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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 April 21, 2025, has been entered.
Priority
Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). The certified copy has been filed in parent Application No. JP2019-144808, filed on August 8, 2019. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55. Applicants claim for priority to the parent Application No. JP2019-144808 is acknowledged. The effective filing date for the claims under examination is August 6, 2019.
Claim Status
In the response filed, April 21, 2025, Applicant has amended claim 3 and canceled claims 1-2 and 10. Applicant’s election without traverse of Group I, claims 3 drawn to a method for producing a tau-related disease model, and provisionally elected the species election of R406W in the reply filed on January 9, 2023, is acknowledged. The restriction mailed on Oct. 14, 2022, has been re-considered in view of the prior art. Therefore, claim 8 is rejoined. Claims 4-7 and 9 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic claim.
Currently, claim 3 and 8 are currently under examination in this office action.
Withdrawn Objections & Rejections
Rejections and/or objections not reiterated from the previous office action are hereby withdrawn due to amendment. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
The rejection of claim 3 under 35 U.S.C. 103 as being unpatentable over Seo J, et al. (J Neurosci : Off J Soc Neurosci. ;37:9917–24; published 2017, hereinafter as “Seo”, prior art of record), in view of Qiang et al., (US20210315938A1, filing date Sept. 2019, claims priority to the provisional US62/728088 filed on Sept. 7, 2018) as evidenced by Tacik et al., (Neuro Appl Neurobio, 2017, 3:200-214; hereinafter “Tacik”, prior art of record) is withdrawn due to Applicants amendment to the claims.
The rejection of claims 3 under 35 U.S.C. 103 as being unpatentable over Seo J, et al. (J Neurosci : Off J Soc Neurosci. ;37:9917–24; published 2017, hereinafter as “Seo”, prior art of record), in view of Gauthier-Kemper, Anne, et al. (Journal of Cell Biology 192.4 (2011): 647-661; published 2011, hereinafter as “Gauthier-Kemper”, prior art of record) and Qiang et al (US 20210315938A1, filing date Sept. 2019, claims priority to provisional 62/728088 filed on Sept. 7, 2018) is withdrawn due to Applicants amendment to the claims.
Claim Objections
Claims 3 and 8 are objected to because of the following informalities: Claim 3 is missing a space in line 21 between “10” and “are” and claim 8 is missing a comma in line 4 between “protein” and “degree”. Appropriate correction is required.
Specification
The use of the terms e.g. StemFit, TrypLE, B27, GlutaMax, Matrigel, Neurobasal (see e.g. para. 18, 48, 25, 50 and 52), which is a tradename, or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore, the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 3 and 8 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method comprising: three-dimensionally culturing pluripotent stem cells having a mutation in Microtubule Associated Protein Tau (MAPT) gene to form a nerve organoids under conditions in the presence of a ROCK inhibitor (i.e. Y-27632), a TGF-β inhibitor (i.e. SB-431542), and a Wnt inhibitor (i.e. IWP-2), does not reasonably provide enablement for the following: forming and dissociating the nerve organoid into single cells and performing two dimensional adherent culture of the single cells under conditions suitable for the single cells to differentiate into or continue to grow as neurons and obtaining a pure population of neurons, which are critical or essential to the practice of the invention but not included in the claim(s). See In re Mayhew, 527 F.2d 1229, 188 USPQ 356 (CCPA 1976). In the instant case the conditions (i.e. inhibitors, growth factors, small molecules etc.) are an important part of the method for generating organoids of a desired tissue-type, because pluripotent stem cells can give rise to multiple tissue organoids.
This rejection is a new rejection necessitated by amendments to the claims.
The specification does not enable any person skilled in the art to which it pertains or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
While determining whether a specification is enabling, one considers whether the claimed invention provides sufficient guidance to make and use the claimed invention, if not, whether an artisan would require undue experimentation to make and use the claimed invention and whether working examples have been provided. When determining whether a specification meets the enablement requirements, some of the factors that need to be analyzed are: the breadth of the claims, the nature of the invention, the state of the prior art, the level of one of ordinary skill, the level of predictability in the art, the amount of direction provided by the inventor, the existence of working examples, and whether the quantity of any necessary experimentation to make and use the invention based on the content of the disclosure is “undue”.
Nature of the Invention: Claims are drawn to a method comprising: three-dimensionally culturing pluripotent stem cells having a mutation in Microtubule Associated Protein Tau (MAPT) gene to form a nerve organoid; dissociating the nerve organoid into single cells and performing two dimensional adherent culture of the single cells under conditions suitable for the single cells to differentiate into or continue to grow as neurons; and obtaining a pure population of neurons from the two-dimensional adherent culture of the single cells; wherein the two-dimensional adherent culture of the single cells is performed in a monolayer for 30 days or more; wherein the neurons are a tau-related disease model and the mutation is one or a plurality of mutations present in exons 9, 10, 12, or 13 or intron 10; wherein the one or plurality of mutations present in exons 9, 10, 12, or 13 are a mutation that encodes a mutant tau protein selected from the group consisting of K257T, I260V, G272V, N279K, K28011, L284L,S285R, N296H, P301L, P301S, S305N, S303S, S305S, V337M, E342V, G389R and R406W, and the one or plurality of mutations present in intron 10 are a mutation in any one or a plurality of bases at nucleotide positions 3(Ex10+3), 12 (Ex10+12), 13(Ex10+13), 14(Ex10+14), 16(Ex10+16), and 19 (Ex10+19) from the 5'-end of intron 10 (See claim 3).
Breadth of the Claims: The claimed invention encompasses a method comprising: three-dimensionally culturing pluripotent stem cells having a mutation in Microtubule Associated Protein Tau (MAPT) gene to form a nerve organoid; dissociating the nerve organoid into single cells and performing two dimensional adherent culture of the single cells under any condition suitable for single cells to differentiate into or continue to grow as neurons (see claim 1). Thus, the claims are drawn to any culture condition for differentiation single cells or growing the single cells into neurons. As such, the claim is vastly broad encompassing embodiments contemplated and not contemplated by the specification.
Specification Guidance/Working Examples: The specification teaches the following:
The applicants have provided one working example for the method of producing a nerve organoid by culturing mutant human induced pluripotent stem cells (mhiPSCs) having the R406W mutation in Microtubule Associated Protein Tau (MAPT) gene, where the mutation was obtained by CRISPR technology under specific conditions as shown in Figure 3 (see Example 2-3), where mhiPSCs were differentiated into neurons (See e.g. spec. page 14-18, Fig. 1 and 3). Specifically, the specification teaches that the nerve organoid was prepared with the medium of “StemFit AK02N medium (Ajinomoto) supplemented with 30μM of Y-27632, 5μM of SB-431542 and 2.5 μM of IWP-2” (see e.g. lines 23-25, page 15) for obtaining embryoid bodies that were cultured for 6 days and induced into forebrain of neural tissue.
Accordingly, the specification only teaches one example of obtaining a nerve organoid from the forebrain of neural tissue with specific medium supplemented with 30μM of Y-27632, 5μM of SB-431542 and 2.5μM of IWP-2, and fails to provide any suitable condition that will enable the production of nerve organoids to differentiate into single cells or continue to be grown as neurons. Thus, the specification fails to provide specific guidance to any condition that will produce a nerve organoid having a mutation in the MAPT gene where the single cells are differentiate to or continue to be grown as neurons. Therefore, the specification only enables specific culture conditions for the single cells to be differentiate to nerve organoids or continue to be grown as neurons (see e.g. lines 23-25, page 15).
State of the Art: Regarding the claim limitation of culture conditions suitable for performing two dimensional adherent culture of the single cells to differentiate into or continue to grow as neurons, at the time of the effective filing, the prior art teaches:
The prior art of Clevers (Cell 165.7: 1586-1597, published 2016) teaches that multiple types of organoids can be grown from pluripotent stem cells (PSCs) (fig. 2), and that certain factors are used to generate certain types of organoids, and that different brain region organoids can be generated from pluripotent stem cells (PSCs) depending on the factors used (page 1587, and Figure 2-3). Therefore, Clevers provides substantial evidence that although methods for generating organoids were known, however Clevers discloses that there is an importance regarding the identity of factors in the medium/methods for generating organoids of a desired tissue-type, since PSCs can give rise to multiple tissue organoids. Thus, based upon the teachings of Clevers, one of ordinary skill in the art would have understood that obtaining nerve organoids from pluripotent stem cells requires specific culture conditions.
Further, the prior art of Iovino, et al., (Brain 138.11: 3345-3359, published 2015) discloses a method of differentiating iPSCs derived from patients with N279K and P301L MAPT mutations in exon 10 to neurons (see e.g. abstract; page 3346 and page 3349) comprises treating cells with a Rock inhibitor (i.e. Y27632) followed a TGF-β inhibitor (i.e. SB431542) to initiate neural induction (see e.g. page 3349). As such, Iovino provides evidence for disclosing a method for forming neurons from iPSCs having mutations in the MAPT gene, which is commensurate with the level of one of ordinary skill in the art. Further, Iovino provides evidence regarding the importance of inhibitors in the culture media in order to produce nerve organoids and neurons, and that not any culture conditions are suitable.
Further, the prior art of Seo (2017, prior art of record) discloses methods regarding three-dimensionally culturing pluripotent stem cells having a mutation in the Microtubule Associated Protein Tau (MAPT) gene (i.e. P301L mutation) forming a nerve organoids (see e.g. abstract, page 9919-9921, fig. 4), wherein the methods use a ROCK inhibitor (Y-27632), a TGF-β inhibitor (SB431532), and a Wnt inhibitor (IWR-1) (see e.g. pages 9919 and 9921). Therefore, the methods presented in Seo provides evidence for disclosing a method for forming neurons from iPSCs having mutations in the MAPT gene. Further, Seo provides evidence regarding the importance of the composition of the culture media with specific inhibitors in order to produce nerve organoids and neurons, and that not any culture conditions are suitable.
Therefore, the state of the art at the time of the invention teaches that specific culture conditions are required to produce nerve organoids or neurons from pluripotent stem cells. Thus, the breadth of any suitable condition to obtain the differentiation of nerve organoids into single cells or continue to be grown as neurons fails to predictably obtain the differentiation of nerve organoids into single cells or continue to be grown as neurons as claimed.
As such, similar to the specification, the art teaches that the claimed any suitable condition for differentiate the nerve organoids into single cells or continue to be grown as neurons fails to predictable obtain the differentiation of a nerve organoid or growth of a nerve organoid having a mutation in the MAPT gene as claimed.
Therefore, in conclusion, the breadth of the claims to a method comprising dissociating the nerve organoid into single cells and performing two dimensional adherent culture of the single cells under conditions suitable for the single cells to differentiate into or continue to grow as neurons is not enabled for any culture condition, as discussed above. The specification solely provides specific guidance to forming a nerve organoids under conditions in the presence of a ROCK inhibitor (i.e. Y-27632), a TGF-β inhibitor (i.e. SB-431542), and a Wnt inhibitor (i.e. IWP-2)(See e.g. Spec. Example 3), as discussed above, and fails to describe any other means of culturing the differentiation of a nerve organoid or growth of a nerve organoid into a neuron.
Therefore, at the time of filing the skilled artisan would need to perform an undue amount of experimentation without a predictable degree of success to implement the invention as claimed.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 3 and 8 are rejected under 35 U.S.C. 103 as being unpatentable over Seo et al. (J Neurosci : Off J Soc Neurosci.;37:9917–24; published 2017, hereinafter as “Seo”, prior art of record), García‐León et al. (Alzheimer's & Dementia 14.10: 1261-1280, published 2018), Imamura et al. (Scientific reports 6.1: 34904; cited IDS 10/13/2023, published 2016), Qiang et al., (US20210315938A1, filing date Sept. 2019, claims priority to the provisional US62/728088 filed on Sept. 7, 2018, prior art of record), and Paonessa et al. (Cell Reports, 2019, 26:582-593, published 01/15/2019, prior art of record), as evidence by Verheyen et al. (Stem cell reports 11.2: 363-379, published 2018), Hutton et al. (Nature 393.6686: 702-705, published 1998).
This rejection is a new rejection necessitated by amendments to the claims. However, since it is substantially similar to a rejection set forth in the final Official action mailed on Jan. 22, 2025, therefore any aspect of applicant's response considered relevant to the rejection as newly set forth is responded to following the statement of rejection.
Regarding claim 3, Seo discloses methods regarding three-dimensionally culturing pluripotent stem cells having a mutation in the Microtubule Associated Protein Tau (MAPT) gene forming a nerve organoids (see e.g. abstract, page 9919-9921, fig. 4). Further, Seo discloses wherein the mutation present in the tau-related disease model is a P301L mutation (see e.g. abstract, page 9919, 9921, Fig. 4), corresponding to the claim limitation of mutations that are present in intron 10 are a mutation of bases at the nucleotide position 16 (Ex10+6). Further, Seo discloses methods using a ROCK inhibitor (Y-27632), a TGF-β inhibitor (SB431532), and a Wnt inhibitor (IWR-1), corresponding to the claim limitation of culturing a nerve organoid under conditions suitable to grow neurons (see e.g. pages 9919 and 9921). Additionally, Seo discloses culturing organoids with the P301L mutation for 35 days with Matrigel (see e.g. page 9919).
Seo is silent regarding the nerve organoids continuing to grow as neurons.
However, the prior art of Garcia-Leon discloses an in vitro tauopathy model with a triple MAPT mutant human induced pluripotent stem cell (iPSC) line, specifically the tau mutations of P301L, N279K, and E10+6 (see e.g. abstract, page 1263). Further, Garcia-Leon discloses differentiating the triple TAU-mutant iPSC to cortical neurons for up to two hundred days (see e.g. page 1263-5, figs. 1-4).
Accordingly, it would have been obvious for a person of ordinary skill in the art to have modified the methods as taught by Seo and incorporate the growth of neurons as taught by Garcia-Leon because Garcia-Leon teaches the continued growth of TAU-mutant P301L iPSC to cortical neurons. Further, both Seo and Garcia-Leon teach iPSC with the TAU mutation of P301L. Thus, a person of ordinary skill in the art would have a reasonable expectation of success. Furthermore, it would have been obvious to combine prior art elements according to known methods to yield predictable results. Additionally, an artisan of ordinary skill in the art of (i.e. generating iPSC models for neurodegenerative diseases) has good reason to pursue the known options within his or her technical grasp (KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (US 2007).
Seo is silent regarding the stem cells having the preferred embodiment of the tau mutation of R406W.
However, the prior art of Imamura discloses methods for culturing induced pluripotent stem cells (iPSC) from patients with the R406W mutation (see e.g. abstract, page 4-5, fig. 1).
Accordingly, it would have been prima facie obvious to one of ordinary skill in the art to use a mutation of the frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) as taught by Imamura (such as R406W) in a method of culturing stem cells with a mutant of FTDP-17 as rendered obvious by Seo (such as P301L) as discussed above. Furthermore, Imamura suggests that FTLD-Tau patient iPSCs would be useful for investigating and understanding converging mechanism underlying tau mediated neurodegeneration due to different MAPT mutations (see page 6-7). Additionally, the prior art of Verheyan discloses iPSC with MAPT mutations (e.g. P301L, P301S, and IVS 10+16), and cites the prior art of Hutton, Mike, et al. (1998), and discloses three missense mutations of tau in the FTDP-17 are G272V, P301L, and R406W. The use of the mutant tau proteins such as those taught by Imamura in place of the mutant tau protein as taught by Seo would be considered obvious since it is prima facie obvious to substitute one known element for another to obtain predictable results. The instant case, both P301L and R406W are both cited in the prior art as mutations of FTDP-17, and one of ordinary skill could have substituted one element for another with predictable results, since both are readily available and are deliverable using similar techniques.
Seo et al does not explicitly state dissociating the nerve organoid into single cells and performing two dimensional adherent monolayer culture of the single cells, wherein obtaining a pure population of neurons from the two-dimensional adherent culture.
However, Qiang et al teaches a method of culturing hiPSCs-derived 3D neural sphere and dissociating into a single cell 2D monolayer culture (Fig. 7, specification pages 26-27 and 30, and Examples of the provisional document). Further, Qiang et al teaches that the dissociated single cells in the adherent 2D monolayer culture highly expressed microtube associated protein (MAP2, green), a general marker for relative mature neuronal cells, thereby indicating a homogenous neuronal population (Spec, page 34, lns 10-15).
Accordingly, it would have been obvious to a person of ordinary skill in the art to have modified the methods of culturing pluripotent stem cells to form a nerve organoid as taught by Seo and to incorporate the dissociation of organoids into a two-dimensional adherent culture of a monolayer of single cells as taught Qiang because Qiang teaches analyzing the characterization of the attached single cells by performing two-dimensional adherent culture of the monolayer of single cells under conditions suitable for the single cells to grow (see e.g. Fig. 7A, Spec page 30 and 33). Further, Qiang teaches characterizing the “real identity” of the cells from the organoids by using a combination of several marker (see e.g. p.34, line 3 of provisional document). In other words, Qiang makes obvious the step of characterizing the cellular composition in a 2D culture of neurons compared to a 3D culture because of the ability to perform co-labeling and definitively being able to identify the labeled cell type (see provisional Fig. 7A-C of Qiang). Further, in regard to obtaining a pure population of neurons from the 2D adherent culture, as stated supra, Qiang et al teaches that dissociated single cells after 2D adherent culture naturally become a homogenous neuronal population (see e.g. pages 35 lns. 14-18), and it would have been obvious to obtain a pure population of neurons because Seo teaches tau is highly expressed in neurons (see e.g. page 9921), therefore making this an obvious cell type to purify and characterize. Furthermore, a person of ordinary skill in the art would have a reasonable expectation of success because both Seo and Qiang discloses methods directed to growing neurons. Thus, it would have been done with a reasonable expectation of success.
Regarding claim 3, as stated supra, Seo discloses culturing organoids with the P301L mutation for 35 days (see e.g. page 9919). Further, Qiang teaches the 2D adherent culture and dissociating to single cells every 3 weeks (i.e. 21 days) for a time period of equal to or greater than 100-120 days (i.e. at least 10 passages (see e.g. pages 30-34, fig. 1-2).
Seo et al. does not explicitly state wherein the adherent culture of single cells is performed in a two-dimensional (2D) monolayer for 30 days or more.
However, the prior art of Paonessa teaches a method comprising a culturing cells having a P301L mutation in MAPT to form a neuronal rosetta type organoid, and dissociation of the rosetta type organoid into cells and then further culturing the cells in a 2D adherent culture under conditions that are suitable for neurons to grow for 120 days (see e.g. Methods, e3).
Accordingly, it would have been obvious to a person of ordinary skill in the art to have modified the method as suggested by Seo and Qiang and incorporate the culturing of the neurons for 120 days as taught Paonessa because Paonessa discloses that the waiting of 4 months in cell culture allows the MAPT P301L neurons to recapitulate the well-described subcellular aspects of early FTD pathology (see e.g. p. 590, 1st). Thus, it would have been obvious to a person of ordinary skill in the art to continue the 2D culture period of the organoid dissociated neurons to not only character the “real identity” of the cells as taught by Qiang, but to also characterize if the cells recapitulate the subcellular aspects of early FTD such as mutant MAPT misvocalization as taught by Paonessa.
Regarding claim 8, as stated supra, Seo discloses culturing the tau-related disease model (i.e. P301S) in the presence of a test substance (e.g. Cdk5, GSK-3β, or inhibit dephosphorylation mediated by phosphatases (see page 9920). The specification indicates that the “test substance is not particularly limited, and examples thereof include a natural compound library, a synthetic compound library, an existing drug library and a metabolite library (see spec. page 13, para. 39). Further, Seo discloses methods for measuring the degree of phosphorylation of the tau protein (i.e. P301S)of the tau-related disease model(see e.g. page 9920-9921, fig. 2).
Hence, the claimed method is prima facia obvious absent evidence to the contrary.
Response to Traversal:
Applicant argues that Paonessa does not teach a monolayer two-dimensional adhesive cell culture of neural progenitor cells for 30 days or more, because the amount of cells as taught by Paonessa were plated at an amount of 1500,000 cells/mm2 (Remarks, page 6-7).
Applicant arguments are acknowledged, have been fully considered, and have been deemed unpersuasive. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). 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). Contrary to Applicants argument, the prior art of Paonessa is not cited for teaching the amount of days for the cell culture. Further, Applicant’s arguments with respect to Paonessa have been considered but are not persuasive because the new ground of rejection does not rely solely on Paonessa for teaching a two-dimensional adhesive cell culture of neural progenitor cells. As stated supra, Qiang teaches the monolayer 2D adherent culture and dissociating to single cells every 3 weeks (i.e. 21 days) for a time period of equal to or greater than 100-120 days (i.e. at least 10 passages)(see e.g. pages 30-34, fig. 1-2). Furthermore, the review article of Pacitti et al. (published April 2019), discloses that a person of ordinary skill in the art would have performed a two-dimensional monolayer culture for organoids as this cell culture technique has greater scalability with less complex directed differentiation and facilitated imaging (see e.g. page 6-8). Furthermore, it is noted that the claims do not recite a claim limitation regarding the amount of cells in the 2D monolayer adherent culture. In view of the foregoing, when all of the evidence is considered, the totality of the rebuttal evidence of nonobviousness fails to outweigh the evidence of obviousness.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 3 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 20 of co-pending Application No. 17/773,784 (reference application) and Seo et al. (J Neurosci : Off J Soc Neurosci. ;37:9917–24; published 2017, hereinafter as “Seo”, prior art of record).
This rejection is a new rejection necessitated by amendments to the claims.
Instant claim 3 is drawn to a method comprising: three-dimensionally culturing pluripotent stem cells having a mutation in Microtubule Associated Protein Tau (MAPT) gene to form a nerve organoid; dissociating the nerve organoid into single cells and performing two dimensional adherent culture of the single cells under conditions suitable for the single cells to differentiate into or continue to grow as neurons; and obtaining a pure population of neurons from the two-dimensional adherent culture of the single cells; wherein the two-dimensional adherent culture of the single cells is performed in a monolayer for 30 days or more; wherein the neurons are a tau-related disease model and the mutation is one or a plurality of mutations present in exons 9, 10, 12, or 13 or intron 10; wherein the one or plurality of mutations present in exons 9, 10, 12, or 13 are a mutation that encodes a mutant tau protein selected from the group consisting of N279K, and, P301S, and the one or plurality of mutations present in intron 10 are a mutation in any one or a plurality of bases at nucleotide positions 16(Ex10+16) (See claim 3).
Claim 1 and 20 of the reference application is drawn to a method of producing a brain organoid comprising a single step of suspension culturing human pluripotent stem cells having a mutation in one or more exon 9 – 13 and having a mutation intron 10 of the MAPT gene. Reference claim 3 is drawn to a method of culturing pluripotent stem cells having a mutation in the MAPT gene to form a nerve organoid. The Reference claim 1 is the genus of instant claim 3 and therefore reference claim 1 anticipates instant claim 3.
Although the conflicting claims are not identical, they are not patentably distinct from each other because the competing claims are drawn to a disclosed species of the instant claims.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure: Sutcliffe, M., Lancaster, M.A. (Turksen, K. (eds) Organoids. Methods in Molecular Biology, vol 1576. Humana, New York, NY, published 2017), Bamba, Yohei, et al. ( Journal of Neuroscience Methods 289: 57-63), published 2017), and Mellios, Nikolaos, et al. (Molecular psychiatry 23.4: 1051-1065, published 2018), Pacitti, et al., (Frontiers in cellular neuroscience 13: 129, published April 2019).
No claim is allowed.
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JOSEPHINE GONZALES
Examiner
Art Unit 1631
/JOSEPHINE GONZALES/ Examiner, Art Unit 1631
/JAMES D SCHULTZ/ Supervisory Patent Examiner, Art Unit 1631