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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 21st, May, 2026 has been entered.
Claim Status
Claims 1-2, 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Claims 17-20, 27-28, 30, 32-34 and 56 are withdrawn.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 1-2, 11-12 and 14-16 are under examination.
Moot Claim Rejections - 35 USC § 112 (b)
The rejection of claims 3-4 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 moot in view of the cancellation of these claims.
Moot Claim Rejections - 35 USC § 112 (d)
The rejection of claims 3-4 under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form as set forth in the previous office action is moot in view of the cancellation of these claims.
Moot Claim Rejections - 35 USC § 103
The rejection of claims 3-4 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”) as set forth in the previous office action is moot in view of the cancellation of these claims.
Withdrawn Claim Rejections - 35 USC § 103
The rejection of claim 15 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”) as set forth in the previous office action is withdrawn to apply a new combination of art below.
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, 14 and 16 remain 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 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 because developing human neural tube is capable of growing into neurons from multiple cortical layers.
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]) and therefore the singular neural rosette structures obtained by the suggested method would also be expected to generate GABAergic neurons.
Hence, the claimed invention as a whole was prima facie obvious.
Response to Arguments
Applicant’s arguments, filed 21st, May, 2026, have been fully considered but are not found persuasive.
Applicant argues hindsight reasoning (pg. 6-7). Specifically, Applicant further argues “The Examiner provides an independent motivation for each individual modification but does not explain why a person of ordinary skill starting from Ashton would have been motivated to layer all three changes at once. Adding XAV939, adding cyclopamine, and replacing the BMP inhibitor with DMH1 each originates from a different reference addressing a different experimental objective. No reference among the four cross-references or contemplates the other two modifications. Here, only knowledge of the Applicant's claimed invention connects these four disparate references into the specific combination recited in Claim 1” (pg. 7).
In response, as fully set forth above, in the grounds of rejection above, each element of the claims is specifically addressed. While Applicant has alleged hindsight, Applicant has not articulated why the specific reasons for each modification set forth in the rejection of record are insufficient. Applicant is directed to MPEP 2142 which states that 35 U.S.C. 103 authorizes a rejection where, to meet the claim, it is necessary to modify a single reference or to combine it with one or more other references. "To support the conclusion that the claimed invention is directed to obvious subject matter, either the references must expressly or impliedly suggest the claimed invention or the examiner must present a convincing line of reasoning as to why the artisan would have found the claimed invention to have been obvious in light of the teachings of the references." Ex parte Clapp, 227 USPQ 972, 973 (Bd. Pat. App. & Inter. 1985). The rejection of record above provides a convincing line of reasoning as to why the artisan would have found the claimed invention to have been obvious in light of the teachings of the references and therefore the preponderance of the evidence is that the combined teachings render the claimed invention obvious.
Further in response, Applicant is reminded that a 35 U.S.C. § 103(a) based test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981). In the instant case, although the claimed invention is not be expressly suggested in any one or all of the references, the preponderance of the evidence is that each modification is obvious for the reasons set forth above and therefore the combined teachings of the references would have suggested to those of ordinary skill in the art all modifications as set forth above.
Applicant argues “The secondary references also operate in materially different experimental contexts from the claimed method” (pg. 7-8). Applicant argues “A person of ordinary skill would have recognized that combining teachings drawn from a ventral interneuron protocol, a 2D mouse monolayer system, a selectivity study in a two-component context, and a 3D human organoid protocol involves significant uncertainty” (pg. 7).
Applicant argues “The Examiner's characterization of DMH1 as a simple substitute for dorsomorphin or noggin does not withstand scrutiny in the context of the claimed four-inhibitor system” (pg. 7). Applicant argues “BMP, Wnt, TGFβ, and SHH signaling pathways are known to extensively cross-talk during neural fate specification, and the behavior of DMH1 in a four-inhibitor cocktail cannot be predicted from its performance in a two-inhibitor system. The Examiner has not addressed how the altered selectivity dynamics of DMH1 would interact with simultaneous Wnt inhibition by XA V939 and SHH inhibition by cyclopamine” (pg. 7).
First in response, it has been held that a prior art reference must either be in the field of the inventor’s endeavor or, if not, then be reasonably pertinent to the particular problem with which the inventor was concerned, in order to be relied upon as a basis for rejection of the claimed invention. See In re Oetiker, 977 F.2d 1443, 24 USPQ2d 1443 (Fed. Cir. 1992). In this case, the arts of Ashton, Maroof, Gaspard and Neely are all analogous art because they are in the field of the inventor’s endeavor (neural cell culture), and are also reasonably pertinent to the particular problem with which the inventor was concerned (neuronal differentiation of cells and dorsal patterning of neural cells).
Additionally on response, while applicant has alleged that combining teachings from the cited art involves significant uncertainty, Applicant has not provided factually objective evidence on the record to oppose the reasonable expectation of success set forth in the grounds of rejection above.
Furthermore, Applicant is reminded that conclusive proof of efficacy is not required to show a reasonable expectation of success. OSI Pharm., LLC v. Apotex Inc., 939 F.3d 1375, 1385, 2019 USPQ2d 379681 (Fed. Cir. 2019) ("To be clear, we do not hold today that efficacy data is always required for a reasonable expectation of success. Nor are we requiring ‘absolute predictability of success.’"); Acorda Therapeutics, Inc. v. Roxane Lab., Inc., 903 F.3d 1310, 1333, 128 USPQ2d 1001, 1018 (Fed. Cir. 2018) ("This court has long rejected a requirement of ‘[c]onclusive proof of efficacy’ for obviousness." (citing to Hoffmann-La Roche Inc. v. Apotex Inc., 748 F.3d 1326, 1331 (Fed. Cir. 2014); PharmaStem Therapeutics, Inc. v. ViaCell, Inc., 491 F.3d 1342, 1364 (Fed. Cir. 2007); Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1364, 1367–68 (Fed. Cir. 2007) (reasoning that "the expectation of success need only be reasonable, not absolute")). In the instant case, one of ordinary skill would have reasonable predictability in making the combinations for the reasons set forth above. Each suggested modification combines or substitutes a known prior art element of a cell culture additive for its intended purpose (the Wnt signaling inhibitor XAV939 of Maroof, the SHH inhibitor cyclopamine of Gaspard, and the use of BMP inhibitor DMH1 of Neely), and each of the cited references use these patterning factors in cell culture protocols to obtain neuronal differentiation or dorsal patterning as set forth above.
In response, concerning the specific selectivity dynamics of DMH1, as stated above, DMH1 is suggested as a known substitute for Dorsomorphin for the reasons set forth above, Because both DMH1 and Dorsomorphin are known BMP1 inhibitors, one of ordinary skill would have had a reasonable expectation of success in using the BMP1 inhibitor of DMH1. As stated above, Applicant is reminded that conclusive proof of efficacy is not required to show a reasonable expectation of success. OSI Pharm., LLC v. Apotex Inc., 939 F.3d 1375, 1385, 2019 USPQ2d 379681 (Fed. Cir. 2019).
Furthermore, concerning the different selectivity profile of DMH1, a known or obvious composition does not become patentable simply because it has been described as somewhat inferior to some other product for the same use." In re Gurley, 27 F.3d 551, 553, 31 USPQ2d 1130, 1132 (Fed. Cir. 1994). In the instant case, DMH1 is still a known BMP1 inhibitors and would be obvious to substitute even if it could be considered inferior because it does not inhibit both BMP and TGF-β1 branches of the TGF-β superfamily like dorsomorphin.
Applicant argues “The rejection also fails to account for the unexpected structural outcome of the claimed method. A critical feature of the claimed invention is the formation of self-organizing single rosette spheroids each comprising a single neural rosette with a single central lumen. As described in the specification at paragraph [0006], structural heterogeneity caused by the formation of multiple rosettes per organoid has been a pervasive and long-recognized problem in the brain organoid field. Prior art methods including those of Lancaster et al. (2013), Pasca et al. (2015), and Kadoshima et al. (2013) consistently produced organoids with multiple organizing centers. The claimed method achieves single-rosette formation at greater than 99% efficiency (Specification at [0047])” (pg. 7). Applicant argues “The near-universal single-rosette formation achieved by the specific four-molecule cocktail constitutes objective evidence of nonobviousness that the Examiner has not addressed.” (pg. 7).
In response, Applicant’s arguments are not found persuasive because Applicant is not appreciating the broadest reasonable interpterion of the claims. The stated “single-rosette formation at greater than 99% efficiency” is not recited by, and therefore is not a requirement of, instant claims, which only require a self-organizing single-rosette spheroid (SOSR)/brain organoid comprising 1) a single neural rosette with a single central lumen, which is met by the primary reference for the reasons stated above. Because this feature is taught by the primary reference, and the suggested modifications above are the substitution of patterning factors that are included in the primary reference of Ashton with other known patterning factors for the same pathway, as well as combinations of known patterning factors, one of ordinary skill would expect to arrive at the taught structural result of the primary reference Ashton of 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]). As stated above, conclusive proof of efficacy is not required to show a reasonable expectation of success, and this teaching of Ashton that meets the structural requirements of instant claims provides enough evidence for a reasonable expectation of success.
Concerning the stated “method achieves single-rosette formation at greater than 99% efficiency” as a possible alleged unexpected result, this is not found persuasive for several reasons discussed below.
In response to Applicant’s arguments, arguments of counsel cannot take the place of
factually supported objective evidence in the record. See In re Schulze, 346 F.2d 500, 602, 145
USPQ 716, 718 (CCPA 1965), In re Huang, 100 F.3d 135, 139-40, 40 USPQ2d 1685, 1689 (Fed.
Cir. 1996); In re De Blauwe, 736 F.2d 699, 705, 222 USPQ 191, 196 (Fed. Cir. 1984). Thus,
Attorney statements regarding the unexpected result are not evidence without a supporting declaration. Specifically, Applicant has not provided objective scientific evidence on the record that the “achieves single-rosette formation at greater than 99% efficiency” is facilitated over prior art methods. Furthermore, as set forth above, the art of Ashton teaches formation of neural structures that comprise singular rosettes and dorsal patterning and therefore this result appears in the art and does not appear to be unexpected.
Concerning the alleged unexpected results, the burden is on the Applicant to establish results are unexpected and significant (MPEP 716.02(b)(I)), Applicants have the burden of explaining the proferred data (and MPEP 716.02(b)(II)), and the objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support (MPEP 716.02(d)(I)).
The evidence relied upon should establish "that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance." Ex parte Gelles, 22 USPQ2d 1318, 1319 (Bd. Pat. App. & Inter. 1992) (Mere conclusions in appellants’ brief that the claimed polymer had an unexpectedly increased impact strength "are not entitled to the weight of conclusions accompanying the evidence, either in the specification or in a declaration."); Ex parte C, 27 USPQ2d 1492 (Bd. Pat. App. & Inter. 1992) (Applicant alleged unexpected results with regard to the claimed soybean plant, however there was no basis for judging the practical significance of data with regard to maturity date, flowering date, flower color, or height of the plant.). See also In re Nolan, 553 F.2d 1261, 1267, 193 USPQ 641, 645 (CCPA 1977) and In re Eli Lilly, 902 F.2d 943, 14 USPQ2d 1741 (Fed. Cir. 1990) as discussed in MPEP § 716.02(c) (MPEP 716.02(b)(I)). Evidence of unexpected properties may be in the form of a direct or indirect comparison of the claimed invention with the closest prior art which is commensurate in scope with the claims. See In re Boesch, 617 F.2d 272, 205 USPQ 215 (CCPA 1980) and MPEP § 716.02(d) - § 716.02(e). See In re Blondel, 499 F.2d 1311, 1317, 182 USPQ 294, 298 (CCPA 1974) and In re Fouche, 439 F.2d 1237, 1241-42, 169 USPQ 429, 433 (CCPA 1971) for examples of cases where indirect comparative testing was found sufficient to rebut a prima facie case of obviousness. (MPEP 716.02(b)(II)).
In the instant case, Applicant’s alleged unexpected results are insufficient to overcome the rejection of record under 35 U.S.C. 103 for several reasons. First, as discussed above, the alleged unexpected results are not supported by factually objective evidence on the record and the result of singular neural rosette structures does not appear unexpected because is achieved by the art of Ashton. Next, Applicant does not provide a comparison to the closest prior art. Because the data cited by Applicant is not compared to the closest prior art, the statistical and practical significance of the data (required by MPEP 716.02(b)(II); see above) are not apparent. Finally, the alleged unexpected results do not appear to be in scope with the claimed invention. The result cited by Applicant is not directly linked to the experimental data, so it is unclear which experimental conditions are required to achieve the 99% efficiency cited by Applicant. Furthermore, the Experimental data that is disclosed requires specific conditions and timings of the claimed components that are not recited in instant claims.
Applicant argues “The Applicant's experiments were grounded in the specific insight that brain organoid formation should recapitulate the developmental transition from a two-dimensional neural plate to a three-dimensional neural tube (Specification at [0007]). This insight is not present in or derivable from any of the cited references” (pg. 7).
In response to applicant's argument, the fact that the inventor has recognized another advantage which would flow naturally from following the suggestion of the prior art (the “should recapitulate the developmental transition from a two-dimensional neural plate to a three-dimensional neural tube”) cannot be the basis for patentability when the differences would otherwise be obvious (each modification suggested and made obvious in the grounds of rejection above). See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985).
Applicant argues the interpretation of the wherein clauses for claims 14 and 15 (pg. 8-9). Specifically, Applicant argues “these claims recite specific structural and compositional characteristics of
the SOSRS product formed by the claimed method. Claim 14 requires that the SOSRS are capable of growing into neurons from multiple cortical layers. Claim 15 requires that the SOSRS express markers for dorsal forebrain selected from CTIP2, SATB2, and Reelin as well as the outer radial glial marker HOPX. These limitations define what the SOSRS product is in terms of its cellular composition and marker expression profile. They are not statements of purpose or intended use. Under MPEP § 2111.04, a "wherein" clause that states a condition that is a material part of the claimed structure or composition is given full patentable weight. Claim 15 is particularly significant because it requires expression of HOPX, a marker of outer radial glial cells. Outer radial glia are a primate-enriched progenitor population that represents a hallmark of advanced cortical development. Ashton does not disclose HOPX expression in its organoids. The expression of HOPX-positive outer radial glia in the SOSRS of the present application reflects a level of cortical maturation and developmental fidelity that is not an automatic consequence of any generic neural differentiation protocol and that is not taught by or inherent in the Examiner's
proposed combination. Even if the Examiner maintains the position that these "wherein" clauses
are non-limiting, the presence of HOPX-positive outer radial glia and developmentally normative
inside-out cortical lamination (Specification at [0141]) constitutes further objective evidence of
unexpected properties supporting nonobviousness.” (pg. 8-9)
First in response, concerning claim 14, as set forth 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. Therefore, this feature is taught by the prior art primary reference and is an expected property of an organoid produced by the suggested method in view of this teaching of the primary reference of Ashton.
It is noted that claim 15 is rejected over a new combination of art below and therefore the arguments drawn to claim 15 are moot in view of the new grounds of rejection below.
New Claim Rejections - 35 USC § 103
Claim 15 is 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”) as applied to claim 1 above and in further view of Watanabe et al. (Cell Rep. 2017 Oct 10;21(2):517-532.; henceforth “Watanabe”).
The teachings of Ashton, Maroof, Gaspard, and Neely above are incorporated herein in their entirety.
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]). Ashton teaches cells in the method can differentiate into glia (para. [0034) and Ashton teaches analyses methods can be used to detect the presence of glia in a in a biomimetic micropatterned neural tissue comprising a singular rosette structure (para. [0090]). Ashton further teaches that human neural organoids that include glial cells have been generated previously (para. [0134]).
However, regarding claim 15, Ashton, Maroof, Gaspard and Neely are silent to expression of the dorsal forebrain marker of CTIP2 and the expression of the radial glial marker of HOPX.
Nevertheless, regarding claim 15, Watanabe teaches a method for obtaining organoids comprising neural rosette structures (pg. 520 col. 2 3rd para.), that have CTIP2+ neurons and outer radial glia after 5 weeks of culture, resulting in larger organoids with enhanced laminar organization (pg. 520 col. 1 1st para.; Figures 1D and 1E, S1A, and S1D). Watanabe teaches that after 8 weeks of culture, the organoids have outer radial glial that express HOPX (pg. 521 col. 2; Figure 3). Watanabe teaches the markers expressed by in vitro week 8 and older organoids were similarly expressed within the gestational week 14 human fetal cortex (Figures 1H and 1I), and efficiently recapitulate the histological organization and patterned expression of key developmental regulators within the human fetal cortex in vivo (pg. 520 col. 1 2nd para.).
Therefore, regarding claim 15, it would have been obvious to a person of ordinary skill in the art before the effective filing data of the claimed invention to practice the method as suggested by Ashton in view of Maroof, Gaspard, and Neely, and combine the known prior art element of the 8 weeks of culture and patterning steps of Watanabe to obtain the predictable result of an 8 week neural organoid that expresses the dorsal forebrain marker CTIP2 and the radial glial marker of HOPX. One of ordinary skill would have been motivated to do so as taught by Watanabe to larger organoids with enhanced laminar organization (pg. 520 col. 1 1st para.; Figures 1D and 1E, S1A, and S1D) and to efficiently recapitulate the histological organization and patterned expression of key developmental regulators within the human fetal cortex in vivo (pg. 520 col. 1 2nd para.). Regarding the reasonable expectation of success, Watanabe evidences culturing steps for 8 weeks to obtain neural organoids that have neurons that express CTIP2 and radial glial cells that express HOPX (pg. 521 col. 2; Figure 3).
Hence, the claimed invention as a whole was prima facie obvious.
Conclusion
No claim is allowable.
Correspondence
Any inquiry concerning this communication or earlier communications from the examiner should be directed to BRIANA N EBBINGHAUS whose telephone number is (703)756-4548. The examiner can normally be reached M-F 9:30 AM to 5:30 PM ET.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Peter Paras can be reached at (571) 272-4517. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/BRIANA N EBBINGHAUS/Examiner, Art Unit 1632
/PETER PARAS JR/Supervisory Patent Examiner, Art Unit 1632
Prosecution Insights