18105DETAILED 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 .
Response to Amendment
The amendment filed on 11/16/2025 has been entered. Claims 1-2, 4, 6, 17 and 19 have been amended. Claims 10 and 13-14 have been cancelled. Claims 1-9, 11-12 and 15-19 remain pending.
The previously raised objections for Claims 1-2, 6, 9 and 17 are withdrawn because the issues have been properly corrected.
Some of the previous rejections for Claims 1-9 and 17-19 under 35 U.S.C. 112(a) are withdrawn because of the proper amendment made to Claims 1 and 17.
The previous rejections for Claims 1-14 and 19 under 35 U.S.C. 112(b) are withdrawn because the claims are either cancelled or properly amended.
Response to Arguments
On Pages 10-11, Remarks, the Applicant argues that the three prior art references (Gotez, Loike and Tyler) uses ultrasound, while the claimed invention uses blast overpressure, and that ultrasound and blast overpressure have different frequency and different waveform.
The Examiner respectfully disagrees. Neither the Claims or the Specification provide details on either frequency or waveform of the termed "repetitive low intensity blast overpressure". Both ultrasound and blast overpressure (as specified in the specification) are mechanical waves that originate from some vibrating source and transmit across some medium such as air and tissue. Hence, a skilled person in the art would not be able to fully differentiate blast overpressure from ultrasound.
Claim Objections
Claims 1-2 and 17 are objected to because of the following informalities:
Claim 1, Lines 1-4, recites “in a subject …, in a subject,”, which should be changed to “in a subject …,
Claim 2, Line 3, recites “improvs”, which should be changed to “improves”.
Claim 17, Lines 3-4, recites “comprising; and in a subject, wherein …”, which should be changed to “comprising.
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.
Claims 17-19 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because Claim 17 is deemed to be a single means claim whose entire scope is not enabled by the original specification. More specifically, “device is capable of safely deliver[ing] pulsed pressure wave to a subject” is a means-plus-function limitation as the only limitation of a claim. As such, the claim is not limited to the structure, material or act disclosed in the specification that performs the claimed function. Thus, the single means limitation that is properly construed will cover all means of performing the claimed function. The long-recognized problem with a single means claim is that it covers every conceivable means for achieving the stated result, while the specification discloses at most only those means known to the inventor. In re Hyatt, 708 F.2d 712, 218 USPQ 195 (Fed. Cir. 1983). A claim of such breadth reads on subject matter that is not enabled by the specification, and therefore, should be rejected under section 112(a) or pre-AIA section 112, first paragraph. See MPEP 2181(V).
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 1-9, 11-12 and 15-19 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, Lines 2 and 5, recite “… subject at risk and in early stage of Alzheimer’s disease …”. A subject cannot be “at risk” and “in early stage” of Alzheimer’s disease at the same time. For present purposes of Examination, the recited phrase is interpreted as “… subject at risk or in early stage of Alzheimer’s disease …”.
Claim 1, Lines 5-7, recites “… subject at risk and in early stage of Alzheimer’s disease or other neurodegenerative diseases, respectively, caused by abnormal accumulation of proteins in the brain”. While Alzheimer’s disease is characterized by abnormal accumulation of proteins in brain (Para 0060), it is not equivalent to state that the disease is caused by such accumulation. For present purposes of examination, the phrase “caused by abnormal accumulation of proteins in the brain” is not taken in to consideration.
Claim 17, Line 2, recites “… subject at risk and in early stage of Alzheimer’s disease …”. A subject cannot be “at risk” and “in early stage” of Alzheimer’s disease at the same time. For present purposes of Examination, the recited phrase is interpreted as “… subject at risk or in early stage of Alzheimer’s disease …”.
Claims 2-9, 11-12, 15-16 and 18-19 are also rejected under 35 U.S.C. 112(b) because they inherit the indefiniteness of the claim(s) they respectively depend upon.
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, 5-6, 8-9 and 11-12 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Goetz et al (US 20180214716 A1; hereafter Goetz).
Regarding Claim 1, Goetz discloses a method to reduce abnormal accumulation of brain proteins (Goetz, Para 0085; “… SUSing reduces Aβ plaques in an Alzheimer's mouse model…”) in a subject at risk and in early stage of Alzheimer's disease or other neurodegenerative diseases in a subject, comprising
a) identifying the subject at risk of and in early stage of Alzheimer's disease or other neurodegenerative diseases (Goetz, Para 0032; “In a subject identified as having Alzheimer's disease the region may be selected from the group consisting of …”), respectively, caused by abnormal accumulation of proteins in the brain; and
b) exposing said subject to repetitive low intensity blast overpressure (Goetz, Para 0079; “The acoustic energy may be applied in a method of the invention at a pressure greater than 0.4 MPa.”) (Goetz, Para 0135; “Preferably the ultrasound is applied in burst mode, or pulsed ultrasound.”) (Goetz, Para 0080; “the step of applying the acoustic energy may be repeated”).
Regarding Claim 2, Goetz discloses a method of claim 1, wherein said method further
a) improvs behavioral deficits; c) reduces brain inflammation; or d) a combination thereof (Goetz, Para 0098; “…restoring cognitive and/or memory function. It is believed that this is achieved by removing pathogenic protein, such as amyloid-β (Aβ)”).
Regarding Claim 3, Goetz discloses a method of claim 1, wherein said low intensity blast overpressure is at subclinical blast level (Goetz, Para 0036; “a clinically safe level of acoustic energy does not result in detectable heating, brain swelling, red blood cell extravasation, haemorrhage or edema.”).
Regarding Claim 5, Goetz discloses a method of claim 1, wherein said subject is exposed to repetitive low intensity blast overpressure intermittently for a prolonged period (Goetz, Para 0092; “APP23 mice, 5 treatments over a period of six weeks”).
Regarding Claim 6, Goetz discloses a method of claim 2, wherein said behavioral deficits include anxiety, impaired cognition, social interactions difficulties, loss of spatial orientation, impairment in short term memory, speech impediment, visuospatial skills impairment, orientation impairment, and difficulty in reasoning or problem-solving, difficulty in handling complex tasks, difficulty in concentrating, planning and organizing or a combination thereof (Goetz, Para 0105; “A subject in need of treatment may be one that exhibits impaired memory function, cognitive function or subclinical or clinical symptoms of a neurodegenerative disease.”).
Regarding Claim 8, Goetz discloses all the limitations of Claim 1 as discussed above, and further discloses comprising at least once administering to said subject an effective amount of one or more therapeutic agent or therapy (Goetz, Para 0056; “a method of the invention also includes the step of administering an agent to promote the increase in permeability of the blood-brain barrier”).
Regarding Claim 9, Goetz discloses all the limitations of Claim 8 above, and further discloses wherein said therapeutic agent i) prevents β-amyloid deposition; ii) reduces β-amyloid production; iii) improves β-amyloid clearance; iv) improves brain inflammation; v) inhibits of BACE1; or vi) a combination thereof (Goetz, Para 0102; “… increasing the permeability of the blood-brain barrier leads to at least one of the following processes: i) clearance of the pathological protein aggregates out of the brain, into the blood, following opening of the blood-brain barrier”)
Regarding Claim 11, Goetz discloses a method of claim 1, wherein said proteins include α-synuclein, tau, amyloid precursor protein (APP), amyloid β protein (Aβ) or a combination thereof (Goetz, Para 0146; “a non-invasive and nonpharmacological therapeutic approach of removing Aβ”).
Regarding Claim 12, Goetz discloses a method of claim 11, wherein said amyloid β protein (Aβ) is Aβ 42 (Goetz, Para 0151; “a 17% reduction was revealed for Aβ42 in SUSed compared to sham-treated mice”).
Claims 15-16 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Loike et al (US 20180126191 A1; hereafter Loike).
Regarding Claim 15, Loike discloses a method to improve brain inflammation in patients at risk for Alzheimer's disease or other neurodegenerative diseases, comprising
a) Identifying a patient at risk of developing Alzheimer's disease or other neurodegenerative diseases caused by abnormal accumulation of proteins in the brain (Loike, Abstract; “Disclosed herein is a method of reducing inflammation in a patient with a chronic condition, such as Parkinson's disease or Alzheimer's disease.”); and
b) Exposing said subject to repetitive low intensity blast overpressure (Loike, Para 0035; “Surface Acoustic Waves (SAW) are low-energy elastic ultrasound waves that are non-thermal.”) (Loike, Para 0044; “The time period of SAW application … can be further broken up into periods separated by a rest period without SAW application.”).
Regarding Claim 16, Loike discloses the method of claim 15, wherein said improvement of brain inflammation include reduction in brain ADAM17, and increase in serum levels of brain-derived TNF-α and IL-6 (Loike discloses performing the repetitive low-energy acoustic wave method to reduce brain inflammation in patient with PD or AD. Specification of current application (Para 151) states that performing the method leads to the effect of reduction in brain ADAM17 and of increase in serum levels of brain-derived TNF-α and IL-6).
Claims 17-19 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Tyler et al (US 20110178441 A1; hereafter Tyler).
Regarding Claim 17, Tyler discloses a device or system to reduce abnormal accumulation of brain proteins (Tyler, Para 0206; “Modulated cellular activity includes but is not limited to changes in … (vi) the protein transcription of the cells, (vii) the protein translation of cells, (viii) the protein phosphorylation of the cells”) in a subject at risk and in early stage of Alzheimer's disease or other neurodegenerative diseases (Tyler, Para 0010; “… treatment of physiological or pathological conditions including, but not limited to, Parkinson's disease, Alzheimer's disease …”), comprising; and in a subject, wherein said device is capable of safely deliver pulsed pressure wave to a subject (Tyler, Para 0073; “a pulsed ultrasound stimulus waveform may be transmitted for about 10 microseconds”) (Tyler, Para 0225; “low intensity pulsed ultrasound waveforms appear to be highly effective in modulating neural activity, safe for prolonged use”).
Regarding Claim 18, Tyler discloses the device of claim 17, wherein said pulsed pressure wave is delivered to said subject at subclinical blast level (Tyler, Para 0225; “low intensity pulsed ultrasound waveforms appear to be highly effective in modulating neural activity, safe for prolonged use”).
Regarding Claim 19, Tyler discloses the device of claim 18, wherein said pulsed pressure wave is delivered to said subject at equal or less than 10 psi (Tyler, Para 0248; “Single ultrasound pulses had … peak rarefactional pressures (pr) of 0.070 to 0.097 MPa”; 0.070 MPa is 10 psi).
Claim Rejections - 35 USC § 103
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 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.
Claim 4 is rejected under 35 U.S.C. 103 as being unpatentable over Goetz in view of Tyler.
Regarding Claim 4, Goetz discloses the method of Claim 1 as discussed above. Goetz does not disclose a method wherein said subclinical blast overpressure is equal or less than 10 psi.
Tyler in the same field of endeavor discloses a method, wherein said subclinical blast overpressure is equal or less than 10 psi (Tyler, Para 0248; “Single ultrasound pulses had … peak rarefactional pressures (pr) of 0.070 to 0.097 MPa”; 0.070 MPa equals to 10 psi). It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Goetz, as suggested by Tyler, in order to limit the blast overpressure to 10 psi or less. One of ordinary skill in the art would have been motivated to make the modification for the benefit of preventing patient from getting injured by blast of high pressure.
Claim 7 is rejected under 35 U.S.C. 103 as being unpatentable over Goetz in view of Eguchi et al (Whole-brain low-intensity pulsed ultrasound therapy markedly improves cognitive dysfunctions in mouse models of dementia - Crucial roles of endothelial nitric oxide synthase. Brain Stimul. 2018 Sep-Oct;11(5):959-973; hereafter Eguchi).
Regarding Claim 7, Goetz discloses all the limitations of Claim 2 as discussed above. Goetz did not clearly and explicitly disclose a method of claim 2, wherein said reduction of abnormal brain accumulation or deposition of beta-amyloid is achieved by a) Decreasing APP-cleaving secretases; b) Increasing trans-endothelial clearance via LRP1; c) Improving paravascular glymphatic AQP4-mediated clearance; or d) A combination thereof.
Eguchi in the same field of endeavor discloses the method of claim 2, wherein said reduction of abnormal brain accumulation or deposition of beta-amyloid is achieved by a) Decreasing APP-cleaving secretases (BACE-1); b) Increasing trans-endothelial clearance via LRP1; c) Improving paravascular glymphatic AQP4-mediated clearance; or d) A combination thereof (Eguchi, Abstract; “we examined whether the whole-brain LIPUS (low intensity pulsed ultrasound) therapy is effective and safe in 2 mouse models of dementia (vascular dementia, VaD and Alzheimer's disease, AD). … it reduced Iba-1-positive microglias and amyloid-β (Aβ) plaque in the AD model.”) (Eguchi, Page 968, Para 4; “… BACE-1 (β-site amyloid precursor protein cleaving enzyme-1) … were significantly decreased by the LIPUS therapy”). It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Goetz, as suggested by Eguchi, in order to decrease APP-cleaving secretases to reduce abnormal brain accumulation of beta amyloid. One of ordinary skill in the art would have been motivated to make the modification because BACE-1 as one type of APP-cleaving enzyme (Eguchi, Table of Abbreviations) directly contributes to Aβ accumulation (Eguchi, Fig. 9 shows a direct relationship between decrease in BACE-1 and decrease in Aβ accumulation).
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/L.Z./ Examiner, Art Unit 3798
/PASCAL M BUI PHO/ Supervisory Patent Examiner, Art Unit 3798