DETAILED ACTION
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, 3, 7, 8 and 10 are rejected under 35 U.S.C. 103 as being unpatentable over Moriwaki (WO 2016047368) in view of Nien (US 20040077032).
With respect to claim 1, Moriwaki discloses a cell peeling device that peels a cell aggregate from a container wall of a culture container. The cell peeling device includes a vibrator (Figure 1:121) that emits an ultrasonic beam onto the cell aggregate across the container wall (Figure 1:Ba). A movement mechanism (Figure 1:103) moves the vibrator to shift a position of the vibrator relative to the culture container, and a control unit (Figure 1:101 and Figure 1:104) controls beam power output of the ultrasonic beam of the vibrator (“The vibrator driver 104 can change the frequency and intensity of the ultrasonic wave emitted from the ultrasonic vibrator 121 in order to perform excellent peeling in accordance with various containers, cells, thicknesses, and the like”). A scanning movement mechanism (Figure 1:102) further facilitates movement of the vibrator. Moriwaki teaches that the cell peeling device may be configured to isolate and remove (i.e., “peel”) individual target cells, or may be used to peel larger cell aggregates using a plurality of vibrators (Figure 8:321) that are operated in unison to expand the vibrated area on the container wall (“even when there are a plurality of cells Cx to be detached, as long as their positions are known in advance, all of them…can be peeled off. Therefore, in this embodiment, even when there are a large number of cells to be detached or when they are distributed over a wide range, they can be efficiently detached in a short time”). Moriwaki discusses detaching specific cells and cell colonies from neighboring cell portions, which requires cutting intercellular junctions. However, it is unclear if Moriwaki describes a mode switching operation in which the beam power output of the vibrator is switched between a first mode (small beam size, high beam intensity) in which the cell aggregate is cut and a second mode (large beam size, low beam intensity) in which the cut-out aggregate is then peeled.
Nien discloses a cell peeling device that peels a cell aggregate from a container wall. A non-contact cutting apparatus (Figure 1:1 and Figure 3:9) operates in a first mode (Figure 5:“step c”) where a peeling portion (Figure 1:52) is cut-out. A second mode (Figure 5:“step e”) is then initiated in which a vibrator (Figure 1:4) is moved by a movement mechanism into contact with the container wall. The vibrator applies a force to peel the peeling portion created in the first mode. This is described in paragraph [0031].
Before the effective filing date of the claimed invention, it would have been obvious to ensure that the Moriwaki control unit is configured to switch the operation of the vibrator between a first cutting mode and a second peeling mode. Moriwaki already teaches that the intensity and frequency of the ultrasonic beam is adjusted by the driver 104 in response to detected environmental conditions. Moriwaki also shows that the ultrasonic beam may be focused to detach individual cells Cx or, alternatively, used to peel off a group of larger cell aggregates (see Fig. 8 embodiment). Accordingly, the Moriwaki system is considered to be fully capable of being used to cut out a boundary in order to create a peeling portion that is then removed as a whole aggregate through the generation of an ultrasonic beam having a larger size and reduced power output. Nien further shows how it is desirable to isolate a target cell aggregate by first performing a cutting step followed by a vibration peeling step. Nien states that this two-mode (cutting followed by peeling) strategy precisely removes specific target cells of interest, and thereby reduces costs, is less time intensive, and eliminates pre- and post-treatment processing when identifying and isolating a target cell aggregate (“capturing biological tissues characterized in that, using the device of the invention, only target tissue cells of interest can be captured”).
With respect to claim 3, Moriwaki and Nien disclose the combination as described above. Moriwaki further teaches that a cell state detection unit (Figure 1:102) is used to optically scan the cells. Moriwaki recognizes that different cell types are characterized by different adhesion strengths, and this information is used by the controller (Figure 1:101) to determine a beam power output appropriate for a target cell type (“the frequency of the ultrasonic wave suitable for peeling the cells cultured and adhered in the glass dish D is about 10 kHz to 1 MHz. For example, in an experiment using NIH/3T3 cells as the cell type, the frequency of the ultrasonic wave is 80 kHz, the output is about 25 W, and the distance between the dish lower surface and the ultrasonic transducer is changed between 15 mm and 35 mm”). The controller will also determine a track through which the vibrator is moved based on the coordinates of the target cell aggregate (“the scanning irradiation mechanism 102 moves the ultrasonic irradiation unit 12 relative to the holding stage 11 in the horizontal direction, so that the ultrasonic irradiation unit 12 is positioned immediately below the cell Cx”).
As discussed above, Moriwaki recognizes that different cell types are characterized by different adhesion strengths and indicates that his information may be stored in a database (“as to which region of cells cultured in the dish D is to be peeled in what manner, for example, processing information is given from the culture management device connected to the cell peeling device via a communication line…Then, based on the analysis results such as the cell type, shape, and size, processing information indicating what kind of peeling processing is performed on the cells in the container is created in advance. Note that information may be exchanged using an appropriate storage medium such as a USB memory, a flash memory card, and an optical disk, instead of communication via a communication line”).
With respect to claim 7, Moriwaki and Nien disclose the combination as described above. Moriwaki shows in Figure 8 that the vibrator may include a plurality of piezoelectric elements (Figure 8:321). As stated above, the control unit may be used to adjust when the vibrators are activated and how close the vibrators are positioned to the cell container.
With respect to claim 8, Moriwaki and Nien disclose the combination as described above. Moriwaki further states that the controller includes a user input feature (“the user inputting coordinate information through an input interface (not shown), for example”), which will typically include a display unit. Display units, including screens, monitors, etc., are considered to be notoriously known in the art.
With respect to claim 10, Moriwaki and Nien disclose the combination as described above. Moriwaki teaches a corresponding method in which the shape of a peeling portion is selected. A track for vibrator movement is calculated corresponding to the shape of the peeling portion (i.e., the position and shape of the target cells). The vibrator is then moved to designated portions along the track and emits an ultrasonic wave. Moriwaki further teaches that a controller performs a condition selection step in which beam power output is adjusted according to environmental conditions (“The vibrator driver 104 can change the frequency and intensity of the ultrasonic wave emitted from the ultrasonic vibrator 121 in order to perform excellent peeling in accordance with various containers, cells, thicknesses, and the like”). In view of Nien, it would have been obvious to ensure that the vibrator conducts a cutting step and a peeling step, wherein the cutting step produces the outline of a peeling portion to be removed as an aggregate during the peeling step.
Claims 4 and 5 are rejected under 35 U.S.C. 103 as being unpatentable over Moriwaki (WO 2016047368) in view of Nien (US 20040077032) as applied to claim 1, and further in view of Sasaki (US 20100015682).
Moriwaki and Nien disclose the combination as described above, however do not expressly state that the vibrator includes one or more acoustic lenses that focus the ultrasonic beam.
Sasaki discloses a cell cutting device that cuts cells from the surface of a culture container. A vibrator (Figure 1:1b) emits an ultrasonic beam onto a cell aggregate. The ultrasonic beam may be focused using one or more acoustic lenses (Figure 1:2) in order to target and dissect individual cells (Figure 1:19). This is described in paragraphs [0041]-[0044] and [0049]-[0059].
Before the effective filing date of the claimed invention, it would have been obvious to further modify the Moriwaki device to include at least one acoustic lens configured to focus the ultrasonic beam. Sasaki teaches that this would allow one to target individual cells without disturbing neighboring cells, thereby enabling cell isolation and patterning on a culture surface (“when the frequency, the duration and the power are appropriate, it is possible to form thin acoustic streaming acting on one cell just below the acoustic lens”). Those of ordinary skill would have found this desirable when the modified Moriwaki device is used to create a peeling portion with fine boundaries.
Allowable Subject Matter
Claims 2, 6 and 9 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Claim 11 is allowed.
The prior art does not appear to teach a step in which the control unit determines beam power output based on the coordinates of the cell aggregate and on a detected state of adhesion of the cell aggregate to the container wall. More specifically, the prior art does not teach specifying a cutting threshold while gradually increasing power output of the ultrasonic wave until the cell aggregate is cut.
Although Moriwaki states that the power output may be varied during operation, Moriwaki does not indicate that the power output is adjusted based on a determined state of cell adhesion.
Nien does not teach that cutting is performed using an ultrasonic beam.
Sasaki teaches ablating cells using a focused ultrasonic beam, but does not describe that the beam power output is updated based on a determined state of cell adhesion.
The Oswald (US 20230311121) reference discusses modifying the beam power output from an acoustic vibrator based on a state of adhesion of a cell of interest, but does not teach the claimed cutting and peeling steps.
The Guo (US 20210364439) reference teaches measuring a state of cell adhesion using applied acoustic waves, but does not teach the claimed cutting and peeling steps.
Response to Arguments
Applicant's arguments filed 18 June 2026 have been fully considered but they are not persuasive.
Moriwaki is directed to separating, cutting and peeling specific cells of interest from a cell sheet. This requires cutting intercellular junctions using the applied ultrasonic beam (“The cell peeling apparatus 1 is an apparatus for peeling cells in a specific region from cells cultured in a medium injected into a sample container such as a petri dish or dish. In this specification, the term “cell” represents a concept including not only a single cell but also a cell mass or a cell colony composed of a plurality of cells. That is, the cell peeling device 1 is used for at least one of a use of peeling a single cell among cells cultured in a sample container and a use of peeling a cell mass or a cell colony composed of a plurality of cells…only the cells at a desired position can be detached”). Moriwaki specifically describes methods for cutting out cells of interest and thereby breaking intercellular junctions (“ultrasonic waves converged on cells to be cut out of a group of cells carried on a flat carrier are irradiated from above, thereby releasing the cells”, emphasis added). It is further noted that “intercellular junction” is a broad term that reads on essentially any cellular, protein, matrix, etc. component that is connected to adjacent cells.
Conclusion
THIS ACTION IS MADE FINAL. 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 NATHAN ANDREW BOWERS whose telephone number is (571)272-8613. The examiner can normally be reached M-F 7am-5pm.
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/NATHAN A BOWERS/Primary Examiner, Art Unit 1799
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