DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Status
Claims 1-4, 11-12, 14-20, 27-28, 30, 32-34 and 56 are pending.
Claims 17-20, 27-28, 30, 32-34 and 56 are withdrawn.
Claims 1-4, 11-12 and 14-16 are under examination.
Withdrawn Objections to the Specification
The objection to the specification as set forth in the previous office action is withdrawn in view of Applicant’s amendments.
Withdrawn Claim Objections
The objection to claims 1-2 due to informalities as set forth in the previous office action is withdrawn in view of Applicant’s amendments.
Withdrawn Claim Rejections - 35 USC § 112(a)
Written Description
The rejection of claims 1-4, 11-12 and 14-16 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement as set forth in the previous office action is withdrawn in view of Applicant’s amendments.
Withdrawn Claim Rejections - 35 USC § 112(b)
The rejection of claim 15 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite as set forth in the previous office action is withdrawn in view of Applicant’s amendments.
New Claim Rejections - 35 USC § 112 (b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 3-4 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 3 recites “inhibiting the BMP signaling pathway,” “inhibiting the Wnt signaling pathway,” “inhibiting the TGFβ signaling pathway” and “inhibiting the SHH signaling pathway.” However, claim 3, upon which claim 1 depends, does not recite “inhibiting the BMP signaling pathway,” “inhibiting the Wnt signaling pathway,” “inhibiting the TGFβ signaling pathway” or “inhibiting the SHH signaling pathway.” Therefore, there is improper antecedent basis for these steps and it is unclear what the metes and bounds of the claim 3 are intended to encompass.
Claim 3 recites “inhibiting the BMP signaling pathway comprises culturing the pluripotent stem cells with a small molecule that inhibits the BMP signaling pathway,” “inhibiting the Wnt signaling pathway comprises culturing the pluripotent stem cells with a small molecule that inhibits the Wnt signaling pathway,” “inhibiting the TGFβ signaling pathway comprises culturing the pluripotent stem cells with a small molecule that inhibits the TGFβ signaling pathway” and “inhibiting the SHH signaling pathway comprises culturing the pluripotent stem cells with a small molecule that inhibits the SHH signaling pathway.” However, claim 1, upon which claim 3 depends, already recites the narrower embodiments of culturing with DMH1, which is a BMP signaling pathway inhibitor, XAV939, which is a WNT signaling pathway inhibitor, SB431542, which is a TGFβ signaling pathway inhibitor, and cyclopamine, which is an SHH signaling pathway inhibitor.
Regarding claim 3, a broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation is considered indefinite, since the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). Note the explanation given by the Board of Patent Appeals and Interferences in Ex parte Wu, 10 USPQ2d 2031, 2033 (Bd. Pat. App. & Inter. 1989), as to where broad language is followed by "such as" and then narrow language. The Board stated that this can render a claim indefinite by raising a question or doubt as to whether the feature introduced by such language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims. Note also, for example, the decisions of Ex parte Steigewald, 131 USPQ 74 (Bd. App. 1961); Ex parte Hall, 83 USPQ 38 (Bd. App. 1948); and Ex parte Hasche, 86 USPQ 481 (Bd. App. 1949). Therefore in the instant case, because the culturing steps recited in dependent claim 3 are broader than the specific small inhibitors recited in claim 1, upon which it depends, the scope of claim 3 is indefinite and the metes and bounds of the claim are unclear.
By nature of its dependency on claim 3, claim 4 is also rejected because it does not clarify the issues.
Claim 4 recites “the small molecule that inhibits the BMP signaling pathway is selected from the group consisting of 4-(6-(4-(piperazin-l-yl)phenyl)pyrazolo[l,5-a]pyrimidin-3-yl)quinoline hydrochloride (LDN193189), 6-[ 4-[2-(l-Piperidinyl)ethoxy ]phenyl]-3-( 4-pyridinyl)- pyrazolo[l,5-a]pyri- midine dihydrochloride (Dorsomorphin), 4-[6-[4-(lMethylethoxy) phenyl]pyrazolo[l,5-a]pyrimidin-3-yl]-quinoline (DMHl), 4-[6-[4-[2-(4- Morpholinyl)ethoxy]phenyl]pyrazolo[l,5-a]pyrimidin-- 3-yl]quinoline (DMH-2), and 5-[6-(4- Methoxyphenyl)pyrazolo[l,5-a]pyrimidin-3-yl]quinoline (ML 347),” “the small molecule that inhibits the Wnt signaling pathway is selected from the group consisting of N-(2-Aminoethyl)-5-chloroisoquinoline-8-sulphonamide dihydrochloride (CKl-7), N-(6-Methyl-2-benzothiazolyl)-2-[(3,4,6,7-tetrahydro-4-oxo-3-phe- nylthieno[3,2- d]pyrimidin-2-yl)thio]-acetamide (IWP2), N-(6-Methyl-2-benzothiazolyl)-2-[(3,4,6,7-tetrahydro- 3-(2-methoxyphenyl)-- 4-oxothieno[3,2-d]pyrimidin-2-yl)thio]-acetamide (IWP4), 2- Phenoxybenzoic acid-[(5-methyl-2-furanyl)methylene]hydrazide (PNU 74654) 2,4-diaminoquinazoline, quercetin, 3,5,7,8-Tetrahydro-2-[ 4-(trifluoromethyl)phenyl]-4H-thiopyrano[ 4,3- d]pyri- midin-4-one (XA V939), 2,5-Dichloro-N-(2-methyl-4-nitrophenyl)benzenesulfonamide (FH 535), N-[4-[2-Ethyl-4-(3-methylphenyl)-5-thiazolyl]-2-pyridinyl]benzamide (TAK 715), Dickkopf-related protein one (DKKl), and Secreted frizzled-related protein 1 (SFRP1),” and “ the small molecule that inhibits the TGFβ signaling pathway is selected from the group consisting of 4-[4-(l,3-benzodioxol-5-yl)-5-(2-pyridinyl)-lH-imidazol-2-yl]benzamide (SB431542), 6-[2-(l, l-Dimethylethyl)-5-(6-methyl-2-pyridinyl)-lH-imidazol-4-yl]quinox- aline (SB525334), 2-(5-Benzo[l,3]dioxol-5-yl-2-ieri-butyl-3H-imidazol-4-yl)-6-methylpyridin- e hydrochloride hydrate (SB-505124), 4-(5-Benzol[l,3]dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)-benzamide hydrate, 4-[ 4-( 1,3-Benzodioxol-5-yl)-5-(2-pyridinyl)- lH-imidazol-2-yl]-benzamide hydrate, left-right determination factor (Lefty), 3-(6-Methyl-2-pyridinyl)-N-phenyl-4-( 4-quinolinyl)- lH-pyrazole-1-carbothi- oamide (A 83-01 ), 4-[ 4-(2,3-Dihydro-1,4-benzodioxin-6- yl)-5-(2-pyridinyl)- lH-imidazol-2-yl]- benzamide (D 4476), 4-[ 4-[3-(2-Pyridinyl)-1H-pyrazol-4-yl]-2-pyridinyl]-N-(tetrahydro-2H-pyra- n-4-yl)-benzamide (OW 788388), 4-[3-(2-Pyridinyl)lH-pyrazol-4-yl]-quinoline (LY 364847), 4-[2-Fluoro-5-[3-(6-methyl-2-pyridinyl)-lH-pyrazol-4-yl]phenyl]-lH-pyrazo- le-1-ethanol (R 268712) or 2-(3-(6-Methylpyridine-2-yl)-lH-pyrazol-4-yl)-l,5-naphthyridine (RepSox),” which includes lists of options of the BMP signaling pathway inhibitor, WNT signaling pathway inhibitor and TGFβ signaling pathway inhibitor. However, claim 1, upon which claim 4 ultimately depends, already recites the required limitations that of culturing with DMH1, which is a BMP signaling pathway inhibitor, XAV939, which is a WNT signaling pathway inhibitor, and SB431542, which is a TGFβ signaling pathway inhibitor.
Regarding claim 4, as stated above, a broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation is considered indefinite, since the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). Therefore in the instant case, because the lists of options of culturing steps recited in dependent claim 4 are broader than the specific small inhibitors recited in claim 1, upon which it depends, the scope of claim 4 is indefinite and the metes and bounds of the claim are unclear.
New 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.
Claims 3-4 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.
Claim 3 recites “inhibiting the BMP signaling pathway comprises culturing the pluripotent stem cells with a small molecule that inhibits the BMP signaling pathway,” “inhibiting the Wnt signaling pathway comprises culturing the pluripotent stem cells with a small molecule that inhibits the Wnt signaling pathway,” “inhibiting the TGFβ signaling pathway comprises culturing the pluripotent stem cells with a small molecule that inhibits the TGFβ signaling pathway” and “inhibiting the SHH signaling pathway comprises culturing the pluripotent stem cells with a small molecule that inhibits the SHH signaling pathway.” However, claim 1, upon which claim 3 depends, already recites the narrower embodiments of culturing with DMH1, which is a BMP signaling pathway inhibitor, XAV939, which is a WNT signaling pathway inhibitor, SB431542, which is a TGFβ signaling pathway inhibitor, and cyclopamine, which is an SHH signaling pathway inhibitor. Because the embodiments recited in claim 3 are broader than those cited in claim 1, claim 3 cannot further limit claim 1.
By nature of its dependency on claim 3, claim 4 is also rejected.
Claim 4 recites “the small molecule that inhibits the BMP signaling pathway is selected from the group consisting of 4-(6-(4-(piperazin-l-yl)phenyl)pyrazolo[l,5-a]pyrimidin-3-yl)quinoline hydrochloride (LDN193189), 6-[ 4-[2-(l-Piperidinyl)ethoxy ]phenyl]-3-( 4-pyridinyl)- pyrazolo[l,5-a]pyri- midine dihydrochloride (Dorsomorphin), 4-[6-[4-(lMethylethoxy) phenyl]pyrazolo[l,5-a]pyrimidin-3-yl]-quinoline (DMHl), 4-[6-[4-[2-(4- Morpholinyl)ethoxy]phenyl]pyrazolo[l,5-a]pyrimidin-- 3-yl]quinoline (DMH-2), and 5-[6-(4- Methoxyphenyl)pyrazolo[l,5-a]pyrimidin-3-yl]quinoline (ML 347),” “the small molecule that inhibits the Wnt signaling pathway is selected from the group consisting of N-(2-Aminoethyl)-5-chloroisoquinoline-8-sulphonamide dihydrochloride (CKl-7), N-(6-Methyl-2-benzothiazolyl)-2-[(3,4,6,7-tetrahydro-4-oxo-3-phe- nylthieno[3,2- d]pyrimidin-2-yl)thio]-acetamide (IWP2), N-(6-Methyl-2-benzothiazolyl)-2-[(3,4,6,7-tetrahydro- 3-(2-methoxyphenyl)-- 4-oxothieno[3,2-d]pyrimidin-2-yl)thio]-acetamide (IWP4), 2- Phenoxybenzoic acid-[(5-methyl-2-furanyl)methylene]hydrazide (PNU 74654) 2,4-diaminoquinazoline, quercetin, 3,5,7,8-Tetrahydro-2-[ 4-(trifluoromethyl)phenyl]-4H-thiopyrano[ 4,3- d]pyri- midin-4-one (XA V939), 2,5-Dichloro-N-(2-methyl-4-nitrophenyl)benzenesulfonamide (FH 535), N-[4-[2-Ethyl-4-(3-methylphenyl)-5-thiazolyl]-2-pyridinyl]benzamide (TAK 715), Dickkopf-related protein one (DKKl), and Secreted frizzled-related protein 1 (SFRP1),” and “ the small molecule that inhibits the TGFβ signaling pathway is selected from the group consisting of 4-[4-(l,3-benzodioxol-5-yl)-5-(2-pyridinyl)-lH-imidazol-2-yl]benzamide (SB431542), 6-[2-(l, l-Dimethylethyl)-5-(6-methyl-2-pyridinyl)-lH-imidazol-4-yl]quinox- aline (SB525334), 2-(5-Benzo[l,3]dioxol-5-yl-2-ieri-butyl-3H-imidazol-4-yl)-6-methylpyridin- e hydrochloride hydrate (SB-505124), 4-(5-Benzol[l,3]dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)-benzamide hydrate, 4-[ 4-( 1,3-Benzodioxol-5-yl)-5-(2-pyridinyl)- lH-imidazol-2-yl]-benzamide hydrate, left-right determination factor (Lefty), 3-(6-Methyl-2-pyridinyl)-N-phenyl-4-( 4-quinolinyl)- lH-pyrazole-1-carbothi- oamide (A 83-01 ), 4-[ 4-(2,3-Dihydro-1,4-benzodioxin-6- yl)-5-(2-pyridinyl)- lH-imidazol-2-yl]- benzamide (D 4476), 4-[ 4-[3-(2-Pyridinyl)-1H-pyrazol-4-yl]-2-pyridinyl]-N-(tetrahydro-2H-pyra- n-4-yl)-benzamide (OW 788388), 4-[3-(2-Pyridinyl)lH-pyrazol-4-yl]-quinoline (LY 364847), 4-[2-Fluoro-5-[3-(6-methyl-2-pyridinyl)-lH-pyrazol-4-yl]phenyl]-lH-pyrazo- le-1-ethanol (R 268712) or 2-(3-(6-Methylpyridine-2-yl)-lH-pyrazol-4-yl)-l,5-naphthyridine (RepSox).” However, claim 1, upon which claim 4 ultimately depends, already recites the required limitations that of culturing with DMH1, which is a BMP signaling pathway inhibitor, XAV939, which is a WNT signaling pathway inhibitor, and SB431542, which is a TGFβ signaling pathway inhibitor. Therefore, the embodiments recited as alternatives for BMP signaling pathway inhibitors, WNT signaling pathway inhibitors and TGFβ signaling pathway inhibitors cannot further limit claim 1, upon which claim 4 ultimately depends, because claim 1 already defines the required elements as specifically DMH1, XAV939, and SB431542.
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.
Withdrawn Claim Rejections - 35 USC § 103
The rejection of claims 1-4, 11-12 and 14-16 under 35 U.S.C. 103 as being unpatentable over Ashton et al. (US-20190024046-A1; see IDS filed 5th, February, 2024; henceforth “Ashton”) in view of Maroof et al. (Cell Stem Cell. 2013 May 2;12(5):559-72.; see IDS filed 5th, February, 2024; henceforth “Maroof”) and Gaspard et al. (Nature. 2008 Sep 18;455(7211):351-7. Epub 2008 Aug 17.; see IDS filed 5th, February, 2024; henceforth “Gaspard”) as set forth in the previous office action is withdrawn in view of Applicant’s amendments.
New Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1-4, 11-12 and 14-16 are rejected under 35 U.S.C. 103 as being unpatentable over Ashton et al. (US-20190024046-A1; see IDS filed 5th, February, 2024; henceforth “Ashton”) in view of Maroof et al. (Cell Stem Cell. 2013 May 2;12(5):559-72.; see IDS filed 5th, February, 2024; henceforth “Maroof”), Gaspard et al. (Nature. 2008 Sep 18;455(7211):351-7. Epub 2008 Aug 17.; see IDS filed 5th, February, 2024; henceforth “Gaspard”) and Neely et al. (ACS Chem Neurosci. 2012 Jun 20;3(6):482-91. Epub 2012 Mar 5.; henceforth “Neely”).
Regarding claim 1, Ashton discloses method, comprising culturing pluripotent stem cells under in vitro conditions that promote neural differentiation in a medium comprising
a BMP inhibitor (“BMP signaling antagonist such as noggin at about 200 ng/ml or dorsomorphin at about 1 μΜ” para. [0080] see also para. [0029]) and TGFβ inhibitor SB431542 (TGFβ signaling antagonist SB431542; para. [0080]; see also para. [0029]),
wherein the culturing results in formation of one or more three-dimensional cell structures from the cultured pluripotent stem cells, wherein each of the formed one or more three-dimensional cell structures is a self-organizing single-rosette spheroid (SOSR)/brain organoid (singular neural rosette structure; abstract; Figures 1, 2A, 15A; para. [0004-0008, 0013-0020, 0023, 0029, 0037, 0051-00580064-0066, 0084-0086, 0089-0091, 0096-0097, 0099-0101, 0106-0130, 0134-0135, 0147-0149; Example 1; claims 1, 13, 15, 20, and 25) comprising 1) a single neural rosette (“singular neural rosette structure”) with a single central lumen (“a 3-D hemispherical structure with a central cavity” para. [0023,0131]; Figures 11A-G, and 2) a dorsal cell fate (“Pax6+/Otx2+ dorsal forebrain phenotype (Pax6+/Otx2+ dorsal forebrain phenotype; para. [0120]; Figure 5B; see also para. [0122, 0135]).
However, regarding claim 1, although Ashton teaches culturing to the dorsal forebrain phenotype (Pax6+/Otx2+ dorsal forebrain phenotype; para. [0120]; Figure 5B) from pluripotent stem cells tissue, Ashton does not disclose the culturing includes a Wnt signaling inhibitor of XAV939.
Nevertheless, regarding claim 1, Maroof teaches a method of culturing pluripotent stem cells comprising inhibiting the BMP, TGFβ signaling pathways (“Neural differentiation of hESCs via the dual SMAD-inhibition protocol using Noggin + SB431542 (NSB) robustly induced FOXG1+/PAX6+ precursors” pg. 560 col. 1 3rd para.), and Wnt signaling pathways (Inhibition of Wnt; pg. 560 col. 1 2nd para.). Maroof teaches a method step of inhibiting the Wnt singling pathway by culturing with a Wnt signaling inhibitor XAV939 from day 0 to day 10 (Figure 1A) to enhance forebrain differentiation (pg. 560 col. 1 1st para.).
Therefore, regarding claim 1, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to practice the method of Ashton, and combine the known prior art element of inhibiting the Wnt signaling pathway by culturing with the Wnt signaling inhibitor XAV939 of Maroof (from day 0-10 Figure 1A) to obtain the predictable result of enhanced forebrain differentiation (pg. 560 col. 1 1st para.). One of ordinary skill would have been motivated to do so as taught by Maroof because culturing with the Wnt signaling inhibitor XAV939 yielded highly Efficient Derivation of Forebrain Fates (Figure 1). Regarding the reasonable expectation of success, Maroof evidences successfully culturing pluripotent stem cells by comprising inhibiting the BMP, TGFβ signaling pathways, and Wnt signaling pathways (Figure 1).
However, regarding claim 1, Ashton and Maroof are silent to a method step of inhibiting SHH signaling by culturing with an SHH signaling inhibitor.
Nevertheless, regarding claim 1, Gaspard teaches a method step of culturing pluripotent stem cells with the SHH inhibitor cyclopamine during the neural progenitor differentiation (Fig. 1a, b, h, n) which caused a massive increase in the expression of dorsal markers, whereas expression of ventral markers was almost abolished (Fig. 1i–n; Pg. 351 col. 2 last para.).
Therefore, regarding claim 1, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to practice the method as suggested by Ashton in view of Maroof and combine the known prior art element of the method step of culturing pluripotent stem cells with the SHH inhibitor cyclopamine during the neural progenitor differentiation of Gaspard to obtain the predictable result of increased expression of dorsal markers. One of ordinary skill would have been motivated to do so as taught by Gaspard to generate a diverse repertoire of neurons that display most salient features of genuine cortical pyramidal neuron (abstract) because the neurons generated in DDM plus cyclopamine displayed a PMI corresponding to pyramidal neurons that was significantly higher than when cyclopamine was not included; pg. 353 col. 1 1st para.). Regarding the reasonable expectation of success, Gaspard evidences culturing pluripotent stem cells with the SHH Inhibitor cyclopamine to arrive at neurons with a dorsal fate (Fig. 1a, b, h, n; Fig. 1i–n; Pg. 351 col. 2 last para.).
However, regarding claim 1, although, as stated above, Ashton teaches culturing with a BMP inhibitor (“BMP signaling antagonist such as noggin at about 200 ng/ml or dorsomorphin at about 1 μΜ” para. [0080] see also para. [0029]), Ashton, Maroof, and Gaspard are silent to the BMP inhibitor of DMH1.
Nevertheless, regarding claim 1, Neely teaches the use of BMP inhibitor DMH1 for culturing pluripotent stem cells under in vitro conditions that promote neural differentiation in a medium (pg. 488 col. 2 “Neuronal Differentiation”). Neely teaches DMH1 is a highly selective, small molecule analogue
of dorsomorphin (pg. 484 col. 1 1st para.; see also pg. 484 col. 2 2nd para.). Neely teaches that DMH1 is a highly specific BMP-antagonist that inhibits signaling through ALK1, ALK2, and ALK3 receptors, with negligible effect on the ALK6 receptor and no other off-target effects (pg. 487 col. 2 “Conclusions”) as opposed to dorsomorphin which has been shown to inhibit the BMP- as well as the TGF-β1 branches of the TGF-β pathways (pg. 487 col. 2 “Conclusions”). Neely teaches the expression of all markers was similarly regulated by Noggin and DMH1 (pg. 483 col. 2 1st para.; see also Figures 2-3). Neely teaches DMH-1-induced neural precursor cells are competent to further differentiate into β3-tubulin and tyrosine-hydroxylase expressing neurons (pg. 483 col. 2 1st para.; see also Figure 6). Neely teaches the combined use of SB431542 and DMH-1 enables us to regulate the two TGF-β signaling pathways specifically and independently in hiPSCs with the exclusive use of small molecules (pg. 483 col. 2 1st para.; pg. 487 col. 2 “Conclusions”). Neely teaches Noggin and DMH1-induced hiPSC neuralization occurs within the same time frame and that the derived neural precursor cells display a very similar transcription factor expression profile (pg. 487 col. 2 “Conclusions”).
Therefore, regarding claim 1, it would have been obvious to a person of ordinary before the effective filing date of the claimed invention to practice the method as suggested by Ashton in view of Maroof, and Gaspard and simply substitute the known prior art element of the DMH-1 of Neely for the dorsomorphin or Noggin of Ashton to obtain the predictable result of a medium for neural differentiation of pluripotent cells. One of ordinary skill would have been motivated to do so as taught by Neely to regulate the two TGF-β signaling pathways specifically and independently in hiPSCs with the exclusive use of small molecules (pg. 483 col. 2 1st para.; pg. 487 col. 2 “Conclusions”). Regarding the reasonable expectation of success, Neely teaches differentiating iPSCs to a neural lineage using a medium with DMH-1 (pg. 488 col. 2 “Neuronal Differentiation”).
Lastly, regarding there wherein clauses of claim 1, as stated above, the primary reference Ashton teaches the culturing results in formation of one or more three-dimensional cell structures from the cultured pluripotent stem cells, wherein each of the formed one or more three-dimensional cell structures is a self-organizing single-rosette spheroid (SOSR)/brain organoid (singular neural rosette structure; abstract; Figures 1, 2A, 15A; para. [0004-0008, 0013-0020, 0023, 0029, 0037, 0051-00580064-0066, 0084-0086, 0089-0091, 0096-0097, 0099-0101, 0106-0130, 0134-0135, 0147-0149; Example 1; claims 1, 13, 15, 20, and 25) comprising 1) a single neural rosette (“singular neural rosette structure”) with a single central lumen (“a 3-D hemispherical structure with a central cavity” para. [0023,0131]; Figures 11A-G, and 2) a dorsal cell fate (“Pax6+/Otx2+ dorsal forebrain phenotype (Pax6+/Otx2+ dorsal forebrain phenotype; para. [0120]; Figure 5B; see also para. [0122, 0135]). Therefore, one of ordinary skill would have had a reasonable expectation of success in obtaining the functional results of “the culturing results in formation of one or more three-dimensional cell structures from the cultured pluripotent stem cell” and where “each of the formed one or more three-dimensional cell structures is a self-organizing single-rosette spheroid (SOSR)/brain organoid comprising 1) a single neural rosette with a single central lumen, and 2) a dorsal cell fate” in the suggested method because Ashton teaches these result from the taught culturing steps.
Regarding claim 2, further to the discussion of claim 1 above, Ashton teaches the pluripotent stem cells are part of a two-dimensional monolayer of pluripotent stem cells (“2-D monolayer” para. [0037, 0096-0097, 0099, 0107, 0110, 0113, 0134, 0136]).
Regarding claims 3-4, further to the discussion of claim 1 above, as stated above (see claim 1 rejection above), in the method as suggested by Ashton in view of Maroof, Gaspard and Neely:
Neely teaches the BMP inhibitor DMH1;
Maroof teaches the Wnt signaling pathway inhibitor XAV939,
Ashton teaches the TGFβ inhibitor SB431542, and
Gaspard teaches the SHH inhibitor cyclopamine.
Regarding claim 11, further to the discussion of claim 1 above, Ashton teaches the culturing is for approximately four days (“a first culture period of about three (3) days to about six (6) days” para. [0065]).
Notably, regarding claim 11, in the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). It is routine procedure to optimize component amounts to arrive at an optimal product that is superior for its intended use, since it has been held where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. See M.P.E.P. §2144.05. In the instant case, the taught range of about 3 days to about 6 days makes obvious the claimed value of about 4 days.
Regarding claim 12, further to the discussion of claim 1 above, Ashton teaches the method further comprises a step of transferring a portion of the cultured pluripotent stem cells onto a gelatinous basement membrane matrix (“subcultured onto a micropatterned surface and then cultured” para. [0065] and “a micropatterned substrate is covered by or coated in a cell culture substrate” which is “an undefined extracellular matrix protein substrate such as Matrigel” para. [0093]).
Regarding claim 14, further to the discussion of claim 1 above, Ashton teaches the singular neural rosette structure is comparable to a portion of the developing human neural tube (para. [0005]; see also para. [0004, 006-0008, 0029, 0037, 0051-0053, 0055-0056, 0064, 0089-0090, 0096-0097, 0099, 0102, 0105, 0115, 0122, 0130, 0134, 0136]; claims 1, 16 and 20), and the structure is therefore is capable of growing into neurons from multiple cortical layers.
Additionally, regarding claim 14, the method as suggested by Ashton in view of Maroof, Gaspard and Neely comprises the active method steps of the instantly claimed method, and therefore the claimed result of SORS that are capable of growing into neurons from multiple cortical layers would naturally follow the recitation of the taught steps.
Furthermore, regarding claim 14, the wherein clause does not recite any additional active method steps, but simply state a characterization or conclusion of the results of process step positively recited (e.g. “the SOSRS are capable of growing into neurons from multiple cortical layers”). Therefore, the "wherein" clause is not considered to further limit the method defined by the claim and has not been given weight in construing the claims. See Texas Instruments, Inc. v. International Trade Comm., 988 F.2d 1165, 1171,26 USPQ2d 1018, 1023 (Fed Cir. 1993) ("A 'whereby' clause that merely states the result of the limitations in the claim adds nothing to the patentability or substance of the claim."). See also Minton v. National Assoc. of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003) ("A whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited."). See also MPEP 2111.04 that a “Claim scope is not limited by claim language that suggests or makes optional but does not require steps to be performed, or by claim language that does not limit a claim to a particular structure” and a “whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.”
Regarding claim 15, further to the discussion of claim 1 above, Ashton teaches the singular neural rosette structure expresses Pax6 and Otx2 markers for dorsal forebrain (“Pax6+/Otx2+ dorsal forebrain phenotype” para. [0120]) . Although Ashton is silent to expression of markers for dorsal forebrain selected from CTIP2, SATB2, Reelin and expression of the outer radial glial marker HOPX, because the method as suggested by Ashton in view of Maroof, Gaspard and Neely comprises the active method steps of the instantly claimed method, the result of expression of markers for dorsal forebrain selected from CTIP2, SATB2, Reelin and expression of the outer radial glial marker HOPX would naturally follow the recitation of the taught steps.
Furthermore, regarding claim 15, the wherein clause does not recite any additional active method steps, but simply state a characterization or conclusion of the results of process step positively recited, and therefore, the "wherein" clause is not considered to further limit the method defined by the claim and has not been given weight in construing the claims. See Texas Instruments, Inc. v. International Trade Comm., 988 F.2d 1165, 1171,26 USPQ2d 1018, 1023 (Fed Cir. 1993).
Regarding claim 16, further to the discussion of claim 1 above, Ashton teaches the singular neural rosette structures can generate GABAergic neurons (para. [0083, 0089]).
Additionally, regarding claim 16, the method as suggested by Ashton in view of Maroof, Gaspard and Neely comprises the active method steps of the instantly claimed method, and therefore the claimed result of SORS that can generate GABAergic neurons would naturally follow the recitation of the taught steps.
Furthermore, regarding claim 16, the wherein clause does not recite any additional active method steps, but simply state a characterization or conclusion of the results of process step positively recited, and therefore, the "wherein" clause is not considered to further limit the method defined by the claim and has not been given weight in construing the claims. See Texas Instruments, Inc. v. International Trade Comm., 988 F.2d 1165, 1171,26 USPQ2d 1018, 1023 (Fed Cir. 1993).
Hence, the claimed invention as a whole was prima facie obvious.
Response to Arguments
Applicants arguments, filed 18th, December, 2025 have been fully considered but are moot in view of the new grounds of rejection above which was necessitated by amendment.
Conclusion
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.
No claim is allowable.
Correspondence
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/BRIANA N EBBINGHAUS/Examiner, Art Unit 1632 /VALARIE E BERTOGLIO/Primary Examiner, Art Unit 1632