DETAILED ACTION
Claims 1-20 are currently pending.
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 .
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1-7 and 16-18 in the reply filed on 7/27/2026 is acknowledged.
Claims 8-15 and 19-20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 7/27/2026.
Priority
Acknowledgment is further made of applicants' claim for foreign priority to KR application 10-2023-0023005, filed 2/21/2023. A certified copy of the foreign priority document is present in the application file.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 2/21/2024 and 8/11/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Specification
The disclosure is objected to because of the following informalities: typographical. The specification recites the term “beta-methanol”, however it appears this should be “beta-mercaptoethanol” (see specification at Example 1, page 22, line 7).
Appropriate correction is required.
Claim Objections
Claim 4 is objected to because of the following informalities: typographical.
Claim 4 recites the term “beta-methanol”, which appears to be “beta-mercaptoethanol” (see specification at Example 1, page 22, line 7). Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 2-3 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
The term “healthy person” in claim 2 is a relative term which renders the claim indefinite. The term “healthy person” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Given the specification does not define what is meant by “healthy person”, one of ordinary skill in the art would not understand the metes and bounds of the term. It is unclear if a “healthy person” is one who has not been diagnosed with Alzheimer’s or other neurodegenerative disease, or is the healthy person in relation to a particular life style, or age of person, or a person who has not had a cancer diagnosis, or a person who has not contracted COVID-19. Hence, appropriate clarification is appreciated.
Since claim 3 depends directly from claim 2, claim 3 inherits the deficiency thereof, and is rejected on the same basis.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 1 and 2 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Sloan et al., (U.S. Patent No. 10,494,602; see PTO-892) (“Sloan”).
Sloan is directed to producing human cortical spheroids from human pluripotent stem cells by in vitro differentiation wherein the produced cortical spheroids (hCS) contain astrocytes, as well as cortical progenitors and neurons for use in analysis, screening programs, and the like (Abstract; col 2, lines 39-42).
Regarding claim 1, Sloan teaches the spheroids are generated from patient cell samples (e.g., fibroblasts that are reprogrammed to induced pluripotent stem cells) that are induced to neural fate in vitro and then differentiated to the cortical spheroids comprising neurons and astrocytes, thus allowing disease-relevant generation and screening of the cells for therapeutic drugs and treatment regimens. Sloan teaches the spheroid cells are subjected to candidate agents, e.g., small molecules (col 2, lines 42-54; col 3, lines 5-20).
Sloan specifically exemplifies the method for producing the human cortical spheroids (i.e., A method for producing spheroids) utilizes a multi-step process, wherein the hiPSCs obtained from patients is induced to a neural fate using culture medium comprising an effective dose of a wnt inhibitor and an inhibitor of BMP and TGFβ pathways and culturing for a period 2 days to about 10 days. Thereafter, the floating spheroids are moved to neural media supplemented with FGF2 and EGF to produce neural progenitors after 1-4 weeks of culture (i.e., induced pluripotent stem cell-neural progenitor cells, iPSC-NPCs) and the neural progenitor cells are differentiated to produce neurons by culturing in the presence of effective doses of BDNF and NT3 (i.e., neuronal differentiation medium, NDM) for about 4 weeks to 7 weeks. Thereafter the spheroids are maintained for extended periods of time (1-12 months) in neural medium absent of growth factors (i.e., glial differentiation medium, GDM) to promote production of astrocytes (col 13, lines 39 to col 15, line 15).
Regarding claim 2, Sloan teaches the hiPSCs are derived from somatic cells obtained from neurologically normal individuals (i.e., healthy person) (col 13, lines 11-14), thus anticipating claim 2.
Claim Rejections - 35 USC § 103
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.
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.
Claim(s) 3-7 are rejected under 35 U.S.C. 103 as being unpatentable over Sloan as applied to claims 1-2 above, and further in view of Anand et al., (US 2019/0017018; PTO-892) (“Anand”), as evidenced by ThermoFisher (Neurobasal, retrieved from the internet; see PTO-892) (“ThermoFisher”).
The teaching of Sloan is set forth above and anticipates claims 1-2.
Regarding claim 3, although Sloan teaches the iPSC-NPCs are alternatively derived from individuals comprising at least one allele encoding a mutation, Sloan does not teach the iPSC-NPCs are obtained from an Alzheimer’s patient having a presenilin 1 gene mutation. However, Anand, like Sloan, is directed to a method for producing spheroids comprising neurons and astrocytes from human iPSCs for use in toxicity and efficacy screening of agents for treating neurological conditions ([0069] and [0101]) and teaches the human iPSCs are obtained from Alzheimer’s patients and can comprise a genetic mutation associated with a neurological defect. Specifically the genetic mutation is in presenilin 1 (PSEN1) ([0183]-[0185]; claims 4 and 24).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to prepare the neural organoids from Alzheimer’s patients comprising a genetic mutation in the presenilin 1 gene, thus meeting the limitation of claim 3.
The person of ordinary skill in the art would have been motivated to modify the method of Sloan to obtain iPSC-NPCs from an Alzheimer’s patient having a presenilin 1 gene mutation, as taught by Anand, for the predictable result of successfully providing neural organoids for toxicity and efficacy screening that mimic the in vivo condition that results from a presenilin 1 gene mutation, thus meeting the limitation of claim 3.
The skilled artisan would have had a reasonable expectation of success in combining the teachings of Sloan and Anand because each of these teachings are directed at methods for producing spheroids comprising neurons and astrocytes.
Regarding claim 4, it is noted as set forth above that Sloan’s neural media reads on the NPC media and Sloan teaches the neural media (NM) contains Neurobasal media, B-27 without vitamin A, GlutaMax™ (i.e., glutamine), 100 U/ml penicillin and 100 μl streptomycin, FGF2 (bFGF) and EGF.
ThermoFisher evidences the Neurobasal media of Sloan necessarily includes non-essential amino acids, sodium pyruvate, and glucose.
Although Sloan teaches the presence of beta-mercaptoethanol in the hiPSC media prior to transfer of spheroids to the neural media, Sloan does not further comment on including beta-mercaptoethanol in the neural media. However, Anand, like Sloan, is directed to a method for producing spheroids comprising neurons and astrocytes ([0101]) from human iPSCs and Anand teaches the inclusion of beta-mercaptoethanol in each of the differentiation media and notes that the inclusion of beta-mercaptoethanol provides a redox condition in the culture environment for proper health and growth of the stem cells ([0129]).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to include beta-mercaptoethanol in the neural media, thus meeting the limitation of claim 4.
The person of ordinary skill in the art would have been motivated to modify the method of Sloan to include beta-mercaptoethanol in the neural media, as taught by Anand, for the predictable result of successfully promoting differentiation in a culture environment that promotes proper health and growth of the stem cell, thus meeting the limitation of claim 4.
The skilled artisan would have had a reasonable expectation of success in combining the teachings of Sloan and Anand because each of these teachings are directed at methods for producing spheroids comprising neurons and astrocytes.
Regarding claims 5-7 and the limitation directed to the use of U-shaped bottom plate, it is noted that although Sloan teaches the use of low-attachment plates (col 30, lines 2-3; col 22, lines 38-39), Sloan does not further teach U-shaped bottom plates for spheroid culture. However, Anand teaches preparing the neural spheroids using low-attachment U-bottom plates ([0007], [0086]; claim 16).
Therefore, it would have been prima facie obvious to one having ordinary skill in the art at the time of filing the invention to substitute Anand’s low-attachment U-bottom plates for the low-attachment plates of Sloan since both low-attachment plates are known to promote production of neural spheroids.
Therefore, one of ordinary skill in the art would recognize this as simply substituting one type of low-attachment culture plate for another useful for the same purpose ((KSR Int’l Co. v. Teleflex, Inc., 550 U.S. 398 (2007) pg 14 and 12).
The skilled artisan would have had a reasonable expectation of success in combining the teachings of Sloan and Anand because each of these teachings are directed at methods for producing spheroids comprising neurons and astrocytes.
Further regarding claim 5 and the limitation the culturing in the NPC medium is performed for 2 to 4 days, it is noted that Sloan teaches a culture period 2 days to about 10 days (col 13, lines 61-67) (claimed range lies within the prior art range).
Further regarding claims 6 and 7 and the limitations of culturing in the NDM medium is performed for 6 to 8 days and culturing in the GDM medium is performed for 12-16 days, it is noted that Sloan teaches culturing in the NDM medium for a culture period starting at day 25 to day 42 (17 days) (col 22, lines 56-63) and the culturing in the GDM medium is conducted for up to several months. However, although Sloan does not teach the specific time periods, it is noted that the parameter of culturing time period is a results effective variable which achieves the recognized result of cell growth and proliferation. Generally, differences in parameters will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such parameter 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 re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (see MPEP 2144.05).
Claim(s) 16-17 are rejected under 35 U.S.C. 103 as being unpatentable over Anand et al., (US 2019/0017018; PTO-892) (“Anand”), in view of Kelleher et al., (PNAS | January 24, 2017 | vol. 114 | no. 4 | 629–631; PTO-892) (“Kelleher”) and Guo et al., (Journal of Alzheimer’s Disease 19 (2010) 1359-1370; PTO-892) (“Guo”).
Anand is directed to a method for producing spheroids comprising neurons and astrocytes from human iPSCs for use in toxicity and efficacy screening of agents for treating neurological conditions ([0069] and [0101]) and teaches the human iPSCs are obtained from Alzheimer’s patients and can comprise a genetic mutation associated with a neurological defect. Specifically the genetic mutation is in presenilin 1 (PSEN1) ([0183]-[0185]; claims 4 and 24). Anand teaches the spheroids are produced from human iPSCs obtained from Alzheimer’s patients by culturing the human iPSC-NPCs in an NPC medium culturing the cells in a neuronal differentiation medium (NDM) and culturing the cells in a glial differentiation medium (GDM) ([0101]; [0103]).
The only difference between Anand and instant claim 16 is Anand does not further teach confirming the deposition of Aβ plaques, formation of hyperphosphorylated tau, or neurodegenerative inflammation in the spheroids. However Kelleher teaches that mutations in the PSEN1 gene, encoding presenilin 1 (PS1), are the most common cause of familial Alzheimer’s disease (FAD) and the mutations result in the production of β-amyloid (Aβ) peptides which in turn trigger neurodegeneration and dementia in FAD (page 629, left col, first para), and Guo teaches of in vitro assays for identifying therapeutic compounds that inhibit buildup of amyloid-β(Aβ) deposits in Alzheimer's disease (AD) brain and teaches using a cell-based tissue assay, where sections of unfixed AD or AD model transgenic mouse brains are mounted on glass slides and the potential therapeutic compounds are added to tissue sections and assayed for binding of fluorescence-tagged Aβ1–42 to the Aβ deposits in AD or transgenic brain tissue is detected with a fluorescence microscope (Abstract; Fig. 4; Table 1).
Thus, Kelleher acknowledges that mutations in PSEN1, as are present in Anand’s spheroids, result in Aβ plaque deposits and Guo teaches it was known to conduct in vitro fluorescence-tagged peptide assays to confirm Aβ plaque deposits.
Therefore, given the intention of Anand is to use the organoid model having the mutations in PSEN1 as a platform for screening of Alzheimer’s disease therapeutic agents for in vivo use in humans, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to confirm Aβ plaque deposition in the in vitro model thus verifying the organoid model would be an effective disease model for screening potential therapeutics that would be effective at inhibiting Aβ plaque deposition, thus meeting the limitation of claim 16.
The person of ordinary skill in the art would have been motivated to modify the method of Anand to include confirming the deposition of Aβ plaques, as taught by Guo, for the predictable result of verifying the organoid model would be an effective disease model of PSEN1 mutations in Alzheimer’s disease.
The skilled artisan would have had a reasonable expectation of success in combining the teachings of Anand with Kelleher and Guo because each of these teachings are directed at Alzheimer’s disease therapies.
Further regarding claim 17 and the limitation that Aβ plaque formation is reduced in a group treated with the candidate substance as compared to a group not treated with the candidate substance, it is noted that Guo, as discussed above, teaches of an in vitro tissue assay used for screening therapeutic candidate substances and determining reduction/blocking of Aβ plaque deposition, thus given the intention of Anand is screening of Alzheimer’s disease therapeutic agents for in vivo use in humans, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to determine a reduction in Aβ plaque deposition in the in vitro model for therapeutic candidates as compared to an untreated group.
The person of ordinary skill in the art would have been motivated to determine a reduction in Aβ plaque deposition for candidate substances, thus obtaining potential Alzheimer’s disease therapies that inhibit plaque deposition. Thus, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
Claim(s) 18 is rejected under 35 U.S.C. 103 as being unpatentable over Anand, in view of Kelleher and Guo, as applied to claim 16 above, and further in view of Sloan (set forth above).
The teaching of Anand, in view of Kelleher and Guo is set forth above.
Regarding claim 18, it is noted that Anand does not further comment on the ratio/concentration of neurons to astrocytes. However, Anand (Fig. 3; [0043]) illustrates the presence of astrocytes and neurons, and further teaches that neurons can be observed in the cell culture in about 1 week, by four (4) weeks of culture neurons of multiple lineage appear, and in about twelve (12) weeks, the organoid develops to a stage that has different types of cells including neurons and astrocytes ([0101]).
Likewise, Sloan (discussed above) is directed to methods for producing spheroids from induced pluripotent stem-neural progenitor cells, wherein the spheroids comprise neurons and astrocytes and the spheroids are for use in cell-based analysis, drug screening programs (Abstract; col 2, lines 39-42). Sloan also teaches that neurons develop early in the differentiation process, and the astrocyte population is initially low for the first month, but the cell population increases to more than 30% with increased culture time (col 3, line 55 to col 4, line 6; col 15, lines 4-15). Sloan teaches that after about seven (7) weeks of differentiation in vitro, 78.8%±2.5 of the cells expressed the neuronal marker 133-tubulin (TUBB3) (FIG. 1c; FIG. 3a) and a small population of cells (7.6%±1.02 at day 76) expressed the astrocyte and radial glial marker GFAP. Sloan further teaches that, at this stage, 36.2%±3.6 of neurons expressed the mature neuronal marker NEUN, (col 22, line 64 to col 23, line 5). Sloan further recognizes that neural stem cells initially maintain an exclusive neurogenic fate, but once the bulk of neurogenesis is completed, the neural progenitors become the primary source of astrocytes, i.e. neurogenesis-to gliogenesis switch (col 25, lines 22-29). Sloan further verified that astrogenesis increases with time in culture (col 25, lines 49-59). Thus, like Anand, Sloan also recognizes that the ratio of neurons to astrocytes is a results effective variable.
Thus, absent any teaching of criticality by the Applicant concerning the ratio (concentration) of neurons to astrocytes, it would be prima facie obvious that one of ordinary skill in the art would recognize this as a result effective variable whose concentration is a matter of routine optimization. Differences in concentration will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such parameter 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 re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (see MPEP 2144.05).
Conclusion
No claim is allowed.
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E. YVONNE PYLA
Primary Examiner
Art Unit 1633
/EVELYN Y PYLA/Primary Examiner, Art Unit 1633
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