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 .
This action is in response to applicant’s “Remarks” filed March 04, 2026. The amendments therein have been thoroughly reviewed and entered. Any previous objection/ rejection not repeated herein has been withdrawn. New and/or modified grounds for rejection necessitated by the amendments are discussed below.
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
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.
Claims 1-64 are rejected under 35 U.S.C. 103 as being unpatentable over Rubin (US 2015/0359702-already of record; hereinafter "Rubin”) in view of Rubin et al., (US 2013/0288260-hereinafter “Rubin II”).
Regarding claims 1, 21, and 40, Rubin discloses a system 10, device and method comprising:
a stage 12; and
an actuator 19 having an axis of movement, the actuator configured to transmit a force at an orthogonal angle (wherein the angle is within 25 degrees of the perpendicular axis of movement) to the stage (see Fig. 1, abstract “[a] vibration device 10 includes top plate assembly 12 and dimensioned to receive actuator plate 19 such that the actuator plate 19 is in direct contact with the top plate assembly 12. The actuator plate 19 transmits thereby a vibration signal represented by an oscillating vibratory force to the top plate assembly 12 to operate the oscillating vibration device."),
wherein the actuator is configured to receive a plurality of orthogonal acceleration signals, wherein the orthogonal acceleration signals comprise an actuator frequency signal and an actuator magnitude signal (see para [0068] “The vibration device of the present disclosure delivers low magnitude vibration signals at a frequency of 30-90 cycles per second (Hz) to provide enhanced physical stimulation of cell growth. Other frequency ranges are also contemplated such as 1-100 Hz and other sub-ranges therein, such as, e.g., 25-35 Hz, including specific frequencies therein, such as, e.g., 10 Hz. The low intensity vibrations are also characterized by their intensity. The intensity can range from 0.01 g to 10 g (where 1.0 g=Earth's gravitational field=9.8 m/s/s), and other sub-ranges therein, such as, e.g., 0.01g to 4.0 g, and specific magnitudes therein, such as, e.g., 0.3 g.", note: as indicated by para [0128] measurable acceleration signals occurs along three orthogonal axes).
Rubin does not specifically disclose the orthogonal acceleration signals include a refractory period signal or a container. Rubin II teaches a device for applying a physical stimulus in a tissue culture setting, the device can be free standing and self-contained. For example, the device can be associated with a piece of tissue culture ware, such as a tissue culture dish or plate, a flask, a rotating platform, wherein a low-magnitude, high-frequency physical signals can be provided by placing the cell, tissue, organ, or organism on a device with a vibrating platform (stage). An example of a device that can be used is the JUVENT 1000 (by Juvent, Inc., Somerset, N.J.) (see also U.S. Pat. No. 5,273,028). The source of the physical signal (e.g., a platform with a transducer, e.g., an actuator, and source of an input signal, e.g., electrical signal) can be variously housed or situated under a standing frame or the like). The source of the physical signal (e.g., a platform with a transducer, e.g., an actuator and a source of an input signal, e.g., electrical signal). Rubin II teaches devices and methods configured to deliver a physical stimulus (e.g., low intensity vibration) to a cell, tissue, organ, or organism according to a schedule in which periods of rest are interposed between applications of the agent or signal (e.g., a therapeutic agent or a therapeutically beneficial signal) to a cell, tissue, organ, or organism. The stimulus is applied at least twice, and the first and second applications are separated by a rest period (i.e., a refractory period) in which no further stimulus is actively applied. The rest period is of a duration (e.g., about 1-6 hours) sufficient to provoke an enhanced response to the second stimulus (see para [0041], [0051] et seq.) Rubin II recognizes the scheduling of therapeutic agents or therapeutically beneficial signals may be as important as the stimuli of signals themselves. As such multiple daily sessions of therapeutic stimuli or physical signals could be leveraged in cases of rehabilitation and recreation (see para [0041] et seq.)
Accordingly, it would have been obvious to one of ordinary skill in the art at the time the claimed invention was effectively filed to have included in the low intensity vibration device for stimulating the differentiation and proliferation of stem cells of Rubin to apply in the actuator signals having a refractory period signal (rest period) as taught by Rubin II, since Rubin II recognizes a sufficient refractory period to produces an increased or desirable effect on a cell, tissue, organ, or organism. These methods can be carried out by providing an assay that includes a cell, tissue, organ, or organism. For example, the assay can be one that tests cellular proliferation or differentiation (e.g., by the expression of phenotypic markers). In the method, one can then stimulate the cell, tissue, organ, or organism twice, for a time sufficient to provide a desired effect on the cell, and separate the two stimuli by a refractory or rest period with no stimulus to allow the cell to reset. These steps are repeated with rest periods and/or stimulation periods of varying length and/or intensity and the parameter being assayed (e.g., cellular proliferation) is then assessed. In this manner, one can determine the treatment regime(s) that produce an increase in the desired effect on the cell, tissue, organ, or organism (Rubin II- see para [0043] et seq.) Rubin II teaches that all responses by cells, tissues, and organisms to a therapeutic stimuli or physical signal can be amplified and enhanced through the use of a rest or refractory period that allows the cells, tissues, and organisms to reset, perhaps at a higher level, before being administered another bout of therapeutic stimuli (see para [0041] et seq.)
Regarding claim 40, Rubin discloses a system 10 comprising:
a stage 12;
an actuator 19 having an axis of movement, the actuator configured to transmit a force at an orthogonal angle to the stage (Fig1, abstract "A vibration system 10 includes top plate assembly 12...and dimensioned to receive actuator plate 19 such that the actuator plate 19 is In direct contact with the top plate assembly 12. The actuator plate 19 transmits thereby a vibration signal represented by an oscillating vibratory force to the top plate assembly 12 to operate the oscillating vibration system.”), wherein the actuator Is configured to receive a plurality of orthogonal acceleration signals, wherein the orthogonal acceleration signals comprise an actuator frequency signal and an actuator magnitude signal (para [0068]), wherein the orthogonal angle is within about 25 degrees perpendicular of the axis of movement. "The vibration system of the present disclosure delivers low magnitude vibration signals at a frequency of 30-90 cycles per second (Hz) to provide enhanced physical stimulation of cell growth. Other frequency ranges are also contemplated such as 1-100 HZ and other sub-ranges therein, such as, e.g., 25-35 Hz, including specific frequencies therein, such as, e.g., 10 Hz. The low intensity vibrations are also characterized by their intensity. The intensity can range from 0.01 g to 10 g (where 1.0 g=earth's gravitational field=9.8 m/s/s), and other sub-ranges therein, such as, e.g., 0.01g to 4.0 g, and specific magnitudes therein, such as, e.g., 0.3 g.”, note: as indicated by para [0128] measurable acceleration signals occur along three orthogonal axes); and
a processor (controller 22) configured to receive the stage frequency signal and the stage magnitude signal and configured to compare the stage frequency signal to the actuator frequency signal and configured to compare the stage magnitude signal to the actuator magnitude signal (para [0010] "The controller determines based on the acceleration data whether to increase, decrease or maintain the electrical signal delivered to the actuator in order to maintain the acceleration of the top plate assembly at a predetermined average acceleration. In one embodiment, the controller maintains the acceleration of the top plate assembly at a predetermined average acceleration of 0.3 G's peak-to-peak.”, para [0133] "The acceleration of the top plate assembly 12 is continuously or Intermittently monitored using the closed loop acceleration feedback system and the acceleration “error” data Is provided to the controller to adjust power to the actuator 50, in real time (e.g., 500 Hz fidelity) to best ascribe to the control signal. Without closed-loop feedback, there is no way of actually knowing if the signal waveform, in terms of intensity or frequency, in terms of simple or compound, Is in fact delivered to the top plate assembly 12." para "[0134] "Based on the comparison between error and control signal, it is determined whether to adjust the power delivered to the actuator 50 to keep the signal delivered to the top plate assembly 12 closer to the control signal as established by the error signal. The controller can determine to increase, decrease or maintain the same power delivered to the actuator 50.)
Rubin does not specifically disclose the orthogonal acceleration signals include a refractory period signal or a container.
Rubin II teaches a device for applying a physical stimulus in a tissue culture setting, the device can be free standing and self-contained. For example, the device can be associated with a piece of tissue culture ware, such as a tissue culture dish or plate, a flask, a rotating platform, wherein a low-magnitude, high-frequency physical signals can be provided by placing the cell, tissue, organ, or organism on a device with a vibrating platform (stage). An example of a device that can be used is the JUVENT 1000 (by Juvent, Inc., Somerset, N.J.) (see also U.S. Pat. No. 5,273,028). The source of the physical signal (e.g., a platform with a transducer, e.g., an actuator, and source of an input signal, e.g., electrical signal) can be variously housed or situated under a standing frame or the like). The source of the physical signal (e.g., a platform with a transducer, e.g., an actuator and a source of an input signal, e.g., electrical signal). Rubin II teaches devices and methods configured to deliver a physical stimulus (e.g., low intensity vibration) to a cell, tissue, organ, or organism according to a schedule in which periods of rest are interposed between applications of the agent or signal (e.g., a therapeutic agent or a therapeutically beneficial signal) to a cell, tissue, organ, or organism. The stimulus is applied at least twice, and the first and second applications are separated by a rest period (i.e., a refractory period) in which no further stimulus is actively applied. The rest period is of a duration (e.g., about 1-6 hours) sufficient to provoke an enhanced response to the second stimulus (see para [0041], [0051] et seq.) Rubin II recognizes the scheduling of therapeutic agents or therapeutically beneficial signals may be as important as the stimuli of signals themselves. As such multiple daily sessions of therapeutic stimuli or physical signals could be leveraged in cases of rehabilitation and recreation (see para [0041] et seq.)
Accordingly, it would have been obvious to one of ordinary skill in the art at the time the claimed invention was effectively filed to have included in the low intensity vibration device for stimulating the differentiation and proliferation of stem cells of Rubin actuator signals having a refractory period signal (rest period) like that taught in Rubin II, since Rubin II recognizes a sufficient refractory period to produces an increased or desirable effect on a cell, tissue, organ, or organism. These methods can be carried out by providing an assay that includes a cell, tissue, organ, or organism. For example, the assay can be one that tests cellular proliferation or differentiation (e.g., by the expression of phenotypic markers). In the method, one can then stimulate the cell, tissue, organ, or organism twice, for a time sufficient to provide a desired effect on the cell, and separate the two stimuli by a refractory or rest period with no stimulus to allow the cell to reset. These steps are repeated with rest periods and/or stimulation periods of varying length and/or intensity and the parameter being assayed (e.g., cellular proliferation) is then assessed. In this manner, one can determine the treatment regime(s) that produce an increase in the desired effect on the cell, tissue, organ, or organism (Rubin II- see para [0043] et seq.) Rubin II teaches that all responses by cells, tissues, and organisms to a therapeutic stimuli or physical signal can be amplified and enhanced through the use of a rest or refractory period that allows the cells, tissues, and organisms to reset, perhaps at a higher level, before being administered another bout of therapeutic stimuli (see para [0041] et seq.)
Regarding claims 2, 41, 58-60, Rubin discloses the actuator frequency signal is between about 30 Hz to about 90 Hz (see para [0068] "The vibration device of the present disclosure delivers low magnitude vibration signals at a frequency of 30-90 cycles per second (Hz)).
Regarding claims 3, 42, 62-64, Rubin discloses the actuator magnitude signal is about 2 G's or less, about 1.5 G's or less, about 1.4 G's or less, about 1.3 G's or less, about 1.2 G's or less, about 1.1 G's or less, about 1 G or less, about 0.9 G's or less, about 0.8 G's or less, about 0.7 G's or less, about 0.6 G's or less, about 0.5 G's or less, about 0.4 G's or less, about 0.3 G's or less, about 0.2 G's or less, or about 0.1 G's or less (see para [0068] “The intensity can range from 0.01 G's to 10 G's (where 1.0 G's =earth's gravitational field=9.8 m/s/s), and other sub-ranges therein, such as, e.g., 0.01 G's to 4.0 G's, and specific magnitudes therein, such as, e.g., 0.3 G's.").
Regarding claims 4 and 43, Rubin discloses the orthogonal acceleration signal further comprises one or more of a duration signal and a doses per time signal (see para [0112] "The Device 10 can be programmed, via one or more of the programming methods described herein and other contemplated methods, according to duration of use, amplitude or magnitude of signal, and/or frequency (e.g., principal and harmonics). In embodiments, the Device 10 can be programmed such that the low magnitude signal can have any type of signal, such as a sinusoidal signal, sawtooth signal, step signal, triangular signal, square signal, pulses, compound signal, etc. A compound signal includes two or more signals, such as, for example, one could program the device 10 to produce a compound signal having a 30 Hz 0.3 G's sine wave as the principal signal, combined with a 90 Hz 0.2 G's sinusoidal signal piggy-backed on top of the principal signal.”).
Regarding claims 5 and 44, Rubin discloses an accelerometer operably attached to the stage, wherein the accelerometer is configured to measure at least one of a stage frequency signal and a stage magnitude signal (see para [0009] “The Device also includes a controller and an accelerometer having three degrees of freedom at an origin and is in operative communication with the controller for detecting movement of the top plate assembly and determining whether the top plate assembly is level with respect to the base plate assembly. The accelerometer further detects acceleration of the top plate assembly and transmits acceleration data to the controller.” note: accelerometer are known to measure magnitude and over time measures frequency.)
Regarding claim 6, Rubin discloses a processor (controller 22) configured to receive the stage frequency signal and the stage magnitude signal and configured to compare the stage frequency signal to the actuator frequency signal and configured to compare the stage magnitude signal to the actuator magnitude signal (para [0010] "The controller determines based on the acceleration data whether to increase, decrease or maintain the electrical signal delivered to the actuator in order to maintain the acceleration of the top plate assembly at a predetermined average acceleration. In one embodiment, the controller maintains the acceleration of the top plate assembly at a predetermined average acceleration of 0.3 G's peak-to-peak.”, para [0133] "The acceleration of the top plate assembly 12 is continuously or Intermittently monitored using the closed loop acceleration feedback system and the acceleration “error” data Is provided to the controller to adjust power to the actuator 50, in real time (e.g., 500 Hz fidelity) to best ascribe to the control signal. Without closed-loop feedback, there is no way of actually knowing if the signal waveform, in terms of intensity or frequency, in terms of simple or compound, Is in fact delivered to the top plate assembly 12." para "[0134] "Based on the comparison between error and control signal, it is determined whether to adjust the power delivered to the actuator 50 to keep the signal delivered to the top plate assembly 12 closer to the control signal as established by the error signal. The controller can determine to increase, decrease or maintain the same power delivered to the actuator 50.).
Regarding claims 7 and 45, Rubin discloses the processor is further configured, if there is a difference between the stage frequency signal and the actuator frequency signal, and/or there Is a difference between the stage magnitude signal and the actuator magnitude signal, to use the actuator frequency signal and/or the actuator magnitude signal as an input to a machine learning model that predicts whether or not a change to the plurality of orthogonal acceleration signals is to be made (see para [0134) "Based on the comparison between error and control signal, it is determined whether to adjust the power delivered to the actuator 50 to keep the signal delivered to the top plate assembly 12 closer to the control signal as established by the error signal. The controller can determine to increase, decrease or maintain the same power delivered to the actuator 50., note: "machine leaning” is deemed broad enough to encompass automated feedback control).
Regarding claims 8 and 46, Rubin discloses the processor is further configured to transmit an updated actuator frequency signal and/or an updated actuator magnitude signal to the actuator based on the predicted change (see para [0134] “Based on the comparison between error and control signal, it is determined whether to adjust the power delivered to the actuator 50 to keep the signal delivered to the top plate assembly 12 closer to the control signal as established by the error signal. The controller can
determine to increase, decrease or maintain the same power delivered to the actuator 50.").
Regarding claims 9 and 47, Rubin discloses the processor is further configured to access historical data and using the historical data as additional input to the machine learning model. (see para [0133] "The acceleration of the top plate assembly 12 is continuously or intermittently monitored using the closed loop acceleration feedback system and the acceleration "error" data is provided to the controller to adjust power to the actuator 50, in real time (e.g., 500 Hz fidelity) to best ascribe to the control signal. Without closed-loop feedback, there is no way of actually knowing if the signal waveform, in terms of intensity or frequency, in terms of simple or compound, is in fact delivered to the top plate assembly 12." See para "[0134] "Based on the comparison between error and control signal, it is determined whether to adjust the power delivered to the actuator 50 to keep the signal delivered to the top plate assembly 12 closer to the control signal as established by the error signal. The controller can determine to increase, decrease or maintain the same power delivered to the actuator 50." Note: it is understood that a closed-loop feedback system is programmed using historical empirical data to know how much to adjust the magnitude and frequency of the device to correct the error.
Regarding claims 10 and 48, Rubin discloses if there is a difference between the stage frequency signal and the actuator frequency signal, the processor Is configured to automatically transmit an updated actuator frequency signal to the actuator, and wherein if there is a difference between the stage magnitude signal and the actuator magnitude signal, the processor is configured to automatically transmit an updated actuator magnitude signal to the actuator (see para [0133] "The acceleration of the top plate assembly 12 is continuously or intermittently monitored using the closed loop acceleration feedback system and the acceleration “error” data is provided to
the controller to adjust power to the actuator 50, in real time (e.g., 500 Hz fidelity) to best ascribe to the control signal. Again, without closed-loop feedback, there is no way of actually knowing if the signal waveform, in terms of intensity or frequency, in terms of simple or compound, is in fact delivered to the top plate assembly 12." See para "[0134] "Based on the comparison between error and control signal, it Is determined
whether to adjust the power delivered to the actuator 50 to keep the signal delivered to the top plate assembly 12 closer to the control signal as established by the error signal. The controller can determine to increase, decrease or maintain the same power delivered to the actuator 50.7).
Regarding claims 11 and 49, Rubin does not explicitly disclose a container supported by the stage, wherein the container comprises a liquid and a plurality of cells.
However, Rubin II teaches a device for applying a physical stimulus in a tissue culture setting, the device can be free standing and self-contained. For example, the device can be associated with a piece of tissue culture ware, such as a tissue culture dish or plate, a flask, a rotating platform, wherein a low-magnitude, high-frequency physical signals can be provided by placing the cell, tissue, organ, or organism on a device with a vibrating platform (stage). An example of a device that can be used is the JUVENT 1000 (by Juvent, Inc., Somerset, N.J.) (see also U.S. Pat. No. 5,273,028). The source of the physical signal (e.g., a platform with a transducer, e.g., an actuator, and source of an input signal, e.g., electrical signal) can be variously housed or situated under a standing frame or the like). The source of the physical signal (e.g., a platform with a transducer, e.g., an actuator and a source of an input signal, e.g., electrical signal). Rubin II teaches devices and methods configured to deliver a physical stimulus (e.g., low intensity vibration) to a cell, tissue, organ, or organism according to a schedule in which periods of rest are interposed between applications of the agent or signal (e.g., a therapeutic agent or a therapeutically beneficial signal) to a cell, tissue, organ, or organism. The stimulus is applied at least twice, and the first and second applications are separated by a rest period (i.e., a refractory period) in which no further stimulus is actively applied. The rest period is of a duration (e.g., about 1-6 hours) sufficient to provoke an enhanced response to the second stimulus (see para [0041], [0051] et seq.) Rubin II recognizes the scheduling of therapeutic agents or therapeutically beneficial signals may be as important as the stimuli of signals themselves. As such multiple daily sessions of therapeutic stimuli or physical signals could be leveraged in cases of rehabilitation and recreation (see para [0041] et seq.)
Accordingly, it would have been obvious to one of ordinary skill in the art at the time the claimed invention was effectively filed to have included in the low intensity vibration device for stimulating the differentiation and proliferation of stem cells of Rubin the actuator signals having a refractory period signal (rest period) since Rubin II recognizes a sufficient refractory period to produces an increased or desirable effect on a cell, tissue, organ, or organism. These methods can be carried out by providing an assay that includes a cell, tissue, organ, or organism. For example, the assay can be one that tests cellular proliferation or differentiation (e.g., by the expression of phenotypic markers). In the method, one can then stimulate the cell, tissue, organ, or organism twice, for a time sufficient to provide a desired effect on the cell, and separate the two stimuli by a refractory or rest period with no stimulus to allow the cell to reset. These steps are repeated with rest periods and/or stimulation periods of varying length and/or intensity and the parameter being assayed (e.g., cellular proliferation) is then assessed. In this manner, one can determine the treatment regime(s) that produce an increase in the desired effect on the cell, tissue, organ, or organism (Rubin II- see para [0043] et seq.) Rubin II teaches that all responses by cells, tissues, and organisms to a therapeutic stimuli or physical signal can be amplified and enhanced through the use of a rest or refractory period that allows the cells, tissues, and organisms to reset, perhaps at a higher level, before being administered another bout of therapeutic stimuli (see para [0041] et seq.)
Regarding claim 45, Rubin discloses a method and system of proliferating cells, comprising: contacting a stage of a device wherein the device comprises the stage and an actuator configured to transmit an orthogonal force to the stage (Fig. 1, abstract "A vibration device 10 includes top plate assembly 12…and dimensioned to receive actuator plate 19 such that the actuator plate 19 is in direct contact with the top plate assembly 12. The actuator plate 19 transmits thereby a vibration signal represented by an oscillating vibratory force to the top plate assembly 12 to operate the oscillating vibration device.”), applying an orthogonal force from the actuator to the stage, wherein the actuator is configured to receive a plurality of the orthogonal acceleration signals, wherein the orthogonal acceleration signals comprise an actuator frequency signal and an actuator magnitude signal (para [0068] "The vibration device of the present disclosure delivers low magnitude vibration signals at a frequency of 30-30 cycles per second (Hz) to provide enhanced physical stimulation of cell growth. Other frequency ranges are also contemplated such as 1-100 HZ and other sub-ranges therein, such as, e.g., 25-35 Hz, including specific frequencies therein, such as, e.g., 10 Hz. The low intensity vibrations are also characterized by their intensity. The intensity can range from 0.01 g to 10 g (where 1.0 g=earth's gravitational field=9.8 m/s/s), and other sub-ranges therein, such as, e.g., 0.01 g to 4.0 g, and specific magnitudes therein, such as, e.g., 0.3 g.", note: as indicated by para [0128] measurable acceleration signals occurs along three orthogonal axes). Rubin does not explicitly disclose a container wherein the container comprises a liquid and a plurality of cells. However, Rubin II teaches a vibrating device for stem cell growth and a container supported by the stage, wherein the container comprises a liquid and a plurality of cells (para [0010] et seq.) Rubin II teaches a device for applying a physical stimulus in a tissue culture setting, the device can be free standing and self-contained. For example, the device can be associated with a piece of tissue culture ware, such as a tissue culture dish or plate, a flask, a rotating platform, wherein a low-magnitude, high-frequency physical signals can be provided by placing the cell, tissue, organ, or organism on a device with a vibrating platform (stage). An example of a device that can be used is the JUVENT 1000 (by Juvent, Inc., Somerset, N.J.) (see also U.S. Pat. No. 5,273,028). The source of the physical signal (e.g., a platform with a transducer, e.g., an actuator, and source of an input signal, e.g., electrical signal) can be variously housed or situated under a standing frame or the like). The source of the physical signal (e.g., a platform with a transducer, e.g., an actuator and a source of an input signal, e.g., electrical signal). Rubin II teaches devices and methods configured to deliver a physical stimulus (e.g., low intensity vibration) to a cell, tissue, organ, or organism according to a schedule in which periods of rest are interposed between applications of the agent or signal (e.g., a therapeutic agent or a therapeutically beneficial signal) to a cell, tissue, organ, or organism. The stimulus is applied at least twice, and the first and second applications are separated by a rest period (i.e., a refractory period) in which no further stimulus is actively applied. The rest period is of a duration (e.g., about 1-6 hours) sufficient to provoke an enhanced response to the second stimulus (see para [0041], [0051] et seq.) Rubin II recognizes the scheduling of therapeutic agents or therapeutically beneficial signals may be as important as the stimuli of signals themselves. As such multiple daily sessions of therapeutic stimuli or physical signals could be leveraged in cases of rehabilitation and recreation (see para [0041] et seq.)
Accordingly, it would have been obvious to one of ordinary skill in the art at the time the claimed invention was effectively filed to have included in the low intensity vibration device for stimulating the differentiation and proliferation of stem cells of Rubin to apply in the actuator signals having a refractory period signal (rest period) since Rubin II recognizes a sufficient refractory period to produces an increased or desirable effect on a cell, tissue, organ, or organism. These methods can be carried out by providing an assay that includes a cell, tissue, organ, or organism. For example, the assay can be one that tests cellular proliferation or differentiation (e.g., by the expression of phenotypic markers). In the method, one can then stimulate the cell, tissue, organ, or organism twice, for a time sufficient to provide a desired effect on the cell, and separate the two stimuli by a refractory or rest period with no stimulus to allow the cell to reset. These steps are repeated with rest periods and/or stimulation periods of varying length and/or intensity and the parameter being assayed (e.g., cellular proliferation) is then assessed. In this manner, one can determine the treatment regime(s) that produce an increase in the desired effect on the cell, tissue, organ, or organism (Rubin II- see para [0043] et seq.) Rubin II teaches that all responses by cells, tissues, and organisms to a therapeutic stimuli or physical signal can be amplified and enhanced through the use of a rest or refractory period that allows the cells, tissues, and organisms to reset, perhaps at a higher level, before being administered another bout of therapeutic stimuli (see para [0041] et seq.)
Regarding claims 12, 31, and 50, Rubin II teaches wherein the plurality of cells are selected from stem cells (see para [0015] et seq.)
Regarding claims 22 and 59-61, Rubin discloses a method wherein the actuator frequency signal is between about 30 Hz to about 90 Hz (see para [0068] "The vibration device of the present disclosure delivers low magnitude vibration signals at a frequency of 30-90 cycles per second (Hz)).
Regarding claims 23 and 62-64, Rubin discloses a method the actuator magnitude signal is about 2 G's or less, about 1.5 G's or less, about 1.4 G's or less, about 1.3 G's or less, about 1.2 G's or less, about 1.1 G's or less, about 1 G or less, about 0.9 G's or less, about 0.8 G's or less, about 0.7 G's or less, about 0.6 G's or less, about 0.5 G's or less, about 0.4 G's or less, about 0.3 G's or less, about 0.2 G's or less, or about 0.1 G's or less (see para [0068] “The intensity can range from 0.01 G's to 10 G's (where 1.0 G's =earth's gravitational field=9.8 m/s/s), and other sub-ranges therein, such as, e.g., 0.01 G's to 4.0 G's, and specific magnitudes therein, such as, e.g., 0.3 G's.").
Regarding claim 24, Rubin discloses a method wherein the orthogonal acceleration signal further comprises one or more of a duration signal and a doses per time signal (see para [0112] "The Device 10 can be programmed, via one or more of the programming methods described herein and other contemplated methods, according to duration of use, amplitude or magnitude of signal, and/or frequency (e.g., principal and harmonics). In embodiments, the device 10 can be programmed such that the low magnitude signal can have any type of signal, such as a sinusoidal signal, sawtooth signal, step signal, triangular signal, square signal, pulses, compound signal, etc. A compound signal includes two or more signals, such as, for example, one could program the device 10 to produce a compound signal having a 30 Hz 0.3 G's sine wave as the principal signal, combined with a 90 Hz 0.2 G's sinusoidal signal piggy-backed on top of the principal signal.).
Regarding claim 25, Rubin discloses a method wherein an accelerometer is operably attached to the stage, wherein the accelerometer is configured to measure at least one of a stage frequency signal and a stage magnitude signal (see para [0009] “The Device also Includes a controller and an accelerometer having three degrees of freedom at an origin and is in operative communication with the controller for detecting movement of the top plate assembly and determining whether the top plate assembly is level with respect to the base plate assembly. The accelerometer further detects acceleration of the top plate assembly and transmits acceleration data to the controller.” note: accelerometer instantaneously measures magnitude and over time measures frequency.)
Regarding claim 26, Rubin discloses a method performed by a processor (controller 22) configured to receive the stage frequency signal and the stage magnitude signal and configured to compare the stage frequency signal to the actuator frequency signal and configured to compare the stage magnitude signal to the actuator magnitude signal (para [0010] "The controller determines based on the acceleration data whether to increase, decrease or maintain the electrical signal delivered to the actuator in order to maintain the acceleration of the top plate assembly at a predetermined average acceleration. In one embodiment, the controller maintains the acceleration of the top plate assembly at a predetermined average acceleration of 0.3 G's peak-to-peak.”, para [0133] "The acceleration of the top plate assembly 12 is continuously or Intermittently monitored using the closed loop acceleration feedback system and the acceleration “error” data Is provided to the controller to adjust power to the actuator 50, in real time (e.g., 500 Hz fidelity) to best ascribe to the control signal. Without closed-loop feedback, there is no way of actually knowing if the signal waveform, in terms of intensity or frequency, in terms of simple or compound, Is in fact delivered to the top plate assembly 12." para "[0134] "Based on the comparison between error and control signal, it is determined whether to adjust the power delivered to the actuator 50 to keep the signal delivered to the top plate assembly 12 closer to the control signal as established by the error signal. The controller can determine to increase, decrease or maintain the same power delivered to the actuator 50.).
Regarding claim 27, Rubin discloses the processor is further configured, if there is a difference between the stage frequency signal and the actuator frequency signal, and/or there Is a difference between the stage magnitude signal and the actuator magnitude signal, to use the actuator frequency signal and/or the actuator magnitude signal as an input to a machine learning model that predicts whether or not a change to the plurality of orthogonal acceleration signals is to be made (see para [0134] "Based on the comparison between error and control signal, it is determined whether to adjust the power delivered to the actuator 50 to keep the signal delivered to the top plate assembly 12 closer to the control signal as established by the error signal. The controller can determine to increase, decrease or maintain the same power delivered to the actuator 50., note: "machine leaning” is deemed broad enough to encompass automated feedback control).
Regarding claim 28, Rubin discloses a method the processor is further configured to transmit an updated actuator frequency signal and/or an updated actuator magnitude signal to the actuator based on the predicted change (see para [0134] “Based on the comparison between error and control signal, it is determined whether to adjust the power delivered to the actuator 50 to keep the signal delivered to the top plate assembly 12 closer to the control signal as established by the error signal. The controller can determine to increase, decrease or maintain the same power delivered to the actuator 50.").
Regarding claim 29, Rubin discloses a method performed by the processor further configured to access historical data and using the historical data as additional input to the machine learning model. (see para [0133] "The acceleration of the top plate assembly 12 is continuously or intermittently monitored using the closed loop acceleration feedback system and the acceleration "error" data is provided to the controller to adjust power to the actuator 50, in real time (e.g., 500 Hz fidelity) to best ascribe to the control signal. Without closed-loop feedback, there Is no way of actually knowing if the signal waveform, in terms of intensity or frequency, in terms of simple or compound, is in fact delivered to the top plate assembly 12." See para "[0134] "Based on the comparison between error and control signal, it is determined whether to adjust the power delivered to the actuator 50 to keep the signal delivered to the top plate assembly 12 closer to the control signal as established by the error signal. The controller can determine to increase, decrease or maintain the same power delivered to the actuator 50." Note: it is understood that a closed-loop feedback system is programmed using historical empirical data to know how much to adjust the magnitude and frequency of the device to correct the error.
Regarding claim 30, Rubin discloses a method wherein if there is a difference between the stage frequency signal and the actuator frequency signal, the processor Is configured to automatically transmit an updated actuator frequency signal to the actuator, and wherein if there is a difference between the stage magnitude signal and the actuator magnitude signal, the processor is configured to automatically transmit an updated actuator magnitude signal to the actuator (see para [0133] "The acceleration of the top plate assembly 12 is continuously or intermittently monitored using the closed loop acceleration feedback system and the acceleration “error” data is provided to
the controller to adjust power to the actuator 50, in real time (e.g., 500 Hz fidelity) to best ascribe to the control signal. Again, without closed-loop feedback, there is no way of actually knowing if the signal waveform, in terms of intensity or frequency, in terms of simple or compound, is in fact delivered to the top plate assembly 12." See para "[0134] "Based on the comparison between error and control signal, it Is determined
whether to adjust the power delivered to the actuator 50 to keep the signal delivered to the top plate assembly 12 closer to the control signal as established by the error signal. The controller can determine to increase, decrease or maintain the same power delivered to the actuator 50.7).
Regarding claims 32 and 51, Rubin II discloses wherein the stem cells are
mesenchymal stem cells (MSCs), see para [0040] et seq.
Regarding claims 31, 33 and 52, neither Rubin or Rubin II disclose wherein the T cells are selected from the group consisting of CD4+ T cells, CD8+ T cells, and CD3+ Pan T cells. However Rubin discloses that all cells respond to mechanical stimuli ( para [0007] "The basis for how cells can sense and respond to such small mechanical signals lies in that cells form networks, which are capable of acting as Integrated units to transduce various stimuli, such as mechanical loading, into coordinated tissue responses. Not surprisingly, this process is extremely complex, both physically and biologically, but occurs continuously as a part of daily living and is essential to the regulation, repair, growth and development of all physiologic systems.”) and Official notice is made that CD4+ T cells, CD8+ T cells, and CD3+ Pan T cells were well known as types of cells subject to analysis. It would have been obvious to one of ordinary skill in the art, at the time of the invention was effectively filed, based on routine experimentation, to apply the device and system disclosed by the combination of Rubin and Rubin II to T cells selected from the group consisting of CD4+ T cells, CD8+ T cells, and CD3+ Pan T calls, to encourage cell growth.
Regarding claims 34 and 53, Rubin II further discloses wherein the plurality of cells are suspended In the liquid, adhered to a surface, or both suspended in the liquid and adhered to the surface (see para [0040] et seq.)
Regarding claims 35 and 54, Rubin II further discloses wherein the surface comprises a two-dimensional surface or a three-dimensional surface, wherein the two-dimensional surface or the three-dimensional surface is selected from the group consisting of an internal surface of the container, a particle within the container, and combinations thereof (para [0044] et seq.)
Regarding claims 36 and 55, Rubin further discloses a processor configured to receive an updated concentration of the plurality of cells in the liquid at a time after the actuator receives a plurality of orthogonal acceleration signals and compare the received, updated concentration of the plurality of cells to a goal concentration of the plurality of cells (see para [0071] et seq.)
Regarding claims 37 and 56, Rubin discloses the processor is configured if
there is a difference between the updated concentration of the plurality of cells and the goal concentration, to use the plurality of orthogonal acceleration signals as an input to a machine learning model that predicts whether or not a change to the plurality of orthogonal acceleration signals is to be made (see para [0128] et seq.)
note: "machine learning” Is deemed broad enough to encompass automated feedback control).
Regarding claims 38 and 57, Rubin discloses wherein the processor is further configured to transmit one or more of an updated actuator frequency signal, an actuator magnitude signal, an updated duration signal, an updated refractory period signal and an updated doses per time signal to the actuator based on the predicted change (para [0043] et seq.)
Regarding claims 39 and 58, Rubin further discloses wherein the processor is further configured to access historical data and using the historical data as additional input to the machine learning model para [0107]. note: it Is understood that a closed-loop feedback system is programmed using historical data to know how
much to adjust the magnitude and frequency of the device.).
Citations to art
In the above citations to documents in the art, an effort has been made to specifically cite representative passages, however rejections are in reference to the entirety of each document relied upon. Other passages, not specifically cited, may apply as well.
Response to Arguments
Applicant's arguments filed March 04, 2026 have been fully considered but they are not persuasive. Applicant argues that Rubin does not teach the creation of refractory periods. Without acquiescing to the merits of the argument, the examiner has applied Rubin II which explicitly recites that the acceleration signal also comprises “a refractory period signal” for the reasons delineated above.
Conclusion
No claims are allowed.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure include:
a. WO 2008/092922 to Guyonnet et al., which disclose a method for applying a mechanical loading to cells, comprising : a step of providing a support (1) having a bearing surface (2) adapted to receive said cells, a step of providing cells on the bearing surface (2) of said support (1), a step of placing said support (1) provided with the cells within a chamber (4) adapted to house said support (1), at least one step of applying a mechanical loading to the support (1) by a loading device (5) which extends at least in part in the chamber (4), a dynamic loading in vibration being applied to the support (1), said dynamic loading having a magnitude and a frequency and being adapted to cause the support (1) to vibrate.
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.
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/P. Kathryn Wright/Primary Examiner, Art Unit 1798
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