DETAILED ACTION
Applicant’s response filed 8/4/2026 has been received and entered into the application file. All arguments have been fully considered. Claims 1, 3, 5, 7, and 9-13 are currently pending. Claims 1, 7, 9 and 13 are currently amended. Claims 2, 4, 6, and 8 are cancelled.
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 .
Specification-Objection Withdrawn
Applicant’s amendment submitted 8/4/2026 is accepted.
REJECTION(S) WITHDRAWN
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.
RE: Rejection of claims 1-13 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite:
It is initially noted that claims 2, 4, 6, 8 are cancelled.
Applicant’s amendment submitted 8/4/2026 has removed the phrase
“human neural cell-like cell”, thus obviating the previous rejection of record.
Therefore, the rejection is withdrawn.
Claim Rejections - 35 USC § 103
RE: Rejection of Claim 7 under 35 U.S.C. 103 as being unpatentable over Hiramine et al., (WO 2021/090877):
The rejection is withdrawn in view of Applicant’s amendment to claim 7 now requiring the limitation of culturing a culture product in a culture medium containing BDNF or GDNF.
RE: Rejection of Claim(s) 1-6 and 9-13 under 35 U.S.C. 103 as being unpatentable over Hiramine et al., (WO 2021/090877), in view of Montaner, as evidenced by PubChem-Phosphatidylcholine; and
Rejection of Claim 8 under 35 U.S.C. 103 as being unpatentable over WO ‘877, in view of Montaner, as evidenced by PubChem, and further in view of Tang-Schomer:
The rejections are withdrawn in view of Applicant’s amendment to claim 1 now requiring the limitation that the lipid comprises triacylglycerol, lysophosphatidylcholine, phosphatidylcholine, phosphatidic acid, and sphingomyelinm, and further requiring the step of culturing a culture product in a culture medium containing BDNF or GDNF.
NEW GROUND(S) OF OBJECTION/REJECTION, NECESSITATED BY AMENDMENT
Claim Objections
Claims 1 and 7 are objected to because of the following informalities: abbreviation. The abbreviation BDNF (brain-derived neurotrophic factor) and GDNF (glial cell line-derived neurotrophic factor) should first be spelled out upon its first usage in a claim. Appropriate correction is required.
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 7 is rejected under 35 U.S.C. 103 as being unpatentable over Hiramine et al., (WO 2021/090877, IDS 4/29/2024, previously cited; see PTO-892 of 5/19/2026 for WIPO English translation) (“WO ‘877”), in view of Quadrato et al., (NATURE, Vol 545, 4 May 2017, page 48-63; see PTO-892) (“Quadrato”).
WO ‘877 teaches of brain organoids (i.e., spheroid) prepared by culturing human pluripotent stem cells having mutations in a microtubule associated protein tau gene (MAPT gene), wherein the mutations in MAPT are in at least one nucleic acid sequence of exon 9, exon 10, exon 11, exon 12 and exon 13, and intron 10, thus resulting in the brain organoids having a phosphorylated 3-repeat tau protein and a phosphorylated 4-repeat tau protein, thus self-aggregation of the tau proteins occurs (Abstract and [0002]). WO ‘877 specifically teaches introducing three mutations in the MAPT gene, i.e., N279K and P301L (exon 10), and E10 +16 (intron 10) ([0003] and [0008]).
Regarding claim 7, WO ‘877 teaches producing the brain organoids by conducting a step 1 suspension-culture of the mutated human pluripotent stem cells having the indicated mutations in the MAPT gene and thus producing tau protein aggregates, wherein the culture medium comprises a bone morphogenetic protein (BMP) signaling pathway inhibitor, and a transforming growth factor β (TGF-β) family signaling pathway inhibitor, wherein cell aggregates (i.e., spheroids) are formed by the suspension culture in step 1 (i.e., a culture product). Thereafter, step 2 of culturing comprises suspension culturing the aggregates (i.e., spheroids) of step 1 in a medium that includes a Wnt signaling enhancer and an extracellular matrix (e.g., Matrigel ([0067]) for 3-14 days, thus promoting differentiation as disclosed in the specification at [0105]. Therefore, this step is considered to read on the claimed culturing a spheroid of a human neural cell-like cell in the presence of a tau protein aggregate. WO ‘877 teaches step 3 of culturing is conducted for 2-700 days in a culture medium (medium 3) that does not include an extracellular matrix (ECM). WO ‘877 teaches the culture method for producing a brain organoid further comprises step 4 which includes dispersing a brain organoid produced by the previous step of culturing without ECM, thus obtaining a cell dispersion, and thereafter step 5 cultures the dispersion for 0.1 to 14 days in the presence of the tau protein aggregate that is encoded by the MAPT gene having said mutations ([0008], [0016], [0046], [0056], [0078], [0096]).
As to the limitation the culture medium contains either of the neurotrophic factors BDNF or GDNF, it is noted that WO ‘877 teaches the choices of extracellular matrix includes Matrigel, and Matrigel comprises a number of growth factors, including nerve growth factor (NGF) (<0.2 ng/ml) (see [0068]), however, WO ‘877 does not exemplify that BDNF or GDNF is added to the culture medium.
Quadrato is directed to human brain organoids as in vitro models of the developing brain, wherein the organoids develop mature features including neural networks (Abstract). Quadrato further teaches the addition of brain-derived neurotrophic factor (BDNF) to the final differentiation medium, thus promoting progressive development of the organoids for over nine months (page 48, right col at Protracted in vitro development of brain organoids).
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 BDNF in the culture method.
The person of ordinary skill in the art would have been motivated to modify the method of WO ‘877 to include a neurotrophic agent, including BDNF, that promotes differentiation to a neural lineage, as taught by Quadrato, for the predictable result of successfully promoting progressive development of the organoids for over nine months, thus meeting the limitation of claim 7.
The skilled artisan would have had a reasonable expectation of success in combining the teachings of WO ‘877 and Quadrato because each of these teachings are directed at methods of culturing brain organoids.
Response to Arguments
Rejections under 35 USC 103:
As set forth above, the rejection of claims 1, 3, 5, 7 and 9-13 have been withdrawn in view of Applicant’s amendments to claims 1 and 7, now requiring the presence of BDNF or GDNF in the culture medium. However, new grounds of rejection have been set forth above regarding amended claim 7, thus addressing the amended limitation directed to the presence of BDNF or GDNF in the culture medium.
Further regarding claim 7 and Applicant’s remarks asserting that Matrigel does not contain NGF, it is noted that Applicant’s remarks have been fully considered but are not found persuasive.
It is noted the reference 1 document referred to in Applicant’s remarks at page 10, retrieved from the indicated web page, clearly shows that Matrigel contains NGF at a concentration less than 0.2 ng/ml (see page 2). This is also supported by Corning® Matrigel® Matrix, Frequently Asked Questions, paragraph 2 “What are the growth factor concentrations in Corning Matrigel matrix?” (retrieved from the internet, see PTO-892).
Allowable Subject Matter
The following is a statement of reasons for the indication of allowable subject matter:
Upon conducting an updated prior art search for a culture method comprising: culturing a spheroid of a pluripotent stem cell that has the ability to differentiate to the neural lineage in the presence of a tau protein aggregate and culturing a culture product in a culture medium containing 5 µg/mL or greater of a lipid, wherein the lipid comprises triacylglycerol, lysophosphatidylcholine, phosphatidylcholine, phosphatidic acid, and sphingomyelin, and wherein the culture medium further comprises BDNF or GDNF, it is noted it appears claim 1 is free of prior art. The prior art does not teach or suggest lipids comprising the combination of triacylglycerol, lysophosphatidylcholine, phosphatidylcholine, phosphatidic acid, and sphingomyelin.
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.
Examiner Contact Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to E. YVONNE PYLA whose telephone number is (571)270-7366. The examiner can normally be reached M-F 9am - 6pm.
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E. YVONNE PYLA
Primary Examiner
Art Unit 1633
/EVELYN Y PYLA/Primary Examiner, Art Unit 1633
