DETAILED ACTION
Applicant' s arguments, filed 03/25/2026, have been fully considered. Applicant has elected Group I with traverse, see below. Examiner notes that claim 21 is not present in the claim set and is interpreted to be cancelled along with claims 19-20. Thus, claims 1-11, 24-27, and 30-31 are the current claims pending and hereby under examination.
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 .
Election/Restrictions
Applicant notes that a preliminary amendment was filed on March 19, 2024; however, Applicant inadvertently filed the original claim set on October 10, 2024, which was the claim set that was restricted. Accordingly, the correct claim set to be examined was filed in the reply filed 03/25/2026. Examiner notes that Applicant has added new claims 28-29 that were not originally presented nor considered in the claim set examined, filed 10/10/2024, and are drawn to a non-elected inventive group. Thus, these claims will not be entered.
Applicant's election with traverse of Group I in the reply filed on 03/25/2026 is acknowledged. The traversal is on the ground(s) that Konafagou does not teach the special technical feature of sonicating the brain of a subject as a baseline sonication pressure to determine a baseline stable cavitation level, and sonicating the brain of the subject at increasing sonication pressures until a target cavitation level is reached. Examiner agrees with Applicant’s arguments and that claims 1-11, 24-27, and 30-31 share a technical relationship; thus, Groups I and II have unity of invention. Applicant timely traversed the restriction (election) requirement in the reply filed on 03/25/2026.
Claims 18 and 22-23 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Claim Objections
Claim 30 is objected to because of the following informalities:
Claim 30, line 1, “comprising” should read “comprises”.
Appropriate correction is required.
Drawings
The drawings are objected to because Fig. 7A depicts a graph with the same label recited twice. Both lines are labeled as “without skull”; however, one should state “with skull”. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Interpretation
The following is a quotation of 35 U.S.C. 112(f):
(f) Element in Claim for a Combination. – An element in a claim for a combination may be expressed as a means or step for performing a specified function without the recital of structure, material, or acts in support thereof, and such claim shall be construed to cover the corresponding structure, material, or acts described in the specification and equivalents thereof.
The following is a quotation of pre-AIA 35 U.S.C. 112, sixth paragraph:
An element in a claim for a combination may be expressed as a means or step for performing a specified function without the recital of structure, material, or acts in support thereof, and such claim shall be construed to cover the corresponding structure, material, or acts described in the specification and equivalents thereof.
The claims in this application are given their broadest reasonable interpretation using the plain meaning of the claim language in light of the specification as it would be understood by one of ordinary skill in the art. The broadest reasonable interpretation of a claim element (also commonly referred to as a claim limitation) is limited by the description in the specification when 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is invoked.
As explained in MPEP § 2181, subsection I, claim limitations that meet the following three-prong test will be interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph:
(A) the claim limitation uses the term “means” or “step” or a term used as a substitute for “means” that is a generic placeholder (also called a nonce term or a non-structural term having no specific structural meaning) for performing the claimed function;
(B) the term “means” or “step” or the generic placeholder is modified by functional language, typically, but not always linked by the transition word “for” (e.g., “means for”) or another linking word or phrase, such as “configured to” or “so that”; and
(C) the term “means” or “step” or the generic placeholder is not modified by sufficient structure, material, or acts for performing the claimed function.
Use of the word “means” (or “step”) in a claim with functional language creates a rebuttable presumption that the claim limitation is to be treated in accordance with 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph. The presumption that the claim limitation is interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is rebutted when the claim limitation recites sufficient structure, material, or acts to entirely perform the recited function.
Absence of the word “means” (or “step”) in a claim creates a rebuttable presumption that the claim limitation is not to be treated in accordance with 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph. The presumption that the claim limitation is not interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is rebutted when the claim limitation recites function without reciting sufficient structure, material or acts to entirely perform the recited function.
Claim limitations in this application that use the word “means” (or “step”) are being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, except as otherwise indicated in an Office action. Conversely, claim limitations in this application that do not use the word “means” (or “step”) are not being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, except as otherwise indicated in an Office action.
This application includes one or more claim limitations that do not use the word “means,” but are nonetheless being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, because the claim limitation(s) uses a generic placeholder that is coupled with functional language without reciting sufficient structure to perform the recited function and the generic placeholder is not preceded by a structural modifier. Such claim limitation(s) is/are:
“collection device” first recited in claim 27;
The identified structure for the corresponding claim limitations are as follows:
“collection device” is identified as “In various aspects, the blood samples and CSF samples are collected using any suitable existing method without limitation” (Page 17, lines 6-8), and “blood (-10 mL) was collected via percutaneous catheter” (Page 58, lines 27-28).
Because this/these claim limitation(s) is/are being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, it/they is/are being interpreted to cover the corresponding structure described in the specification as performing the claimed function, and equivalents thereof.
If applicant does not intend to have this/these limitation(s) interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, applicant may: (1) amend the claim limitation(s) to avoid it/them being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph (e.g., by reciting sufficient structure to perform the claimed function); or (2) present a sufficient showing that the claim limitation(s) recite(s) sufficient structure to perform the claimed function so as to avoid it/them being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph.
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 1-11, 24-27, and 30-31 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.
Regarding claims 1 and 30, the claims are directed towards a method for performing a liquid biopsy; however, there is no structure recited for obtaining a biological sample. In light of the claim interpretation of a “collection device” as described above that is recited in claim 27, the claim will be interpreted to require a “collection device” to obtain the biological sample, the collection device being a percutaneous catheter or its equivalents. Claims 2-5, 24-26, and 30-31 are also rejected due to their dependence on claim 1.
Regarding claim 1, the claim is directed towards “a method for performing a liquid biopsy to diagnose a brain disorder …”. However, there is no recitation of diagnosing a brain disorder. How is the brain disorder diagnosed? Is the brain disorder diagnosed based on the biomarker or by some other means during the FUS-BBBO method? Is there a specific biomarker at a certain concentration, or when present, that aids in a specific diagnosis of a brain disorder? For examination purposes, the claim will be interpreted such that the biopsied biomarker is used in the determination of a brain diagnosis.
Regarding claim 3, the claim refers to the determining the baseline stable cavitation level and the target cavitation level (TCL). However, claim 1 only refers to determining a baseline stable cavitation level. Does the TCL also need to be determined, and, if so, how is it determined? Is determining the TCL different than determining the baseline cavitation level, or is it just a predetermined level above the baseline stable cavitation level as recited in claim 5? For examination purposes, the claim will be interpreted such that the TCL is a predetermined cavitation level above the baseline stable cavitation level. Claim 4 is also rejected due to its dependence on claim 3.
Regarding claims 4 and 9, the claims recites that the baseline stable cavitation level and TCL are “produced” by processing cavitation signals using a FFT. How are these levels “produced”? Is there an algorithm or threshold that is used to set these levels? Applicant should clarify how processing cavitation levels using an FFT “produces” these cavitation levels. For examination purposes, the claim will be interpreted such that the signals are processed with a FFT and cavitation levels are chosen for each of these levels.
Regarding claims 6-8 and 10, claims 7 and 10 recite that a passive cavitation detection (PCD) transducer is used to detect the various cavitation levels. However, claims 6 and 8 recite wherein the processor is configured to detect the cavitation levels. Thus, it is unclear which structure is detecting the cavitation levels. For examination purposes, claims 6-8 and 10 will be interpreted such that a PCD transducer is detecting the cavitation levels. Claims 9, 11, and 27 are also rejected due to their dependence on claims 6 and 8.
Regarding claim 30, the claim refers to a “CSF sample”; however, the acronym is not defined. The specification refers to a “CSF sample” (see page 5, lines 4 and 7; page 16, lines 19, 23, and 27; and page 17, lines 6-7), but the acronym is not defined in the specification. The Examiner will assume “CSF” refers to cerebrospinal fluid. However, in light of the claim interpretation of a collection device above, it remains unclear if the CSF is meant to refer to cerebrospinal fluid as there is no disclosure of a spinal tap or equivalent for sampling cerebrospinal fluid. Applicant should clarify what CSF is.
Regarding claim 31, it is unclear what is meant by determining “at least part of the biology of the brain disorder”. There is no mention of “biology” in the specification. The specification does refer to “diagnosing the brain disorder” through the detected biomarkers. For examination purposes, the claim will be interpreted such that the method further comprises the step of “diagnosing the brain disorder …”.
Allowable Subject Matter
The following is a statement of reasons for the indication of allowable subject matter:
Pacia et. al. (“Feasibility and safety of focused ultrasound-enabled liquid biopsy in the brain of a porcine model” – cited by Applicant) teaches a method for performing a liquid biopsy after performing focused ultrasound blood-brain barrier opening on a subject. Pacia teaches injecting an amount of microbubbles into the subject (Page 4, “3. FUS sonication” paragraph, “Fifteen seconds after FUS sonication began, perflutren lipid-shelled microbubbles (Definity, Lantheus Medical Imaging, North Billerica, MA) were administered intravenously with a dose of 0.2 mL/kg body weight and followed with a 3 mL saline flush”). After the microbubbles are injected, the subject is sonicated to open the blood-brain barrier using a focused ultrasound blood-brain barrier opening (FUS-BBBO) device to release or increase the concentration of at least one biomarker from a brain of the subject into blood of the subject (Page 2, paragraph 2, “We proposed that FUS-induced BBB disruption enables a “two-way transfer” between the brain and blood circulation and introduced the FUS-enabled liquid biopsy technique (FUS-LBx)23”). The blood-brain barrier is opened by sonicating the brain of the subject at a baseline sonication pressure (See Fig. 2.4 below, where a stable cavitation level of 0 is shown in the first 15 seconds prior to microbubble injection and an increase is shown after microbubble injection).
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Pacia then obtains a biological sample comprising the at least one biomarker (Page 5, “7. Blood collection and analysis” paragraph, “Blood was collected before and after FUS sonication to quantify the concentration of brain-specific biomarkers in the blood using enzyme-linked immunosorbent assays (ELISA) … representative brain-specific biomarkers, GFAP and MBP”).
The Examiner interprets the limitation of “determine a baseline stable cavitation level” as determining a level of stable cavitation occurring in the presence of microbubbles. Pacia does not teach or suggest determining this baseline cavitation level; rather, Pacia sonicates the brain at a constant pressure throughout the method to deliver different cavitation doses, see Fig. 5A below. Thus, Pacia also fails to sonicate the brain at increasing sonication pressures until a target cavitation level is reached.
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Chen et. al. (“The size of blood–brain barrier opening induced by focused ultrasound is dictated by the acoustic pressure”) teaches a method of opening the blood brain barrier using focused ultrasound sonication, wherein the ultrasound sonication is applied at increasing pressures (Page 2, “Focused Ultrasound Sonication” section, paragraph 4, applied at pressures 0.31, 0.51, and 0.84 MPa) in order to open the blood brain barrier. A baseline reading is taken prior to microbubble injection (Pages 2-3, “Focused Ultrasound Sonication” section, paragraph 4, “About 6 seconds after sonication started, MBs mixed with one of the four dextrans were injected into the tail vein of each mouse (see the experiment timeline in Figure 1B). The cavitation emission signals acquired within that 6 seconds provided baselines for cavitation quantification.”).
Chen is concerned that the inertial cavitation (IC) may damage tissue, and Chen found that an IC threshold (where IC begins to occur) was between 0.51 and 0.84 MPa. “This finding was consistent with previous PCD studies showing that agents with MW < 3 kDa were successfully delivered across the BBB with SC only. Our histologic evaluation showed that at 0.51MPa no microscopic tissue damage was observed (Figure 5A), which was in good agreement with a growing body of literature showing that SC only can induce BBB opening without any evident tissue damage (Page 7, “Microbubble Cavitation Emissions” section, paragraph 2). Thus, Chen teaches increasing the sonication pressure to a target cavitation level where BBB opening occurs but where IC is not present.
However, as described above, Chen teaches that a baseline reading is taken before microbubbles are injected. Thus, no cavitation is occurring and a “stable baseline cavitation level” cannot be determined.
As such, alone or in combination, the closest prior art of record fails to teach or suggest the limitation of sonicating the brain at a baseline sonication pressure to determine a baseline stable cavitation level.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to NOAH MICHAEL HEALY whose telephone number is (703)756-5534. The examiner can normally be reached Monday - Friday 8:30am - 5:30pm ET.
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/NOAH M HEALY/Examiner, Art Unit 3791
/JASON M SIMS/Supervisory Patent Examiner, Art Unit 3791
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