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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 11/12/2025 has been entered.
Claim Status
Claims 1-10 are pending and being examined.
Response to Amendment
The amendments and remarks, filed on 11/12/2025, has been entered. The claim amendments overcome the previous prior art rejection, and a new prior art rejection is applied to address the claim amendments.
The amendments and remarks, filed on 11/12/2025, has been entered. The claim amendments overcome the 112(b) rejection of claim 1.
Claim Rejections - 35 USC § 112
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 1-10 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. Claim 1 recites limitations “each well being physically isolated from all adjacent wells so as to prevent inter-well fluid communication, thereby enabling independent formation and evaluation of a three-dimensional micro-tissue in each well…each well is bounded laterally by walls that extend fully to the plate top surface, without any shared channel, trench, or gap permitting fluid communication between adjacent well”. Applicants do not provide support for the structural limitations “each well being physically isolated from all adjacent wells” and “each well is bounded laterally by walls that extend fully to the plate top surface without any shared channel, trench, or gap permitting fluid communication between adjacent well”. Further, there is no discussion of the functional limitations of “prevent[ing] inter-well fluid communication”. Applicant’s fail to provide evidence in the specification to support the limitations. Claims 2-10 are rejected by virtue of dependency on claim 1.
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 1-10 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 limitation "the aggregation factor corresponding to the total volume divided by the bottom surface area wherein volume and surface are based on the same fundamental units" in lines 18-20. The limitation is unclear as the applicant has amended the claim and removed the limitation “unit length”. Examiner notes that the applicant recites the volume and surface area are the same fundamental units. Thus, it is unclear how the aggregation factor would be a unitless value. Specifically, it is unclear as the aggregation factor corresponds to the volume (“cubed” as it’s a three-dimensional measurement) divided by the surface area (“squared” as it is a two-dimensional measurement) would not result in a unitless value. For the purpose of prosecution, the examiner refers to the instant specification in paragraph [0024] wherein dividing the total volume by the surface area gives the aggregation height. The aggregation height is divided by a unit length of 1 mm to correspond to the unitless aggregation factor. Thus, for purpose of prosecution, the examiner applies a unit length of 1 to the calculations provided below. Claims 2-10 are rejected by virtue of dependency on claim 1.
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 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) 1-8 and 10 are rejected under 35 U.S.C. 103 as being unpatentable over Fang et al (WO 2016069892 A1; hereinafter “Fang”; FOR filed on 5/13/2025; already of record) in view of Yamada et al (WO 2006040871 A1); .
Regarding claim 1, Fang teaches a system for obtaining a three-dimensional micro-tissue (Fang; para [7]; device provided for generation and culture of 3D cell aggregates), comprising: a cell culture device (Fang; Fig. 26, 27; para [206]; cell culture apparatus 3100), comprising:
a plurality of wells (Fang; Fig. 27; para [206]; the plurality of wells 3115), each well comprising:
an opening at an upper surface of the device, the opening characterized by an opening cross-sectional area (Fang; Fig. 27; para [206]; top aperture 3118);
a bottom located towards a lower surface of the device, the bottom characterized by a bottom surface area inside the well (Fang; Fig. 27; para [206]; the bottom surface 3112), the bottom surface area comprising a planar portion (Fang; Fig. 27; examiner notes that the bottom surface is flat as seen in Fig. 27), and the bottom characterized by transparency effective to permit imaging or spectroscopy inside each well (Fang; para [39]; the well-bottom is transparent); and
a wall extending from the opening to the bottom (Fang; Fig. 27; para [193]; a sidewall surface 3120 extending from the top aperture 3118 to the bottom surface 3112), the wall defining:
a total volume between the opening and the bottom (Fang; Fig. 27; para [204]; A combination of the bottom surface 3112, the pen tip area 3116 and a portion of the sidewall surface 3120 may define a cell culture volume 3140);
a neck located below the opening (Fang; Fig. 27; para [206]; a point 3123 along the sidewall surface 3120 that is between the top aperture 3118 and the pen tip area 3116), the neck characterized by a neck cross-sectional area parallel to the opening (Fang; Fig. 27; examiner notes that the neck cross-sectional is interpreted as the space/area which where point 3123 is located, thus would be parallel with the opening of the well);
a concentrating volume between the neck and the opening (Fang; Fig. 27; examiner interprets the concentrating volume to be the volume above the point 3123); and
a culturing volume between the neck and the bottom (Fang; Fig. 27; examiner interprets the concentrating volume to be the volume below the point 3123);
each well characterized by an aggregation factor of greater than 800, the aggregation factor corresponding to the total volume divided by the bottom surface area wherein volume and surface area are based on the same fundamental units (Fang; para [192, 195, 196])1; and
the bottom limited in diameter between 100 and 400 microns (Fang; para [198]; the pen tip area 3116 may be defined by a diametric dimension 3144 across the sidewall surface 3120… a diametric dimension 3144 of about, e.g., greater than or equal to 400 micrometers, greater than or equal to 550 micrometers, etc. or, less than or equal to 800 micrometers, less than or equal to 700 micrometers, less than or equal to 600 micrometers, etc. or any range within the aforementioned values)2.
1 Fang teaches that the microwells may have a depth in a range from about 50 micrometers to about 700 micrometers, such as about 100 micrometers to 500 micrometers (Fang; para [192]). Additionally, Fang teaches the diametric dimension of the top aperture 3118 may be about, e.g., greater than or equal to 300 micrometers, greater than or equal to 500 micrometers, greater than or equal to 800 micrometers, greater than or equal to 1000 micrometers, greater than or equal to 1500 micrometers, greater than or equal to 2000 micrometers, etc. or, less than or equal to 7000 micrometers, less than or equal to 6000 micrometers, less than or equal to 4000 micrometers, less than or equal to 2500 micrometers, less than or equal to 1700 micrometers, less than or equal to 1200 micrometers, etc. or any range within the aforementioned values (Fang; para [195]). Further, Fang teaches the diametric dimension of the bottom surface may be about, e.g., greater than or equal to 0 micrometers, greater than or equal to 50 micrometers, greater than or equal to 75 micrometers, greater than or equal to 100 micrometers, greater than or equal to 200 micrometers, greater than or equal to 275 micrometers, etc. or, less than or equal to 700 micrometers, less than or equal to 500 micrometers, less than or equal to 400 micrometers, less than or equal to 300 micrometers, less than or equal to 250 micrometers, less than or equal to 150 micrometers, etc. or any range within the aforementioned value (Fang; para [196]). The examiner notes that Fang teaches a wide range of dimensions for the diameter of the opening, length/depth of the well, and the diameter of the bottom surface. Further, Fang teaches the shape of the concentrating volume being defined by a truncated paraboloid (Fang; para [201]; Fig. 28) and the culturing volume being defined by a cylinder (Fang; para [196]; Fig. 28). There is no established criticality or evidence showing an unexpectedly good result occurring form the claimed parameters. Therefore, the claimed range overlaps or falls within the prior art range; in cases where the claimed range overlaps or falls within the prior art range, a prima facie case of obviousness of the range exists. The examiner notes that the total volume would equal the volume of the truncated paraboloid (approximately 2.9x107 µm3 if the opening/larger diameter is 500 µm, the lower diameter is 50 µm, the depth of the well is 100 µm) + volume of the cylinder (3.9x105 µm3 if the diameter is 50 µm, the height of the lower well is 50 µm)/ surface area of the circle (approximately 7854 µm2 if the diameter is 50) would give you a factor of approximately 3742. It would have been obvious to one having ordinary skill in the art to have selected the surface area of the lower section and the total volume in the range that corresponds to the claimed aggregation factor of being 800 as Fang teaches that the well dimensions are sized to allow the spheroid to expand to the ideal size (Fang; para [192]).
2 The claimed range overlaps or falls within the prior art range; in cases where the claimed range overlaps or falls within the prior art range, a prima facie case of obviousness of the range exists. It would have been obvious to one having ordinary skill in the art to have selected the portion of the bottom diameter to between 100 and 400 microns in the range that corresponds to the claimed range. See MPEP 2144.05(I).
Fang does not teach each well being physically isolated from all adjacent wells so as to prevent inter-well fluid communication, thereby enabling independent formation and evaluation of a three-dimensional micro-tissue in each well; each well is bounded laterally by walls that extend fully to the plate top surface, without any shared channel, trench, or gap permitting fluid communication between adjacent well.
However, Yamada teaches an analogous art each well being physically isolated from all adjacent wells so as to prevent inter-well fluid communication, thereby enabling independent formation and evaluation of a three-dimensional micro-tissue in each well (Yamada; para [42]; protrusions 21 are provided in a lattice pattern on the front surface of the well plate 14 so as to partition each of the wells 20, and mineral oil or the like is stored in a rectangular section partitioned by the protrusions 21); each well is bounded laterally by walls that extend fully to the plate top surface, without any shared channel, trench, or gap permitting fluid communication between adjacent well (Yamada; Fig. 4a, 4b; para [42]; protrusions 21 are provided in a lattice pattern on the front surface of the well plate 14 so as to partition each of the wells 20, and mineral oil or the like is stored in a rectangular section partitioned by the protrusions 21). The examiner notes that Fig. 4b shows that the protrusions extend to the top/opening of the well plate 14. Thus, it would have been obvious to one of ordinary skill in the art before the effective filing date to have modified the wells of Fang to be physically isolated from all adjacent wells and bounded laterally by walls that extend fully to the plate top surface as taught by Yamada, because Yamada teaches that the protrusions partition each well to provide a different culture environment for each single cell by shielding each well from each other (Yamada; para [42]).
Regarding claim 2, modified Fang teaches the system of claim 1, each well characterized by one or more of:
the aggregation factor between 800 and 40,000 (see claim 1).
Regarding claim 3, modified Fang teaches the system of claim 1, the concentrating volume in each well being between about 10 µL and about 1500 µL, and the culturing volume in each well being between about 1 µL and about 250 µL (see superscript “1” in claim 1). Examiner notes that the concentrating volume is 2.9x107 µm3 and culturing volume is 3.9x105 µm3 would be 0.029 µL and 0.00039 µL, respectively. Thus, it would have been obvious to one of ordinary skill in the art to choose dimensions for the upper radius, lower radius, and depth be within the claimed limitations. There is no established criticality or evidence showing an unexpectedly good result occurring form the claimed parameters. Therefore, the claimed range overlaps or falls within the prior art range; in cases where the claimed range overlaps or falls within the prior art range, a prima facie case of obviousness of the range exists. It would have been obvious to one having ordinary skill in the art to have selected the culturing volume in each well that corresponds to the claimed aggregation range of between about 1 µL and about 250 µL. See MPEP 2144.05(I).
Regarding claim 4, modified Fang teaches the system of claim 1,
at least a portion of the wall in each well between the opening and the neck defining at least one of: a cylinder, a cone with a truncated apex at the neck, a paraboloid with a truncated vertex at the neck, and a hyperboloid that decreases in diameter towards the neck (Fang; Fig. 27; para [201]; the upper sidewall surface 3124 and the lower sidewall surface 3122 may be defined by a shape that is, e.g., parabolic, conical, stepped, various angles, curved, etc. The upper and lower sidewall surfaces 3124, 3122 may have the same or different shapes).
Regarding claim 5, modified Fang teaches the system of claim 1, at least one of:
the opening of each well characterized by one or more of:
a horizontal surface area in mm2 of from about 0.75 to 325,
an average horizontal dimension in mm of between about 0.5 to about 10 (Fang; para [195]);
the bottom in each well characterized by one or more of:
the bottom surface area in μm2 of from about 7500 to 125,000; and
an average horizontal dimension in μm of between about 100 to about 400 (Fang; para [196]); and
the neck in each well characterized by one or more of:
the neck cross-sectional area in μm2 of from about 7500 to 125,000; and
an average horizontal dimension in μm of between about 100 to about 400 (Fang; para [195, 196]).
3 There is no established criticality or evidence showing an unexpectedly good result occurring form the claimed parameters. Therefore, the claimed range overlaps or falls within the prior art range; in cases where the claimed range overlaps or falls within the prior art range, a prima facie case of obviousness of the range exists. It would have been obvious to one having ordinary skill in the art to have selected an average horizontal dimension in mm that corresponds to the range of between about 0.5 to about 10. See MPEP 2144.05(I). Fang teaches the diametric dimension of the top aperture 3118 may be about, e.g., greater than or equal to 300 micrometers, greater than or equal to 500 micrometers, greater than or equal to 800 micrometers, greater than or equal to 1000 micrometers, greater than or equal to 1500 micrometers, greater than or equal to 2000 micrometers, etc. or, less than or equal to 7000 micrometers, less than or equal to 6000 micrometers, less than or equal to 4000 micrometers, less than or equal to 2500 micrometers, less than or equal to 1700 micrometers, less than or equal to 1200 micrometers, etc. or any range within the aforementioned values (Fang; para [195]).
4 There is no established criticality or evidence showing an unexpectedly good result occurring form the claimed parameters. Therefore, the claimed range overlaps or falls within the prior art range; in cases where the claimed range overlaps or falls within the prior art range, a prima facie case of obviousness of the range exists. It would have been obvious to one having ordinary skill in the art to have selected an average horizontal dimension in μm that corresponds to the range of between about 100 to about 400. See MPEP 2144.05(I). Fang teaches the diametric dimension of the bottom surface may be about, e.g., greater than or equal to 0 micrometers, greater than or equal to 50 micrometers, greater than or equal to 75 micrometers, greater than or equal to 100 micrometers, greater than or equal to 200 micrometers, greater than or equal to 275 micrometers, etc. or, less than or equal to 700 micrometers, less than or equal to 500 micrometers, less than or equal to 400 micrometers, less than or equal to 300 micrometers, less than or equal to 250 micrometers, less than or equal to 150 micrometers, etc. or any range within the aforementioned value (Fang; para [196]).
5 There is no established criticality or evidence showing an unexpectedly good result occurring form the claimed parameters. Therefore, the claimed range overlaps or falls within the prior art range; in cases where the claimed range overlaps or falls within the prior art range, a prima facie case of obviousness of the range exists. It would have been obvious to one having ordinary skill in the art to have selected an average horizontal dimension in μm that corresponds to the range of between about 100 to about 400. See MPEP 2144.05(I). The examiner notes that the neck would fall within the required range depending on the diameter of the opening and the diameter of the bottom surface, because the neck cannot be smaller in diameter than the bottom surface and larger in diameter than the opening.
Regarding claim 6, modified Fang teaches the system of claim 1, the cell culture device comprising one or more of: polystyrene, polycarbonate, polyethylene, polypropylene, polyoxymethylene, a cyclic polyolefin, a fluoropolymer, glass, quartz, sapphire, silicon, and a silicone polymer (Fang; para [225]; The devices, wells, sidewalk, well-bottom, and other features described herein are formed of any suitable material. Preferably, material intended to contact cells or culture media are compatible with the cells and the media. Typically, cell culture components are formed from polymeric material. Examples of suitable polymeric material include polystyrene).
Regarding claim 7, modified Fang teaches the system of claim 1, at least a portion of the cell culture device comprising a material that is opaque (Fang; para [39]; the sidewall or sidewalls is opaque).
Regarding claim 8, modified Fang teaches the system of claim 1, each well comprising one or more of: a biocompatible coating, a coating configured for mitigating cell adhesion, a covalently attached monolayer, a metal film, and an irradiated layer (Fang; para [187]; Coatings can be introduced by any suitable method known in the art including printing, spraying, condensation, radiant energy, ionization techniques or dipping. The coatings may then provide either covalent or non-covalent attachment sites. Such sites can be used to attach moieties, such as cell culture components).
Regarding claim 10, modified Fang teaches the system of claim 1, at least one well being loaded with one or more of: a suspension of cells, cell clusters, and/or tissue fragments in the concentrating volume; the three-dimensional micro-tissue on the bottom in the culturing volume; and a concentration gradient in the three-dimensional micro-tissue, the concentration gradient corresponding to one or more of: a gas, a metabolite, a nutrient, a biomolecule, an imaging contrast agent, and a therapy for evaluation (Fang; para [8, 12]; cells are grown in three dimensions, such as spheroids… the systems, devices, and methods comprise culture media (e.g., comprising nutrients (e.g., proteins, peptides, amino acids), energy (e.g., carbohydrates), essential metals and minerals (e.g., calcium, magnesium, iron, phosphates, sulphates), buffering agents ( e.g., phosphates, acetates), indicators for pH change ( e.g., phenol red, bromo-cresol purple), selective agents (e.g., chemicals, antimicrobial agents), etc.)).
Claim(s) 9 is rejected under 35 U.S.C. 103 as being unpatentable over Fang in view of Yamada et al (WO 2006040871 A1) and in view of Lichtenberg et al (US 20180187136 A1; hereinafter “Lichtenberg”; filed 7/1/2016; already of record).
Regarding claim 9, modified Fang teaches the system of claim 1, with the cell culture device.
Fang does not teach a lid configured to cover each cell culture device; a sealing element configured to provide a hermetic or modulated flow seal for one or more of: each well independently between the lid and the cell culture device.
However, Lichtenberg teaches an analogous art of devices for propagating at least one microtissue (Lichtenberg; Abstract) comprising a lid configured to cover each cell culture device (Lichtenberg; Fig. 5; para [124]; a system (100) comprising a multiwell plate (1), and a corresponding second multiwell plate (50)); a sealing element configured to provide a hermetic or modulated flow seal (Lichtenberg; Fig. 5; para [126]; the corresponding multiwell plate (50) can be placed on top of the multiwell-plate (1), preferably in form-fitting manner) for one or more of: each well independently between the lid and the cell culture device (Lichtenberg; Fig. 6; as seen in Fig. 6, each well is independent from one another with a respective array of wells 52 aligned above the well 2). The examiner notes that the sealing element and the lid are a single structure as seen in Fig. 2 of the instant specification, thus for purpose of prosecution the examiner interprets the sealing element to be part of the lid. It would have been obvious to one of ordinary skill in the art before the effective filing date to have modified the cell culture device of modified Fang to comprise the lid as taught by Lichtenberg, because Lichtenberg teaches that lid supplies the medium to each well (Lichtenberg; para [131]).
Response to Arguments
Applicant’s arguments filed, 2/1/2025, have been considered and are found to be persuasive. However, the arguments are directed towards the claim amendments. The examiner notes that the previous prior art rejection is withdrawn and a new prior art rejection is applied to address the claim amendments.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Austin Q Le whose telephone number is (571)272-7556. The examiner can normally be reached Monday - Friday 9am - 5pm.
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/A.Q.L./Examiner, Art Unit 1796
/ELIZABETH A ROBINSON/Supervisory Patent Examiner, Art Unit 1796