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 .
Election/Restrictions
This action is in response to the papers filed on 07/20/2026. Claims 1-20 are currently pending as per claims filed on 04/03/2024.
Applicant’s election without traverse of Group II, which include claims 15-20 drawn to a method for producing patterned organoids in the reply filed on 07/20/2026 is acknowledged.
Claims 1-14 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected subject matter, there being no allowable generic or linking claim.
The requirement for restriction between Groups I-II is still deemed proper and is therefore made FINAL.
Therefore, claim 15-20 are subject to examination to which the following grounds of rejection are applicable.
Priority
This application claims benefit to PRO 63/493,881 filed on 04/03/2023.
Information Disclosure Statement
No IDS has been filed.
Claim Objections
Claim 17 is objected to because of the following informalities: Claim 17 recites, “…a sonic hedgehog agonist.” The claim should accurately represent sonic hedgehog as a signaling pathway. 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.
Claims 15-20 are rejected under 35 U.S.C. 103 as being unpatentable over Asthana et al. (WO2021108346A1) in view of Xue et al. (US20240060039A1) and Höhnel et al. (US20180264465A1) as evidenced by Valiulahi et al. (Valiulahi Parvin et al., Stem cell reports, 2021).
For ease of reference, instant claim 15 is provided below:
Claim 15. A method for producing a patterned organoid, the method comprising: seeding one or more microwells defined in a microwell layer with a plurality of cells to generate a cell aggregate; adding one or more morphogens to a chemical reservoir defined by a partitioning layer, the partitioning layer comprising a wall that divides the chemical reservoir from one or more medium chambers, wherein the one or more microwells are defined within the one or more medium chambers; diffusing the one or more morphogens through a diffusion medium disposed beneath the microwell layer, wherein the diffusion medium is in fluid communication with the chemical reservoir; releasing the one or more morphogens through openings defined at respective base regions of the one or more microwells, wherein each respective opening extends between the microwell and the diffusion medium; forming a morphogenic gradient within the one or more microwells along a vertically oriented differentiation axis defined by each of the one or more microwells; and obtaining a patterned organoid from the cell aggregate comprised of cells differentiated according to the morphogenic gradient.
Regarding Claim 15, Asthana et al. teaches microwell perfusion plates for 3D cell culture (Abstract). Specifically, Asthana teaches cell seeding into microwells to form 3D cell cultures, wherein the microwells are provided in a microwell membrane and each microwell includes a top and bottom opening (Pg. 2, Paragraph [0005]). With respect to the microwells, Asthana teaches a through-pore microwell membrane having an array of microwells that include a top and bottom opening. The microwell membrane positioned above and on the porous membrane (Pg. 5, Paragraph [0025]; Pg. 12, Paragraphs [0068-0075]). Asthana teaches a bottom outlet channel positioned below the porous membrane, a cell culture well positioned above the microwell membrane, and an outlet medium reservoir in fluid communication with the bottom outlet channel (Pg. 13, Paragraphs [0077]-[0080]). Asthana teaches separate fluid containing regions defined by the device body, including the cell culture well and outlet medium reservoir (Pgs. 13-14, Paragraphs [0079]-[0086]).
Asthana does not teach the use of a morphogen or the diffusion of said morphogen through an underlying diffusion medium and through the basal microwell opening toward the cell aggregate, or formation of a morphogenic gradient along a vertically oriented differentiation axis.
Höhnel et al. teaches a device and methods for aggregating cells (Pg. 2, Summary of the Invention). Höhnel teaches U-bottom hydrogel microwells for formation and long-term culture of cell aggregates and further teaches integration of a microfluidic network for the local and timed delivery of molecules of interest to allow for selective manipulation of the formed aggregates (Pg. 2, Paragraphs [0024] and [0028]). Höhnel teaches the microfluid channels may be positioned beneath the plane of the microwells, aligned with the microwells, and less than 500µm from the microwell bottoms (Pg. 2, Paragraphs [0037]-[0041]; Pg. 7, Paragraphs [0132]-[0135]). Höhnel teaches that the channels are micromolded below the microwell plane in close proximity to the microwells to ensure diffusion of the desired molecule within 24h for local and temporal biochemical manipulation of spheroids (Pg. 8, Paragraph [0171]).
Höhnel does not teach that the diffusible molecule to specifically be a morphogen used to obtain a patterned organoid.
Xue et al. teaches spatially asymmetric delivery of compositions containing morphogens to generate neural spheroids. Specifically, Xue teaches generation of neural spheroids with spatially patterned differentiation, through the use of chemical gradients across developing 3D neural tissue (Pg. 2, Paragraphs [0014] and [0016]). Xue teaches neural-tube patterning is regulated by developmental signalling molecules including from sonic hedgehog (SHH) pathway and retinoic acid (Pg. 4, Paragraph [0039]). Xue teaches a device having a central tissue-containing channel and top and bottom channels separated from the central channel by respective semipermeable structures that allow chemical exchange between channels (Pg. 5, Paragraph [0043]). Chemicals supplied to the reservoir associated the top or bottom channel may flow form the respective reservoir through the semipermeable structure and contact and/or influence developing neural tissue in the central channel (Pg. 5, Paragraph [0045]). Xue teaches generation of an orthogonal chemical gradient by providing chemicals to the top and bottom channel, which can include SHH pathway signaling agents or retinoic acid (Pgs. 7-8, Paragraphs [0063] and [0065]). Xue teaches these methods, including the chemical gradient, can be used to facilitate dorsal-ventral patterned neural differentiation (Pg. 8, Paragraph [0066]).
It would have been prima facie obvious for one of ordinary skill in the art before the filing of the instant application to modify the microwell culture system of Asthana to allow for localized delivery of a bioactive molecule from a basal position, toward a microwell contained cell aggregate as taught by Höhnel, and to further include the teachings of Xue which describe the use of chemical gradient to direct spatially patterned neural differentiation to ultimately obtain a patterned organoid.
One having ordinary skill in the art seeking to obtain a patterned organoid would have been motivated with a reasonable expectation of success to combine these teachings and modify the plate culture system of Asthana because Höhnel shows it is possible for the local and timed delivery of molecules of interest to allow for selective manipulation of the formed aggregates (Pg. 2, Paragraphs [0024] and [0028]), while Xue shows that one can employ a developmental signaling agent in a culture apparatus with a molecule delivery system to provide a signaling agent asymmetrically relative to developing tissue in the microwell producing a chemical gradient that will direct spatially patterned neural differentiation Pg. 2, Paragraphs [0014] and [0016];Pg. 4, Paragraph [0039]).
Regarding Claim 16 - 20, The combined teaching of Asthana, Höhnel and Xue render obvious the method of claim 15 as described above in the 103 rejection, the contents of which are incorporated herein in their entirety. Moreover, Xue’s teachings are specifically in the field 3D culture to produce spatially patterned neural differentiation and generate forebrain, midbrain, and hindbrain spheroids (Pg. 2, Paragraphs [0014] and [0016]), and Xue describes “…chemical gradient promotes generation of a neural tube-like tissue exhibiting anterior-posterior and dorsal-ventral patterns…” Pg. 2, Paragraph [0016]). Further, Xue provides both an SHH pathway agonist and retinoic acid (with respect to instant claims 17 and 19) as exemplary components to be supplied to the cells via the established chemical gradient (Pg. 4, Paragraph [0039]).
It would have therefore been prima facie obvious to one having ordinary skill in the art before the filing of the instant application to combine the teachings of Asthana, Höhnel and Xue as described in the 103 rejection of claim 15 above, and to further include these additional teaching of Xue to obtain the inventions of claims 16-20. One would have been motivated with a reasonable expectation of success to provide the specific methodology and chemical gradient (including the components of an SHH pathway agonist and retinoic acid), as taught by Xue, within the combined culture methodology described in the 103 rejection of claim 15 above, as Xue shows that an orthogonal chemical gradient can successfully be used to generate specific spatial patterns for neural cells cultured in a microwell culture system and the usage within an organoid culture method/system would allow for one to predictably obtain the neuro-organoid and dorsal-ventral patterned forebrain organoid of claims 16 and 18, respectively. Additionally, retinoic acid is a known caudalizing morphogen and shown previously to direct a hindbrain fate, as evidenced by Valiulahi et al. (Summary of Valiulahi et al.). Therefore, hindbrain organoids subject to a retinoic acid based concentration gradient would predictably develop different rostro-caudal identities as evidenced by Valiulahi et al. and allow one to arrive at the invention of claim 20.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KODYE LEE ABBOTT whose telephone number is (703)756-1111. The examiner can normally be reached M-F 8-5.
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, Maria G. Leavitt can be reached on (571) 272-1085. 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.
/KODYE LEE ABBOTT/Examiner, Art Unit 1634
/CHRISTOPHER M BABIC/Supervisory Patent Examiner, Art Unit 1633
Prosecution Insights