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 January 25, 2024 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement has been considered by the examiner.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Section 33(a) of the America Invents Act reads as follows:
Notwithstanding any other provision of law, no patent may issue on a claim directed to or encompassing a human organism.
Claim 12 is rejected under 35 U.S.C. 101 and section 33(a) of the America Invents Act as being directed to or encompassing an organism. See also Animals - Patentability, 1077 Off. Gaz. Pat. Office 24 (April 21, 1987) (indicating that human organisms are excluded from the scope of patentable subject matter under 35 U.S.C. 101). Claim 12 recites “wherein the moveable device is mounted on a set of motorized actuators and is aimed at the target paw by a human operator”, which encompasses the target paw and a human operator as part of the claimed invention. In order to overcome this rejection, the claim could be amended to recite “wherein the moveable device is mounted on a set of motorized actuators and is configured to be aimed at the target paw by a human operator”.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-29 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 “one or more enclosures for individual rodents” in line 3. It is unclear if this means that each individual rodent has one or more enclosures, or if there is one enclosure per individual rodent. The claim only requires at least one enclosure, so does this mean that a single enclosure could be configured to house multiple individual rodents or only one rodent? Additionally, claim 1 line 7 recites “a target paw of the rodent”, which indicates that the device is only configured to measure one rodent. Is this limitation intended to mean “a target paw of one of the individual rodents”? Further clarification is required. Claims 2-16 are rejected based on their dependence on claim 1.
Claim 2 recites the limitation "the opaque, magnetically connectable cubicles”" in line 4. There is insufficient antecedent basis for this limitation in the claim, as the recitation of “opaque cubicle” in line 2. It is unclear if the opaque cubicle is required to be magnetically connectable, or if there are opaque cubicles and separate opaque magnetically connectable cubicles. Line 5 describes that the cubicles “separate the rodents”, however it is unclear from what the rodents are being separated. Additionally, line 1 of claim 2 recites “said enclosures each comprise a separate clear tube and opaque cubicle”. Claim 1 only requires one enclosure, which creates indefiniteness when the claim recites “the opaque, magnetically connectable cubicles separate the rodents” in lines 4-5. Is each cubicle required to be magnetically connectable, even if there is only one enclosure, and therefore only one cubicle? What is the cubicle magnetically connectable to if there is only one cubicle present? A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 2 recites the broad recitation “opaque cubicle”, and the claim also recites “opaque, magnetically connectable cubicles” which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims. Further clarification is required.
Claim 2 recites “its” in line 3, and “them” in line 5. It is unclear what the terms “its” and “them” are referring to, which renders the claim indefinite.
Claim 6 recites the limitation “the indenter arm” in line 3. There is insufficient antecedent basis for this limitation in the claim.
Regarding claim 14, the phrase "such as" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Claim 17, lines 7-8 recites “a target paw of the rodent”, which indicates that the device is only configured to measure one rodent (“the rodent”). This creates indefiniteness because line 3 of claim 17 recites “one or more rodents”. Is this limitation intended to mean “a target paw of one of the one or more rodents”? If there are more than one rodents, are each of the rodents measured, or only one rodent and one target paw regardless of the number of rodents and enclosures? Further clarification is required. Claims 18-29 are rejected based on their dependence on claim 17.
Claim 18 recites the limitation "the opaque, magnetically connectable cubicles”" in line 4. There is insufficient antecedent basis for this limitation in the claim, as the recitation of “opaque cubicle” in line 2. It is unclear if the opaque cubicle is required to be magnetically connectable, or if there are opaque cubicles and separate opaque magnetically connectable cubicles. Line 5 describes that the cubicles “separate the rodents”, however it is unclear from what the rodents are being separated. Additionally, line 1 of claim 18 recites “said enclosures each comprise a separate clear tube and opaque cubicle”. Claim 17 only requires one enclosure, which creates indefiniteness when the claim recites “the opaque, magnetically connectable cubicles separate the rodents” in lines 4-5. Is each cubicle required to be magnetically connectable, even if there is only one enclosure, and therefore only one cubicle? What is the cubicle magnetically connectable to if there is only one cubicle present? A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 18 recites the broad recitation “opaque cubicle”, and the claim also recites “opaque, magnetically connectable cubicles” which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims. Further clarification is required.
Claim 18 recites “its” in line 3, and “them” in line 5. It is unclear what the terms “its” and “them” are referring to, which renders the claim indefinite.
Claim 22 recites the limitation “the indenter arm” in line 3. There is insufficient antecedent basis for this limitation in the claim.
Regarding claim 23, the phrase "like" in line 4 renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Regarding claim 27, the phrase "such as" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 27-28 rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 28 recites “The method according to claim 28”, which is not in proper dependent form as a claim cannot be dependent on itself since it does not further limit the subject matter. Claim 27 is rejected for being dependent on claim 28, which is not properly dependent. For the purpose of examination, it is interpreted that claim 27 and claim 28 are dependent on claim 26, however further clarification is required. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1, 3-6, 8-12, 16-17, 19-22, 24-25, and 29 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by “A New Apparatus for Recording Evoked Responses to Painful and Non-painful Sensory Stimulation in Freely Moving Mice” (Zhang et al, 2021) (hereinafter referred to as “Zhang”).
Regarding claim 1, Zhang teaches an apparatus for automated measurement of pain and responses to various somatosensory stimuli in laboratory rodents, comprising:
one or more enclosures for individual rodents (Fig. 1A – “chamber”);
a platform on which said one or more enclosures are positioned (Figs. 1-2 – Fig. 2A “upper platform”);
a moveable device positioned underneath said platform and enclosures (Fig. 1A – “stimulator”) and configured to:
aim at a target paw of the rodent (Page 5, Col. 1: Control Unit - “targeting the stimulator to the mouse paw”),
deliver one or more different stimulus modalities, alone or in combination, to the target paw (Page 5, Col. 1: Tactile Stimulator – ‘tactile stimulator was constructed in-house to be interchangeable with the laser stimulator”),
detect changes in position of the target paw with millisecond precision (Page 9, Col. 2: Results: “There was a significant increase of hind paw guarding time after 10 ms laser stimulation compared to 3 or 5 ms”; 13, Col. 1: Discussion – “In addition to paw withdrawal, we also measured other pain-induced behaviors like guarding, flinching and freezing”), and
collect video of rodent activity before, during and after stimulation (Page 4, Col. 2 – Control Unit: “the video would start recording 3 s before the stimulation and continue recording 30 s after the stimulation.”; Page 9, Col. 1: Results – “to facilitate the alignment of the stimulation and the behaviors via video”); and
a controller operably connected to the moveable device (Page 2, Col. 2: Custom Made Apparatus for Sensory Testing – “The horizontal position of the stimulator could be freely determined by manually moving the connected control stick (Figure 1A).”) and configured to:
coordinate all aspects of stimulation using programmed instructions (Page 4, Col. 1: Control Unit - “separate control unit (Figures 2D, 3) was designed to handle the following functions: i. Triggering of the laser/tactile stimulator either manually or automatically; ii. Triggering the red LED indicator (in view of the lateral camera); iii. Controlling recording intervals of the lateral camera as required by the experiment; iv. Initiate trials with random timing within a pre-set minimum and maximum time interval.”),
synchronize recorded data with stimulus timing and calculate withdrawal latency therefrom (Page 3, Col. 1: Custom Made Apparatus for Sensory Testing - “This signal facilitates synchronization of stimulation and recording, measuring paw withdrawal latency”), and
automatically record all data, metadata, and calculations to electronic files (Page 5, Col. 1: Control Unit – “All electrophysiological and video data was recorded on a PC for later offline analysis”).
Regarding claim 3, Zhang teaches the apparatus according to claim 1, wherein the platform is made of an optically clear material, and wherein the moveable device includes a light source of selected wavelength(s) to provide optogenetic stimulation (Page 2, Col. 2: Custom Made Apparatus for Sensory Testing – “We used an infrared laser stimulator (MRC Systems GmbH, Germany) of 1470 nm and with pulse durations from 1 – 100 ms (pulse energy 1.2 – 306 mJ) (Figure 1B). A pilot laser of 650 nm (red light, visible to naked eye) indicted the position of the laser beam.”, “A circular grid plate (100 mm in diameter) was produced by a 3D printer (Formlabs Form2, United States) and inserted in the hole in the top plate to create a floor for the animal that allows laser/tactile stimulation to be conducted without obstruction (Figures 2A,B). A transparent plexiglass cylinder (120 mm in diameter) was then placed vertically on top of the circular grid, bordering the experimental arena of the mouse (Figure 1A).”; Page 7, Col. 2: Stimulation, Electrophysiology, and Behavior – “In order to apply different energies we applied laser pulse durations of different durations: 3 ms (2.3 mJ), 5 ms (5 mJ), and 10 ms (11.7 mJ). These pulses are far shorter than the subsequent activation of central neuronal networks or behavioral reactions, allowing for appropriate alignment of evoked potentials. Stimulations were done when the animal was immobile such that the paw could be targeted.”; Page 2, Col. 1: Introduction - “brief infrared laser pulses are widely used as nociceptive stimuli”).
Regarding claim 4, Zhang teaches the apparatus according to claim 1, wherein the platform is made of an optically clear material, and wherein the moveable device includes infrared (IR) light for thermal stimulation via radiant heating (Page 2, Col. 2: Custom Made Apparatus for Sensory Testing – “We used an infrared laser stimulator (MRC Systems GmbH, Germany) of 1470 nm and with pulse durations from 1 – 100 ms (pulse energy 1.2 – 306 mJ) (Figure 1B). A pilot laser of 650 nm (red light, visible to naked eye) indicted the position of the laser beam.”, “A circular grid plate (100 mm in diameter) was produced by a 3D printer (Formlabs Form2, United States) and inserted in the hole in the top plate to create a floor for the animal that allows laser/tactile stimulation to be conducted without obstruction (Figures 2A,B). A transparent plexiglass cylinder (120 mm in diameter) was then placed vertically on top of the circular grid, bordering the experimental arena of the mouse (Figure 1A).”).
Regarding claim 5, Zhang teaches the apparatus according to claim 1, wherein the platform is metal grating, and wherein the moveable device includes a mechanical indenter which stimulates by physical contact with the target paw (Page 2, Col. 2: Custom Made Apparatus for Sensory Testing – “We used an infrared laser stimulator (MRC Systems GmbH, Germany) of 1470 nm and with pulse durations from 1 – 100 ms (pulse energy 1.2 – 306 mJ) (Figure 1B). A pilot laser of 650 nm (red light, visible to naked eye) indicted the position of the laser beam.”, “A circular grid plate (100 mm in diameter) was produced by a 3D printer (Formlabs Form2, United States) and inserted in the hole in the top plate to create a floor for the animal that allows laser/tactile stimulation to be conducted without obstruction (Figures 2A,B). A transparent plexiglass cylinder (120 mm in diameter) was then placed vertically on top of the circular grid, bordering the experimental arena of the mouse (Figure 1A).”).
Regarding claim 6, Zhang teaches the apparatus according to claim 5, wherein the mechanical indenter is configured to measure force applied to the paw and to detect withdrawal based on changes in force as the target paw is withdrawn from the indenter arm (Fig. 4 – “Electronic design of the tactile stimulator. The 27 V signal is reduced to 5 V to power the NE555 chip which is responsible for the duration of the pulse sent to the actuator. U5 regulates the output voltage to 24 V when the input voltage is equal to, or more than 27 V: Using an input voltage of less than 27 V reduces the force applied to the actuator and increases the actuation time.”; Fig. 5F - “View of the lateral camera showing the moment of paw withdrawal following laser stimulation.”).
Regarding claim 8, Zhang teaches the apparatus according to claim 1, wherein said one or more stimulus modalities include combinations of light, heat, mechanical and chemical agents (Page 9, Col. 1: Results - “The apparatus was tested for painful heat stimuli, using a laser beam, and for tactile stimulation with an electrically driven mechanical actuator (Figure 2E).”; Page 3, Col. 2: Custom Made Apparatus for Sensory Testing “different responses to laser- and mechanical stimuli which both activated the LED in the same manner”).
Regarding claim 9, Zhang teaches the apparatus according to claim 1, wherein said moveable device is configured to provide different stimulus modalities sequentially to test different stimulus modalities on separate trials (Page 7, Col. 2: Stimulation, Electrophysiology, and Behavior – “Tactile stimulations were applied 3–6 times onto the right hind paw of the mouse while it was awake and immobile. Then, the tactile stimulator was replaced by the laser which was used to stimulate the right hind paw for 3–6 times.”).
Regarding claim 10, Zhang teaches the apparatus according to claim 1, wherein said moveable device is configured to provide two or more different stimulus modalities together on a given trial (Page 10, Col. 2: Discussion – “The trigger signal of the stimulus is synchronized with LFP recordings by a custom made control unit, while behavioral reactions are recorded by a lateral camera which is synchronized with the stimulus by an indicator-LED light.”; Page 7, Col. 2: Stimulation, Electrophysiology, and Behavior – “Experimental trials were conducted after habituation. The indicator LED was turned toward the lateral camera for video recording. Before the real stimulation, both mechanical and laser stimuli were tested without targeting on the mouse (targeting the empty space of the grid plate), to make sure that the stimulation worked and that the red light of the indicator LED did not evoke any paw withdrawal or other pain-like behaviors.”).
Regarding claim 11, Zhang teaches the apparatus according to claim 1, wherein said moveable device includes a source of red light configured to be aimed at said target paw in order to assist aiming by identifying a photostimulation zone prior to initiating photostimulation with other wavelengths of light (Page 9, Col. 1: Results – “The indicator LED beside the chamber shined red light toward the lateral camera when stimulation was triggered, to facilitate the alignment of the stimulation and the behaviors via video.”; Page 2, Col. 2: Custom Made Apparatus for Sensory Testing – “We used an infrared laser stimulator (MRC Systems GmbH, Germany) of 1470 nm and with pulse durations from 1 – 100 ms (pulse energy 1.2 – 306 mJ) (Figure 1B). A pilot laser of 650 nm (red light, visible to naked eye) indicted the position of the laser beam.”).
Regarding claim 12, Zhang teaches the apparatus according to claim 1, wherein the moveable device is mounted on a set of motorized actuators and is aimed at the target paw by a human operator via computer using a joystick or keypad (Page 9, Col. 1: Results - “The apparatus was tested for painful heat stimuli, using a laser beam, and for tactile stimulation with an electrically driven mechanical actuator (Figure 2E). The position of the laser beam and the actuator can be manually controlled by a control stick under guidance by a video-image from underneath the animal (Figures 1A, 2C).”).
Regarding claim 16, Zhang teaches the apparatus according to claim 1, wherein a red light source is used to illuminate the target paw and a photodetector is used to measure changes in the reflectance of red light off the target paw before, during and after stimulation in order to detect withdrawal of the target paw with millisecond precision (Pages 2-3: Custom Made Apparatus for Sensory Testing – “The camera
also recorded a red indicator-LED light on top of the mouse platform indicating when the laser or the mechanical stimulation had been triggered. This signal facilitates synchronization of stimulation and recording, measuring paw withdrawal latency and aligning evoked potentials. The LED light was directed toward the lateral camera and was not visible to the animal to be sure not to trigger any behavioral reaction, confirming that the LED and the laser light themselves provided no relevant cues.”; Page 4, Col. 2: Control Unit – “Trigger two was set to 100 ms and is used to drive the red LED in view of the lateral camera (100 ms is sufficient time to produce a reliable video signal when the laser is triggered), and this trigger was also fed into the electrophysiological recording system for synchronization with the LED-on period in the video.”; Page 13, Col. 1: Discussion – “Time of stimulation was indicated by a LED, allowing accurately measurement of paw withdraw latency and further behavioral responses.”).
Regarding claim 17, Zhang teaches a method for automated measurement of pain and responses to various somatosensory stimuli in laboratory rodents, comprising:
confining one or more rodents individually in one or more enclosures (Fig. 1A – “chamber”) in which said one or more enclosures are located on a platform (Figs. 1-2 – Fig. 2A “upper platform”);
directing a moveable device positioned underneath said platform and enclosures (Fig. 1A – “stimulator”) to:
aim different sources of stimulation, alone or in combination, at a target paw of the rodent (Page 5, Col. 1: Control Unit - “targeting the stimulator to the mouse paw”),
deliver one or more different stimulus modalities, alone or in combination, to the target paw (Page 5, Col. 1: Tactile Stimulator – ‘tactile stimulator was constructed in-house to be interchangeable with the laser stimulator”),
detect changes in position of the target paw with millisecond precision (Page 9, Col. 2: Results: “There was a significant increase of hind paw guarding time after 10 ms laser stimulation compared to 3 or 5 ms”; 13, Col. 1: Discussion – “In addition to paw withdrawal, we also measured other pain-induced behaviors like guarding, flinching and freezing”), and
collect video of rodent activity before, during and after stimulation (Page 4, Col. 2 – Control Unit: “the video would start recording 3 s before the stimulation and continue recording 30 s after the stimulation.”; Page 9, Col. 1: Results – “to facilitate the alignment of the stimulation and the behaviors via video”); and
using a controller operably connected to the moveable device (Page 2, Col. 2: Custom Made Apparatus for Sensory Testing – “The horizontal position of the stimulator could be freely determined by manually moving the connected control stick (Figure 1A).”) to:
coordinate all aspects of stimulation using programmed instructions (Page 4, Col. 1: Control Unit - “separate control unit (Figures 2D, 3) was designed to handle the following functions: i. Triggering of the laser/tactile stimulator either manually or automatically; ii. Triggering the red LED indicator (in view of the lateral camera); iii. Controlling recording intervals of the lateral camera as required by the experiment; iv. Initiate trials with random timing within a pre-set minimum and maximum time interval.”),
synchronize recorded data with stimulus timing and calculate withdrawal latency therefrom (Page 3, Col. 1: Custom Made Apparatus for Sensory Testing - “This signal facilitates synchronization of stimulation and recording, measuring paw withdrawal latency”), and
automatically record all data, metadata, and calculations to electronic files (Page 5, Col. 1: Control Unit – “All electrophysiological and video data was recorded on a PC for later offline analysis”).
Regarding claim 19, Zhang teaches the method according to claim 17, wherein the platform is made of an optically clear material, and wherein the moveable device includes a light source of selected wavelength(s) to provide optogenetic stimulation (Page 2, Col. 2: Custom Made Apparatus for Sensory Testing – “We used an infrared laser stimulator (MRC Systems GmbH, Germany) of 1470 nm and with pulse durations from 1 – 100 ms (pulse energy 1.2 – 306 mJ) (Figure 1B). A pilot laser of 650 nm (red light, visible to naked eye) indicted the position of the laser beam.”, “A circular grid plate (100 mm in diameter) was produced by a 3D printer (Formlabs Form2, United States) and inserted in the hole in the top plate to create a floor for the animal that allows laser/tactile stimulation to be conducted without obstruction (Figures 2A,B). A transparent plexiglass cylinder (120 mm in diameter) was then placed vertically on top of the circular grid, bordering the experimental arena of the mouse (Figure 1A).”; Page 7, Col. 2: Stimulation, Electrophysiology, and Behavior – “In order to apply different energies we applied laser pulse durations of different durations: 3 ms (2.3 mJ), 5 ms (5 mJ), and 10 ms (11.7 mJ). These pulses are far shorter than the subsequent activation of central neuronal networks or behavioral reactions, allowing for appropriate alignment of evoked potentials. Stimulations were done when the animal was immobile such that the paw could be targeted.”; Page 2, Col. 1: Introduction - “brief infrared laser pulses are widely used as nociceptive stimuli”).
Regarding claim 20, Zhang teaches the method according to claim 17, wherein the platform is made of an optically clear material, and wherein the moveable device includes infrared (IR) light for thermal stimulation via radiant heating (Page 2, Col. 2: Custom Made Apparatus for Sensory Testing – “We used an infrared laser stimulator (MRC Systems GmbH, Germany) of 1470 nm and with pulse durations from 1 – 100 ms (pulse energy 1.2 – 306 mJ) (Figure 1B). A pilot laser of 650 nm (red light, visible to naked eye) indicted the position of the laser beam.”, “A circular grid plate (100 mm in diameter) was produced by a 3D printer (Formlabs Form2, United States) and inserted in the hole in the top plate to create a floor for the animal that allows laser/tactile stimulation to be conducted without obstruction (Figures 2A,B). A transparent plexiglass cylinder (120 mm in diameter) was then placed vertically on top of the circular grid, bordering the experimental arena of the mouse (Figure 1A).”).
Regarding claim 21, Zhang teaches the method according to claim 17, wherein the platform is metal grating, and wherein the moveable device includes a mechanical indenter which stimulates by physical contact with the target paw (Page 2, Col. 2: Custom Made Apparatus for Sensory Testing – “We used an infrared laser stimulator (MRC Systems GmbH, Germany) of 1470 nm and with pulse durations from 1 – 100 ms (pulse energy 1.2 – 306 mJ) (Figure 1B). A pilot laser of 650 nm (red light, visible to naked eye) indicted the position of the laser beam.”, “A circular grid plate (100 mm in diameter) was produced by a 3D printer (Formlabs Form2, United States) and inserted in the hole in the top plate to create a floor for the animal that allows laser/tactile stimulation to be conducted without obstruction (Figures 2A,B). A transparent plexiglass cylinder (120 mm in diameter) was then placed vertically on top of the circular grid, bordering the experimental arena of the mouse (Figure 1A).”).
Regarding claim 22, Zhang teaches the method according to claim 21, wherein the mechanical indenter is configured to measure force applied to the paw and to detect withdrawal based on changes in force as the target paw is withdrawn from the indenter arm (Fig. 4 – “Electronic design of the tactile stimulator. The 27 V signal is reduced to 5 V to power the NE555 chip which is responsible for the duration of the pulse sent to the actuator. U5 regulates the output voltage to 24 V when the input voltage is equal to, or more than 27 V: Using an input voltage of less than 27 V reduces the force applied to the actuator and increases the actuation time.”; Fig. 5F - “View of the lateral camera showing the moment of paw withdrawal following laser stimulation.”).
Regarding claim 24, Zhang teaches the method according to claim 17, wherein said moveable device includes a source of red light configured to be aimed at said target paw in order to assist aiming by identifying a photostimulation zone prior to initiating photostimulation with other wavelengths of light (Page 9, Col. 1: Results – “The indicator LED beside the chamber shined red light toward the lateral camera when stimulation was triggered, to facilitate the alignment of the stimulation and the behaviors via video.”; Page 2, Col. 2: Custom Made Apparatus for Sensory Testing – “We used an infrared laser stimulator (MRC Systems GmbH, Germany) of 1470 nm and with pulse durations from 1 – 100 ms (pulse energy 1.2 – 306 mJ) (Figure 1B). A pilot laser of 650 nm (red light, visible to naked eye) indicted the position of the laser beam.”).
Regarding claim 25, Zhang teaches the method according to claim 17, wherein the moveable device is mounted on a set of motorized actuators and is aimed at the target paw by a human operator via computer using a joystick or keypad (Page 9, Col. 1: Results - “The apparatus was tested for painful heat stimuli, using a laser beam, and for tactile stimulation with an electrically driven mechanical actuator (Figure 2E). The position of the laser beam and the actuator can be manually controlled by a control stick under guidance by a video-image from underneath the animal (Figures 1A, 2C).”).
Regarding claim 29, Zhang teaches the method according to claim 17, wherein a red light source is used to illuminate the target paw and a photodetector is used to measure changes in the reflectance of red light off the target paw before, during and after stimulation in order to detect withdrawal of the target paw with millisecond precision (Pages 2-3: Custom Made Apparatus for Sensory Testing – “The camera
also recorded a red indicator-LED light on top of the mouse platform indicating when the laser or the mechanical stimulation had been triggered. This signal facilitates synchronization of stimulation and recording, measuring paw withdrawal latency and aligning evoked potentials. The LED light was directed toward the lateral camera and was not visible to the animal to be sure not to trigger any behavioral reaction, confirming that the LED and the laser light themselves provided no relevant cues.”; Page 4, Col. 2: Control Unit – “Trigger two was set to 100 ms and is used to drive the red LED in view of the lateral camera (100 ms is sufficient time to produce a reliable video signal when the laser is triggered), and this trigger was also fed into the electrophysiological recording system for synchronization with the LED-on period in the video.”; Page 13, Col. 1: Discussion – “Time of stimulation was indicated by a LED, allowing accurately measurement of paw withdraw latency and further behavioral responses.”).
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.
Claims 13-15 and 26-28 are rejected under 35 U.S.C. 103 as being unpatentable over “A New Apparatus for Recording Evoked Responses to Painful and Non-painful Sensory Stimulation in Freely Moving Mice” (Zhang et al, 2021) in view of US 20150146939 A1 (Datta et al.).
Regarding claim 13, Zhang teaches the apparatus according to claim 1, wherein the moveable device is mounted on a set of motorized actuators (Page 9, Col. 1: Results - “The apparatus was tested for painful heat stimuli, using a laser beam, and for tactile stimulation with an electrically driven mechanical actuator (Figure 2E).”).
Zhang does not teach the stimulus is aimed at the target paw automatically by a neural network pre-trained to recognize and track the target paw.
However,
Datta teaches the stimulus is aimed at the target paw automatically by a neural network pre-trained to recognize and track the target paw ([0176]; [0100] “An investigation can then be conducted into how the overall behavioral state of the animal changes (these changes are measured as alterations in the density and distribution of the animal's postural clusters) when the animal is offered a particular stimulus (including but not limited to odors, tastes, tactile stimuli, auditory stimuli, visual stimuli, stimuli designed to cause the animal pain or itch),”; [0127] “Mice can be videotaped walking in a straight line on glass, and their paws can be detected using computer vision algorithms”; [0032] “a system for studying the behavior of an animal in an experimental area, comprising: a stimulus device for stimulating the animal”).
It would have been obvious for one of ordinary skill in the art before the effective filing date of the invention to have modified the apparatus taught by Zhang to include a neural network recognizing and tracking the target paw to aim the stimulus. One would have motivated to make this modification because Zhang describes in the Discussion on Page 10 that “The device allows for manual or automatic triggering of laser- or other kinds of stimulations (for example tactile)”. Datta describes that using video images of the mice, computer vision and neural networks may be implemented in the software to recognize the anatomy and behavior of the mice, which allows the tracking to be automated and the rodent to be continuously monitored, as suggested in [0127] and [0176] of Datta.
Regarding claim 14, Zhang teaches the apparatus according to claim 13, wherein initiation of stimulation is made contingent on various factors ascertained from video, such as whether the rodent is stationary, has assumed a certain posture, and/or is engaged in a certain behavior Page 7, Col. 2: Stimulation, Electrophysiology, and Behavior – “Stimulations were done when the animal was immobile such that the paw could be targeted. The interval between two stimuli was dependent on the behavior of the animal. Only when the mouse was awake and resting quiescently on its four paws, the stimulation was applied.”).
Zhang does not teach assessed by artificial intelligence.
However,
Datta teaches assessed by artificial intelligence ([0122] “machine learning algorithm”; [0176] “convolution neural networks and deep belief network … characterize how alterations in genotype or stimulus might alter behaviors as they evolve over time.).
It would have been obvious for one of ordinary skill in the art before the effective filing date of the invention to have modified the apparatus taught by Zhang to include assessing rodent behavior using artificial intelligence. One would have motivated to make this modification because machine learning and neural network artificial intelligence can analyze and classify behavior of the mice in an automated way without significant human intervention, as suggested by Datta ([0096-0098]).
Regarding claim 15, Zhang teaches the apparatus according to claim 13, wherein software coordinates interleaved testing of a cohort of rodents positioned on the platform so that many rodents can be rapidly tested sequentially, but where each rodent is not re-tested before a minimum acceptable period has elapsed, thus enabling high-throughput testing of the cohort (Page 7, Col. 2: Stimulation, Electrophysiology, and Behavior – “Stimulations were done when the animal was immobile such that the paw could be targeted. The interval between two stimuli was dependent on the behavior of the animal. Only when the mouse was awake and resting quiescently on its four paws, the stimulation was applied. In many cases the mouse was actively exploring the chamber, such that intervals between stimuli lasted as long as half an hour or longer. The shortest interval between stimuli was set at 30 s”).
Regarding claim 26, Zhang teaches the method according to claim 17, wherein the moveable device is mounted on a set of actuators (Page 9, Col. 1: Results - “The apparatus was tested for painful heat stimuli, using a laser beam, and for tactile stimulation with an electrically driven mechanical actuator (Figure 2E).”).
Zhang does not teach the stimulus is aimed at the target paw automatically by a neural network pre-trained to recognize and track the target paw.
However,
Datta teaches the stimulus is aimed at the target paw automatically by a neural network pre-trained to recognize and track the target paw ([0176]; [0100] “An investigation can then be conducted into how the overall behavioral state of the animal changes (these changes are measured as alterations in the density and distribution of the animal's postural clusters) when the animal is offered a particular stimulus (including but not limited to odors, tastes, tactile stimuli, auditory stimuli, visual stimuli, stimuli designed to cause the animal pain or itch)”; [0127] “Mice can be videotaped walking in a straight line on glass, and their paws can be detected using computer vision algorithms”; [0032] “a system for studying the behavior of an animal in an experimental area, comprising: a stimulus device for stimulating the animal”.
It would have been obvious for one of ordinary skill in the art before the effective filing date of the invention to have modified the method taught by Zhang to include a neural network recognizing and tracking the target paw to aim the stimulus. One would have motivated to make this modification because Zhang describes in the Discussion on Page 10 that “The device allows for manual or automatic triggering of laser- or other kinds of stimulations (for example tactile)”. Datta describes that using video images of the mice, computer vision and neural networks may be implemented in the software to recognize the anatomy and behavior of the mice, which allows the tracking to be automated and the rodent to be continuously monitored, as suggested in [0127] and [0176] of Datta.
Regarding claim 27, Zhang teaches the method according to claim 28, wherein initiation of stimulation is made contingent on various factors ascertained from video, such as whether the rodent is stationary, has assumed a certain posture, and/or is engaged in a certain behavior Page 7, Col. 2: Stimulation, Electrophysiology, and Behavior – “Stimulations were done when the animal was immobile such that the paw could be targeted. The interval between two stimuli was dependent on the behavior of the animal. Only when the mouse was awake and resting quiescently on its four paws, the stimulation was applied”).
Zhang does not teach assessed by artificial intelligence.
However,
Datta teaches assessed by artificial intelligence ([0122] “machine learning algorithm”; [0176] “convolution neural networks and deep belief network … characterize how alterations in genotype or stimulus might alter behaviors as they evolve over time”).
It would have been obvious for one of ordinary skill in the art before the effective filing date of the invention to have modified the method taught by Zhang to include assessing rodent behavior using artificial intelligence. One would have motivated to make this modification because machine learning and neural network artificial intelligence can analyze and classify behavior of the mice in an automated way without significant human intervention, as suggested by Datta ([0096-0098]).
Regarding claim 28, Zhang teaches the method according to claim 28, wherein software coordinates interleaved testing of a cohort of rodents positioned on the platform so that many rodents can be rapidly tested sequentially, but where each rodent is not re-tested before a minimum acceptable period has elapsed, thus enabling high-throughput testing of the cohort (Page 7, Col. 2: Stimulation, Electrophysiology, and Behavior – “Stimulations were done when the animal was immobile such that the paw could be targeted. The interval between two stimuli was dependent on the behavior of the animal. Only when the mouse was awake and resting quiescently on its four paws, the stimulation was applied. In many cases the mouse was actively exploring the chamber, such that intervals between stimuli lasted as long as half an hour or longer. The shortest interval between stimuli was set at 30 s”).
Claims 7 and 23 are rejected under 35 U.S.C. 103 as being unpatentable over “A New Apparatus for Recording Evoked Responses to Painful and Non-painful Sensory Stimulation in Freely Moving Mice” (Zhang et al, 2021) in view of US 20090270757 A1 (Backonja, Miroslav).
Regarding claim 7, Zhang teaches the apparatus according to claim 5, wherein the mechanical indenter is adapted to provide other somatosensory modalities requiring contact with the paw (Page 11, Col. 1: Discussion - “Furthermore, the apparatus is able to carry other types of stimulators, as demonstrated with the tactile stimulation”), including:
needle prick using a sharp-tipped probe (Page 5, Col. 1: Tactile Stimulator – “At this position, any standard hyperdermic needle is easily mounted, allowing to use a wide range of different thicknesses and lengths as well as sharp or blunt tips.”).
Zhang does not explicitly teach heating or cooling using a Peltier device, application of chemicals including for cooling or for heating, and dynamic touch using a rotary brush.
However,
Bakconja teaches heating or cooling using a Peltier device ([0005] “contacting the skin with a water circulating thermode, an ohmic heating element, or a Peltier device.”; [0028] “Any other device capable of producing heat, such as wire coil, Peltier element, semiconductor crystal, etc., may be used as well.”),
application of chemicals including for cooling or for heating ([0046] “chemical (capsaicin, menthol, histamine)”), and
dynamic touch using a rotary brush ([0046] “mechanical (brush, pressure, pinprick and punctate)”).
It would have been obvious for one of ordinary skill in the art before the effective filing date of the invention to have modified the apparatus taught by Zhang to include other stimulation devices including a Peltier device, capsaicin for colling, and a rotary brush. One would have been motivated to make this modification because subjects may have different reactions to different types of stimuli which can illicit positive and negative sensory reactions from the subject, as suggested by Backonja ([0045-0046]).
Regarding claim 23, Zhang teaches the method according to claim 21, wherein the mechanical indenter is adapted to provide other somatosensory modalities requiring contact with the paw (Page 11, Col. 1: Discussion - “Furthermore, the apparatus is able to carry other types of stimulators, as demonstrated with the tactile stimulation”), including:
needle prick using a sharp-tipped probe (Page 5, Col. 1: Tactile Stimulator – “At this position, any standard hyperdermic needle is easily mounted, allowing to use a wide range of different thicknesses and lengths as well as sharp or blunt tips.”).
Zhang does not explicitly teach heating or cooling using a Peltier device, application of chemicals including for cooling or for heating, and dynamic touch using a rotary brush.
However,
Backonja teaches heating or cooling using a Peltier device ([0005] “contacting the skin with a water circulating thermode, an ohmic heating element, or a Peltier device.”; [0028] “Any other device capable of producing heat, such as wire coil, Peltier element, semiconductor crystal, etc., may be used as well.”),
application of chemicals like acetone for cooling or for capsaicin for heating ([0046] “chemical (capsaicin, menthol, histamine)”),
and dynamic touch using a rotary brush ([0046] “mechanical (brush, pressure, pinprick and punctate)”).
It would have been obvious for one of ordinary skill in the art before the effective filing date of the invention to have modified the method taught by Zhang to include other stimulation devices including a Peltier device, capsaicin for colling, and a rotary brush. One would have been motivated to make this modification because subjects may have different reactions to different types of stimuli which can illicit positive and negative sensory reactions from the subject, as suggested by Backonja ([0045-0046]).
Claims 2 and 18 are rejected under 35 U.S.C. 103 as being unpatentable over “A New Apparatus for Recording Evoked Responses to Painful and Non-painful Sensory Stimulation in Freely Moving Mice” (Zhang et al, 2021) in view of US 20160150758 A1 (Salem et al.).
Regarding claim 2, Zhang teaches the apparatus according to claim 1, wherein said enclosures each comprise a separate clear tube and opaque cubicle, wherein the clear tube is used to transfer each rodent from its home cage to the testing platform and to house the rodent during testing on the platform (Page 7, Col. 1: Surgery for Electrode Implantation - “After surgery, the animals were placed into their cage and the environment was maintained at 28C until the animals woke up. Immediately after waking, the animals were transferred to the housing scantainer for 1 week of recovery before recording.”; Page 2, Col. 2: Custom Made Apparatus for Sensory Testing – “A transparent plexiglass cylinder (120 mm in diameter) was then placed vertically on top of the circular grid, bordering the experimental arena of the mouse (Figure 1A)”; Page 7, Col. 1-2- Stimulation, Electrophysiology, and Behavior – “A cardboard partition was placed between the apparatus and the experimenter to prevent visual contact”).
Zhang does not explicitly teach wherein the opaque, magnetically connectable cubicles separate the rodents and position them at a desired spacing and alignment on the platform.
However,
Salem teaches wherein the opaque, magnetically connectable cubicles separate the rodents and position them at a desired spacing and alignment on the platform ([0046] “the door assembly 160 of the SCORHE enclosure 100 includes a hinged door 102 with a magnetic latch 104 to allow for insertion and removal of the home cage 20 from the rack 300 without removing the enclosure from the rack system … the bottom surface 141 may include combinations of transparent, translucent, or opaque portions”; [0040] “a ventilated cage rack system 300 that is compatible with the SCORHE 10 to increase the functionality of the rack system while also while maintaining the efficiency of using a readily-available multi-cage ventilated rack”).
It would have been obvious for one of ordinary skill in the art before the effective filing date of the invention to have modified the apparatus taught by Zhang to include a magnetically connectable cubicle. One would have been motivated to make this modification because the magnetic component allows the cage (cubicle) to be removed easily without the entire enclosure being moved for testing, as suggested by Salem ([0046]).
Regarding claim 18, Zhang teaches the method according to claim 17, wherein said enclosures each comprise a separate clear tube and opaque cubicle, wherein the clear tube is used to transfer each rodent from its home cage to the testing platform and to house the rodent during testing on the platform (Page 7, Col. 1: Surgery for Electrode Implantation - “After surgery, the animals were placed into their cage and the environment was maintained at 28C until the animals woke up. Immediately after waking, the animals were transferred to the housing scantainer for 1 week of recovery before recording.”; Page 2, Col. 2: Custom Made Apparatus for Sensory Testing – “A transparent plexiglass cylinder (120 mm in diameter) was then placed vertically on top of the circular grid, bordering the experimental arena of the mouse (Figure 1A)”; Page 7, Col. 1-2- Stimulation, Electrophysiology, and Behavior – “A cardboard partition was placed between the apparatus and the experimenter to prevent visual contact”).
Zhang does not explicitly teach wherein the opaque, magnetically connectable cubicles separate the rodents and position them at a desired spacing and alignment on the platform.
However,
Salem teaches wherein the opaque, magnetically connectable cubicles separate the rodents and position them at a desired spacing and alignment on the platform ([0046] “the door assembly 160 of the SCORHE enclosure 100 includes a hinged door 102 with a magnetic latch 104 to allow for insertion and removal of the home cage 20 from the rack 300 without removing the enclosure from the rack system … the bottom surface 141 may include combinations of transparent, translucent, or opaque portions”; [0040] “a ventilated cage rack system 300 that is compatible with the SCORHE 10 to increase the functionality of the rack system while also while maintaining the efficiency of using a readily-available multi-cage ventilated rack”).
It would have been obvious for one of ordinary skill in the art before the effective filing date of the invention to have modified the method taught by Zhang to include a magnetically connectable cubicle. One would have been motivated to make this modification because the magnetic component allows the cage (cubicle) to be removed easily without the entire enclosure being moved for testing, as suggested by Salem ([0046]).
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to EVELYN GRACE PARK whose telephone number is (571)272-0651. The examiner can normally be reached Monday - Friday, 9AM - 5:00PM.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Robert (Tse) Chen can be reached at (571)272-3672. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/EVELYN GRACE PARK/Examiner, Art Unit 3791 /TSE W CHEN/Supervisory Patent Examiner, Art Unit 3791