 or “the ventral midbrain cells express Otx-2, Lmx1a, FoxA2 and Msx-1”of claim 78 or “the ventral midbrain cells comprise cells that are Pax6-“ of claim 79. One would have been motivated to combine the teachings of Cosset-2019 and Hao because Cosset-2019 teaches a method of producing dopamine organoids that are suitable sources of dopamine neurons for cell therapy in Parkinson’s disease and that can be used for drug testing by contacting hES cells with a BMP inhibitor and TGFβ inhibitor and Hao teaches a BMP inhibitor that is DMH1 and a TGFβ inhibitor that is DMH2.
Regarding the neural cells express one or more of Otx-2, Lmx1a, and FoxA2 of claim 1 and or that the method excludes contacting the cells with a further compound not comprising a SMAD inhibitor and BMP4 inhibitor of claims 63 – 65, Gonzalez teaches a method of contacting human embryonic stem cells with DMH1 in N2B27 medium for 7 days to form neural stem cells (hPSC-NSCs) that express Pax6 and are ventral midbrain neuroectodermal cells which are precursors to dopaminergic neurons (col. 2, lines 53 – 57; col. 17, lines 20 – 67; Figure 3). Gonzalez teaches further differentiation of the hPSC-NSCs to dopamine precursors and then to dopamine neuron cells that express Foxa2 and by culturing the hPSC-NSCs with FGF8 and purmorphamine for 7 days followed by culturing with guggulsterone which is a naturally occurring steroid (col. 18, lines 35 – 67; col. 19, lines 1 – 13; Figure 6). Gonzalez does not teach the method of Example 1 and 4 include contacting the hPSC or hPSC-NSCs with a SMAD inhibitor (claim 63, 65) or a BMP4 inhibitor (claim 64, 65) (col. 17, lines 20 – 67; col. 18, lines 35 – 67; col. 19, lines 1 – 13). Gonzalez teaches the neurons secreted dopamine (col. 19, lines 9 – 26).
Regarding claim 78, Gonzalez teaches the hPSC-NSCs express FoxA2, Lmx1a, Otx2 (col. 2, lines 48 – 52; col. 3, lines 23 – 27 and 65 – 67; col. 4, lines 1 – 2; Figure 3; col. 5, lines 7 – 9; col. 10, lines 15 – 20). Gonzalez does not teach the hPSC-NSCs express “Msx-1”. However, Gonzalez teaches neural stem cells can be identified by increased expression of Mash1, Otx2, Lmx1a and FoxA2 (col. 9, lines 38 – 48). Gonzalez teaches the dopamine precursors were produced by culturing hPSC-NSC with FGF8 and purmorphamine (col. 18, lines 40 – 45), where purmorphamine is a small molecule that mimics Shh protein as evidenced by Bahrami (page 5671, right col. para. 2). Lmx1a induces the expression of Msx1 and together they activate Mash1 to drive dopamine neuron neurogenesis, and FoxA2 converges on Ngn2/Mash1 via the Msx1-Lmx1a pathway, and the Shh-FoxA2 pathway converges on Msx1 as evidenced by Yeap (Figure 1; page 4, para. 1). Therefore, as Gonzalez teaches the hPSC-NSCs express FoxA2, Mash1, and Lmx1a, the hPSC-NSCs would also express Msx1.
Regarding claim 79, the hPSC-NSCs were 95% positive for PAX6 and therefore comprise cells that do not express PAX6 (col. 17, lines 36 – 39).
Gonzalez teaches Parkinson’s disease (PD) is a neurological disorder caused by a progressive degeneration of midbrain dopamine neurons and there is currently no cure for PD (col. 1, lines 50 – 67; col. 13, lines 4 – 11). Gonzalez teaches the localized nature of the loss of dopamine neurons makes cell replacement therapy an attractive approach to treating PD patients (col. 1, lines 65 – 67; col. 2, line 1). Gonzalez teaches implantation of neuronal cells such as neural stem cells and dopamine neurons have already been shown to improve the motor symptoms in PD animal models (col. 2, lines 1 – 5). Gonzalez teaches it is critical to be able to generate a homogenous population of NSCs which will in turn generate a homogenous population of dopamine neurons (col. 2, lines 1 – 10).
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 Cosset-2019 regarding a method of forming dopamine organoids from hES cells by contacting hES cells with a BMP inhibitor and a TGFβ inhibitor with the teachings of Hao regarding DMH1 is a BMP inhibitor and DMH2 is a TGFβ inhibitor with the teachings of Gonzalez regarding a method of forming dopamine neurons by contacting hES cells with DMH1 to arrive at the claimed method for differentiating stem or progenitor cells into neural
cells or for producing neural cells from stem or progenitor cells, the method comprising contacting the stem or progenitor cells with DMH1 and DMH2, wherein the neural cells express one or more neural cell markers wherein the one or more neural cell markers include one or more of Otx-2, Lmx1a and FoxA2, and the method further comprises contacting the cells with a Rho Kinase (ROCK) inhibitor and further wherein the method excludes contacting the cells with LDN193189 and SB431542, to thereby provide said neural cells. One would have been motivated to combine the teachings of Cosset-2019, Hao, and Gonzalez in a method of producing dopamine neurons to treat Parkinson’s disease and or test therapeutics for Parkinson’s disease as Cosset-2019 teaches establishment of relevant cellular models is crucial both to better understand the pathological mechanism of these diseases and identify new therapeutic targets and strategies and Cosset-2019 teaches such a model would not only allow screening of therapeutic molecules but also can be used to optimize neural protocol differentiation for example in the context of transplantation in Parkinson’s disease and Cosset-2019 teaches the dopamine organoid not only represents a suitable source of dopamine neurons for cell therapy in Parkinson’s disease but also can be used for drug testing and Gonzalez teaches there is no cure for Parkinson’s disease and cell replacement therapy is an attractive approach to treating PD patients and Gonzalez teaches implantation of neuronal cells such as neural stem cells and dopamine neurons have already been shown to improve the motor symptoms in PD animal models and Gonzalez teaches it is critical to be able to generate a homogenous population of NSCs which will in turn generate a homogenous population of dopamine neurons. One would have a reasonable expectation of success in combining the teachings as Cosset-2019 teaches the cells express neural markers Nurr1 and TH and early loss of tyrosine hydroxylase (TH) activity followed by a decline in TH protein expression is a hallmark of Parkinson’s disease and Gonzalez teaches the dopamine neurons formed from DMH1 treated hES cells secreted dopamine.
53. Claim 52, 54, and 57 is/are rejected under 35 U.S.C. 103 as being unpatentable over Cosset-2019 (Cosset, Erika, et al. JoVE (Journal of Visualized Experiments) 148 (2019): e59682.), hereinafter Cosset-2019 which is cited on the IDS filed 09/17/2025 in view of Hao (Hao, Jijun, et al. ACS chemical biology 5.2 (2010): 245-253; previously cited), hereinafter Hao which is cited on the IDS filed 07/24/2023 in view of Gonzalez (US9926529-B2; Filed 04/23/2013; Published 03/27/2018; previously cited), hereinafter Gonzalez which is cited on the IDS filed 07/24/2023 as evidenced by Bahrami (Bahrami N, et. al. Mol Neurobiol. 2017 Sep;54(7):5668-5675), hereinafter Bahrami and Yeap (Yeap YJ, et. al. Int J Mol Sci. 2023 Jan 28;24(3):2523), hereinafter Yeap as applied to claims 1, 8, 10, 13, 14, 21, 31, 33, 51, 61, 63 – 66, and 76 – 79 above, and further in view of Mohedas (Mohedas, Agustin H., et al. ACS chemical biology 8.6 (2013): 1291-1302.), hereinafter Mohedas in view of Hao (Hao, Jijun, et al. ACS chemical biology 5.2 (2010): 245-253; previously cited), hereinafter Hao which is cited on the IDS filed 07/24/2023.
Cosset-2019 in view of Hao and Gonzalez make obvious the limitations of claim 1 as set forth above. Cosset-2019, Hao, and Gonzalez do not teach K02288 of claims 52, 54, and 57. However, Cosset-2019 teaches the method uses a dual-SMAD inhibition cocktail (page 3, 4. hESC-derived dopaminergic organoids for PD studies, step 1). Cosset-2019 teaches the cells express neural markers Nurr1 and TH (Figure 3; page 3, last para.). Cosset-2019 teaches the lack of relevant in vitro models is an important obstacle on medical progress for neuropathologies (Abstract). Cosset-2019 teaches establishment of relevant cellular models is crucial both to better understand the pathological mechanism of these diseases and identify new therapeutic targets and strategies (Abstract). Cosset-2019 teaches such a model would not only allow screening of therapeutic molecules but also can be used to optimize neural protocol differentiation for example in the context of transplantation in Parkinson’s disease (Abstract). Cosset-2019 teaches the dopamine organoid not only represents a suitable source of dopamine neurons for cell therapy in Parkinson’s disease but also can be used for drug testing (Abstract). Cosset-2019 teaches Parkisonian symptoms are associated with the bilateral degeneration of dopaminergic neurons leading to the disappearance of dopaminergic axons (page 1, last para.; page 2, para. 1). Cosset-2019 teaches early loss of tyrosine hydroxylase (TH) activity followed by a decline in TH protein expression is a hallmark of Parkinson’s disease (page 2, para. 1).
Gonzalez teaches DMH1 is a BMP inhibitor (col. 2, lines 64 – 65). Gonzalez teaches there is currently no cure for Parkinson’s disease and the localized nature of the loss of dopamine neurons makes cell replacement therapy an attractive approach (col. 1, lines 62 – 67). Gonzalez teaches implantation of neuronal cells such as neural stem cells and dopamine neurons have already been shown to improve the motor symptoms in Parkinson’s disease animal models (col. 2, lines 1 – 4). Gonzalez teaches it is critical to be able to generate a homogenous population of NSCs which will in turn generate functional dopamine neurons either in situ or in vitro, depending on whether the terminal differentiation occurs in the patient’s brain or in culture (col. 2, lines 5 – 10).
Hao teaches DMH1 is a BMP inhibitor but does not inhibit ALK5 (TGFβ) while DMH2 has a lower IC50 for ALK2 (BMP) inhibition and inhibits ALK5 with an IC50 of 1578 nM (Table 2).
Regarding K02288 of claim 52, 54, and 57, Mohedas teaches K02288 is a BMP inhibitor that inhibits ALK2 with an IC50 of approximately 1.2 nM (page 1294, left col. last para. and right col. para. 1; Figure 2b, 2d). Mohedas teaches K02288a inhibits the TGFβ receptor ALK5 better than DMH1 with an IC50 value of 236 nM (Figure 2b, 2d). Mohedas teaches K02288 also inhibits ALK1, 3, and 4 with lower IC50 values compared to DMH1 (Figure 2b). Mohedas teaches ALK1, 2, and 3 are type I receptors that phosphorylate BMP receptor responsive SMAD proteins 1, 5, or 8 to regulate gene transcription (page 1291, left col.). Mohedas teaches activin and TGFβ ligands recruit TGFβ or Activin type II receptors with a set of type I receptors including ALK4 and 5 to activate SMADs 2 and 3 to regulate distinct transcriptional programs (page 1291, left col. and right col. para. 1).
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 Cosset-2019 regarding a method of forming dopamine organoids from hES cells by contacting hES cells with a dual-SMAD inhibition cocktail comprising a BMP inhibitor and a TGFβ inhibitor with the teachings of Hao regarding DMH1 is a BMP inhibitor and DMH2 is a TGFβ inhibitor with the teachings of Gonzalez regarding a method of forming dopamine neurons by contacting hES cells with DMH1 with the teachings of Mohedas regarding K02288 is both a BMP inhibitor and TGFβ inhibitor that can inhibit ALK1, 3, and 4 with lower IC50 values compared to DMH1 and inhibits ALK5 with a lower IC50 compared to DMH2 to arrive at the claimed method where the compound comprises DMH1, DMH2, and K02288. One would have been motivated to combine the teachings of Cosset-2019, Hao, Gonzalez, and Mohedas in a method of optimizing a dual-SMAD inhibition to produce dopamine neurons to treat Parkinson’s disease and or test therapeutics for Parkinson’s disease as Cosset-2019 teaches establishment of relevant cellular models is crucial both to better understand the pathological mechanism of these diseases and identify new therapeutic targets and strategies and Cosset-2019 teaches such a model would not only allow screening of therapeutic molecules but also can be used to optimize neural protocol differentiation for example in the context of transplantation in Parkinson’s disease and Cosset-2019 teaches the dopamine organoid not only represents a suitable source of dopamine neurons for cell therapy in Parkinson’s disease but also can be used for drug testing and Gonzalez teaches there is no cure for Parkinson’s disease and cell replacement therapy is an attractive approach to treating PD patients and Gonzalez teaches implantation of neuronal cells such as neural stem cells and dopamine neurons have already been shown to improve the motor symptoms in PD animal models and Gonzalez teaches it is critical to be able to generate a homogenous population of NSCs which will in turn generate a homogenous population of dopamine neurons. One would have a reasonable expectation of success in combining the teachings as Cosset-2019 teaches the method using the dual-SMAD inhibitor cocktail cells produces cells that express neural markers Nurr1 and TH and early loss of tyrosine hydroxylase (TH) activity followed by a decline in TH protein expression is a hallmark of Parkinson’s disease and Gonzalez teaches the dopamine neurons formed from DMH1 treated hES cells secreted dopamine and Hao teaches DMH1 is a BMP inhibitor and DMH2 is a TGFβ inhibitor and Mohedas teaches K02288 inhibits ALK1, 3, 4, and 5.
Maintained Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
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54. Claims 1, 8, 10, 11, 13 – 15, 20 – 21, 24, 25, 31, 33, 47 – 49, 51, 52, 54, 57, 61, 63 – 66, and 75 remain and new claims 76 – 79 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1, 2, 9, 11, 16, 19, 29, 30, 33, 34, 38, 42, 51, 54, 55, 62, 67, 69 of copending Application No. 18855867 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because instant claim 1 is anticipated by reference claim 1, 9, and 19. Although maintained, the rejection has been revised in view of Applicant’s amendment to claim 1.
Instant claim 1 is recites a method for differentiating stem or progenitor cells into neural cells or for producing neural cells from stem or progenitor cells, the method comprising contacting the stem or progenitor cells with a compound selected from DMH1, DMH2, or K02288, or combinations thereof, wherein the neural cells express one or more neural cell markers wherein the one or more neural cell markers include one or more of Otx-2, Lmx1a and FoxA2, and the method further comprises contacting the cells with a Rho Kinase (ROCK) inhibitor and further wherein the method excludes contacting the cells with LDN193189 and SB431542, to thereby provide said neural cells.
Reference claim 1 recites a method for differentiating stem or progenitor cells into neural cells, the method comprising (i) contacting the stem or progenitor cells with a differentiation composition, wherein the differentiation composition comprises one or more of the ALK inhibitors: DMH1, DMH2, K02288, and A83-0l; and (ii) culturing the cells in microwells to form spheroids and/or neurospheres. Reference claim 2 recites a method for differentiating stem or progenitor cells into neural cells, the method comprising (i) contacting the stem or progenitor cells with a differentiation composition; and (ii) culturing the cells in microwells to form spheroids and/or neurospheres. Reference claim 1 does not limit the compound but reference claim 9 recites the method of claim 1, wherein the ALK inhibitors exclude LDN193189 and/or SB431542, thus limiting the compound that recited in instant claim 1. Reference claim 1 does not recite a ROCK inhibitor but reference claim 19 recites the method of claim 1, wherein the method further comprises contacting the stem or progenitor cells with a Rho Kinase (ROCK) inhibitor and wherein the ROCK inhibitor comprises Y27632. Instant claim 20 recites the method of claim 1 wherein the ROCK inhibitor comprises Y27632. Therefore reference claim 1 is in essence a “species” of the generic invention of instant claim 1. It has been held that a generic invention is “anticipated” by a “species” within the scope of the generic invention. See In re Goodman, 29 USPQ2d 2010 (Fed. Cir. 1993).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Applicant’s Arguments/Response to Arguments
55. Applicant Argues: Applicant asserts that the amendment to claim 1 renders the objection moot.
Response to Argument: Claim 1 remains objected to because in line 6, “the cells” should read “the stem or progenitor cells” to clarify which cells are being referred to as the claim recites “stem and progenitor cells” and “neural cells”.
Applicant Argues: Applicant asserts the amended claims are clear and requests withdrawal of the rejections under 35 USC 112(b).
Response to Argument: In response, the claims 63 – 66 remain rejected because it is unclear if the claims are referring to a second unrecited step of further contacting the stem or progenitor cells or contacting the neural cells because the claim recites “further compound” but claim 1 does not recite any additional steps.
Applicant Argues: Applicant asserts the amended claims are non-obvious as claims 19, 28, and 72 have been incorporated into claim 1.
Response to Argument: In response, amended claim 1 is rendered obvious in view of the teachings of Gonzalez as evidenced by Bahrami and Yeap in view of Stover as set forth above. Amended claim 1 is rendered obvious in view of the teachings of Cosset-2019 in view of Hao in view of Gonzalez as evidenced by Bahrami and Yeap as set forth above.
Applicant Argues: Applicant asserts based on the effective filing date of the instant application and reference application, the double patenting rejection should be withdrawn.
Response to Argument: Because the claims are rejected under 35 USC 112 and 103, the rejection is maintained per MPEP 1490 (VI) (D).
Conclusion
No claims 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.
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/Z.M.B./Examiner, Art Unit 1632
/Tracy Vivlemore/Supervisory Primary Examiner, Art Unit 1638
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