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 .
Claims 1, 3, 4, 6 and 8-10 are pending in this application, Claim 10 is acknowledged as withdrawn, Claims 1, 3, 4, 6, 8 and 9 were examined on their merits.
The objection to the Drawings for referencing Trademarked material has been withdrawn due to the Applicant’s amendments to the Drawings filed 08/08/2025.
The objection to the Abstract because it is too short to describe
the disclosure sufficiently to assist readers in deciding whether there is a need for
consulting the full patent text for details, has been withdrawn due to the Applicant’s amendments to the Abstract filed 08/08/2025.
The rejection of Claims 1, 3-6, 8 and 9 under 35 U.S.C. § 112(b) or 35 U.S.C. § 112 (pre-AlA), 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applications subject to pre-AlA 35 U.S.C. 112, the applicant), regards as the invention, has been withdrawn due to the Applicant’s amendments to the Abstract filed 08/08/2025 and Remarks filed 08/08/2025 regarding “High Contact Screening” being a common term in the art being found to be persuasive.
The rejection of Claim 6 (inadvertently referred to as Claim 8 in the prior action) under 35 U.S.C. § 112(b) or 35 U.S.C. § 112 (pre-AlA), 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inventor (or for applications subject to pre-AlA 35 U.S.C. 112, the applicant), regards as the invention, has been withdrawn due to the Applicant’s amendments to the claim filed 08/08/2025.
Claim Rejections - 35 USC § 103
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.
Claim(s) 1, 3, 4, 6 and 8 are newly rejected under 35 U.S.C. § 103 as being unpatentable over Nakazawa et al. (US 2011/0003389 A1), of record, in view of Ellis et al. (WO 2018/011558 A1), translation, of record, Ejiri et al. (WO 2015/182159 A1), cited in the IDS, and Apfel (US 2020/0017811 A1), cited in the IDS, as necessitated by Applicant’s amendments to the claims filed 08/08/2025.
Nakazawa et al. teaches a method of producing an organoid, comprising the
steps of:
inoculating a microwell of a microwell plate with 2x105 HepG2 (human liver
cancer cell line) cells and culturing for 14 days thereby forming an organoid (Pg. 15,
Paragraph [0180], reading on Claims 1 and 3;
and wherein some of the organoids are 300 µm in diameter (Pg. 3, Paragraph
0055] and Fig. 37), reading on Claim 4.
Nakazawa et al. did not teach a method wherein the cell culture plate comprises
0-2 vol.% of extracellular matrix (ECM) based hydrogel, as required by Claim 1;
or wherein the microwell plate comprises:
a well plate comprising a plurality of main wells and a plurality of sub wells formed at lower portions of the main wells to be injected with a cell culture solution and comprising recessed parts on a bottom surface thereof; and a connector for high content screening (HCS),
which supports the well plate, and the connector for high content screening (HCS) comprises a base equipped with a fixing means so as to be attached to and detached from a lower end of the well plate and a cover positioned on an upper portion of the well plate to be coupled to the base,
the main well has a step and includes a space part between the step and the subwell and the subwell has an inclined surface formed so as to taper toward the recessed part,
and the step has an inclination angle ranging from 10 to 60° with respect to a wall of the main well, and
the inclined surface between the between the subwell and the recessed part ranges from 40-50°,
wherein the main well has an individual volume ranging from 100 to 300 µl,
the recessed part has an individual volume ranging from 20 to 50 µl, and an individual volume ratio of the main well to the recessed part is 1 : 0.1 to 0.5 on average, as now required by Claim 1;
wherein the sub wells have an upper end diameter ranging from 3.0 to 4.5 mm,
the recessed parts have an upper end diameter ranging from 0.45 to 1.5 mm,
and a ratio of the diameter of the sub wells to the diameter of the recessed parts ranges from 1:0.1 to 0.5, as now required by Claim 6;
or wherein the space part has a height (ah) ranging from 2.0 to 3.0 mm on average,
the sub well has a height (bh) ranging from 1.0 to 2.0 mm on average, and
a height ratio (ah:bh) of the space part to the sub well ranges from 1:0.3 to 1, as now required by Claim 8.
Ellis et al. teaches a method of culturing organoids comprising seeding the cells into a cell culture medium comprising about 1-99% v/v (encompassing the claimed 0-2 vol. %) of the extracellular matrix-based hydrogel MATRIGEL™ (Pg. 16, Claims 1, 5 and 8).
Ejiri et al. teaches a cell culture plate comprising a plurality of main wells and a plurality of subwells therein recessed on the bottom surface (Fig. 1 and Pg. 13, Lines 516-524);
wherein the subwells have a tapered recess (Fig. 6) with an inclination angle of 1-20° (overlapping the claimed 10-60° angle) (Pg. 4, Lines 144-147) and wherein the hemispherical or truncated cone shape promotes formation of a cell mass (Pg. 19, Lines 773-775).
With regard to Claim 1, Apfel teaches a 3D cell culture plate usable for culturing spheroids (the Examiner notes that the terms “spheroid” and “organoid” are used interchangeably in the instant Specification, see Pg. 2, Paragraph [0046] of the published application) (Abstract and Paragraphs [0005], [0010], [0156] and Figs. 1A, 1J).
The 3D cell culture plate comprises a plurality of main wells (wider top portion) each having a subwell formed at the lower portion of the main well (narrower lower portion) to be injected with cell culture media and comprising recessed parts on a bottom surface (narrowest lower portion/bottom) (see Figs. 1A, 1B, 1F, 1J, 2). The well plate further comprising a connector, the connector including a base intended to be removably affixed to the lower end of the well plate, and a base equipped with means to attach and detach from the lower end of the microwell plate and a lid which is positioned over the top of the microwell plate which is capable of attaching and detaching from the base (see Fig. 1Ju, #124, Fig. 2 and Pg. 9, Paragraph [0098]). As Apfel teach a connector with the components as claimed, the connector as taught is necessarily capable of being used for large-capacity and high-speed high content screening (see also, Para. 8, 120, 157). The main well (wider top portion) has a neck, which is a step, formed so as to be tapered at a predetermined site, (see Figs. 1A, 1B, 1F). The step having an inclination angle with respect to a wall of the main well of 30° (see Figs. 1A, 1F; see also Paragraphs [0045], [0049] and[0050]).
With regard to Claim 1, Apfel teaches that the concentrating volume, which is the main well, has an individual volume of 100, 125, 150, 175, 200, 225, or 250 µL (Pg. 2, Paragraph [0026]), which is fully encompassed within the claimed volume range 100 to 300 µL. The culturing volume, which is the recessed part, has an individual volume of 20, 25, 30, 40 or 50 µL (Pg. 3, Paragraph [0032]), which is fully encompassed within the claimed volume range of 20 to 50 µL.
An individual volume ratio of the main well to the recessed part is 10:1 (1:0.1) (Pg. 3, Paragraph [0033]), which is fully encompassed within the claimed volume ratio of 1:0.1 to 0.5.
With regard to Claims 1 and 6, Apfel teaches that the subwell (intermediate sloping portion) has a surface formed so as to taper toward the recessed part (bottom portion). The recessed parts have an upper end diameter (#126/126’') of 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, or 1.5 mm (Pg. 7, Paragraph [0079] and Fig. 1F), which are fully encompassed within the claimed diameter range of 0.45 to 1.5mm. As determined from Fig. 1F, the ratio of the horizontal dimension of the upper end of the recessed part (#126/126') to the upper end of the sub well (top of the intermediate sloping portion), is 5:1. Thus, the sub well can have an upper end diameter including 3.0, 3.5, or 4.0 mm (based on 0.6, 0.7, or 0.8 mm upper end diameter of recessed parts). The inclined surface between the subwell and the recessed part, as determined from Fig. 1F, is 50°, which is fully encompassed within the claimed inclination of from 40 to 50°. As determined from Fig. 1F, the ratio of the horizontal dimension of the upper end of the recessed part (#126/126') to the horizontal dimension of the upper end of the sub well (top of the intermediate sloping portion), is 5:1, which is fully encompassed within 10:1 (1:0.1) to 2:1 (1:0.5).
With regard to Claims 1 and 8, referring to Fig. 1F, Apfel teaches that the main well (top portion) comprises a space part (intermediate sloping portion) between the step (junction of the top portion with the intermediate portion) and the subwell (bottom portion). The culturing volume, which is the subwell, has a height of 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2.0 mm. with an average height of 1.5 mm (Pg. 3, Paragraph [0034]), which is fully encompassed within the claimed height range of 1.0 to 2.0 mm on average. As determined from Fig. 1F, the height ratio of the space part to the sub well is about 1:1. As such, the space part may have a height including 2.0 mm, as based upon a 1:1 ratio with the taught subwell height of 2.0 mm (see Paragraph [0034]). A height of 2.0 mm is fully encompassed within the claimed range 2.0 to 3.0 mm on average.
It would have been obvious to those of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of Nakazawa et al. of producing an organoid in a multi-well plate with the use of a cell culture medium comprising about 1-99% v/v MATRIGEL™ to culture organoids as taught by Ellis et al. because this would provide a solid support for the organoid. Those of ordinary skill in the art would have been motivated to make this modification in order to provide a cell culture medium which will also support the organoid growth in three dimensions. There would have been a reasonable expectation of success in making this modification because both references are drawn to the same field of endeavor, that is, the culture and propagation of organoids.
It would have been further obvious to those of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of Nakazawa et al. and Ellis et al. of producing an organoid in a multi-well plate with the cell culture plate of Ejiri et al. comprising a plurality of main wells with subwells recessed therein having a tapered recess because this would promote cell mass formation (aggregation) which is a precursor to organoid formation. It would been further obvious to modify the main wells of Ejiri et al. to include a step tapered recess (Fig. 6) with an inclination angle of 1- 20° (overlapping the claimed 10-60° angle) because this would also promote cell mass formation along with the subwells. Those of ordinary skill in the art would have been motivated to make this modification in order to promote organoid growth from plated cells. There would have been a reasonable expectation of success in making this modification because the Nakazawa reference is drawn to the culture and propagation of organoids and Ejiri et al. teaches a multiwell cell culture plate suitable for formation of cell aggregates (precursors to organoid formation).
It would have been further obvious to those of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of Nakazawa et al., Ellis et al. and Ejiri et al. of producing an organoid in a multi-well plate to use the microplate system of Apfel because this would provide an organoid culturing system suitable for culturing and characterizing multiple organoids. Those of ordinary skill in the art would have been motivated to make this modification in order to have a multi- organoid culturing system that can also be used testing and analysis thereof.
There would have been a reasonable expectation of success in making this modification because at least Nakazawa, Ejiri and Apfel are all drawn to multiwell plate methods or systems.
Claim(s) 1, 3, 4, 6, 8 and 9 are rejected under 35 U.S.C. § 103 as being unpatentable over Nakazawa et al. (US 201 1/0003389 A1), of record, in view of Ellis et al. (WO 2018/01 1558 A1), translation, of record, Ejiri et al., (WO 2015/182159 A1), translation, cited in the IDS, and Apfel (US 2020/0017811 A1), cited in the IDS, as applied to Claims 1, 3, 4, 6 and 8 above, and further in view of Sato et al. (US 8,642,339 B2), of record.
The teachings of Nakazawa et al., Ellis et al., Ejiri et al. and Apfel were discussed above.
None of the above references taught a method wherein the cells are seeded into the subwells at 100-300 cells/well, as required by Claim 9.
Sato et al. teaches a method of organoid formation wherein 100 cells/well are plated before culturing 14 days to form organoids (Column 20, Lines 44-46).
While the references listed above do not specifically teach the limitation of Claim 9, that the cells are seeded into the subwells at 100-300 cells/well, one of ordinary skill in the art would recognize that the concentration of cells seeded into a well is a result- effective, optimizable variable. Nakazawa et al. teaches inoculating a microwell of a microwell plate with 2x105 HepG2 cells and culturing for 14 days thereby forming an organoid while Sato et al. teaches a method of organoid formation wherein 100 cells/well are plated before culturing 14 days to form organoids. These are endpoints in a useful concentration range which encompasses the claimed range of 100-300 cells/well. This is motivation for someone of ordinary skill in the art to practice or test the subwell inoculation cells/well values widely to find those that are functional or optimal to sufficiently produce the desired organoids which then would be inclusive or cover the instantly claimed values. Absent any teaching of criticality by the Applicant concerning the number of cells/well, it would be prima facie obvious that one of ordinary skill in the art would recognize these limitations are an optimizable variable which can be met as a matter of routine optimization (see MPEP § 2144.05 (II)(B). Those of ordinary skill in the art before the effective filing date of the claimed invention would have been motivated to make this modification in order to obtain microwell plate with the requisite number of cells/well to produce the desired organoids. There would have been a reasonable expectation of success in making these modifications because at least the Nakazawa and Sato the references are reasonably drawn to the same field of endeavor, that is, the production of organoids from cultured cells.
Response to Arguments
Applicant’s arguments, see Remarks, filed 08/08/2025, with respect to the above withdrawn objections/rejection have been fully considered and are persuasive.
Applicant's arguments filed 08/08/2025 have been fully considered but they are not persuasive.
The Applicant argues that with regard to the first inclination angle of 10-60°, the claimed range provides almost no effect on the recessed part when changing the culture medium as compared to a lower inclination angle. Applicant notes that inclination angles greater than the claimed range makes it impossible to design space parts with a diameter of 6-9 mm, the approximate diameter of two subwells (Remarks, Pg. 8, Lines 32-36 and Pg. 9, Lines 1-7).
This is not found to be persuasive for the following reasons, as discussed above and in the prior action, Apfel teaches the main well (wider top portion) has a neck, which is a step, formed so as to be tapered at a predetermined site, (see Figs. 1A, 1B, 1F). The step having an inclination angle with respect to a wall of the main well of 30° (see Figs. 1A, 1F; see also Paragraphs [0045], [0049] and[0050)). Therefore, as the first inclination angle of the prior art falls within the claimed inclination range, the same properties and characteristics as the claimed invention would also be expected in the prior art.
The Applicant argues that with regard to the second inclined surface, when the inclined surface is greater than 50°, not all of the cells enter the subwell properly during seeding causing the cells to grow outside the subwell and when the angle is less than 40° it won’t be connected to the external design of the well (Remarks, Pg. 10, Lines 1-4).
This is not found to be persuasive for the following reasons, as discussed above and in the prior action, Apfel teaches the inclined surface between the subwell and the recessed part, as determined from Fig. 1F, is 50°, which is fully encompassed within the claimed inclination of from 40 to 50°. Therefore, as the inclined surface angle of the prior art falls within the claimed inclination range, the same properties and characteristics as the claimed invention would also be expected in the prior art.
The Applicant argues that Apfel fails to teach or suggest the two angular ranges or the “space part” as now claimed (Remarks, Pg. 13, Lines 1-7).
This is not found to be persuasive for the reasoning provided in the above new rejections.
Conclusion
No claims are 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 PAUL C MARTIN whose telephone number is (571)272-3348. The Examiner can normally be reached Monday-Friday 12pm-8pm EST.
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, Sharmila G Landau can be reached at (571) 272-0614. 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.
/PAUL C MARTIN/Examiner, Art Unit 1653
/SHARMILA G LANDAU/Supervisory Patent Examiner, Art Unit 1653