DETAILED ACTION
Claims 1-20 are currently pending.
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 .
Priority
Acknowledgement is made of the instant application being a national stage entry under 35 USC 371 of international application PCT/IB2022/051484, filed 2/18/2022, which claims the benefit of provisional application No. 63/151,082, filed 2/19/2021.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 11/16/2023, 3/26/2024, 5/8/2025, 3/16/2026 and 3/25/2026 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Claim Objections
Claims 1-3, 9, 13, 16, and 18 are objected to because of the following informalities: typographical.
Claim 1 recites the phrases “wellunit”, “therebyseparating” and “oneor”.
Claim 2 recites the phrase “ashared”.
Claim 3 recites the phrase “arrange”.
Claim 9 recites the phrases “pluralityof” and “wellsection”.
Claim 13 recites the phrase “bottomesurface”.
Claim 16 recites the phrases “anothervia” and “thefirst”.
Claim 18 recites the phrases “oneor” and “atemperature”.
Appropriate correction is required.
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.
Claims 1, 12-14, 16 and 20 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.
Claims 1, 12, 16 and 20 recite the phrase “fresh culture environment”.
Claims 12-14 and 20 recite the phrase “fresh hydrogel”.
The term “fresh” is a relative term which renders the claims indefinite. The term “fresh” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. The specification does not further define the boundaries of the fresh environment or the fresh hydrogel. There is no indication in the disclosure as to whether or not the “fresh” hydrogel includes a hydrogel that has been returned to the liquid state and thereafter polymerized, or includes a hydrogel that has not been in contact with cells/organoids, or includes hydrogel material that is not considered stale or expired or decayed in some manner.
Likewise, although the specification ([0008]) discloses a fresh culture environment includes depositing a fresh hydrogel on a bottom surface of the primary well, the ambiguity of a ‘fresh’ hydrogel, does not clarify the metes and bounds of the limitation.
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(s) 1-13 and 15-20 are rejected under 35 U.S.C. 103 as being unpatentable over Clinton et al (Current Protocols in Cell Biology, vol. 82, no. 1, March 30, 2019, 22 pages; IDS 11/16/2023) (“Clinton”), in view of Cho et al., (US 2019/0390149; IDS 11/16/2023) (“Cho”).
Clinton is directed to methods for three-dimensional (3D) in vitro culture of human organoids using an embedded 3D “dome” technique (INTRODUCTION and Figure 1).
Regarding claims 1-8, 12-13, 15-16 and 18-20, Clinton’s Figure 1 illustrates culturing one or more organoids in an ECM (extracellular matrix) hydrogel wherein the cell/ECM droplet is dispensed to a well unit, incubated at 37° C to polymerize the hydrogel thus forming the “dome”, and thereafter the hydrogel dome is overlayed with cell culture medium and subjected to in vitro culture to promote organoid growth.
Clinton (at pages 8-9) teaches the organoids are then separated from the hydrogel for subsequent passaging, wherein the ECM hydrogel is dissipated into fragments and removed by cooling the hydrogel with cold liquid medium (4°C, page 3, paragraph 4; i.e., about 4°C or less), by dispensing the cold liquid medium since cold liquid medium can facilitate a return of the hydrogel to a liquid state (claims 4-6 and 18). The hydrogel fragments are removed from the well. Clinton further teaches using mechanical disruption/dissociation following ECM hydrogel to dissociate the organoids into single cells or fragments (i.e., organoid fragments and corresponding debris), wherein mechanical disruption comprises pipetting up and down 20 to 30 times to break up the organoids into smaller fragments (i.e., applying at least one shear force to the one or more organoids in the liquid handler (claims 7 and 19)), i.e., manipulating the liquid handler to cause the one or more organoids to move vertically within the liquid handler (claim 8)). Clinton further teaches the dissociated single cells or multicellular fragments are re-suspended in a volume of ECM (i.e., creating a fresh culture environment comprising the plurality of organoid fragments, embedded in the fresh hydrogel prior to depositing (claims 1, 12-13) and dispensed back into culture vessels as 3D domes (i.e., depositing the plurality of organoid fragments and the corresponding debris into the primary well via the liquid handler) and further cultured at 37° C (claims 15 and 20) (pages 8-9).
Clinton differs from the instant invention in that Clinton does not further teach a microwell plate comprising secondary wells connected to the primary wells via at
least one channel. However, the use of a microwell plate having a separate reservoir, secondary well, for the supply of nutrients and medium in methods for culturing organoids have been described in Cho.
Cho is directed to organoid culture and a microfluidic organoid culture device that comprises a first chamber for storing culture medium and a second chamber for culturing an organoid wherein a channel fluidly interconnects adjacent chambers (Abstract; [0002]-[0007]; FIG. 1). Cho teaches the organoids are cultured through three-dimensional (3D) culture using the well-known hydrogel Matrigel, which is a liquid that contains water as a dispersion medium and is hardened (polymerized), through the sol-gel phase transition, thus losing fluidity and forming a porous structure. ([0075]-[0079]). Cho’s culture device 100 comprises various well units (i.e., well unit of a microwell plate) including at least one first chamber 101 for storing the culture medium, at least one second chamber 102 for culturing the organoid, and a channel 103 that interconnects the adjacent chambers so the culture medium is shared throughout the culture device ([0055]-[0056]; FIG. 1).
Cho’s FIG. 1 is copied immediately below for Applicant’s convenience:
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Cho’s hydrogel comprising the organoid is disposed in well section 102 and thus reads on the claimed “primary well section of the well unit”. Cho’s disclosed chamber 101 for storing the culture medium reads on “a secondary well unit”. The chambers 101 and 102 are interconnected by channel 103, thus Cho’s teaching reads on “a primary well section that is fluidly connected to a secondary well section via at least one channel, the hydrogel being disposed in the primary well section of the well unit”.
Thus, Cho has established it was known to use a microwell plate having a primary well section that is fluidly connected to a separate reservoir, i.e., secondary well, for the supply of nutrients and medium in methods for culturing organoids, wherein a hydrogel is disposed in the primary well section of the well unit.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to employ the microwell plate disclosed by Cho for culturing and passaging organoids since Cho teaches numerous advantages including the production of highly functional organoids in a highly efficient manner, thus enhancing the availability of organoids for new drug development with the benefit of improving drug development costs, and further providing a culture system having excellent universality and one that is easily optimized to differ in shape and specification so as to be suitable for culturing different types of organoids having various shapes and sizes ([0022]-[0025]).
The person of ordinary skill in the art would have been motivated to modify the method of Clinton to include culturing in a microwell plate as taught by Cho, for the predictable result of successfully enhancing the availability of organoids for new drug development.
The skilled artisan would have had a reasonable expectation of success in combining the teachings of Clinton and Cho because each of these teachings are directed at three-dimensional culturing of organoids in a hydrogel.
Further regarding claim 2 and the limitation the at least on channel is formed by at least on gap between a bottom surface of the well unit and a bottom portion of a shared sidewall of the primary well section and the secondary well section, it is noted Cho’s FIG. 1 illustrates the interconnected channel is a gap located between the shared walls of the chambers 101 and 102, located at the bottom surface of the interconnected wells, thus meeting the limitation of claim 2.
Further regarding claim 3, Cho teaches the channel (FIG. 1 #103) allows the culture medium to move between the chambers and the channel has a width of 0.6 to 1.0 mm and a height of 0.1 to 0.5 mm (i.e., height of the gap is in a range of about ten (10) microns up to about one hundred (100) microns) ([0083]). In the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). MPEP 2144.05
Further regarding claims 9-11 and 16 and the limitation of transferring the plurality of hydrogel fragments from the primary well section into the secondary well section of the well unit via the at least one channel (claim 9), the limitation of flushing the at least one channel to remove at least one of a debris fragment or an organoid fragment from the at least one channel (claim 10), the limitation of moving the corresponding debris to the secondary well section of the well unit via the at least one channel (claim 11), and the limitation removing the hydrogel from the first well unit via the supply well of the first well unit, the one or more cellular bodies remaining within the culture well of the first well unit (claim 16), it is noted as discussed above, Cho’s FIG. 1 illustrates the primary and secondary well sections (chambers 101 and 102) are connected via channels 103, and the channels have a height ranging from 0.1-0.5 mm and have a width ranging from 0.6-1 mm. Cho, at [0086], further teaches the culture medium provided in chambers 101 and 102, via the channel 103, is a medium for supplying and transporting nutrients, oxygen, or the like, and capable of removing waste. Thus, absent evidence to the contrary, it is considered that Cho’s microwell device would permit transfer of hydrogel fragments via channel 103, thus meeting the limitations of claims 9-11 and 16.
Regarding claim 17 and the limitation the channel is sized and shaped to prevent passage of objects sized greater than about 25 µm between the culture well and the supply well, it is noted that the limitation “greater than about 25 µm” includes preventing passage of objects having sizes larger than 5 mm, 50 mm or 500mm, for example.
Cho teaches the smallest dimension of the interconnected channel (103) is a height ranging from 0.1-0.5 mm (100-500 µm). Therefore, Cho’s channel is sized and shaped to prevent passage of objects sized greater than 0.1-0.5 mm and therefore the prior art range overlaps the claimed range. In the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). MPEP 2144.05
Claim(s) 14 is rejected under 35 U.S.C. 103 as being unpatentable over Clinton, in view of Cho, as applied to claims 1-13 and 15-20 above, and further in view of Vulto et al., (US 2020/0063081; IDS11/16/2023) (“Vulto”).
The teaching of Clinton, in view of Cho, is set forth above.
Regarding claim 14, it is noted that Clinton teaches the organoid fragments are embedded in the fresh hydrogel prior to depositing on the bottom surface of the primary well section. Clinton does not further comment on embedding the organoid fragments in fresh hydrogel after the fresh hydrogel is deposited on the bottom surface of the primary well section. However, Vulto is directed to three-dimensional cell aggregate (i.e., organoid) culture in microfluidic culture devices (Abstract), and Vulto, at [0164], teaches the hydrogel is preloaded with the cell or cells of interest (i.e. organoid fragments) prior to depositing on the culture surface, or alternatively the cells (i.e. organoid fragments) are embedded in the hydrogel after the hydrogel is deposited to the culture surface.
Thus, Vulto has established it was well known in the art of culturing organoids in hydrogels that organoid fragments could be embedded in the hydrogel prior to or after the hydrogel is deposited on the surface of the primary well section.
Accordingly, it would have been obvious to one of ordinary skill in the art at the time the invention was made to modify the method taught by Clinton, in view of Cho, by substituting embedding the organoid fragments in the hydrogel after the hydrogel is deposited on the cultures surface. Thus, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
Accordingly, it would have been prima facie obvious to one having ordinary skill in the art at the time of filing the invention to substitute embedding the organoid fragments in the hydrogel after the hydrogel is deposited on the cultures surface since both embedding prior to and after depositing the hydrogel on the bottom surface of the primary well section are known to successfully produce organoids. Therefore, one of ordinary skill in the art would recognize this as simply substituting one type of embedding technique for another useful for the same purpose ((KSR Int’l Co. v. Teleflex, Inc., 550 U.S. 398 (2007) pg 14 and 12).
The skilled artisan would have had a reasonable expectation of success in combining the teachings of Vulto with the cited prior art because each of these teachings are directed at organoid culture.
Conclusion
No claim is allowed. No claim is free of prior art.
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