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 .
Claims 1-22 are the currently pending claims hereby under examination.
Claim Objections
Claims 11, 14, and 18-19 are objected to because of the following informalities:
In claim 11, lines 3-8: the list (a)-(f) all begin with capital letters (ex: "Delivering" in step 'a') and should be revised to lowercase letters;
In claim 11, line 8: step (f) currently says “repeating steps a–d …”, but based on the structure of the claim, the intended outcome is to determine whether the subsequent startle response has been reduced compared to the initial response, and to reach that final goal, it would logically require repeating steps (a)–(e) rather than only (a)–(d), because (e) is the comparison step that determines reduction;
In claim 14, line 2: “response” should be “responses”;
In claim 18, line 3: The ordered step sequence begins with "b" instead of "a," which is a drafting error that should be corrected (also carries through subsequent items (c)-(g));
In claim 18, lines 3-8: the list (b)-(g) all begin with capital letters (ex: "Delivering" in step 'b') and should be revised to lowercase letters; and
In claim 19, line 2: “response” should be “responses”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claim 10 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as failing to set forth 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 10 recites “elevated activity in the hippocampus … indicates … PTSD.” The specification does not provide sufficient written description of this diagnostic correlation. Although [0004] of the Instant Application states that increased hippocampal activity may indicate PTSD, the it does not describe how “elevated” is determined (relative baseline or comparator), what imaging/analysis conditions apply (task vs. rest, sequence, ROI, statistical threshold), or any representative data or examples supporting the correlation. Accordingly, the application fails to reasonably convey to a person of ordinary skill in the art that the inventors were in possession of the claimed diagnostic rule.
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 10, 14-17, and 19-20 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as failing to set forth 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 9 recites “an increased startle response in the subject indicates that the subject has a mental disorder” in lines 1–2. The phrase “increased startle response” is a relative term and therefore indefinite because it is unclear what frame of reference, baseline or comparator is used to determine the increase. It is ambiguous whether the increase is relative to the subject’s own prior response, a control group, a population average, or another benchmark. The Examiner is interpreting “increased startle response” as a heightened physiological reflex relative to some baseline/comparative response, but this interpretation is not compelled by the claim language or specification, leaving the scope subject to multiple reasonable interpretations.
Claim 10 recites “elevated activity in the hippocampus as measured by fMRI indicates that the subject has post-traumatic stress disorder (PTSD)” in lines 1–2. The terms “elevated activity” and “indicates” render the scope indefinite because the claim fails to specify the reference standard for “elevated” (e.g., the subject’s baseline, a control cohort, or population norms), the imaging/analysis conditions (e.g., task vs. resting-state, pulse sequence, region-of-interest definition, statistical threshold), and the decision criterion by which hippocampal activity “indicates” PTSD. Absent these parameters, a person of ordinary skill in the art cannot determine the bounds of the claim with reasonable certainty. The Examiner is interpreting this phrase as an attempt to correlate neuroimaging data with diagnostic categories, but it lacks sufficient definition.
Claim 14 recites "obtaining the same measurement from the subject" in lines 2-3. The scope of "same measurement" is ambiguous, rendering the claim indefinite. The Examiner is interpreting that this is attempting to identify a type of startle response (much like claim 7) and limiting the initial and subsequent response to the same type of response measurement, not the same measurement itself. Also, if the initial and subsequent responses were the same measurement itself, claim 14 would be indefinite since it would contradict the recitations of claim 11 that indicate these responses were separate and distinct from each other.
Claims 15-17 are rejected by virtue of their dependence from claim 14.
Claim 19 recites "obtaining the same measurement from the subject" in lines 2-3. The scope of "same measurement" is ambiguous, rendering the claim indefinite. The Examiner is interpreting that this is attempting to identify a type of startle response (much like claim 7) and limiting the first and second responses to the same type of response measurement, not the same measurement itself. Also, if the first and second responses were the same measurement itself, claim 14 would be indefinite since it would contradict the recitations of claim 11 that indicate these responses were separate and distinct from each other.
Claim 20 is rejected by virtue of its dependence from claim 19.
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.
Claims 1-5 are rejected under 35 U.S.C. 101 because the claimed invention is directed to non-statutory subject matter. The claims do not fall within at least one of the four categories of patent eligible subject matter because the claims are directed to "A set of acoustic signals for delivery to a subject". Transitory forms of signal transmission (often referred to as "signals per se"), such as a propagating electrical or electromagnetic signal or carrier wave are not directed to any of the statutory categories (see MPEP 2106.03).
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-2, 4, 6-8, 11-16, and 18-22 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Galazyuk et al. (US 20180085034 A1), hereto referred as Galazyuk.
Regarding claim 1, Galazyuk teaches a set of acoustic signals for delivery to a subject (Galazyuk, ¶[0022]: “Pre-pulse inhibition is an auditory effect in which an initial pulse of sound can inhibit the startle response that occurs in response to a subsequent loud noise (i.e., auditory startle stimulus)”, this shows that acoustic signals including pre-pulse and startle (pulse) sounds are delivered to a subject), wherein the set comprises at least one pre-pulse stimulus and at least one pulse stimulus (Galazyuk, ¶[0023]: “The method includes the steps of delivering a pre-pulse auditory stimulus to the subject 12, allowing a stimulus gap to pass 14, delivering an auditory startle stimulus to the subject 16, and determining if the startle response of the subject has decreased 18”, this explicitly shows the use of a pre-pulse auditory stimulus in the set and the use of a pulse stimulus in the set).
Regarding claim 2, Galazyuk teaches that the at least one pre-pulse stimulus has a frequency of 200 Hz, 300 Hz, 400 Hz, 500 Hz, 1000 Hz, 3000 Hz, 4000 Hz, or 5000 Hz and an amplitude of 15 dB, 25 dB, or 45 dB (Galazyuk, ¶[0031]: “The decibel level of the pre-pulse auditory stimulus can start, for example, at 40 decibels, followed by pre-pulse auditory stimuli at 45 db, 50 db, 55 db, 60 db, and so forth, until a decrease in the startle response is detected”, this shows that pre-pulse stimuli can be delivered at least at 45 dB; ¶[0061]: “Prepulse stimulus were 20 ms pure tones with a 1 ms rise/fall time presented at six different frequencies (4, 12.5, 16, 20, 25, and 31.5 kHz) 100 ms before the startle stimulus”, this shows that specific pre-pulse stimuli at defined frequencies are disclosed, including 4 kHz (4000 Hz)).
Regarding claim 4, Galazyuk teaches that the at least one pulse stimulus has a frequency of 200 Hz, 300 Hz, 400 Hz, 500 Hz, 1000 Hz, 3000 Hz, 4000 Hz, or 5000 Hz and an amplitude of 65 dB, 80 dB, or 105 dB (Galazyuk, ¶[0025]: “Suitable startle stimulus typically include one or more audible wavelengths delivered at a volume of from 50 to 130 decibels (dB) sound pressure level (SPL)”, this teaches amplitudes encompassing 65 dB, 80 dB, and 105 dB; ¶[0025]: “Accordingly, in some embodiments, a startle stimulus from 70 to 110 dB SPL, or from 80 to 100 dB SPL can be used”, this further confirms coverage of 80 dB and 105 dB within the disclosed startle stimulus amplitude ranges; ¶[0025]: “Different subjects have differing startle-stimulus response functions, which are known or can be easily determined by one skilled in the art... Suitable audible wavelengths differ depending on the nature of the subject. For example, suitable audible wavelengths for a human subject range from 20 Hz to 20 kHz”, this shows that the listed pulse stimulus frequencies of 200 Hz through 5000 Hz are within the disclosed range for subjects to which a skilled artisan would naturally choose from depending on the particulars of the subject; ¶[0025]: “Typically the startle stimulus will include multiple (e.g., wide-band) audible frequencies”, this shows that the startle (pulse) stimulus may include or encompass the claimed discrete frequencies as part of wide-band content).
Regarding claim 6, Galazyuk teaches that a method for evaluating an acoustic startle reflex in a subject, the method comprising: delivering the set of any of the preceding claims to the subject (see any of the above rejections of claims 1, 2, and 4); and measuring a startle response in the subject (Galazyuk, ¶[0023]: “The method includes the steps of delivering a pre-pulse auditory stimulus to the subject 12, allowing a stimulus gap to pass 14, delivering an auditory startle stimulus to the subject 16, and determining if the startle response of the subject has decreased 18”, this explicitly shows delivery of the set of stimuli to the subject and measurement of the startle response).
Regarding claim 7, Galazyuk teaches that the startle response is selected from the blink reflex, pupil dilation, skin conductive response, and brain activity in fMRI (Galazyuk, ¶[0029]: “The blink of the eye which is the reflex of the orbicularis oculi muscle was found to have a latency of about 20 to 40 milliseconds”, this shows measurement of a blink reflex as a startle response; ¶[0088]: “The amygdala, hippocampus, prefrontal cortex, auditory cortex and many other structures have been flagged as the source of this top-down modulation. To this extent, it seems that PPI audiometry has the potential to assess large portions of the auditory neuraxis and other neocortical regions”, this shows that brain activity, including in the hippocampus, can be measured in association with startle and PPI). The Examiner interprets this limitation to require at least one of the listed physiological responses as a measure of the startle reflex.
Regarding claim 8, Galazyuk teaches that measuring the blink reflex comprises measuring the speed, magnitude, and/or duration of the blink reflex in the subject (Galazyuk, ¶[0029]: “The blink of the eye which is the reflex of the orbicularis oculi muscle was found to have a latency of about 20 to 40 milliseconds”, this shows that the blink reflex is measured in terms of its timing, which corresponds to speed and duration. The magnitude of the reflex can be inferred from the amplitude of the blink response).
Regarding claim 11, Galazyuk teaches a method for performing acoustic neuromodulation in a subject, comprises: (Galazyuk, Abstract: “determining if the startle response of the subject has decreased compared with a control value… repeating these steps until the pre-pulse auditory stimulus administered has a value sufficient to cause a decrease in the startle response of the subject”, this shows that Galazyuk teaches a feedback-driven method in which auditory stimuli are delivered and repeated until the subject’s startle response is reduced, which constitutes acoustic neuromodulation in a subject by adaptively adjusting sound stimulation to modify neural responsiveness; ¶[0088]: “many higher nuclei can modulate these effects as well … a large degree of top-down modulation can influence prepulses … PPI audiometry could be a useful tool to assess neuroplastic changes in awake behaviorally responsive animals”, shows that the method uses auditory stimuli in a feedback loop to modulate a neural reflex and assess neuroplastic change, which constitutes acoustic neuromodulation);
a. delivering an acoustic stimulus to the subject (Galazyuk, ¶[0024]: “The method includes delivering auditory stimuli to the subject”, this shows delivery of acoustic stimuli to a subject; ¶[0025]: “The auditory startle stimulus is a loud sound sufficient to cause the subject to be startled and exhibit a startle response”, this shows that the acoustic stimulus is an audible sound designed to elicit a startle response);
b. measuring an initial startle response in the subject (Galazyuk, ¶[0030]: “a startle algorithm is used to measure the startle response of the subject”, this teaches measuring the startle response after stimulus delivery);
c. delivering the acoustic stimulus to the subject (Galazyuk, ¶[0041]: “delivering an auditory startle stimulus to the subject 36”, this teaches a subsequent delivery of an acoustic startle stimulus within the method flow);
d. measuring a subsequent startle response in the subject (Galazyuk, ¶[0041]: “measuring the startle response of the subject 38”, this teaches measuring the startle response again after the subsequent stimulus delivery);
e. comparing the startle responses in the subject (Galazyuk, ¶[0031]: “A decrease can be identified by comparing the startle response with a control value for the startle response. A control value can be a startle response previously determined for the subject... ”, this teaches comparing measured startle responses, where comparison to a control serves the same functional purpose as comparing initial and subsequent responses); and
f. repeating steps a–d when the subsequent startle response in the subject is not reduced compared to the initial startle response, or ceasing delivery of the acoustic stimulus to the subject when the subsequent startle response in the subject is reduced compared to the initial startle response (Galazyuk, ¶[0023]: “these steps are repeated until the delivered pre-pulse auditory stimulus has a value sufficient to cause a decrease in the startle response of the subject”, this teaches repeating the sequence until a decrease is achieved, which functionally corresponds to repeating when not reduced and ceasing when reduced).
Regarding claim 12, Galazyuk teaches that the acoustic stimulus comprises a pulse stimulus having a frequency of 200 Hz, 300 Hz, 400 Hz, 500 Hz, 1000 Hz, 3000 Hz, 4000 Hz, or 5000 Hz and an amplitude of 65 dB, 80 dB, or 105 dB (Galazyuk, ¶[0025]: “The method includes delivering both a pre-pulse auditory stimulus and an auditory startle stimulus to the subject. The auditory startle stimulus is a loud sound sufficient to cause the subject to be startled and exhibit a startle response”, this shows that the claimed “pulse stimulus” corresponds to Galazyuk’s auditory startle stimulus within the method framework; ¶[0025]: “Suitable startle stimulus typically include one or more audible wavelengths delivered at a volume of from 50 to 130 decibels (dB) sound pressure level (SPL)”, this teaches amplitudes encompassing 65 dB, 80 dB, and 105 dB; ¶[0025]: “Accordingly, in some embodiments, a startle stimulus from 70 to 110 dB SPL, or from 80 to 100 dB SPL can be used”, this further confirms coverage of 80 dB and 105 dB within the disclosed startle stimulus amplitude ranges; ¶[0025]: “Different subjects have differing startle-stimulus response functions, which are known or can be easily determined by one skilled in the art... Suitable audible wavelengths differ depending on the nature of the subject. For example, suitable audible wavelengths for a human subject range from 20 Hz to 20 kHz”, this shows that the listed pulse stimulus frequencies of 200 Hz through 5000 Hz are within the disclosed range for subjects to which a skilled artisan would naturally choose from depending on the particulars of the subject; ¶[0025]: “Typically the startle stimulus will include multiple (e.g., wide-band) audible frequencies”, this shows that the startle (pulse) stimulus may include or encompass the claimed discrete frequencies as part of wide-band content).
Regarding claim 13, Galazyuk teaches delivering a pre-pulse stimulus to the subject prior to each pulse stimulus, wherein the pre-pulse stimulus has a frequency of 200 Hz, 300 Hz, 400 Hz, 500 Hz, 1000 Hz, 3000 Hz, 4000 Hz, or 5000 Hz and an amplitude of 15 dB, 25 dB, or 45 dB (Galazyuk, ¶[0026]: “A pre-pulse auditory stimulus is delivered to the subject prior to delivery of the auditory startle stimulus”, this shows delivery of a pre-pulse prior to the startle (pulse) stimulus; see also Abstract describing repeating the pre-pulse → gap → startle sequence as an iterative method step, supporting that each delivered pulse in the method is preceded by a pre-pulse, Abstract: “repeating these steps until the pre-pulse auditory stimulus administered has a value sufficient to cause a decrease in the startle response of the subject”, explanation of iterative delivery in sequence; ¶[0026]: “The frequency of the pre-pulse auditory stimulus can be any wavelength audible to the subject”, together with Galazyuk, ¶[0025]: “suitable audible wavelengths for a human subject range from 20 Hz to 20 kHz”, this teaches that the enumerated frequencies 200 Hz through 5000 Hz fall within the disclosed audible range for human subjects; ¶[0061]: “Prepulse stimulus were 20 ms pure tones with a 1 ms rise / fall time presented at six different frequencies ( 4 , 12.5 , 16 , 20 , 25 , and 31.5 kHz ) 100 ms before the startle stimulus”, this shows the experimental paradigm in which each startle (pulse) presentation is preceded by a prepulse delivered 100 ms earlier (additionally 4kHz = 4000Hz); ¶[0031]: “The decibel level of the pre-pulse auditory stimulus can start, for example, at 40 decibels, followed by pre-pulse auditory stimuli at 45 db, 50 db, 55 db, 60 db, and so forth, until a decrease in the startle response is detected”, this shows that pre-pulse stimuli can be delivered at least at 45 dB; ¶[0026]: “The pre-pulse auditory stimulus can be delivered at a volume from 10 to 80 dB SPL … in further embodiments the pre-pulse auditory stimulus is delivered at 10 to 60 dB SPL”, this teaches pre-pulse amplitudes that encompass 15 dB, 25 dB, and 45 dB within the disclosed ranges).
Regarding claim 14, Galazyuk teaches that measuring the initial and subsequent startle response in the subject comprises obtaining the same measurement from the subject (Galazyuk, ¶[0031]: “repeating the steps of delivering the pre-pulse auditory stimulus, allowing a gap of time to pass, delivering an auditory startle stimulus, and measuring the startle response”, this shows that the method measures the startle response repeatedly using the same startle-response measurement across iterations, corresponding to obtaining the same measurement for both the initial and subsequent startle responses; ¶[0030]: “in some embodiments, a startle algorithm is used to measure the startle response of the subject”, this teaches that a single defined measurement method is applied to quantify the startle response, supporting that both the initial and subsequent measurements are the same type of measurement; ¶[0029]: “The method also includes measuring the startle response of the subject, and determining if the startle response of the subject to the auditory startle stimulus has decreased compared with a control value for the startle response”, this shows that the same startle-response measure is used for comparison, aligning with obtaining the same measurement from the subject for initial and subsequent assessments).
Regarding claim 15, Galazyuk teaches that the measurement is selected from the blink reflex, pupil dilation, skin conductive response, and brain activity in fMRI (Galazyuk, ¶[0029]: “The blink of the eye which is the reflex of the orbicularis oculi muscle was found to have a latency of about 20 to 40 milliseconds”, this shows measurement of a blink reflex as a startle response; ¶[0088]: “The amygdala, hippocampus, prefrontal cortex, auditory cortex and many other structures have been flagged as the source of this top-down modulation. To this extent, it seems that PPI audiometry has the potential to assess large portions of the auditory neuraxis and other neocortical regions”, this shows that brain activity, including in the hippocampus, can be measured in association with startle and PPI). The Examiner interprets this limitation to require at least one of the listed physiological responses as a measure of the startle reflex.
Regarding claim 16, Galazyuk teaches that measuring the blink reflex comprises measuring the speed, magnitude, and/or duration of the blink reflex in the subject (Galazyuk, ¶[0029]: “The blink of the eye which is the reflex of the orbicularis oculi muscle was found to have a latency of about 20 to 40 milliseconds”, this shows that the blink reflex is measured in terms of its timing, which corresponds to speed and duration. The magnitude of the reflex can be inferred from the amplitude of the blink response).
Regarding claim 18, Galazyuk teaches that a method of evaluating paired-pulse inhibition (PPI) in a subject, comprising performing the following steps in order: (Galazyuk, ¶[0022]: “Methods of evaluating hearing using pre-pulse inhibition are described. Pre-pulse inhibition is an auditory effect in which an initial pulse of sound can inhibit the startle response that occurs in response to a subsequent loud noise”, this teaches evaluation using pre-pulse inhibition (PPI) in the acoustic startle framework, where it assesses inhibition of a startle response by a preceding pulse; ¶[0023]: “The method includes the steps of delivering a pre-pulse auditory stimulus to the subject 12, allowing a stimulus gap to pass 14, delivering an auditory startle stimulus to the subject 16, and determining if the startle response of the subject has decreased 18”, this shows an ordered sequence of steps consistent with “performing the following steps in order”);
b. delivering an acoustic stimulus to the subject (Galazyuk, ¶[0024]: “The method includes delivering auditory stimuli to the subject”, this shows delivery of acoustic stimuli to a subject; ¶[0025]: “The auditory startle stimulus is a loud sound sufficient to cause the subject to be startled and exhibit a startle response”, this shows that the acoustic stimulus is an audible sound designed to elicit a startle response);
c. measuring an initial startle response in the subject (Galazyuk, ¶[0030]: “a startle algorithm is used to measure the startle response of the subject”, this teaches measuring the startle response after stimulus delivery);
d. delivering the acoustic stimulus to the subject (Galazyuk, ¶[0041]: “delivering an auditory startle stimulus to the subject 36”, this teaches a subsequent delivery of an acoustic startle stimulus within the method flow);
e. measuring a subsequent startle response in the subject (Galazyuk, ¶[0041]: “measuring the startle response of the subject 38”, this teaches measuring the startle response again after the subsequent stimulus delivery);
f. comparing the startle responses in the subject (Galazyuk, ¶[0031]: “A decrease can be identified by comparing the startle response with a control value for the startle response. A control value can be a startle response previously determined for the subject... ”, this teaches comparing measured startle responses, where comparison to a control serves the same functional purpose as comparing initial and subsequent responses); and
g. repeating steps a–d when the subsequent startle response in the subject is not reduced compared to the initial startle response, or ceasing delivery of the acoustic stimulus to the subject when the subsequent startle response in the subject is reduced compared to the initial startle response (Galazyuk, ¶[0023]: “these steps are repeated until the delivered pre-pulse auditory stimulus has a value sufficient to cause a decrease in the startle response of the subject”, this teaches repeating the sequence until a decrease is achieved, which functionally corresponds to repeating when not reduced and ceasing when reduced).
Regarding claim 19, Galazyuk teaches that measuring the first and second startle response in the subject comprises obtaining the same measurement from the subject (Galazyuk, ¶[0031]: “repeating the steps of delivering the pre-pulse auditory stimulus, allowing a gap of time to pass, delivering an auditory startle stimulus, and measuring the startle response”, this shows that the method measures the startle response repeatedly using the same startle-response measurement across iterations, corresponding to obtaining the same measurement for both the first and second startle responses; ¶[0030]: “in some embodiments, a startle algorithm is used to measure the startle response of the subject”, this teaches that a single defined measurement method is applied to quantify the startle response, supporting that both the first and second measurements are the same type of measurement; ¶[0029]: “The method also includes measuring the startle response of the subject, and determining if the startle response of the subject to the auditory startle stimulus has decreased compared with a control value for the startle response”, this shows that the same startle-response measure is used for comparison, aligning with obtaining the same measurement from the subject for first and second assessments).
Regarding claim 20, Galazyuk teaches that the measurement is selected from the blink reflex, pupil dilation, skin conductive response, and brain activity in fMRI (Galazyuk, ¶[0029]: “The blink of the eye which is the reflex of the orbicularis oculi muscle was found to have a latency of about 20 to 40 milliseconds”, this shows measurement of a blink reflex as a startle response; ¶[0088]: “The amygdala, hippocampus, prefrontal cortex, auditory cortex and many other structures have been flagged as the source of this top-down modulation. To this extent, it seems that PPI audiometry has the potential to assess large portions of the auditory neuraxis and other neocortical regions”, this shows that brain activity, including in the hippocampus, can be measured in association with startle and PPI). The Examiner interprets this limitation to require at least one of the listed physiological responses as a measure of the startle reflex.
Regarding claim 21, Galazyuk teaches that the pre-pulse stimulus has a frequency of 200 Hz, 300 Hz, 400 Hz, 500 Hz, 1000 Hz, 3000 Hz, 4000 Hz, or 5000 Hz and an amplitude of 15 dB, 25 dB, or 45 dB (Galazyuk, ¶[0026]: “A pre-pulse auditory stimulus is delivered to the subject prior to delivery of the auditory startle stimulus”, this shows delivery of a pre-pulse prior to the startle (pulse) stimulus; see also Abstract describing repeating the pre-pulse → gap → startle sequence as an iterative method step, supporting that each delivered pulse in the method is preceded by a pre-pulse, Abstract: “repeating these steps until the pre-pulse auditory stimulus administered has a value sufficient to cause a decrease in the startle response of the subject”, explanation of iterative delivery in sequence; ¶[0026]: “The frequency of the pre-pulse auditory stimulus can be any wavelength audible to the subject”, together with Galazyuk, ¶[0025]: “suitable audible wavelengths for a human subject range from 20 Hz to 20 kHz”, this teaches that the enumerated frequencies 200 Hz through 5000 Hz fall within the disclosed audible range for human subjects; ¶[0061]: “Prepulse stimulus were 20 ms pure tones with a 1 ms rise / fall time presented at six different frequencies ( 4 , 12 . 5 , 16 , 20 , 25 , and 31 . 5 kHz ) 100 ms before the startle stimulus”, this shows the experimental paradigm in which each startle (pulse) presentation is preceded by a prepulse delivered 100 ms earlier (additionally 4kHz = 4000Hz); ¶[0031]: “The decibel level of the pre-pulse auditory stimulus can start, for example, at 40 decibels, followed by pre-pulse auditory stimuli at 45 db, 50 db, 55 db, 60 db, and so forth, until a decrease in the startle response is detected”, this shows that pre-pulse stimuli can be delivered at least at 45 dB; ¶[0026]: “The pre-pulse auditory stimulus can be delivered at a volume from 10 to 80 dB SPL … in further embodiments the pre-pulse auditory stimulus is delivered at 10 to 60 dB SPL”, this teaches pre-pulse amplitudes that encompass 15 dB, 25 dB, and 45 dB within the disclosed ranges).
Regarding claim 22, Galazyuk teaches that the pulse stimulus has a frequency of 200 Hz, 300 Hz, 400 Hz, 500 Hz, 1000 Hz, 3000 Hz, 4000 Hz, or 5000 Hz and an amplitude of 65 dB, 80 dB, or 105 dB (Galazyuk, ¶[0025]: “The method includes delivering both a pre-pulse auditory stimulus and an auditory startle stimulus to the subject. The auditory startle stimulus is a loud sound sufficient to cause the subject to be startled and exhibit a startle response”, this shows that the claimed “pulse stimulus” corresponds to Galazyuk’s auditory startle stimulus within the method framework; ¶[0025]: “Suitable startle stimulus typically include one or more audible wavelengths delivered at a volume of from 50 to 130 decibels (dB) sound pressure level (SPL)”, this teaches amplitudes encompassing 65 dB, 80 dB, and 105 dB; ¶[0025]: “Accordingly, in some embodiments, a startle stimulus from 70 to 110 dB SPL, or from 80 to 100 dB SPL can be used”, this further confirms coverage of 80 dB and 105 dB within the disclosed startle stimulus amplitude ranges; ¶[0025]: “Different subjects have differing startle-stimulus response functions, which are known or can be easily determined by one skilled in the art... Suitable audible wavelengths differ depending on the nature of the subject. For example, suitable audible wavelengths for a human subject range from 20 Hz to 20 kHz”, this shows that the listed pulse stimulus frequencies of 200 Hz through 5000 Hz are within the disclosed range for subjects to which a skilled artisan would naturally choose from depending on the particulars of the subject; ¶[0025]: “Typically the startle stimulus will include multiple (e.g., wide-band) audible frequencies”, this shows that the startle (pulse) stimulus may include or encompass the claimed discrete frequencies as part of wide-band content).
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 3 and 5-6 are rejected under 35 U.S.C. 103 as being unpatentable over Galazyuk et al. (US 20180085034 A1), hereto referred as Galazyuk.
Galazyuk teaches claim 1 as described above.
Regarding claim 3, Galazyuk does not explicitly teach that the at least one pre-pulse stimulus has a frequency of 3000 Hz. Rather, Galazyuk discloses delivery of pre-pulse auditory stimuli at various frequencies such as 4 kHz, 12.5 kHz, 16 kHz, 20 kHz, 25 kHz, and 31.5 kHz (Galazyuk, ¶[0061]) and suggests a range of frequencies encompassing any audible wavelength (Galazyuk, ¶[0026]–[0027]). However, Galazyuk does not explicitly disclose a pre-pulse frequency of 3000 Hz.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified Galazyuk to include a pre-pulse frequency of 3000 Hz, since selecting the precise frequency of the pre-pulse stimulus is a matter of routine optimization of a result-effective variable. Galazyuk expressly teaches that the frequency of the pre-pulse auditory stimulus can be any wavelength audible to the subject and may be varied across embodiments (Galazyuk, ¶[0026]–[0027]).
The modification would have been feasible because Galazyuk already contemplates multiple different frequencies and does not restrict the pre-pulse to specific disclosed values. A person of ordinary skill in the art would have been motivated to adjust the pre-pulse frequency to 3000 Hz in order to provide ample information about the functionality of the auditory system and to test the startle reflex at varying points in the audible spectrum (Galazyuk, ¶[0006]).
The benefit of this combination would be to broaden the range of test conditions for assessing auditory processing and startle reflex inhibition, thereby improving the robustness and diagnostic value of the method.
Regarding claim 5, Galazyuk does not explicitly teach that the at least one pulse stimulus has a frequency of 3000 Hz. Rather, Galazyuk discloses startle (pulse) stimuli delivered across the audible frequency spectrum for humans (20 Hz to 20 kHz) and provides examples of stimulus intensity ranging from 70–110 dB SPL (Galazyuk, ¶[0025], ¶[0061]). However, Galazyuk does not explicitly disclose a startle stimulus at 3000 Hz.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified Galazyuk to include a pulse frequency of 3000 Hz, since selecting the precise frequency within the disclosed audible range is a matter of routine optimization of a result-effective variable. Galazyuk expressly teaches that frequencies may be varied across embodiments and does not restrict the startle stimulus to the examples given and even states that “[d]ifferent subjects have differing startle-stimulus response functions, which are known or can be easily determined by one skilled in the art… Suitable audible wavelengths differ depending on the nature of the subject. For example, suitable audible wavelengths for a human subject range from 20 Hz to 20 kHz” (Galazyuk, ¶[0025]).
The modification would have been feasible because Galazyuk already demonstrates implementation of stimuli across a broad frequency spectrum, and 3000 Hz falls squarely within that range. A person of ordinary skill in the art would have been motivated to adjust the pulse frequency to 3000 Hz in order to test startle responses at different points of the spectrum and to broaden diagnostic flexibility.
The benefit of this modification would be to enable more targeted evaluation of the auditory system by probing the mid-range frequencies that are particularly relevant for speech and communication, thereby improving the diagnostic sensitivity of startle reflex testing and enhancing the reliability of assessments across different subjects.
Regarding claim 6, Galazyuk teaches that a method for evaluating an acoustic startle reflex in a subject, the method comprising: delivering the set of any of the preceding claims to the subject (see the above rejection of claims 3 and 5); and measuring a startle response in the subject (Galazyuk, ¶[0023]: “The method includes the steps of delivering a pre-pulse auditory stimulus to the subject 12, allowing a stimulus gap to pass 14, delivering an auditory startle stimulus to the subject 16, and determining if the startle response of the subject has decreased 18”, this explicitly shows delivery of the set of stimuli to the subject and measurement of the startle response).
Claims 9 and 17 are rejected under 35 U.S.C. 103 as being unpatentable over Galazyuk et al. (US 20180085034 A1), hereto referred as Galazyuk, and further in view of Gordon et al. (US 20050273017 A1), hereto referred as Gordon.
Galazyuk teaches claims 6 and 15 as described above.
Regarding claim 9, Galazyuk does not teach that an increased startle response in the subject indicates that the subject has a mental disorder. Galazyuk discloses methods of measuring startle responses using prepulse inhibition and auditory startle stimuli to evaluate auditory system function (Galazyuk, ¶[0023], ¶[0025]). However, Galazyuk does not disclose that an increased startle response is indicative of a mental disorder.
Gordon teaches that abnormal startle and physiological responses are associated with psychiatric disorders, including schizophrenia and PTSD. For example, Gordon states: (Gordon, ¶[0423]: “PTSD patients have additionally been found to show increased levels of arousal, as indexed by increased baseline heart rate and Skin conductance levels and increased skin conductance and heart rate responses to auditory startle stimuli and trauma-related stimuli”). Gordon also notes that “People with Schizophrenia have been found to show decreased and delayed skin conductance responses to auditory Stimuli… They have also shown decreased habituation to Startle Stimuli and decreased prepulse inhibition” (Gordon, ¶[0413]). This establishes the connection between altered startle response and mental disorders.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified Galazyuk in view of Gordon to include the understanding that an increased startle response in the subject indicates the presence of a mental disorder.
The combination would have been feasible because Galazyuk already provides the methodology for eliciting and measuring startle responses, while Gordon provides the clinical correlation to psychiatric conditions. One of ordinary skill in the art would have recognized that the same startle testing framework disclosed in Galazyuk could be applied to detect abnormal responses indicative of mental illness.
The benefit of the combination would be to expand the utility of Galazyuk’s startle response testing from evaluating hearing function to also serving as a diagnostic tool for psychiatric disorders, thereby increasing the clinical relevance and application of the method.
Regarding claim 17, Galazyuk does not teach that measuring brain activity in fMRI comprises measuring activity in the hippocampus. Rather, Galazyuk teaches that higher brain regions, including the hippocampus, modulate startle and that PPI can assess activity across broad neural circuitry (Galazyuk, ¶[0088], “The amygdala, hippocampus, prefrontal cortex, auditory cortex and many other structures have been flagged as the source of this top-down modulation… PPI audiometry has the potential to assess large portions of the auditory neuraxis and other neocortical regions”), but Galazyuk does not disclose using fMRI to measure hippocampal activity.
Gordon teaches both the use of fMRI and that hippocampal activity is characterized in PTSD with fMRI findings, and further includes an fMRI startle paradigm: (Gordon, ¶[0325], “Functional magnetic resonance imaging (fMRI) monitors minute changes in blood flow in the brain that indicate which areas are active during different tasks”, this shows fMRI is used to localize activity in specific brain areas; ¶[0328]–[0333], “In paradigm 4A (faces with HAPPY) the fMRI stimuli are… S=Startle (tone), duration 50 ms”, this shows Gordon’s fMRI includes a startle-related stimulus; ¶[0423], “functional MRI studies have found increased amygdala activity, decreased hippocampal and medial prefrontal cortical activity…”, this shows hippocampal activity is measured and reported in fMRI studies).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified Galazyuk in view of Gordon to measure brain activity in fMRI comprising measuring activity in the hippocampus. Gordon expressly teaches fMRI as a tool that “indicate[s] which areas are active” and provides a startle-related fMRI paradigm (Gordon, ¶[0325]; ¶[0328]–[0333], shows that fMRI can be run during startle-related tasks and localize regional activity), while Gordon’s PTSD discussion identifies hippocampal activity changes observed with fMRI (Gordon, ¶[0423]). Given Galazyuk’s identification of hippocampus as part of the startle modulation network (Galazyuk, ¶[0088]), a person of ordinary skill would have found it straightforward to designate the hippocampus as a region of interest within the fMRI acquisition and analysis. Targeting the hippocampus as an fMRI region of interest during startle-related tasks would focus measurement on a structure specifically implicated in the condition of interest and known to show altered activity in fMRI studies (Gordon, ¶[0423]).
Claim 10 is rejected under 35 U.S.C. 103 as being unpatentable over Galazyuk et al. (US 20180085034 A1), hereto referred as Galazyuk, and further in view of Linnman et al. (Linnman C, Zeffiro TA, Pitman RK, Milad MR. An fMRI study of unconditioned responses in post-traumatic stress disorder. Biol Mood Anxiety Disord. 2011 Nov.), hereto referred as Linnman.
Galazyuk teaches claim 7 as described above.
Regarding claim 10, Galazyuk does not teach that elevated activity in the hippocampus as measured by fMRI indicates that the subject has post-traumatic stress disorder (PTSD). Specifically, Galazyuk teaches that higher brain nuclei, including the hippocampus, modulate prepulse effects on startle but does not disclose that elevated hippocampal activity as measured by fMRI indicates PTSD (Galazyuk, ¶[0088]: “The amygdala , hippocampus , prefrontal cortex , auditory cortex and many other structures have been flagged as the source of this top - down modulation”).
Linnman shows increased hippocampal BOLD activity in PTSD under an aversive unconditioned-stimulus (US) fMRI paradigm: (Linnman, p.5, 'Results - Brain responses to the unconditioned stimuli': “Within the a priori regions of interest (ROI), subjects with PTSD displayed additional significant hyper - reactivity in the bilateral amygdala , left hippocampus , right dorsal ACC , bilateral posterior insula , left anterior insula , and bilateral caudate and putamen”, this teaches increased hippocampal reactivity in PTSD during the US measured via fMRI; 'Results - Brain responses to the omitted US': “subjects with PTSD displayed significantly greater activity in hippocampus”, this reports greater BOLD reactivity in PTSD in medial temporal regions adjacent to hippocampus during US; p. 6, 'Discussion': “The ROI analysis further revealed the amygdala , hippocampus , dorsal ACC , insula and caudate nucleus to be hyperactive in the PTSD US response”, this teaches hippocampal hyperactivity in PTSD during the aversive US measured with fMRI).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified Galazyuk in view of Linnman to interpret elevated activity in the hippocampus as measured by fMRI as indicative of PTSD within the startle-based assessment framework.
The combination would have been feasible because both references implicate the same defensive/startle-related circuitry and are implemented with standard fMRI measurements of limbic ROIs; Galazyuk places the hippocampus in the top-down modulatory network for PPI, while Linnman demonstrates hippocampal hyper-reactivity in PTSD under aversive US. Substituting one reflexive aversive probe (electric shock US in Linnman) for another (acoustic startle in Galazyuk) is a routine choice of result-effective variable to interrogate the same circuitry using the same imaging methods.
The combination yields an objective, neurophysiological marker (elevated hippocampal BOLD) integrated into the established startle-testing workflow, improving diagnostic sensitivity and clinical utility by linking a quantified limbic response to PTSD within a single-session assessment.
Note: As drafted, the limitation that elevated hippocampal activity on fMRI indicates PTSD is not supported by the record. Galazyuk identifies the hippocampus as part of top-down modulation of startle but does not teach fMRI measurement of hippocampal activity, and Gordon summarizes PTSD neuroimaging as showing decreased hippocampal activity/function and smaller hippocampal volume (Gordon, ¶[0423], ¶[0426]). Task-evoked findings involving the hippocampus are heterogeneous and do not establish a reliable startle-linked increase. If Applicant intends to rely on a hippocampal biomarker, amending the claims with respect to an abnormal formulation (or, alternatively, on startle-linked autonomic responses or on amygdala measures that are supported by the record) , or the submission of evidence specifying the comparator, paradigm, ROI, and decision criteria for “elevated” may be appropriate.
Conclusion
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