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 .
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, March 17, 2026, Applicant has amended claims 3 and 8 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 Claims 4-7 and 9 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic claim.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 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Withdrawn Objections & Rejections
Rejections and/or objections not reiterated from the previous office action are hereby withdrawn due to amendment.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.
Specification
The objection to the Specification is withdrawn because the use of the terms e.g. StemFit, TrypLE, B27, GlutaMax, Matrigel, Neurobasal (see e.g. para. 18, 48, 25, 50 and 52), which is a tradename, or a mark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 amended in the specification submitted and entered on March 17, 2026.
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 repeated with regard to claims 3 and 8 for the same reasons of record as set forth in the Official action mailed on Dec. 18, 2025. A response to applicant' s traversal follows the reiterated rejection below.
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.
Response to Traversal:
Applicant argues that the claim amendments overcome the 112 rejection (Remarks, page 7-8).
Applicant arguments are acknowledged, have been fully considered, and have been deemed unpersuasive. As discussed above, the 112 rejection is directed to the scope of 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).
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; previously presented), García‐León et al. (Alzheimer's & Dementia 14.10: 1261-1280, published 2018; previously presented), Imamura et al. (Scientific reports 6.1: 34904; cited IDS 10/13/2023, published 2016; previously presented), Qiang et al., (US20210315938A1, filing date Sept. 2019, claims priority to the provisional US62/728088 filed on Sept. 7, 2018, prior art of record; previously presented), and Paonessa et al. (Cell Reports, 2019, 26:582-593, published 01/15/2019, prior art of record; previously presented), as evidence by Verheyen et al. (Stem cell reports 11.2: 363-379, published 2018; previously presented), Hutton et al. (Nature 393.6686: 702-705, published 1998; previously presented).
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 Dec. 18, 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). 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, the stem cells having the tau mutations of E10+16 and the preferred embodiment of the tau mutation of R406W.
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+16 (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). Garcia-Leon teaches culturing hiPSCs having mutations N279K, P301L and E10+16 in the MAPT gene (“human pluripotent stem cells comprising a microtubule-associated protein tau (MAPT) gene that comprises an N279K mutation and a P301S mutation in exon 10 and an E10 + 16 mutation in intron 10”) and differentiation to cortical neurons (Figure 1; page 1263, left col. paragraph 1; page 1272, left col. para. 1; page 1275, left col. para. 2; page 1276, left col. paragraph 4). Garcia-Leon teaches culturing these triple mutant hiPSCs in a N2B27 culture medium comprising SB431542 (“an inhibitor of transforming growth factor β (TGF-β) family signaling”) and LDN193189 (“an inhibitor of bone morphogenetic (BMP) signaling”) for neural induction (“first culture media”) and then plating the resulting cells in N2B27 medium for formation of neural precursor cells (NPCs) (“second culture media” and “an inhibitor of transforming growth factor β (TGF-β) family signaling”) and culturing the NPCs in N2B27 media for terminal neuronal differentiation (“third culture media that does not comprise extracellular matrix”) (page 1276, left col. para. 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).
As stated supra, 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 and Garcia-Leon (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 26-28 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 the P301 L mutation in Seo does not correspond to the claimed (Ex10+16) mutation. Applicant further argues that Seo does not provide teachings of a Matrigel for 35 days (Remarks page 10).
Applicant arguments are acknowledged, have been fully considered, and have been deemed partially persuasive.
In response to applicant's argument, the Examiner is thankful for Applicant for pointing out the clerical errors. Further, the Examiner has clarified that Garcia-Leon is recited for teaching the tau mutations of E10+16 (see e.g. abstract, page 1263), as discussed above.
In response to applicant’s argument that Seo does not teach 35 days. As discussed above, it is already acknowledged that 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.
Further, it is noted that the MPEP § 2144.05 (II) states, “Generally, differences in time, concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In reAller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 (“The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.”); In reHoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969) (Claimed elastomeric polyurethanes which fell within the broad scope of the references were held to be unpatentable thereover because, among other reasons, there was no evidence of the criticality of the claimed ranges of molecular weight or molar proportions.). For more recent cases applying this principle, see Merck & Co. Inc.v.Biocraft Lab. Inc., 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989); In reKulling, 897 F.2d 1147, 14 USPQ2d 1056 (Fed. Cir. 1990); and In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997); Smith v. Nichols, 88 U.S. 112, 118-19 (1874) (a change in form, proportions, or degree “will not sustain a patent”); In re Williams, 36 F.2d 436, 438 (CCPA 1929) (“It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions.”). See also KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007) (identifying “the need for caution in granting a patent based on the combination of elements found in the prior art.”).
In the instant case, neither the specification nor Applicant have provided evidence of that the claimed number of days is critical, thus the the prior art of Paonessa is relied upon teaching 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, one of ordinary skill in the art would have considered altering the number of days discloses in Seo to comprise a period of more than 30 days as taught by Paonessa to have been prima facie obvious at the time of filing
Applicant argues that Qiang discussed a 3D suspension culturing system (Remarks, page 11). Applicant asserts that the teaching of Qiang do not make the claim element of performing a 2D adherent culture of the dissociated cells for greater than 30 days obvious (Remarks, page 12).
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).
In the instant case, the prior art of Qiang et al is already acknowledged for teaching a method of culturing hiPSCs-derived 3D neural sphere and then dissociating into a single cell 2D monolayer culture (Fig. 7, specification pages 26-28 and 30, and Examples of the provisional document). As discussed above, Qiang et al discloses that the “3ml sphere suspension cultures at D5 and D11 were attached on 3 Matrigel (Coming) coated wells (of a 6-well plate) and maintained in the same medium used for continuous differentiation for an additional 7 days when neural rosettes formed in the center of the attached sphere (see e.g. page 27-28). Therefore, it is unclear how Qiang does not teach culturing in a 2D monolayer. As discussed above, the prior art of Paonessa is disclosed for 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). In response to applicant's argument that Qiang does not make the claim element of performing a 2D adherent culture of the dissociated cells for greater than 30 days obvious, the 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, 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.
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 and 8 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 23-28 of co-pending Application No. 17/773784. Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims are drawn to a species of the reference claims.
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 Dec. 18, 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.
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).
Reference claim 23-28 are drawn to a method of making a brain organoid, comprising: suspension culturing human pluripotent stem cells comprising a microtubule-associated protein tau (MAPT) gene that comprises an N279K mutation and a P301S mutation in exon 10 and an E10 + 16 mutation in intron 10 in a first culture media comprising an inhibitor of bone morphogenetic protein (BMP) signaling and an inhibitor of transforming growth factor β (TGF-β) family signaling to produce a first culture preparation; suspension culturing the first culture preparation in a second culture media comprising a GSK-3B inhibitor, an inhibitor of transforming growth factor β (TGF-β) family signaling, and an extracellular matrix mixed therein to produce a second culture preparation; and culturing the second culture preparation in a third culture media that does not comprise extracellular matrix to produce a cultured brain organoid comprising a ratio of 4R p-tau/3R p-tau of at least 1.
The reference claims 23-28 are genus of the instant claim 3 and 8, therefore reference claims 23-28 anticipates instant claim 3 and 8. 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.
Response to Traversal:
Applicant argues that the claims 1 and 20 of co-pending Application No. 17/773,784 have been canceled and therefore render the rejection moot and request withdrawal of this rejection.
Applicant arguments are acknowledged, have been fully considered, and have been deemed partially persuasive. Applicant has filed new claims 23-28 which are still drawn to a method of making a brain organoid, comprising: suspension culturing human pluripotent stem cells comprising a microtubule-associated protein tau (MAPT) gene that comprises an N279K mutation and a P301S mutation in exon 10 and an E10 + 16 mutation in intron 10 in a first culture media comprising an inhibitor of bone morphogenetic protein (BMP) signaling and an inhibitor of transforming growth factor β (TGF-β) family signaling to produce a first culture preparation. As discussed above, the reference claims 23-28 are genus of the instant claim 3 and 8, therefore reference claims 23-28 anticipates instant claim 3 and 8. Therefore, 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. Thus, provisional nonstatutory double patenting rejection has been amended as necessitated by Applicants amendments to the claims.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JOSEPHINE GONZALES whose telephone number is (571)272-1794. The examiner can normally be reached M-Th: 9AM - 5:00PM (EST). 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, Doug Schultz can be reached at 571-272-0763. 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.
/JOSEPHINE GONZALES/ Examiner, Art Unit 1631
/JAMES D SCHULTZ/ Supervisory Patent Examiner, Art Unit 1631
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