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 .
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 3/15/24 is being considered by the examiner.
Claim Status
Claims 1, 11-16, and 18-30 are pending and are examined.
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.
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.
Claims 1, 11, 12, 13, 14, 15, 16, 18, 19, 20, 21, 22, 23, 27, 28, 29, and 30 are rejected under 35 U.S.C. 103 as being unpatentable over Taninaka (US Pub 2008/0206802), in view of Sandoz (US Pub 2020/0318048).
Regarding Claim 1, Taninaka teaches a stationary trough chip for microinjection of organoids, comprising:
a body (chamber 52) including a series of wells (chambers, 52, 55, 56), a well having a plurality of troughs (cell containing portions of chip 53) disposed therein ([0075] A silicon cell chip 53 having several cell containing portions to individually hold cells is adhered to the bottom tier of the cell-containing chamber 52.).
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Taninaka is silent to each of the wells having a plurality of troughs.
Sandoz teaches [0103] Turning now to FIG. 4, there is shown a plan view of a cell culture device 10 in the form of a multi-well plate. The cell culture device 10 contains a plurality of cell culture chambers 12 in the form of wells, the wells containing either a plurality of concentric grooves 17 or containing a microfluidic channel 18. The wells are arranged linearly in rows. A row can be configured to contain at least one well containing the concentric grooves 17. A row can be configured to contain at least one well containing the concentric grooves 17 and at least one well.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have added a plurality of troughs to each of the wells, as taught by Sandoz, to the device of Taninaka, to allow for trapping individual spheroids, as taught by Sandoz in [0050].
Regarding Claim 11, modified Taninaka teaches the stationary trough chip for microinjection of claim 1, wherein each of the plurality of troughs contains a semi-solid substrate structure for seeding the organoids ([0075] A silicon cell chip 53 having several cell containing portions to individually hold cells is adhered to the bottom tier of the cell-containing chamber 52. [0076] A suction hole (now shown) is provided in the bottom of each cell containing portion of the silicon cell chip 53. Cells 54 are thereby suctioned and fixed via the suction openings (not shown) arranged in the bottom tier of the cell-containing chamber 52.)
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Regarding Claim 12, Taninaka teaches a method of organoid microinjection, comprising:
(a) providing a microinjection system comprising an X-Y stage, a capillary needle having a tip containing an injectable substance, and a video camera positioned above the X-Y stage ([0032] FIG. 2 is a conceptual schematic of a microinjection device according to the first embodiment. A base 11 includes therein a coaxial-lighting high-powered inverted microscope 12 with a focusing function that allows vertical movements of an objective lens 13. A controller-attached XY stage 30 is supported by and fixed on the base 11. The XY stage 30 transports a transparent container 21, such as a petri dish for calibration and a cell reaction chip that holds cells, to an observation position. [0033] Inside the high-powered inverted microscope 12, an excitation light source 14, a filter 15, a collimator lens 16, and a half mirror 17 are arranged as a set, and also a cooled CCD camera 18, a fluorescence filter 19, and a reflection mirror 20 are arranged as a set.);
(b) providing a stationary trough chip comprising a body including a plurality of wells arranged in rows and columns, a well having a plurality of troughs (chambers, 52, 55, 56), (cell containing portions of chip 53);
(c) placing the stationary trough chip on the X-Y stage;
(d) selecting a first organoid in a first trough of the stationary trough chip;
(e) moving at least one of the X-Y stage and the capillary needle to align the tip of the capillary needle with the first organoid; and
(f) piercing the first organoid and injecting it with the injectable substance ([0036] A coaxial-lighting high-powered upright microscope 24 that has a focusing unit that moves an objective lens in a vertical direction along the Z axis and a CCD camera 25 that photographs a microscope image captured by the high-powered upright microscope 24 are arranged above the XY stage 30. Hence, the top surface of the transparent container 21 is observed through the bottom surface by the high-powered inverted microscope 12, and the top surface of the transparent container 21 is also observed directly by the high-powered upright microscope 24.).
Taninaka is silent to each of the wells having a plurality of troughs and a plurality of organoids disposed in at least one of the troughs.
Sandoz teaches [0050] FIG. 4 is a plan view of a multi-well plate containing wells with a plurality of concentric grooves for trapping individual spheroids. [0103] Turning now to FIG. 4, there is shown a plan view of a cell culture device 10 in the form of a multi-well plate. The cell culture device 10 contains a plurality of cell culture chambers 12 in the form of wells, the wells containing either a plurality of concentric grooves 17 or containing a microfluidic channel 18. The wells are arranged linearly in rows. A row can be configured to contain at least one well containing the concentric grooves 17. A row can be configured to contain at least one well containing the concentric grooves 17 and at least one well.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have added a plurality of troughs to each of the wells, as taught by Sandoz, to the device of Taninaka, to allow for trapping individual spheroids, as taught by Sandoz in [0050].
Regarding Claim 13, modified Taninaka teaches the method of claim 12, wherein moving at least one of the X-Y stage and the capillary needle to align the tip of the capillary needle with the first organoid includes moving the X-Y stage along a plane in which the stationary trough chip is disposed ([0038] A controller-equipped transport stage 33 is arranged on the XY stage to determine the positions of a capillary tube 31 and a capillary tube holder 32. The capillary tube holder 32 is connected to a discharging mechanism 35 with a tube 34.).
Regarding Claim 14, modified Taninaka teaches the method of claim 12, wherein moving at least one of the X-Y stage and the capillary needle to align the tip of the capillary needle with the first organoid includes moving the capillary needle along a plane in which the stationary trough chip is disposed [0030] capillary; [0038] A controller-equipped transport stage 33 is arranged on the XY stage to determine the positions of a capillary tube 31 and a capillary tube holder 32. The capillary tube holder 32 is connected to a discharging mechanism 35 with a tube 34.
Regarding Claim 15, modified Taninaka teaches the method of claim 12, further comprising a step of selecting a second organoid in the first trough of the stationary trough chip, moving at least one of the X-Y stage and the capillary needle to align the tip of the capillary needle with the second organoid, piercing the second organoid with the tip of capillary needled, and injecting it with the substance ([0070] For example, although not shown in the drawings, a cell reaction chip in which several cell cultivation chambers are provided on a transparent base plate is mounted on the XY stage 30. The cell in each cell cultivation chamber together with a culture medium is brought into the field of view of the high-powered upright microscope 24. The desired amount of the fluorescent reagent solution 36 is injected into the cells through the capillary tube 31 with the pressure and the pressurizing time being controlled, while the positions of the cells are being monitored through the high-powered upright microscope 24. [0071] As described above, according to the first embodiment, the correlation between the injection amount, the pressure, and pressurizing time is obtained by the two-step calibration, and the amount discharged through the point of the capillary tube is adjusted based on the correlation with respect to the pressure applied to the capillary tube and the pressurizing time. Thus, the injection amount can be quantitatively controlled with high accuracy.).
Regarding Claim 16, modified Taninaka teaches the method of claim 15, wherein the second organoid is injected with the same injectable substance that was injected into the first organoid or wherein the second organoid is injected with a second injectable substance that is different from the injectable substance injected into the first organoid ([0070] For example, although not shown in the drawings, a cell reaction chip in which several cell cultivation chambers are provided on a transparent base plate is mounted on the XY stage 30. The cell in each cell cultivation chamber together with a culture medium is brought into the field of view of the high-powered upright microscope 24. The desired amount of the fluorescent reagent solution 36 is injected into the cells through the capillary tube 31 with the pressure and the pressurizing time being controlled, while the positions of the cells are being monitored through the high-powered upright microscope 24. [0071] As described above, according to the first embodiment, the correlation between the injection amount, the pressure, and pressurizing time is obtained by the two-step calibration, and the amount discharged through the point of the capillary tube is adjusted based on the correlation with respect to the pressure applied to the capillary tube and the pressurizing time. Thus, the injection amount can be quantitatively controlled with high accuracy.).
Regarding Claim 18, modified Taninaka teaches the method of claim 12, further comprising the step of logging information on the first substance and the location of the first organoid ([0078] The fluorescence intensity is measured and compared with the correlation between the total sum I of the fluorescence intensities and the volume V of droplet calculated from the first measurement chamber 55. It is thereby converted to an injection amount. [0086] If the fluorescent reagent solution is not reactive only by a contact with the cells, one of every few cell containing chambers of a cell reaction chip in which cell containing chambers are arranged in a two-dimensional matrix can be used as a calibration chamber. The examiner notes the fluorescent reagent solution in contact with the cells would give the location of the organoid.).
Regarding Claim 19, modified Taninaka teaches the method of claim 12, wherein providing a stationary trough chip comprising a body includes providing a stationary trough chip having six wells ([0075] A silicon cell chip 53 having several cell containing portions to individually hold cells is adhered to the bottom tier of the cell-containing chamber 52.).
Regarding Claim 20, modified Taninaka teaches the method of claim 12 and providing a stationary trough chip comprising a body includes providing a body having wells ([0073] FIG. 7 is a schematic of a cell container according to the second embodiment. A cell container 50 includes a two-tiered cell-containing chamber 52, and a first measurement chamber 55 and a second measurement chamber 56, both single-tiered, which are arranged in a transparent plastic base plate 51. [0075] A silicon cell chip 53 having several cell containing portions to individually hold cells is adhered to the bottom tier of the cell-containing chamber 52. [0076] A suction hole (now shown) is provided in the bottom of each cell containing portion of the silicon cell chip 53. Cells 54 are thereby suctioned and fixed via the suction openings (not shown) arranged in the bottom tier of the cell-containing chamber 52.
Taninaka is silent to providing a stationary trough chip comprising a body includes providing a body having wells with each well including three troughs aligned in a column.
Regarding the limitation, three troughs aligned in a column, In re Kuhle, 526 F.2d 553, 188 USPQ 7 (CCPA 1975) (the particular placement of a contact in a conductivity measuring device was held to be an obvious matter of design choice). See MPEP 2144.04VI.C.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have arranged three troughs aligned in a column in the device of Tananika, to allow for an alternative vertical configuration.
Regarding Claim 21, Taninaka teaches a microinjection system comprising:(a) a stationary trough chip comprising a series of wells, a well having a plurality of troughs disposed therein (chambers, 52, 55, 56), (cell containing portions of chip 53); (b) an apparatus having an X-Y stage having for receiving the stationary trough chip, the stage being translatable along an X axis and a Y axis defining an X-Y plane; (c) a capillary needle having a tip and a lumen therethrough open at both ends, which is positioned above the stationary trough chip; and, (d) a video camera positioned above the X-Y stage and capable of recording a video stream comprising a frame view of a trough and the tip of the capillary needle, the video camera translatable along a Z-axis perpendicular to the X-Y stage ([0032] FIG. 2 is a conceptual schematic of a microinjection device according to the first embodiment. A base 11 includes therein a coaxial-lighting high-powered inverted microscope 12 with a focusing function that allows vertical movements of an objective lens 13. A controller-attached XY stage 30 is supported by and fixed on the base 11. The XY stage 30 transports a transparent container 21, such as a petri dish for calibration and a cell reaction chip that holds cells, to an observation position. [0033] Inside the high-powered inverted microscope 12, an excitation light source 14, a filter 15, a collimator lens 16, and a half mirror 17 are arranged as a set, and also a cooled CCD camera 18, a fluorescence filter 19, and a reflection mirror 20 are arranged as a set.); (b) providing a stationary trough chip comprising a body including a plurality of wells arranged in rows and columns, each of the plurality of wells having a plurality of troughs and a plurality of organoids disposed in at least one of the troughs; (c) placing the stationary trough chip on the X-Y stage; (d) selecting a first organoid in a first trough of the stationary trough chip; (e) moving at least one of the X-Y stage and the capillary needle to align the tip of the capillary needle with the first organoid; and (f) piercing the first organoid and injecting it with the injectable substance ([0036] A coaxial-lighting high-powered upright microscope 24 that has a focusing unit that moves an objective lens in a vertical direction along the Z axis and a CCD camera 25 that photographs a microscope image captured by the high-powered upright microscope 24 are arranged above the XY stage 30. Hence, the top surface of the transparent container 21 is observed through the bottom surface by the high-powered inverted microscope 12, and the top surface of the transparent container 21 is also observed directly by the high-powered upright microscope 24.).
Taninaka is silent to each of the wells having a plurality of troughs.
Sandoz teaches [0103] Turning now to FIG. 4, there is shown a plan view of a cell culture device 10 in the form of a multi-well plate. The cell culture device 10 contains a plurality of cell culture chambers 12 in the form of wells, the wells containing either a plurality of concentric grooves 17 or containing a microfluidic channel 18. The wells are arranged linearly in rows. A row can be configured to contain at least one well containing the concentric grooves 17. A row can be configured to contain at least one well containing the concentric grooves 17 and at least one well.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have added a plurality of troughs to each of the wells, as taught by Sandoz, to the device of Taninaka, to allow for trapping individual spheroids, as taught by Sandoz in [0050].
Regarding Claims 22, 23, 27, and 28, modified Taninaka teaches the microinjection system of claim 21.
Taninaka is silent to each of the plurality of troughs is approximately 500 um deep, and each of the plurality of troughs is approximately 600 um in length.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have configured each of the plurality of troughs is approximately 500 um deep, and each of the plurality of troughs is approximately 600 um in length, in the device of Taninaka, to allow for micron dimensions in the microinjection device, as taught by Taninaka.
Regarding Claim 24, modified Taninaka teaches the microinjection system of claim 21, wherein the capillary needle is provided by a micromanipulator comprising a capillary holder having a distal end and a proximal end and a lumen therethrough open at both ends in which the capillary needle is releasably gripped by the distal end of the capillary holder and wherein the micromanipulator enables the translation of the capillary needle along the X, Y, and Z axes ([0038] A controller-equipped transport stage 33 is arranged on the XY stage to determine the positions of a capillary tube 31 and a capillary tube holder 32. The capillary tube holder 32 is connected to a discharging mechanism 35 with a tube 34.).
Regarding Claim 25, modified Taninaka teaches the microinjection system of claim 24, wherein an injection tubing having a distal end and a proximal end is provided wherein the distal end of the injection tubing is releasably gripped by the proximal end of the capillary holder and the proximal end of the injection tubing is releasably connected to a microinjector capable of providing precise and reproducible injections of femtoliter to microliter amounts of fluids ([0005] Among injection devices available on the market, however, there is no product until today that is characterized in its quantifying ability in introducing a substance to a cell. This is because there is no means in principle other than microinjection for adjusting the introduction amount, and because it is difficult to adopt commonly-used measurement factors such as concentration and electric conductivity due to the volume injected to the cell as small as the order of picolitter (pl) and femtoliter (fl) and also the small flow rate. [0052] In the measurement, the volume V of the droplet 37 is within a range between 10 femtoliters and 100 picoliters as appropriate. Fig. 2 [0046] e. The capillary tube 31 is pressurized by the discharging mechanism 35 to drop a minute quantity of the fluorescent reagent solution 36 into the petri dish 41. See Fig. 2, reference sign 34 for tubing).
Regarding Claim 26, Taninaka teaches in a microinjection system comprising an apparatus having an X-Y stage,
the stage being translatable along an X axis and a Y axis defining an X-Y plane; a capillary needle having a tip and a lumen therethrough open at both ends; and,
a video camera positioned above the X-Y stage and capable of recording a video stream comprising a frame view of X-Y stage, the video camera translatable along a Z-axis perpendicular to the X-Y stage,
the improvement comprising:
a stationary trough chip comprising a series of wells, a well having a plurality of troughs disposed therein for receiving a multiplicity of organoids (chambers, 52, 55, 56), (cell containing portions of chip 53), wherein the organoids are positioned within the trough in a row on the same plane and the stationary trough chip is positioned on the X-Y stage (the organoids are intended use of the device since these are not positively recited) ([0032] FIG. 2 is a conceptual schematic of a microinjection device according to the first embodiment. A base 11 includes therein a coaxial-lighting high-powered inverted microscope 12 with a focusing function that allows vertical movements of an objective lens 13. A controller-attached XY stage 30 is supported by and fixed on the base 11. The XY stage 30 transports a transparent container 21, such as a petri dish for calibration and a cell reaction chip that holds cells, to an observation position. [0033] Inside the high-powered inverted microscope 12, an excitation light source 14, a filter 15, a collimator lens 16, and a half mirror 17 are arranged as a set, and also a cooled CCD camera 18, a fluorescence filter 19, and a reflection mirror 20 are arranged as a set. [0036] A coaxial-lighting high-powered upright microscope 24 that has a focusing unit that moves an objective lens in a vertical direction along the Z axis and a CCD camera 25 that photographs a microscope image captured by the high-powered upright microscope 24 are arranged above the XY stage 30. Hence, the top surface of the transparent container 21 is observed through the bottom surface by the high-powered inverted microscope 12, and the top surface of the transparent container 21 is also observed directly by the high-powered upright microscope 24.).
Taninaka is silent to each of the wells having a plurality of troughs.
Sandoz teaches [0103] Turning now to FIG. 4, there is shown a plan view of a cell culture device 10 in the form of a multi-well plate. The cell culture device 10 contains a plurality of cell culture chambers 12 in the form of wells, the wells containing either a plurality of concentric grooves 17 or containing a microfluidic channel 18. The wells are arranged linearly in rows. A row can be configured to contain at least one well containing the concentric grooves 17. A row can be configured to contain at least one well containing the concentric grooves 17 and at least one well.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have added a plurality of troughs to each of the wells, as taught by Sandoz, to the device of Taninaka, to allow for trapping individual spheroids, as taught by Sandoz in [0050].
Regarding Claim 29, Taninaka teaches the microinjection system of claim 26, wherein the capillary needle is provided by a micromanipulator comprising a capillary holder having a distal end and a proximal end and a lumen therethrough open at both ends in which the capillary needle is releasably gripped by the distal end of the capillary holder and wherein the micromanipulator enables the translation of the capillary needle along the X, Y, and Z axes ([0038] A controller-equipped transport stage 33 is arranged on the XY stage to determine the positions of a capillary tube 31 and a capillary tube holder 32. The capillary tube holder 32 is connected to a discharging mechanism 35 with a tube 34. [0046] e. The capillary tube 31 is pressurized by the discharging mechanism 35 to drop a minute quantity of the fluorescent reagent solution 36 into the petri dish 41.).
Regarding Claim 30, Taninaka teaches the microinjection system of claim 29, wherein an injection tubing having a distal end and a proximal end is provided wherein the distal end of the injection tubing is releasably gripped by the proximal end of the capillary holder and the proximal end of the injection tubing is releasably connected to a microinjector capable of providing precise and reproducible injections of femtoliter to microliter amounts of fluids ([0038] A controller-equipped transport stage 33 is arranged on the XY stage to determine the positions of a capillary tube 31 and a capillary tube holder 32. The capillary tube holder 32 is connected to a discharging mechanism 35 with a tube 34. Fig. 2 [0046] e. The capillary tube 31 is pressurized by the discharging mechanism 35 to drop a minute quantity of the fluorescent reagent solution 36 into the petri dish 41. See Fig. 2, reference sign 34 for tubing).
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JACQUELINE BRAZIN whose telephone number is (571)270-1457. The examiner can normally be reached M-F 8-5.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Charles Capozzi can be reached at 571-270-3638. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JB/
/CHARLES CAPOZZI/Supervisory Patent Examiner, Art Unit 1798
