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 .
Applicants' preliminary amendments to the claims filed on 10-14-2025 have been received and entered. Claims 1-35 and 38-43 have been canceled. Claims 36 and 37 have been amended. Claims 44-48 have been added. Claims 36-37, 44-48 are pending.
Election/Restrictions
Applicant’s election without traverse of Group II (claims 36 and 37) in the reply filed on 04-04-2025 is acknowledged.
Claims 1-35 and 38-43 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected subject matter, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 04-04-2025. It is noted that claims 1-35 and 38-43 are also canceled in the response filed on 04-04-2025.
Claims 36-37, 44-48 are under consideration.
Priority
This application claims priority from US provisional application No 63/223,139 filed on 07/19/2021.
Withdrawn-Claim Rejections - 35 USC § 103
Claim 37 was rejected under 35 U.S.C. 103 as being unpatentable over Kuwahara et al (Pub .No.: US 2017/0313976 A1, Pub. Date: Nov. 2, 2017) in view of Wataya et al (PNAS , August 19, 2008 , vol. 105 , no. 33, Doi: 10.1073ypnas.0803078105) and Wang et al (Biochemical and Biophysical Research Communications 483 (2017) 216e222, Doi: 10.1016/j.bbrc.2016.12.163) and Meng et al (Development (2018) 145, dev152595. doi:10.1242/dev.152595). In view of Applicants' amendment of base claim 37, introducing the limitation “wherein the retinoic acid (RA) pathway aqonist is TTNPB, and wherein the Akt pathway antagonist is MK2206”, the previous rejections of claims are hereby withdrawn. Applicants' arguments with respect to the withdrawn rejections are thereby rendered moot. The claims are however subject to new rejections over the prior art of record, as set forth below.
Claim Objections
Claim 47 is objected to because of the following informalities:
The item (iv) should read (ii) because there are only 2 items in claim 47:
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Appropriate correction is required.
Maintained in modified form and New-Claim Rejections - 35 USC § 103-Necessitated by amendments
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.
Claim interpretation:
The specification of the claimed invention teaches that the WNT pathway agonist is selected from the group consisting of CHIR99021, CHIR98014, SB 216763, SB 415286, LY2090314, 3F8, A 1070722, AR-A 014418, BIO, AZD 1080, WNT3A, and combinations thereof (Page 12, lines 7-9). Thus, these factors are interpreted as WNT pathway agonists.
The specification of the claimed invention teaches that the SHH pathway agonist is selected from the group consisting of Purmorphamine, GSA 10, SAG, and combinations thereof (Page 12, lines 20-21). Thus, these factors are interpreted as SHH pathway agonist.
The specification of the claimed invention teaches that the BMP pathway antagonist is selected from the group consisting of LDN193189, DMH1, DMH2, Dorsomorphin, K02288, LDN214117, LDN212854, follistatin, ML347, Noggin, and combinations thereof (Page 13, lines 1-3). Thus, these factors are interpreted as BMP pathway antagonist.
The specification of the claimed invention teaches that the AKT pathway antagonist is selected from the group consisting of MK2206, GSK690693, Perifosine (KRX-0401), Ipatasertib (GDC- 0068), Capivasertib (AZD5363), PF-04691502, AT 7867, Triciribine (NSC154020), ARQ751, Miransertib (ab235550), Borussertib, Cerisertib, and combinations thereof (Page 13, lines 14-17). Thus, these factors are interpreted as AKT pathway antagonist.
The specification of the claimed invention teaches that the MEK pathway antagonist is selected from the group consisting of PD0325901, Binimetinib (MEKl 62), Cobimetinib (XL518), Selumetinib, Trametinib (GSKl 120212), CI-1040 (PD-184352), Refametinib, ARRY-142886 (AZD-6244), PD98059, U0126, BI-847325, RO 5126766, and combinations thereof (Page 14, lines 4-7). Thus, these factors are interpreted as MEK pathway antagonist.
The specification of the claimed invention teaches that the RA pathway agonist is selected from the group consisting of: retinoic acid, Sr11237, adapalene, EC23, 9-cis retinoic acid, 13-cis retinoic acid, 4-oxo retinoic acid, and All-trans Retinoic Acid (ATRA) (Page 14, lines 26-28). Thus, these factors are interpreted as RA pathway agonist.
The specification of the claimed invention teaches that the LXR pathway agonist is selected from the group consisting of GW3965, T0901317, DMHCA, AZ876, and combinations thereof (Page 15, lines 11-12). Thus, these factors are interpreted as LXR pathway agonist.
The specification of the claimed invention teaches that the BMP pathway agonist is selected from the group consisting of BMPs (such as BMP7), sb4, ventromorphins, and combinations thereof (Page 15, lines 23-25). Thus, these factors are interpreted as BMP pathway agonist.
The specification of the claimed invention teaches that the TGFβ pathway antagonist is selected from the group consisting of A 83-01, SB-431542, GW788388, SB525334, TP0427736, RepSox, SD-208, and combinations thereof (Page 16, lines 4-5). Thus, these factors are interpreted as TGFβ pathway antagonist.
The specification of the claimed invention teaches that the mTOR pathway antagonist is selected from the group consisting of AZD3147, rapamycin, sirolimus, temsirolimus, everolimus, ridaforolimus, umirolimus, zotarolimus, torin-1, torin-2, vistusertib, MHY1485, AZD8055, and combinations thereof (Page 16, lines 16-19). Thus, these factors are interpreted as mTOR pathway antagonist.
Claim 36, 44-45 are rejected under 35 U.S.C. 103 as being unpatentable over Kuwahara et al (Pub .No.: US 2017/0313976 A1, Pub. Date: Nov. 2, 2017) in view of Wataya et al (PNAS , August 19, 2008 , vol. 105 , no. 33, Doi: 10.1073ypnas.0803078105).
Regarding to claim 36, Kuwahara et al teach a method for producing neural cells or a neural tissue including culturing pluripotent stem cells in a medium containing differentiation -inducing factor to obtain an aggregate containing neural cells or a neural tissue ([0019], item [1]-(3) on page 1). The “neural tissue” refers to a tissue constituted of neural cells including midbrain ([0105], page 8). Kuwahara et al teach “the aggregate is cultured in suspension in the presence or absence of a differentiation-inducing factor to give an aggregate containing neural cells or a neural tissue” ([0215], page 17), and “ Examples of the differentiation-inducing factor widely used by those of ordinary skill in the art include a BMP signal transduction inhibiting substance, …. a Shh signal transduction pathway activating substance, …. a FGF signal transduction pathway inhibiting substance, …. a Wnt signal transduction pathway activating substance ….” ([0216], page 17), and “Examples of the FGF signal transduction pathway inhibiting substance include ….. MAP kinase cascade inhibiting substance ( e. g., MEK inhibitor, MAPK inhibitor, ERK inhibitor ), PI3 kinase inhibitor, Akt inhibitor and so on” ([0305], page 25). Kuwahara et al stated that “a differentiation- inducing factor or a differentiation induction method suitable for the intended cell or tissue can be selected.” ([0216], page 18), and “a differentiation-inducing factor (e.g., a Wnt signal transduction pathway inhibiting substance, a TGFβ family signal transduction pathway inhibiting substance and the like) may be added simultaneously” ([0229], page 18). Thus, all the differentiation-inducing factors as described above may be added simultaneously together. (Note: Kuwahara et al teaches the TGFβ family signal transduction pathway inhibiting substance is a BMP signal transduction pathway inhibiting substance ([0019], item [7] on page 2))
Kuwahara et al teaches culturing the aggregate obtained in the second step in suspension in the presence or absence of a differentiation-inducing factor to obtain an aggregate containing neural cells or a neural tissue (see Abstract and [0215], page 17). Further, Kuwahara et al teaches differentiation -inducing factor include, but are not particularly limited to, in vivo gene product such as growth factor and the like ([0216], page 17). Kuwahara et al teaches the use of inhibiting or activating substance of fibroblast growth factor (FGF) signal transduction pathway as a differentiation-inducing factor to obtain an aggregate containing neural cells ([0216], page 17). Thus, Kuwahara et al teaches aggregate containing neural cells can be obtained with or without growth factor (such as fibroblast growth factor). However, Kuwahara et al does not specifically teach lacking exogenously-added growth factors. Wataya et al cures the deficiency.
Wataya et al teaches embryonic stem (ES) cells differentiate into neuroectodermal progenitors, and instead of the addition of inductive signals, minimization of exogenous patterning signaling plays a key role in rostral hypothalamic specification of neural progenitors derived from pluripotent cells (Abstract). Wataya et al showed that ES cell-derived neuroectodermal cells robustly differentiate into cells expressing regional markers of the embryonic rostral hypothalamus when cultured in a strictly chemically defined medium (CDM; growth factor-free chemically defined medium is gfCDM), free of KSR and other growth factors including insulin (Page 11796, right column, 2nd para.).
Since Kuwahara et al teaches culturing aggregate in suspension in the presence or absence of a differentiation-inducing factor such as growth factor ( [0215], page 17) and Wataya et al teaches minimization of exogenous patterning signaling (abstract) using growth factor-free chemically defined medium free of KSR and other growth factors (Page 11796, right column, 2nd para.) can positively affect differentiation of neuroectodermal progenitors; therefore, a person of ordinary skill in the art before the effective filing date of the rejected claims would be motivated to optimize and not use exogenously-added growth factors in cell culture media for differentiation of neural cells.
Therefore, it would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the rejected claims to combine the teachings of Kuwahara et al and Wataya et al to use medium lacking exogenously-added growth factors as instantly claimed, with a reasonable expectation of success. Said modification amounting to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would have been motivated to do so because Wataya et al provide explicit advantage of minimization of exogenous patterning signaling plays a key role in differentiation of neural progenitors derived from pluripotent cells (Abstract). Wataya et al stated that the present study has identified a key condition necessary for differentiation of rostral hypothalamic progenitors from ES cells, i.e., no exogenous patterning signals added at the naive neuroectodermal stage (Page 11800, right column, 4th para.). One of ordinary skill in the art would have had a reasonable expectation of success in doing so because Wataya et al was successful in differentiation of neuroectodermal progenitors with detailed instructions and data.
Regarding to claim 44-45, Kuwahara et al teach a BMP signal transduction pathway inhibiting substance (e.g ., LDN193189 , Chordin , Noggin ), or a combination thereof ([0171], page 13), and LDN193189 is generally used at a concentration of 1 -2000 nM ([0148], page 12).
Claim 37, 46, 47, and 48 are rejected under 35 U.S.C. 103 as being unpatentable over Kuwahara et al (Pub .No.: US 2017/0313976 A1, Pub. Date: Nov. 2, 2017) in view of Wataya et al (PNAS , August 19, 2008 , vol. 105 , no. 33, Doi: 10.1073ypnas.0803078105) and Wang et al (Biochemical and Biophysical Research Communications 483 (2017) 216e222, Doi: 10.1016/j.bbrc.2016.12.163) and Meng et al (Development (2018) 145, dev152595. doi:10.1242/dev.152595), and Osafune et al (Pub. No.: US 2014/0363888 A1, Pub. Date: Dec. 11, 2014), and Abe et al (Pub. No.: US 2018/0136196 A1, Pub. Date: May 17, 2018).
Regarding to claim 37, Kuwahara et al teach aggregate is cultured in suspension in the presence or absence of a differentiation -inducing factor to give an aggregate containing neural cells or a neural tissue ([0215], page 17), and “Examples of the differentiation -inducing factor widely used by those of ordinary skill in the art include a BMP signal transduction activating substance , a BMP signal transduction pathway inhibiting substance …… a FGF signal transduction pathway inhibiting substance ([0216], page 17). Examples of the BMP signal transduction pathway activating substance include BMP proteins such as BMP2, BMP4, BMP7 etc. ([0234], page 19). The TGFβ family signal transduction pathway inhibiting substance is a BMP signal transduction pathway inhibiting substance ([0019], item [7] on page 2), and a BMP signal transduction pathway inhibiting substance is LDN193189 ([0365], page 29). Kuwahara et al also teach “Examples of the FGF signal transduction pathway inhibiting substance include …... Akt inhibitor and so on” ([0305], page 25). Kuwahara et al stated that “a differentiation- inducing factor or a differentiation induction method suitable for the intended cell or tissue can be selected.” ([0216], page 18), and “a differentiation-inducing factor (e.g., a Wnt signal transduction pathway inhibiting substance, a TGFβ family signal transduction pathway inhibiting substance and the like) may be added simultaneously” ([0229], page 18). Thus, all the differentiation-inducing factors as described above may be added simultaneously together.
Kuwahara et al teach a serum-free medium or serum medium containing a differentiation-inducing factor ([0232], page 19), and the serum-free medium or serum containing medium may contain a known growth factor, an additive and a chemical substance that promote the growth , and examples of the chemical substance that promotes the growth include retinoids (e.g., retinoic acid ) and taurine” ([0315], page 26) and “a serum - free medium or serum-containing medium to be used for such medium is not particularly limited as long as it is as mentioned above. For example , a serum-containing medium which is a DMEM -F12 medium supplemented with …. retinoic acid ……” ([0370], page 30).
Kuwahara et al does not teach a liver X receptor (LXR) pathway agonist. Wang et al cures the deficiency.
Wang et al teaches LXR agonists promote the proliferation of neural progenitor cells through MEK-ERK pathway (title). T0901317 treatment may promote the neural migration and differentiation in the cerebellar cortex. Moreover, administration of GW3965 or T0901317 could exert neuroprotective effects in the multiple mouse models of neurodegenerative diseases or CNS disorders and improved cognitive performance (Page 217, left column, 1st para.). Wang et al revealed that LXR agonists can enhance the proliferation of NPCs via MEK/EKR-dependent pathway (Page 217, left column, 1st para.).
Therefore, it would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the rejected claims to combine the teachings of prior art to modify the method of Kuwahara et al by using a liver X receptor (LXR) pathway agonist such as T0901317, GW3965 or T0901317 in cell culture medium with neural progenitor cells as taught by Wang et al as instantly claimed, with a reasonable expectation of success. Said modification amounting to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would have been motivated to do so because Wang et al provide explicit advantage of using LXR agonists to promote the proliferation of neural progenitor cells through MEK-ERK pathway (title and abstract). One of ordinary skill in the art would have had a reasonable expectation of success in doing so because Wang et al provide proof of principles for using LXR agonists to enhance the proliferation of NPCs via MEK/EKR-dependent pathway.
Kuwahara et al does not teach a mammalian target of rapamycin (mTOR) pathway antagonist. Meng et al cures the deficiency.
Meng et al teach important roles for mTOR in promoting the differentiation of adult stem cells, driving the growth and proliferation of stem and progenitor cells, and dictating the differentiation program of multipotent stem cell populations (Abstract). Also, mTOR signaling is crucial for the maintenance and differentiation of neural stem cells (NSCs) and for brain development (Page 5, left column, last para), and the chemical inhibition of AKT and mTORC1 is sufficient to promote NSC differentiation in vitro and in vivo (Page 5, right column, last para.). Rapamycin and paralogs allosterically inhibit mTORC1 activity by interacting with FKBP12 (Page 1, right column, 1st para).
Therefore, it would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the rejected claims to combine the teachings of prior art to modify the method of Kuwahara et al by using Rapamycin and paralogs as chemical inhibition of mTORC1 to promote NSC differentiation in vitro and in vivo as taught by Meng et al as instantly claimed, with a reasonable expectation of success. Said modification amounting to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would have been motivated to do so because Meng et al teaches that mTOR signaling is crucial for the maintenance and differentiation of neural stem cells and for brain development (Page 5, left column, last para), and the chemical inhibition of AKT and mTORC1 is sufficient to promote NSC differentiation in vitro and in vivo (Page 5, right column, last para.). One of ordinary skill in the art would have had a reasonable expectation of success in doing so because Meng et al provide proof of principle for using chemical inhibition of mTOR signaling to promote NSC differentiation in vitro and in vivo.
Kuwahara et al does not specifically teach lacking exogenously-added growth factors. Wataya et al cures the deficiency.
Wataya et al teach embryonic stem (ES) cells differentiate into neuroectodermal progenitors, and instead of the addition of inductive signals, minimization of exogenous patterning signaling plays a key role in rostral hypothalamic specification of neural progenitors derived from pluripotent cells (Abstract). Wataya et al showed that ES cell-derived neuroectodermal cells robustly differentiate into cells expressing regional markers of the embryonic rostral hypothalamus when cultured in a strictly chemically defined medium (CDM; growth factor-free chemically defined medium is gfCDM), free of KSR and other growth factors including insulin (Page 11796, right column, 2nd para.).
Therefore, it would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the rejected claims to combine the teachings of Kuwahara et al and Wataya et al to use medium lacking exogenously-added growth factors as instantly claimed, with a reasonable expectation of success. Said modification amounting to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would have been motivated to do so because Wataya et al provide explicit advantage of minimization of exogenous patterning signaling plays a key role in differentiation of neural progenitors derived from pluripotent cells (Abstract). Wataya et al stated that the present study has identified a key condition necessary for differentiation of rostral hypothalamic progenitors from ES cells, i.e., no exogenous patterning signals added at the naive neuroectodermal stage (Page 11800, right column, 4th para.). One of ordinary skill in the art would have had a reasonable expectation of success in doing so because Wataya et al was successful in differentiation of neuroectodermal progenitors with detailed instructions and data.
Although Kuwahara et al teach the use of retinoids (e.g., retinoic acid ) ([0315], page 26), Kuwahara et al do not teach the retinoic acid (RA) pathway aqonist is TTNPB. Osafune et al cure the deficiency.
Osafune et al teach a method for producing an intermediate mesoderm cell from a human pluripotent stem cell, the method comprising culturing a human pluripotent stem cell in a medium comprising a retinoic acid derivative ( see claim 1, page 12 of Osafune et al), and the retinoic acid derivative is AM580 or TTNPB ( see claim 2, page 12 of Osafune et al).
Therefore, it would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the rejected claims to combine the teachings of prior art to modify the method of Kuwahara et al by using TTNPB as retinoic acid derivative as taught by Osafune et al as instantly claimed, with a reasonable expectation of success. Said modification amounting to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would have been motivated to do so because Osafune et al stated that use of a retinoic acid derivative, such as AM580 or TTNPB, at high concentrations results in more effective induction of differentiation into intermediate mesoderm cells ([0037], page 2), and there are 3 RAR subtypes (i.e., alpha, beta, and gamma), and a retinoic acid derivative, such as AM580 or TTNPB, is capable of selectively activating an RAR subtype associated with differentiation into intermediate mesoderm cells. Accordingly, side effects can be prevented by eliminating unnecessary signals ([0038], page 2). One of ordinary skill in the art would have had a reasonable expectation of success in doing so because Osafune et al were successful in using a retinoic acid derivative for cellular differentiation with working examples and data.
Although Kuwahara et al teach the use of FGF signal transduction pathway inhibiting substance such as Akt inhibitor ([0305], page 26), Kuwahara et al do not teach Akt pathway antagonist is MK2206. Abe et al cure the deficiency.
Abe et al teach a medium additive, medium com position and a culture method and the like, capable of efficiently culturing cells or tissues in a well dispersed state (Abstract) such as somatic cells including brain, nerve tissue and the like ([0083], page 6) or stem cells including neural stem cells ([0084], page 6). Abe et al teach the use of MK2206 in table 24 (Page 20, see below)
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Therefore, it would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the rejected claims to combine the teachings of prior art to modify the method of Kuwahara et al by using MK2206 as medium additive in a medium composition capable of
efficiently culturing cells or tissues in a well dispersed state as taught by Abe et al as instantly claimed, with a reasonable expectation of success. Said modification amounting to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would have been motivated to do so because Abe et al stated that “since proliferation of cells or tissues can be promoted by the culture method of the present invention , the cells or tissues can be efficiently cultured” ([0144], page 10), and “ an appropriate medium can be selected and used according to the kind of the cells or tissues to be cultured, the purpose of culture, and the like” ([0067], page 5), and “the concentration of agar in the medium composition is a concentration which can improve dispersion of cells and spheres without substantially increasing the viscosity of the medium composition and can prevent association of spheres” ([0118], page 9) and the usefulness of the medium composition of the present invention in cell culture is concretely explained in the Experimental Examples ([0187], page 13). One of ordinary skill in the art would have had a reasonable expectation of success in doing so because Abe et al were successful in using a MK2206 in culture medium with working examples and data.
Regarding to claim 46 and 48, Kuwahara et al teach “The concentrations of the TGFβ family signal transduction pathway inhibiting substance …... A-83-01 is generally used at a concentration of 0.05 -50µM, …. ([0148], page 12). Note: 0.05 -50µM = 50 nM to 50,000 nM.
Regarding to claim 47, Osafune et al teach “TTNPB concentration in a medium is, for example, 1 mM, 10 nM, 25 nM, 50 nM, 100 nM, 500 nM, 750 nM …. ” ([0091], page 7).
Response to Arguments
Applicant's arguments filed 10-14-2025 have been fully considered but they are not persuasive. The rejections necessitated by amendments are as described above. Relevant arguments are discussed below:
1. Applicant argues that amended claim 36 is directed to a singular culture medium that comprises five agents - a WNT pathway agonist (e.g., CHIR99021 ), an SHH pathway agonist (e.g., Purmorphamine), a BMP pathway antagonist (e.g., LDN193189), an Akt pathway antagonist (e.g., MK2206), and a MEK pathway antagonist (e.g., PD0325901). Examples 3 and 4 of the application as filed demonstrate that cells cultured in the recited culture medium express biomarkers of the midbrain (such as OTX2 and LMX1A) and early neural cell (such as Nestin), indicating successful differentiation of the pluripotent stem cells (PSCs) into midbrain neural stem cells (NSCs)
In contrast, Kuwahara teaches a three-step method for generating neural tissues, in which the first step utilizes a culture medium comprising 1) a transforming growth factor beta (TGFl3) signal transduction pathway inhibiting substance and/or a SHH signal transduction pathway activating substance and 2) a factor for maintaining undifferentiated state; the second step utilizes a serum-free medium containing a SHH signal transduction pathway activating substance; and the third step optionally utilizes a differentiation-inducing factor. Kuwahara describes that the factor for maintaining undifferentiated state is an FGF signal transduction pathway activating substance, i.e., "For example, for the culturing of human pluripotent stem cells, human factor for maintaining undifferentiated states (e.g., bFGF, FGF4, FGF8, EGF, Nodal, Activin A, Activin B, TGFl3 1, TGFl3 2 etc.) are used" (see paragraph [0133]).
The Examiner suggests that Kuwahara provides a singular culture medium comprising each of the five agents of claim 36, however, Kuwahara teaches different culture media across the various steps of differentiation. For example, step (1) uses a factor for maintaining an undifferentiated state (e.g., an FGF pathway activating substance, such as bFGF), whereas auxiliary step (A) that utilizes the cell aggregate containing a retinal tissue that is produced from steps (1 )-(3) of Kuwahara for further cell differentiation, uses an FGF signal pathway inhibiting substance (see paragraph [299]), wherein examples of the FGF signal pathway inhibiting substance can include, "FGF receptor, FGF receptor inhibitor (e.g., SU-5402, AZD4547, BGJ398), MAP kinase cascade int1ibitinn substance (e.g., MEK inhibitor, MAPK inhibitor, ERK int1ibitor), Pl3 kinase int1ibitor, Akt inhibitor and so on" (Kuwahara, 11 [0305]), Therefore, Kuwahara does not teach the culture medium oi claim 36. Furthermore, a person of skill in the art would not be motivated to combine the components of each of the individual culture media from distinct steps into a single culture medium, as they would understand that the cells at each stage of Kuwahara.'s method would require different factors from me other stages (Remarks, page 4-5).
Response to Arguments:
It appears that Applicant is arguing that the cited references do not expressly suggest the claimed invention. However, it is well established in case law that a reference must be considered not only for what it expressly teaches, but also for what it fairly suggests. In re Burkel, 201 USPQ 67 (CCPA 1979). Furthermore, in the determination of obviousness, the state of the art as well as the level of skill of those in the art are important factors to be considered. The teaching of the cited references must be viewed in light of these factors. Applicants also engaged in selective reading of the teachings of Kuwahara et al to formulate the grounds for arguments that Kuwahara et al do not teach a singular culture medium containing recited components in the claims. This is not persuasive because of following reasons: Kuwahara et al teach a medium containing differentiation-inducing factor ([0019], item [1]-(3) on page 1) and “ Examples of the differentiation-inducing factor widely used by those of ordinary skill in the art include a BMP signal transduction inhibiting substance, …. a Shh signal transduction pathway activating substance, …. a FGF signal transduction pathway inhibiting substance, …. a Wnt signal transduction pathway activating substance ….” ([0216], page 17), and “Examples of the FGF signal transduction pathway inhibiting substance include ….. MAP kinase cascade inhibiting substance ( e. g., MEK inhibitor, MAPK inhibitor, ERK inhibitor ), PI3 kinase inhibitor, Akt inhibitor and so on” ([0305], page 25). Kuwahara et al stated that “a differentiation- inducing factor or a differentiation induction method suitable for the intended cell or tissue can be selected.” ([0218], page 17), and “a differentiation-inducing factor (e.g., a Wnt signal transduction pathway inhibiting substance, a TGFβ family signal transduction pathway inhibiting substance and the like) may be added simultaneously” ([0229], page 18). Thus, all the differentiation-inducing factors as described above may be added simultaneously together. (Note: Kuwahara et al teaches the TGFβ family signal transduction pathway inhibiting substance is a BMP signal transduction pathway inhibiting substance ([0019], item [7] on page 2)).
Also, Kuwahara et al teach embodiments which use differentiation-inducing factors that encompass both activating and inhibiting substance widely used by those of ordinary skill in the art such as substances for WNT, BMP, and FGF signal transduction pathway (including MEK inhibitor, and Akt inhibitor) (see [0216 ], page 17, and [0305], page 25) and these factors may be added simultaneously ([0229], page 18). Thus, one of ordinary skill in the art would use either activating and inhibiting substance in the medium or both.
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In view of foregoing, in absence of evidence of any unexpected results, it would have been prima facie obvious for one of ordinary skill in the art seeking to produce a culture medium would use teachings of Kuwahara et al to arrive at the invention. Given that different factors/inhibitors recited in the claims were commercially available and were routinely used in different combination for culturing cells for proliferation and/or differentiation before effective filing date of the claimed invention, it would have been prima facie obvious for one of ordinary skill in the art to combine different agents/factors each of which is taught by the prior art references as described above to be useful for the same purpose in order to produce a new culture medium that is to be used for the very same purpose. In the instant case, the idea of combining them flows logically and has been taught in the prior art references. Further, patentable distinction is not evident between the claimed cultures medium and those taught by the cited references before the effective filing date. One of ordinary skill in the art would have had reasonable expectation of success in doing so because Kuwahara et al were successful in producing neural cells or a neural tissue using the above described medium and methods.
As per MPEP 716.01(c) (II), arguments presented by the applicant cannot take the place of evidence in the record. In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965) and In re De Blauwe, 736 F.2d 699, 705, 222 USPQ 191, 196 (Fed. Cir. 1984). Examples of statements which are not evidence and which must be supported by an appropriate affidavit or declaration include statements regarding unexpected results, commercial success, solution of a long-felt need, inoperability of the prior art, invention before the date of the reference, and allegations that the author(s) of the prior art derived the disclosed subject matter from the inventor or at least one joint inventor.
Conclusion
No claim is 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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/KHOA NHAT TRAN/Examiner, Art Unit 1632
/PETER PARAS JR/Supervisory Patent Examiner, Art Unit 1632