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 .
DETAILED ACTION
Claim Status
Claims 1-2 and 9-15 are currently pending in this application.
Election/Restriction
Applicant’s election with traverse of Group I, claims 1-8, in the reply filed on Dec. 3, 2025 is acknowledged. Claims 9-15 have been withdrawn for being drawn to non-elected subject matter, and claims 1-2 have been considered on the merits.
Priority
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, Application No. EP20205010.0, fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for claim 1 regarding culturing pluripotent stem cells after 4 to 7 days in a device, culturing in the device “for 5 days in a serum-free medium comprising 10 µM ROCK inhibitor” to form neurospheres or for claim 2 regarding a method comprising said 4 to 7 day step followed by said 5 day step before preceding to the 30 to 50 days step in culture dishes. See instant pg. 10-11; Example 5-9, which instead describes only from the 5 day step forward applied to resuspend pluripotent stem cells and continuing the final culturing for, e.g., 50-100 days. Therefore, the earliest effective filing date of the claims is the filing date of the instant application, 11/2/2021. If applicant believes the earlier application provides support for this disclosure, applicant should point out such support with particularity by paragraph and line number in the reply to this Action.
Specification Objections
The disclosure is objected to because of the following informalities:
The disclosure also has numerous typographical errors regarding the term “flask” or “flasks” misspelled as “flaks.” Appropriate correction is required.
Claim Objections
Claims 1 and 2 are objected to for comprising formal graphic characters (dots or bullets) which unnecessarily introduces printing difficulties as only printable ASCII characters are preferred. See MPEP §608.01. Note, where a claim sets forth a plurality of elements or steps, each element or step of the claim should be separated by a line indentation (37 CFR 1.75(i), MPEP §608.01(m)).
Claims 1 and 2 inconsistently use the terms “stem pluripotent cells,” “pluripotent stem cells,” and “pluripotent cells,” unnecesarily introducing ambiguity as to whether these are referring to the same object or genus having the same scope.
Status of Rejections
The previous claim rejections under 35 USC §§ 112(a), 112(b), 112(d), 102, and 103 in view of the claim amendments, except as maintained below or as specifically modified in light of current claim amendments.
Claim Interpretation
In the claims, the term “neurosphere” is interpreted as a free-floating 3D cellular aggregate comprising neural precursor cells and being mostly spherical in shape, such as, e.g., wherein the standard deviation of diameter measurements at different axes is less than 5%. See instant pg. 5, lines 24-25; pg. 7, lines 6-9.
In the claims, the term “brain organoid” is interpreted as a mostly spherical 3D cellular aggregate comprising brain cell types and cytoarchitecture resembling human brain tissue(s). Brain organoids may also be referred to in the prior art as “neural organoids,” “cerebral organoids” or “mini-brains.” See instant pg. 5, line 25, to pg. 6, line 4; pg. 7, lines 6-9.
In the claims, the term “homogeneous” is defined in the instant application as meaning essentially all the neurospheres or brain organoids of a given plurality of such all have a similar diameter, shape, anatomy, cytoarchitecture, functionality and cell diversity. See instant pg. 6, lines 19-22; pg. 7, lines 1-25; pg. 2, lines 21-22. Further in claim 2, the neurospheres formed in the first culturing step are considered “homogeneous” as the same exact steps are performed as in claim 1, which may be critical to ensure the resulting brain organoids are homogeneous.
In the claims, the phrase “receives the same number of pluripotent cells” is interpreted as encompassing the “same” only statistically or approximately instead of meaning strictly identical in absolute cell count, e.g., ~10,000 cells each. See instant pg. 8, lines 22-24; Example 5.
Claim Rejections - 35 USC § 112(a), New Matter (new)
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 1-2 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the invention of claim 1 or 2, comprising both a 4-7 day culturing of pluripotent cells with SB431542 and dorsomorphin and a 5 day culturing of pluripotent stem cells with ROCK inhibitor. This lacks support in the application as filed and thus constitutes new matter.
37 CFR 1.118(a) states “No amendment shall introduce new matter into the disclosure of an application after the filing date of the application”. In the instant case, the claim 1 recitation of the limitations “cultured for 4 to 7 days” and then the pluripotent stem cells are cultured to form neuropsheres by culturing for 5 days in a medium comprising 10 µM ROCK inhibitor is considered new matter. Upon review of the instant specification, examiner could not find explicit or implicit support for this limitation in the instant filing or in any priority document. Rather, the specification (pg. 16-17) only seems to mention culturing for 5 days in a medium comprising 10 µM ROCK inhibitor to form neurospheres, such as wherein preceding this the pluripotent stem cells were maintained in mTeSRI on plates coated with Matrigel (Example 1).
Regarding claim 2, the recitation of the limitations “pluripotent cells are cultured for 4 to 7 days” in medium “comprising 5 µM SB431542 and 0.5 µM dorsomorphin” simlar to the discussion of claim is considered new matter. Upon review of the instant specification, examiner could not find explicit or implicit support for this limitation in the instant filing or in any priority document. Rather, the specification (pg. 16-17) only seems to mention producing brain orgnaoids by methods comprising culturing for 5 days in a medium comprising 10 µM ROCK inhibitor to form neurospheres, such as wherein preceding this, the pluripotent stem cells were maintained in mTeSRI on plates coated with Matrigel (Example 1). Alternatively, the specification notes following the method of Gabriel et al. 2017 (Example 2), which only includes dorsomorphin and SB431542 in the organoid medium of the “third” step after the ROCK inhibitor culturing for 5 days to cause differentiating of iPSCs into neurospheres (Fig. 1). Thus, at the time the application was filed, an Artisan of skill would not recognize from the disclosure that Applicant was in possession of the process of instant claim 1 or 2.
MPEP 2163.06 notes “If new matter is added to the claims, the examiner should reject the claims under 35 U.S.C. 112, first paragraph-written description requirement”. In re Rasmussen, 650 F.2d 1212, 211 USPQ 323 (CCPA 1981) teaches that “Whenever the issue arises, the fundamental factual inquiry is whether a claim defines an invention that is clearly conveyed to those skilled in the art at the time the application was filed…If a claim is amended to include subject matter, limitation or terminology not present in the application as filed, involving a departure from, addition to, or deletion from the disclosure of the application as filed, the examiner should conclude that the claimed subject matter is not described in that application.
Claim Rejections - 35 USC § 112(a) - Written Description (new)
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 1-2 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The claimed invention as a whole is not adequately described if the claims require essential or critical elements that are not adequately described in the specification and that is not conventional in the art as of applicant’s effective filing date. Possession may be shown by actual reduction to practice, clear depiction of the invention in a detailed drawing, or by describing the invention with sufficient relevant identifying characteristics such that a person skilled in the art would recognize that the inventor had possession of the claimed invention. Pfaff v. Wells Electronics, Inc., 48 USPQ2d 1641,1646 (1998).
In making a determination of whether the application complies with the written description requirement under 35 U.S.C. 112(a) or 35 U.S.C. 112, first paragraph, it is necessary to understand what Applicant is claiming and what Applicant has possession of.
The claims are directed to methods of producing homogeneous neurospheres or neurospheres that develop into homogeneous brain organoids via active step(s) of culturing. The claims are specific in that the culturing steps must comprise two subsequent independent steps of: (1) direct differentiation of pluripotent cells for about 4-7 days at 37° C 5% CO2 in a serum-free medium composition comprising 5 µM SB431542 and 0.5 µM dorsomorphin AND (2) culturing the aforementioned pluripotent cells for 5 days at 37° C, 5% CO2, in serum-free medium comprising with 10 µM ROCK inhibitor.
In analyzing whether the written description requirement is met for genus claims, it is first determined whether a representative number of species have been described. In the instant case, the specification fails to provide any representative species, with the closes being:
(1-a) direct differentiation of pluripotent cells for about 4-7 days at 37° C 5% CO2 in a serum-free medium composition comprising 5 pM SB431542 and 0.5 pM dorsomorphin (pg. 10, line 24, to pg. 11, line 4; pg. 12, lines 11-14) OR
(1-b) culturing pluripotent cells for 5 days at 37° C, 5% CO2, in serum-free Neural induction medium (NIM) (Stemcell Technologies) supplemented with 10 pM of an unnamed ROCK inhibitor (Example 5; Fig. 1B-C); and
(2) forming brain organoids over about 30-50 days at 37° C 5% CO2 in a serum-free medium composition comprising 5 pM SB431542 and 0.5 pM dorsomorphin (pg. 11, lines 27-31; Example 2; FIG. 1B-D, FIG. 2A, 2C, 3-5; pg. 3).
Thus, the instant application describes no representative species of either claims 1 or 2. The claims fail to recite, and the specification fails to disclose, the necessary structure/function/action-taking step(s) nexus between the combination of each of: culturing conditions and durations that predictably ensures the formation of neurospheres or brain organoids, such as forming a homgeneous population thereif. The prior art provides additional guidance as to specific methods validated to work under specific conditions. The prior art teaches methods of developing neurospheres from pluripotent stem cells (embryonic stem cells) without forming any embryoid body via suspension culturing for 4-7 days in a serum-free medium often comprising TGF-β and BMP receptors inhibitors (SB431542 and dorsomorphin) and/or a ROCK inhibitor (e.g., Y-27632) (Li et al., BMC Neurosci 10: 122 (2009) at Fig. 1; pg. 2, right col., 2nd para.; Birenboim et al., J Neurosci Methods 214: 9-14 (2013), IDS ref., at Fig. 1, 3A-B, Abstract; pg. 10, left col., 2nd para.; Gabriel et al., J Vis Exp 122: 55372 (2017) at pg. 2-3, Protocol, Initiation of neuroectoderm, steps 3-6).
However the prior art is silent as to any method comprising subsequent and separate steps of (1) direct differentiation of pluripotent cells for about 4-7 days at 37° C 5% CO2 in a serum-free medium composition comprising 5 µM SB431542 and 0.5 µM dorsomorphin AND (2) culturing the aforementioned pluripotent cells for 5 days at 37° C, 5% CO2, in serum-free medium comprising with 10 µM ROCK inhibitor. Moreover, the prior art notes unpredictability of neural progenitor generation/maintenance by applying ROCK inhibition to pluripotent cells already induced to differentiate into neural lineages by exposure to inhibitors, e.g., SB431542 and dorsomorphin, (Kim et al., Stem Cells 33: 674-85 (2015). The instant disclosure fails to bridge this gap in understanding.
In view of the instant specification, the current claims were not sufficiently described for the precise steps of the claims regarding culturing conditions, such as to ensure homogenous neurosphere formation and/or brain organoid formation, such as ensuring expression of all the requisite markers PAX6, SOX2, Nestin, DCX, TUJ1, Synapsin-1, GAD67, Tau, MAP2, CTIP, alpha-Synuclein and VGlut-1. Because it is unpredictable based on the art that such hybrid methods would perform as the individual method steps alone. The skilled artisan could not rely upon the disclosure in the specification such that the specification would sufficiently describe that Applicant was in possession of a single method comprising all the culturing steps recited to ensure the predictable production of homogeneous neurospheres or brain organoids by the claimed methods.
Response to arguments
Applicant’s arguments in the response of 8/24/26 regarding the 112(a) rejections (pg. 7) but not found persusaive. Instead of choosing a step 1 between alternative types (a) and (b) as in the previous office action, the instant claims have combined both 1(a) and 1(b) into a single method claim with a specific order of steps. This was not suggested in the previous Office action and introduces methods having new unpredictabilities in view of the disclosure and the prior art.
Claim Rejections - 35 USC § 112(b) (maintained, new)
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 1-2 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.
Claim 1 recites the term “stem pluripotent cells,” which is not accepted term in the art, thus, the scope of this term is unclear without a definition. Neither the claim nor the instant specification defines this term, and thus, a person of ordinary skill in the art would not be appraised of the metes and bounds of this term in the claim. Claim 1 also recites “wherein the pluripotent stem cells are cultured for 4 to 7 days,” which lacks sufficient antecedent basis for the term “pluripotent stem cells.”
Claims 1 and 2 each recites the term “homogeneous” regarding either a plurality of neurospheres or brain organoids, respectively. As the term “homogeneous” in view of the instant specification encompasses wherein “essentially” all have a “similar” diameter, shape, anatomy, cytoarchitecture, functionality, and cell diversity (pg. 6, lines 18-21), the term “homogeneous” is indefinite because the claims, specification and prior art all fail to provide a standard for ascertaining the requisite degree for “essentially all” and “similar” diameter, shape, anatomy, cytoarchitecture, functionality, and cell diversity. When a term of degree is used in a claim (i.e., homogeneous), the examiner should determine whether the specification provides some standard for measuring that degree and if the specification does not provide some standard for measuring that degree, “a determination must be made as to whether one of ordinary skill in the art could nevertheless ascertain the scope of the claim (e.g., a standard that is recognized in the art for measuring the meaning of the term of degree). See MPEP 2173.05(b) (I). As “homogenous” may mean identical as well as “similar” such as in terms of diameter, shape, anatomy, cytoarchitecture, functionality, and cell diversity encompassing an unknown level of variance and deviations from identical, a person of ordinary skill in the art would not be appraised of the metes and bounds of the scope of the requisite level of homogeniety when not identical.
Claims 1 and 2 each recites “recieves the same number of cells,” which may be determined statistically as noted in a previous section. Claim 1 and 2 is indefinite because neither the claims nor the instant specification explains how the “same number” is achieved by statistics beyond mentioning preferred embodiments using a figure-8 movement during seeding as the seeded cells are settling into the microwells (pg. 8, lines 14-17; Example 5). Furthermore, the specification seems to mention that prior art methods cannot achieve this due to human pipetting errors (id.). Thus, the scope of “same” number of cells is left to the knowledge and experience of one of ordinary skill, but no such standard or metes and bounds for “same” is yet established in the prior art by applicant.
Claim 2 recites the term “the pluripotent stem cells are cultured for 5 days,” which lacks sufficient antecedent basis for the term “pluripotent stem cells.”
Response to arguments
Applicant’s arguments in the response of 8/24/26 regarding indefiniteness (pg. 7-8) were full considered but only found partially persusaive.
With regard to the term homogeneous, applicant argues the claims as amended make the term clear; however it is the relativeness of the term that is at issue and nowhere do the amended claims define or limit the term homogeneous, e.g., with a standard for measuring a degree homogeneity along with a border degree for falling within or without the claim scope, such as an art recognized homogeneity standard known in the prior art.
With regard to canceled claim 7, applicant argues in the response (pg. 7) that by performing the methods as instantly recited, the “same” number of cells is inevitably distriubted into each microwell. This is not found persuasive both for being a circular definition for “same” and because the assertion appears to be false in view of the instant specification noting that “it is difficult to evenly distribute the cells” and “thus ensure an equal number of cells in each microwell” when the number of compartments is not limited, e.g., other than 24 compartments (pg. 9, last para., continued to pg. 10). The prior art also notes this can be a challenge even when using a constant cell or cellular aggregate number (Yang et al., ACS Omega 4: 18136-46 (2019) at pg. 18136, right col., 1st para.).
As noted previously, this may be accomplished by the exemplary techinque of using a figure-8 movement during seeding as the seeded cells are settling (pg. 8, lines 14-17; Example 5); however, nowhere do the claims require any such technique nor exclude pipeting techniques prone to errors or limit the compartment number/size. Thus, the relative number of cells distributed in each well is not clearly the same based on the methods steps as recited in the claims at a high level of generality lacking such a limitation(s).
It would remedial to either remove the term “same number” from the claims, and the number of cells in each well remains inevitably as is without naming it, or to add a more particular limitation(s) to ensure a level of sameness matching the statistical discussion and methods taught in the instant specification, e.g., by requiring a step with a figure-8 movement during seeding as the seeded cells are settling. The issue is what a person skilled in the art would recognize as the metes and bounds of the statistically determined “same” number of cells, the relativeness of which is viewed in light of the specification as well as the prior art (see MPEP 2173.05(b) (I).
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 ERIC J ROGERS whose telephone number is (571)272-8338. The examiner can normally be reached Monday - Friday 9:00-6:00.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Tracy Vivlemore can be reached on (571) 272-2914. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/ERIC J ROGERS/Examiner, Art Unit 1638
/JAMES D SCHULTZ/Supervisory Patent Examiner, Art Unit 1631
