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 .
Applicant’s amendments to the claims filed on 05-18-2026 have been received and entered. Claims 4, 6 have been amended. Claims 5, 7-9 have been canceled. Claims 1-4, 6 are pending in the instant application.
Election/Restrictions
Applicant’s election without traverse of Group II, claims 4-9, in the reply filed on 11-11-2025 is acknowledged.
Claims 1-3 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected subject matter, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 11-11-2025.
Claims 4, 6 are under consideration.
Priority
This application is a 371 of PCT/KR2021/014414 filed on 10/15/2021 which claim priority from foreign application KR 10-2020-0134618 filed on 10/16/2020. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Should applicant desire to obtain the benefit of foreign priority under 35 U.S.C. 119(a)-(d) prior to declaration of an interference, a certified English translation of the foreign application must be submitted in reply to this action. 37 CFR 41.154(b) and 41.202(e).
Failure to provide a certified translation may result in no benefit being accorded for the non-English application.
Maintained in modified form-Claim Rejections - 35 USC § 112- necessitated by amendments
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 4, 6 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 base claim 4 recites the phrase “selecting organoids from one or more specific brain regions depending on a purpose of using a mini-brain structure” is vague and indefinite because it appears to implicitly require isolating/cutting off cellular organoids/tissue from living brain. However, the specification of the claimed invention stated that “the brain organoids are formed through self-organization, self-proliferation, and tissue-specific lineage differentiation after culturing induced pluripotent stem cells in a medium containing a signal transducer in an in vivo-like substrate environment.” (see para. [3], page 2 of the instant disclosure). The specification of the claimed invention does not provide guidance for isolating/cutting off cellular organoids/tissue from brain for generating a mini-brain structure. Also, there is no step of culturing and differentiating induced pluripotent stem cells recited in the claims. Therefore, it is unclear if the claimed method requires a step of isolating/cutting off organoids/tissue from brain or culturing /differentiating induced pluripotent stem cells into brain organoid.
Furthermore, the phrase “depending a purpose of using a mini-brain structure” is unclear because the claims do not specify how “using a mini-brain structure” can function as selecting criteria for the brain organoid or how the use of a mini-brain structure can be related to structure/function of the organoid.
Claim 6 is included in the rejection because they directly or indirectly depend from the rejected claims. Appropriate correction is required.
Response to Arguments
Applicant's arguments filed on 05-18-2026 have been fully considered but they are not persuasive.
1. Applicant disagrees that “the present invention is directly related to selecting specific organoids of a particular brain region (such as cerebral, midbrain, cerebellar, or thalamic organoids) that have already been prepared, rather than isolating or dissecting cell organoids or tissues from the brain. As clearly shown above, Example 3 describes an example in which pre-formed thalamic organoids, cerebral organoids, and midbrain organoids were selected and combined to produce mini-brain structure 1, as well as an example in which pre-formed cerebellar organoids, cerebral organoids, and midbrain organoids were selected and combined to produce mini-brain structure 2. Thus, as mentioned above, claim 1 is not required a step of isolating/cutting off organoids/tissue from brain or culturing /differentiating induced pluripotent stem cells into brain organoid" since the above steps are not essential of the present invention” (Remarks, page 6).
Response to Arguments:
In response to applicant's argument that “the present invention is directly related to selecting specific organoids of a particular brain region (such as cerebral, midbrain, cerebellar, or thalamic organoids) that have already been prepared, rather than isolating or dissecting cell organoids or tissues from the brain”, although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). As currently written, the base claim 4 reciting the phrase “selecting organoids from one or more specific brain regions” encompasses selecting (isolating/cutting off) cellular organoids/tissue from living brain. However, the specification of the claimed invention does not provide guidance for isolating/cutting off cellular organoids/tissue from brain for generating a mini-brain structure. Also, there is no step of culturing and differentiating induced pluripotent stem cells recited in the claims. Applicant also argues that “culturing /differentiating induced pluripotent stem cells into brain organoid" are not essential of the present invention; however, under the broadest reasonable interpretation, the terms of the claim are presumed to have their plain meaning consistent with the specification as it would be interpreted by one of ordinary skill in the art (See MPEP 2111). The claims do not exclude selecting living human brain as an example.
2. Applicant stated that the Office Action further asserts that "Furthermore, the phrase "depending a purpose of using a mini-brain structure" is unclear because the claims do not specify how "using a mini-brain structure" can function as selecting criteria for the brain organoid or how the use of a mini-brain structure can be related to structure/function of the organoid." claim 4 has been amended to recite "wherein the mini-brain structure is formed any one of cerebrum organoid, midbrain organoid, cerebellum organoid, thalamus organoid and the combination thereof." (remarks, page 6).
Response to Arguments:
With the claim as currently written, the step of “selecting organoids from one or more specific brain regions depending on a purpose of using a mini-brain structure” requires to know “a purpose of using a mini-brain structure” in order to select the organoids. The newly added claim amendments “wherein the mini-brain structure is formed any one of cerebrum organoid, midbrain organoid, cerebellum organoid, thalamus organoid and the combination thereof” does not clarify “a purpose of using a mini-brain structure”. A person of ordinary skill in the art would not know how to select organoids from one or more specific brain regions depending on a purpose of using a mini-brain structure to form cerebrum organoid, midbrain organoid, cerebellum organoid, thalamus organoid and the combination thereof.
Maintained in modified form-Claim Rejections - 35 USC § 102- necessitated by amendments
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 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.
Claims 4, 6 are rejected under 35 U.S.C. 102 (a)(1) as being anticipated by Bagley et al (Nat Methods 14, 743–751 (2017), doi:10.1038/nmeth.4304, 10 MAY 2017).
Claim interpretation:
Claim 5 requires “a combination inducer”, and the specification of the claimed invention teaches that “the combination inducer comprises one or more selected from the group consisting of Matrigel, collagen, gelatin, and a brain extracellular matrix extracted from an animal brain tissue” (see the instant specification [19], page 5). Thus, combination inducer is interpreted as matrigel, collagen, gelatin, or a brain extracellular matrix extracted from an animal brain tissue.
the term “gradually” is not defined in the instant disclosure in a limiting way. Thus, the term “gradually” is interpreted broadly as routine laboratory techniques to transfer one culture to another.
Regarding to claim 4, Bagley et al teach that “ Different brain regions can be cultured in vitro within 3D cerebral organoids, …… Here, we describe a coculture method combining brain regions of choice within one organoid tissue. By fusing organoids of dorsal and ventral forebrain identities, we generate a dorsal–ventral axis …. Our results demonstrate that cerebral organoid fusion cultures can model complex interactions between different brain regions. Combined with reprogramming technology, fusions should offer researchers the possibility to analyze complex neurodevelopmental defects using cells from neurological disease patients and to test potential therapeutic compounds” (Abstract) (For the preamble and the claimed: “wherein the mini-brain structure is formed any one of cerebrum organoid, midbrain organoid. cerebellum organoid. thalamus organoid and the combination thereof.”).
Bagley et al teach Cerebral organoid generation and fusion (see the first page of the Method, right column, 2nd and 3rd para. and Figure 2):
“The protocol for generating ventral and dorsal organoids and the characterization of cerebral organoid fusions was tested using a feeder-dependent hiPSC line ……. organoids were grown in 10 cm cell culture dishes containing 25 mL of differentiation medium, and after the first media exchange they were maintained on an orbital shaker with medium exchange every 5–7 d.” (see the first page of the Method, right column, 2nd para. ).
“To create organoid fusions, EBs were grown separately and individually patterned using either dorsalUnt, dorsalCycA, or ventral protocols as described above. During Matrigel embedding, two EBs were transferred into the same parafilm well and embedded in a single droplet (~30 µL) of Matrigel. The EBs were gently positioned as close together as possible using a 20 µL pipet tip to ensure the EBs would remain in close proximity within the middle of the solidified Matrigel droplet. The fusion process is very efficient, and it occurs within 1 week when EBs are positioned as close as possible. If EBs were not positioned close enough, then visible space remained between organoids 1 week after embedding. These ‘failed’ fusions were removed by aspiration. In addition, if the Matrigel droplet disassembled during the embedding process or during additional feedings before fusion had been completed, these organoids were also removed by aspiration.” (see the first page of the Method, right column, 3rd para. ).
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Bagley et al teach “two EBs were transferred into the same parafilm well and embedded in a single droplet (~30 µL) of Matrigel. The EBs were gently positioned as close together as possible using a 20 µL pipet tip to ensure the EBs would remain in close proximity within the middle of the solidified Matrigel droplet. The fusion process is very efficient, and it occurs within 1 week when EBs are positioned as close as possible” (see the first page of the Method, right column, 3rd para. ) (For the claimed: inducing each of the organoids to be combined into a single organism by adding a combination inducer, which induces each of the organoids to be combined, to the mixed culture medium, after the mixing of the culture media, and then incubating the mixed culture medium)
Bagley et al teach “To create organoid fusions, EBs were grown separately and individually patterned using either dorsalUnt, dorsalCycA, or ventral protocols as described above. During Matrigel embedding, two EBs were transferred into the same parafilm well and embedded in a single droplet (~30 µL) of Matrigel ……The fusion process is very efficient, and it occurs within 1 week when EBs are positioned as close as possible” (see the first page of the Method, right column, 3rd para. ), and Figure 2e teaches Ventral::dorsalCycA organoid fusion cryosections from organoids of different ages (Day 32, 46, 58, 80) (see Figure 2e, page 745). It is note that , according to the Method and Figure 2, since two EBs are transferred and mixed (1:1) as in Figure 2, the amount of two EBs are equally mixed. Also, since the fusion process occurs within 1 week and organoid fusion of different ages (Day 32, 46, 58, 80) were obtained and suspended over one week. (For the claimed: wherein the regulating of the culture medium composition is performed in a manner of gradually mixing one culture medium 1 which one organoid is suspended with another culture media in which an equal amount of another organoid is suspended over one week)
Bagley et al teach “two EBs were transferred into the same parafilm well and embedded in a single droplet (~30 µL) of Matrigel. The EBs were gently positioned as close together as possible using a 20 µL pipet tip to ensure the EBs would remain in close proximity within the middle of the solidified Matrigel droplet. The fusion process is very efficient, and it occurs within 1 week when EBs are positioned as close as possible” (see the first page of the Method, right column, 3rd para.) (For the claimed: wherein in the mixing of the culture media, the container for placing the organoids is used to enable each of the organoids to be adjacent in the mixed culture med1uffi and to control an adjacent position of each of the organoids).
Regarding to claim 6, Bagley et al teach “The protocol for generating ventral and dorsal organoids and the characterization of cerebral organoid fusions was tested using a feeder-dependent hiPSC line ……. organoids were grown in 10 cm cell culture dishes containing 25 mL of differentiation medium, and after the first media exchange they were maintained on an orbital shaker with medium exchange every 5–7 d.” (see the first page of the Method, right column, 2nd para. ).
Response to Arguments
Applicant's arguments filed on 05-18-2026 have been fully considered but they are not persuasive.
1. Applicant disagrees that “The technical gist of the present invention lies not in the mere production of brain organoids themselves, but rather in a method for manufacturing a "mini-brain structure" capable of emulating actual human brain functions by selectively combining pre-existing organoids to form a unified tissue ….. Thus, it is evident that the core of the present invention resides not in the production of brain organoids *per se*, but in the formation of a mini-brain structure by selectively combining pre-existing organoids to constitute a unified tissue. Accordingly, the method for manufacturing the mini-brain structure according to the present invention has been designed to ensure that the selected organoids effectively coalesce to form a unified tissue structure” (Remarks, page 12-13).
Response to Arguments:
It is noted that Bagley et al teach cerebral organoid fusion not just production of brain organoids: “Our results demonstrate that cerebral organoid fusion cultures can model complex interactions between different brain regions. Combined with reprogramming technology, fusions should offer researchers the possibility to analyze complex neurodevelopmental defects using cells from neurological disease patients and to test potential therapeutic compounds” (Abstract). As described above, Figure 2 of Bagley et al teach fused cerebral organoids as a model for cell migration with ventral::dorsalCycA organoid fusion structure. Thus, Bagley et al teach formation of a mini-brain structure by selectively combining pre-existing ventral and dorsal organoids to constitute a unified tissue
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2. Applicant states that the present invention recognizes the necessity of using a specific culture medium to form organoids of a particular brain region, as well as the problem wherein organoids from different brain regions undergo cell death if mixed directly; consequently, the invention addresses this issue by gradually adding an equal volume of the medium specific to the other organoid-over a predetermined period-into the medium in which the first organoid is suspended, before finally mixing the organoids together.
Specifically-as demonstrated in Example 3-in order to construct a "mini-brain" structure by combining thalamic, cerebral, and midbrain organoids (which are cultured in suspension), the present invention entails the following steps: gradually mixing an equal volume of the final medium for cerebral organoids and the final medium for midbrain organoids into the final medium containing suspended thalamic organoids over the course of one week; gradually mixing an equal volume of the final medium for thalamic organoids and the final medium for midbrain organoids into the final medium containing suspended cerebral organoids over the course of one week; and gradually mixing an equal volume of the final medium for thalamic organoids and the final medium for cerebral organoids into the final medium containing suspended midbrain organoids over the course of one week
(remarks, page 13-14).
Response to Arguments:
It is noted that Bagley et al were successfully in mixing organoids of different brain regions together without cell death: “To create organoid fusions, EBs were grown separately and individually patterned using either dorsalUnt, dorsalCycA, or ventral protocols as described above. During Matrigel embedding, two EBs were transferred into the same parafilm well and embedded in a single droplet (~30 µL) of Matrigel. The EBs were gently positioned as close together as possible using a 20 µL pipet tip to ensure the EBs would remain in close proximity within the middle of the solidified Matrigel droplet. The fusion process is very efficient, and it occurs within 1 week when EBs are positioned as close as possible. If EBs were not positioned close enough, then visible space remained between organoids 1 week after embedding. These ‘failed’ fusions were removed by aspiration. In addition, if the Matrigel droplet disassembled during the embedding process or during additional feedings before fusion had been completed, these organoids were also removed by aspiration” (second page of the method, right column, 3rd para.).
In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies:
“the invention addresses this issue by gradually adding an equal volume of the medium specific to the other organoid-over a predetermined period-into the medium in which the first organoid is suspended, before finally mixing the organoids together”
the present invention entails the following steps: gradually mixing an equal volume of the final medium for cerebral organoids and the final medium for midbrain organoids into the final medium containing suspended thalamic organoids over the course of one week; gradually mixing an equal volume of the final medium for thalamic organoids and the final medium for midbrain organoids into the final medium containing suspended cerebral organoids over the course of one week; and gradually mixing an equal volume of the final medium for thalamic organoids and the final medium for cerebral organoids into the final medium containing suspended midbrain organoids over the course of one week.
These are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
3. Applicant states that the present invention recognizes that the specific positioning of organoids is a critical factor in the construction of mini-brain structures designed for specific purposes; accordingly, by varying the relative positioning of organoids derived from different brain regions, the invention enables the facile production of mini-brain structures exhibiting diverse morphological characteristics.
Therefore, it is clearly evident that the function of a mini-brain structure varies depending on the specific binding positions of its constituent organoids. Accordingly, the present invention utilizes an organoid-positioning vessel (1)-designed to control the relative adjacency of individual organoids-to facilitate the facile fabrication of mini-brain structures with distinct morphologies by varying the binding positions of organoids representing different brain regions.
(remarks, page 14-16)
Response to Arguments:
It is noted that Bagley et al teach that the specific positioning of organoids is a critical factor: “The fusion process is very efficient, and it occurs within 1 week when EBs are positioned as close as possible. If EBs were not positioned close enough, then visible space remained between organoids 1 week after embedding. These ‘failed’ fusions were removed by aspiration. In addition, if the Matrigel droplet disassembled during the embedding process or during additional feedings before fusion had been completed, these organoids were also removed by aspiration” (second page of the method, right column, 3rd para.).
4. Applicant states that
Bagley et al. describes a structure comprising a combination of a dorsal forebrain organoid and a ventral forebrain organoid designed to perform specific functions; however, it involves directly mixing the dorsal forebrain organoid and the ventral forebrain organoid without disclosing "wherein the regulating of the culture medium composition is performed in a manner of gradually mixing one culture medium in which one organoid is suspended with another culture media in which an equal amount of another organoid is suspended over one week" as recited in claim 4 (Remarks, page 16)
Response to Arguments:
First, it is noted that the term “gradually” is not defined in the instant disclosure in a limiting way. Thus, the term “gradually” is interpreted broadly as routine laboratory techniques to transfer one culture to another.
Second, Bagley et al. describes a structure comprising a combination of a dorsal forebrain organoid and a ventral forebrain organoid. Thus, Bagley et al teach mixing culture medium of a dorsal forebrain organoid with another culture media of a ventral forebrain organoid.
Third, according to the method and Figure 2 of Bagley et al., since two EBs are transferred and mixed (1:1) as in Figure 2, the amount of two EBs are equally mixed. Also, as described above since the fusion process occurs within 1 week and organoid fusion of different ages (Day 32, 46, 58, 80) were obtained and suspended over one week.
5. Applicant argues that “Bagley et al. makes no mention whatsoever of the fact that the function of the resulting structure varies depending on the specific site at which the respective organoids are combined, nor does it utilize a vessel for organoid placement to control the relative positioning of the adjacent organoids” (Remarks, page 16).
Response to Arguments:
It is noted that Bagley et al teach that the specific positioning of organoids is a critical factor: “During Matrigel embedding, two EBs were transferred into the same parafilm well and embedded in a single droplet (~30 µL) of Matrigel. The EBs were gently positioned as close together as possible using a 20 µL pipet tip to ensure the EBs would remain in close proximity within the middle of the solidified Matrigel droplet. The fusion process is very efficient, and it occurs within 1 week when EBs are positioned as close as possible. If EBs were not positioned close enough, then visible space remained between organoids 1 week after embedding. These ‘failed’ fusions were removed by aspiration. In addition, if the Matrigel droplet disassembled during the embedding process or during additional feedings before fusion had been completed, these organoids were also removed by aspiration” (second page of the method, right column, 3rd para.). Nevertheless, per MPEP 2112 (I): something which is old does not become patentable upon the discovery of a new property: "[T]he discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer." Atlas Powder Co. v. IRECO Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999). Thus, the claiming of a new use, new function or unknown property which is inherently present in the prior art does not necessarily make the claim patentable. In re Best, 562 F.2d 1252, 1254, 195 USPQ 430, 433 (CCPA 1977).
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/KHOA NHAT TRAN/Examiner, Art Unit 1632
/PETER PARAS JR/Supervisory Patent Examiner, Art Unit 1632
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