DETAILED ACTION
This office action is responsive to original claims filed on 090/20/2024. Presently, Claims 1-4, 6, 8-13, 15, 18-19, 21, 25-26, 32, 35, 43-44 and 54-56 remain pending.
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 .
Claim Objections
Claims 3, 6, 9, 11, 15 and 25 are objected to because of the following informalities:
Claim 3, Line 5, recites “is administered a subject”, which should be changed to “is administered into a subject”.
Claim 6, Line 1, recites “the detection marker and/or the is”, which should be changed to “the detection marker is”.
Claim 9, Line 5, recites “administered a subject”, which should be changed to “administered into a subject”.
Claim 11, Line 2, recites “detection agent”, which should be changed to “detection marker”.
Claim 15, Line 4, recites “complexed a liposome”, which should be changed to “complexed with a liposome”.
Claim 25, Line 1, recites “the size range corresponds to a monoclonal antibody”, which should be changed to “the size range corresponds to size range of a monoclonal antibody”.
Appropriate correction is required.
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 8-9, 11-13, 15, 21, 25-26, 32 and 35 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 8, Line 2, recites “molecules or molecular complexes … which can potentially pass through the disrupted target tissue”. The term “potentially” renders the claim indefinite, as one can argue that molecules of any size can “potentially” pass through a tissue. For present purposes of examination, the term “potentially” is not considered in interpreting the above recited phrase.
Claim 9, Lines 2-3, recites “a molecule that is … present in the target tissue but not in tissues outside the target tissue”. It is unclear whether the described presence of such molecule is under normal conditions, or when the target tissue is disrupted, or both. For present purposes of examination, the recited phrase is interpreted to be “a molecule that is … present in the target tissue but not in tissues outside the target tissue under normal conditions”.
Claim 11, Line 2, recites “the molecule that is predominantly present in the target tissue”, which differs from “a molecule that is present in the target” in Line 3 of Claim 1. For present purposes of examination, the recited phrase in Claim 11 is interpreted as “the molecule that is present in the target tissue”.
Claim 11, Lines 1-3, recites “the detection agent or the molecule that is predominantly present in the target tissue but substantially not present in tissues outside the target tissue under normal conditions”. It is unclear whether the underlined limitation is to specify “the molecule” only, or both “the detection agent” and “the molecule”. For present purposes of examination, the Examiner interprets the underlined limitation to specify “the molecule” but not “the detection agent”.
Claim 11, Lines 1-3, recites “the measurement of the detection agent or the molecule that is predominantly present in the target tissue but substantially not present in tissues outside the target tissue under normal conditions”. It is unclear whether the limitation of “under normal conditions” is used to specify the presence and not-presence of the molecule, or to specify “the measurement”, or both. For present purposes of examination, the Examiner interprets the limitation of “under normal conditions” to specify both “the measurement” and the presence and not-presence of the molecule.
Claim 11, Lines 1-3, recites “the degree of permeability is normalized using the measurement of the detection agent or the molecule … under normal conditions”. In Claim 3, the degree of permeability is calculated based on a measurement of the molecule, and/or, a measurement of the detection marker. It is unclear whether degree of permeability calculated based on a substance (e.g. the molecule) is normalized by a normal-condition measurement of the same substance (i.e. the molecule), or can be normalized by a normal-condition measurement of the other substance (i.e. the detection marker). For present purposes of examination, the Examiner interprets the degree of permeability calculated based on a substance (e.g. the molecule) to be normalized by a normal-condition measurement of the same substance.
Claim 13, Line 2, recites “the species of NSE or S100B that is detected”. There is insufficient antecedent basis for the limitation of “the species of NSE or S100B”. For present purposes of examination, the Examiner interprets “the species of NSE or S100B” to refer to “species of NSE or S100B as the brain protein”, and accordingly the limitation of “detected” to refer to “measured”.
Claim 32, Line 2, recites “to detect acoustic signals, wherein the target species”. There is insufficient antecedent basis for this limitation in the claim. For present purposes of examination, the recited phrase is interpreted as “to detect acoustic signals, wherein target species to be detected”.
Claims 12, 15, 21, 25-26 and 35 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 § 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.
Claims 1-2, 8, 18-19, 21, 25-26, 32, 35 and 43-44 are rejected under 35 U.S.C. 103 as being unpatentable over Levy et al (WO 2019002940 A1; hereafter Levy), in view of Vlachos et al (Phys. Med. Biol. 55 (2010) 5451–5466; hereafter Vlachos).
With regard to Claim 1, Levy discloses a system for disrupting target tissue for treatment (Levy, Para 0013; “… a system for disrupting target tissue for treatment …”), the system comprising:
(a) an ultrasound transducer for sonicating a target volume to cause disruption of a target tissue therein and thereby increase a permeability thereof (Levy, Para 0013; “an ultrasound transducer for generating and delivering one or more sonications of shaped energy beams to the target volume for causing disruption of the target tissue in a region corresponding to the target volume so as to increase tissue permeability therein”),
(b) a magnetic resonance imaging (MRI) device (Levy, Para 0013; “… the system includes an imaging device for acquiring a digital representation of one or more portions of a target volume of the target tissue”; Para 0034; “The imager 122 may be, for example, a magnetic resonance imaging (MRI) device …”); and
(c) a controller (Levy, Para 0013; “… the system includes … a controller, responsive to the imaging device, configured to …”) configured to:
(i) monitor a degree of permeability of the target tissue caused by the disruption (Levy, Para 0013; “… a controller, responsive to the imaging device, configured to generate a tissue permeability map indicating regions of increased tissue permeability and estimates of the tissue permeability due to the disruption …”); and
(ii) at least one of: (1) cause the ultrasound transducer to cease sonicating the target volume when the degree of permeability reaches a threshold (Levy, Para 0039; “… by adjusting the ultrasound intensity and/or duration, the tissue permeability of the target region can be increased to a desired degree … the ultrasound procedure is monitored by the controller 108 based on image information from the imager 122 in real-time until the focal zones generated from the series of sonications collectively occupy the target volume 202 …”; This disclosure suggests that the controller causes the ultrasound procedure to continue until tissue permeability reaches a “desired degree”, i.e. some threshold); and (3) change an ultrasound intensity (Levy, Para 0039; “… the controller 108 may adjust an ultrasound parameter (e.g., frequency, power, application duration, etc.) of a subsequent series of sonications …”),
wherein the controller is responsive to the MRI device (Levy, Para 0013; “… a controller, responsive to the imaging device, configured to …”; Para 0034; “The imager 122 may be, for example, a magnetic resonance imaging (MRI) device …”).
Levy does not clearly and explicitly disclose the controller configured to present the degree of permeability of the target tissue to an operator, and to evaluate the degree of permeability based on a measurement of at least one of ΔR1, ΔR2*, T1 or T2*.
Vlachos in the same field of endeavor discloses the controller configured to present the degree of permeability of the target tissue to an operator (Vlachos, Figure 4 shows multiple maps of permeability), and to evaluate the degree of permeability based on a measurement of at least one of ΔR1, ΔR2*, T1 or T2* (Vlachos, Abstract; “The spatial permeability of the BBB-opened region was assessed using dynamic contrast-enhanced MRI (DCE-MRI).”; Page 5455, Para 1; “Gadodiamide (Gd-DTPA) has been shown to reduce the longitudinal relaxation rate when it diffuses to the extravascular extracellular region, thus enhancing the T1 signal intensity in the region, where the BBB opening has occurred.” In this disclosure, “longitudinal relaxation rate” is R1, so its reduction corresponds to the recited “ΔR1” in Application. The disclosure also discloses “T1”). It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Levy, as suggested by Vlachos, in order to display permeability maps to an operator and to evaluate the degree of permeability based on a measurement of one of the listed MRI parameters. One of ordinary skill in the art would have been motivated to make the modification of displaying the permeability map for the benefit of visualizing the magnitude and range of the increased permeability in the targeted tissue so as to properly plan the following treatment, and to make the modification of evaluating permeability degree based on one of the MRI parameters for the benefit of DCE-MRI based on either T1- or T2*-shortening mechanism being one of the few available and the most reliable technique for non-invasively mapping tissue permeability in vivo (Vlachos, Page 5452, Para 3; “Dynamic contrast-enhanced MRI (DCE-MRI) has been thoroughly used in past studies to compute the permeability in such applications as embolic stroke, various types of cancer and injuries …”).
With regard to Claim 2, Levy and Vlachos disclose the system of claim 1. Levy further discloses wherein the degree of permeability corresponds to an upper limit of a size distribution of molecules or molecular complexes that can pass through the disrupted target tissue (Levy, Para 0015; “… each permeability level associated with a tissue region in the target volume and indicating a maximal size of molecules capable of entering the associated tissue region.”).
With regard to Claim 8, Levy and Vlachos disclose the system of claim 1. Levy further discloses wherein the degree of permeability corresponds to molecules or molecular complexes having a size range that can potentially pass through the disrupted target tissue (Levy, Para 0044; “The permeability map 402 may include tissue permeability levels (e.g., permeability of molecules having various sizes) at the target and/or non-target region or, more specifically, openings of the BBB region and/or its surrounding region.”).
Levy does not clearly and explicitly disclose measuring concentration of molecules or molecular complexes.
Vlachos further discloses measuring concentration of molecules or molecular complexes (Vlachos, Page 5455, Para 2; “The change in signal intensity before and after tracer administration corresponds to the changes in Gd-DTPA concentration, CGd, in the EES, where BBB opening was generated.” Here the disclosed “EES” is extra-vascular extra-cellular space, which is separated from vascular space by blood brain barrier). It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Levy and Vlachos, as further suggested by Vlachos, in order to determine a concentration of molecules that pass through the disrupted target tissue. One of ordinary skill in the art would have been motivated to make the modification for the benefit of enabling fully quantitative determination of tissue permeability, with potentially higher accuracy, by utilizing tracer-concentration based kinetic analysis.
With regard to Claim 18, Levy and Vlachos disclose the system of claim 1, but do not clearly and explicitly disclose wherein a relationship between the measurement and the degree of permeability is established by calibration.
Vlachos further discloses wherein a relationship between the measurement and the degree of permeability is established by calibration (Vlachos, Page 5456, Equation (2) is a model of the relationship between tracer concentration (Cp) and a parameter on degree of permeability (Ktrans). Ct is derived from T1- or T2* shortened signal from DCE MRI images. To establish the relationship for a specific case such as a target tissue, a calibration process is performed to combine tracer concentration values in both tissue (Ct) and plasma (Cp) at multiple time points after tracer injection, to derive the value of Ktrans, as disclosed in the end part of Para 1 of Page 5456). It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Levy and Vlachos, as further suggested by Vlachos, in order to establish a relationship between the measurement and the degree of permeability by calibration. One of ordinary skill in the art would have been motivated to make the modification for the benefit of improved precision for the determined degree of permeability by taking into consideration of all involved factors so as to reduce the impact of measurement noise or artefact.
With regard to Claim 19, Levy and Vlachos disclose the system of claim 18, but do not clearly and explicitly disclose wherein the calibration includes a machine learning component.
Vlachos further discloses wherein the calibration includes a machine learning component (Vlachos, Page 5456, Para 1; “The temporal Gd-DTPA concentration Ct(t) measurements, derived experimentally from (1) can then be fitted to (4), in order to estimate the variables Ktrans and Kep. The Levenberg-Marquardt algorithm is again used to calculate those variables for every pixel or a selected region of interest.”. In this disclosure, machine learning is used to analyze or learn tracer concentration values at multiple time points after tracer injection, thereby determining permeability parameter Ktrans. Such learning process is driven by minimizing cost function by the Levenberg-Marquardt algorithm). It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Levy and Vlachos, as further suggested by Vlachos, in order to use machine learning for the calibration. One of ordinary skill in the art would have been motivated to make the modification for the benefit of improved computational efficiency and accuracy as compared to manual or non-machine-learning approach.
With regard to Claim 21, Levy and Vlachos disclose the system of claim 8. Levy further discloses wherein the molecule or molecular complex includes a visualization agent (Levy, Para 0007; “… the permeability map is generated using an MRI contrast agent selected based on the molecular size of the therapeutic agent to be administered for treatment”; Here the disclosed “MR contrast agent” is a visualization agent).
With regard to Claim 25, Levy and Vlachos disclose the system of claim 8. Levy further discloses wherein the size range corresponds to a monoclonal antibody, a viral vector, a liposome, a nucleic acid or a protein (Levy, Para 0007; “… the permeability map is generated using an MRI contrast agent selected based on the molecular size of the therapeutic agent to be administered for treatment”; Para 0019; “The therapeutic agent may include Busulfan, Thiotepa, CCNU (lomustine), BCNU (carmustine), ACNU (nimustine), Temozolomide, Methotrexate, Topotecan, Cisplatin, Etoposide, Irinotecan /SN-38, Carboplatin, Doxorubicin, Vinblastine, Vincristine, Procarbazine, Paclitaxel, Fotemustine, Ifosfamide /4-Hydroxyifosfamide /aldoifosfamide, Bevacizumab, 5-Fluorouracil, Bleomycin, Hydroxyurea, Docetaxel, and/or Cytarabine (cytosine arabinoside, ara-C)/ara-U.”. Among the listed agents, at least Bevacizumab is a monoclonal antibody and a protein).
With regard to Claim 26, Levy and Vlachos disclose the system of claim 8. Levy further discloses wherein the molecule or molecular complex is selected from a liposome, a quantum dot, a dextran, a protein, a viral vector, a visualization agent, and a nucleic acid (Levy, Para 0007; “… the permeability map is generated using an MRI contrast agent selected based on the molecular size of the therapeutic agent to be administered for treatment”; Here the disclosed “MR contrast agent” is a visualization agent).
With regard to Claim 32, Levy and Vlachos disclose the system of claim 1. Levy further discloses wherein the transducer is configured also to detect acoustic signals (Levy, Para 0047; “… the acoustic response may be detected using a cavitation detection device 124 (shown in FIG. 1) and/or the ultrasound transducer array 102.”), wherein the target species corresponds to a molecule or molecular complex coupled to an acoustic agent (Levy, Para 0047; “…by detecting the acoustic response emanating from the microbubbles localized at the target region 202 …”; here “microbubbles” corresponds to the recited “acoustic agent” in Application. Drug can be coupled to the agent, as disclosed in Para 0004; “drugs are encapsulated in "nanobubbles" that are injected to the target region”).
With regard to Claim 35, Levy and Vlachos disclose the system of claim 32. Levy further discloses wherein the controller is further configured to:
evaluate the degree of permeability at least in part based on a combination of an acoustic measurement and an MRI image (Levy, Para 0046; “By monitoring the contrast change in the MRI images (due to penetration of the MRI contrast agent into the disrupted tissue), a map reflecting tissue permeability based on the size of the MRI contrast agent can be generated.”; Para 0047; “Additionally or alternatively, the permeability map 402 may be established based at least in part on a localized acoustic response …”);
update a target acoustic dose level (Levy, Para 0039; “… the controller 108 may adjust an ultrasound parameter (e.g., frequency, power, application duration, etc.) of a subsequent series of sonications based on the image information acquired in the previous series of sonications.”) at least in part based on a combination of an acoustic measurement and an MRI image (Levy, Para 0050; “The permeability map generated using the MRI contrast agent, the localized acoustic response or the computational simulation, alone or in combination with one another …”), or
control an ultrasound treatment based at least in part on the updated target acoustic dose level (Levy, Para 0039; “… the controller 108 may adjust an ultrasound parameter … of a subsequent series of sonications …”).
With regard to Claim 43, Levy and Vlachos disclose the system of claim 1. Levy further discloses comprising an administration device for introducing microbubbles into the target tissue (Levy, Para 0016; “the system may further include an administration device for administering a microbubble seed to the target volume …”).
With regard to Claim 44, Levy and Vlachos disclose the system of claim 1, in which Levy and Vlachos disclose a method of disrupting target tissue for treatment (Levy, Para 0017; “the invention relates to a method of disrupting target tissue for treatment and evaluating disruption of the target tissue.”), the method comprising the steps of:
sonicating a target volume to cause disruption of a target tissue therein using the system of claim 1 and thereby increase a permeability thereof (Levy, Para 0013; “an ultrasound transducer for generating and delivering one or more sonications of shaped energy beams to the target volume for causing disruption of the target tissue in a region corresponding to the target volume so as to increase tissue permeability therein”);
monitoring a degree of permeability of the target tissue caused by the disruption (Levy, Para 0013; “… a controller, responsive to the imaging device, configured to generate a tissue permeability map indicating regions of increased tissue permeability and estimates of the tissue permeability due to the disruption …”); and at least one of
(i) ceasing sonication of the target volume when the degree of permeability reaches a threshold (Levy, Para 0039; “… by adjusting the ultrasound intensity and/or duration, the tissue permeability of the target region can be increased to a desired degree … the ultrasound procedure is monitored by the controller 108 based on image information from the imager 122 in real-time until the focal zones generated from the series of sonications collectively occupy the target volume 202 …”; This disclosure suggests that the controller causes the ultrasound procedure to continue until tissue permeability reaches a “desired degree”, i.e. some threshold),
(ii) presenting the degree of permeability of the target tissue to an operator (Vlachos, Figure 4 shows multiple maps of permeability.), and
(iii) changing an ultrasound intensity (Levy, Para 0039; “… the controller 108 may adjust an ultrasound parameter (e.g., frequency, power, application duration, etc.) of a subsequent series of sonications …”).
Claims 3-4, 6 and 9-13 are rejected under 35 U.S.C. 103 as being unpatentable over Levy, in view of Vlachos and Janigro et al (US 20030170747 A1; hereafter Janigro).
With regard to Claim 3, Levy and Vlachos disclose the system of claim 2. Levy further discloses wherein the degree of permeability is calculated based at least in part on: (ii) a measurement inside the target tissue of a detection marker (MRI contrast agent) that is administered a subject in which the degree of permeability is calculated (Levy, Para 0046; “By monitoring the contrast change in the MRI images (due to penetration of the MRI contrast agent into the disrupted tissue), a map reflecting tissue permeability based on the size of the MRI contrast agent can be generated.”).
Levy and Vlachos do not clearly and explicitly disclose wherein the degree of permeability is calculated based at least in part on: a measurement of a molecule that is present in the target tissue but substantially not present in tissues outside the target tissue under normal conditions.
Janigro in the same field of endeavor discloses wherein the degree of permeability is calculated based at least in part on: a measurement of a molecule (S100β) that is present in the target tissue but substantially not present in tissues outside the target tissue under normal conditions (Janigro, Para 0060; “The upper histogram (FIG. 3A) summarizes concentrations of S100β, GFAP, and NSE, in serum and cerebral spinal fluid (CSF) as derived from the literature …”. Further shown in Fig. 3, in brain tissue with intact BBB, S100β is present in CSF (part of brain) but substantially absent in serum). It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Levy and Vlachos, as suggested by Janigro, in order to determine degree of permeability based on a measurement of a molecule predominantly present in target tissue under normal conditions. One of ordinary skill in the art would have been motivated to make the modification for the benefit of high sensitivity of such measurement of the molecules to change in degree of permeability in target tissue (Janigro, Para 0068; “S100β is the preferred peripheral marker for BBB opening is because there is more S100β in the brain than in the blood under normal conditions. It is not necessary to have damage for production of S100β to have an increased concentration in plasma. All that is necessary is an opening of the barrier.”).
With regard to Claim 4, Levy, Vlachos and Janigro disclose the system of claim 3. Levy further discloses wherein the target tissue is brain (Levy, Para 0042; “In some embodiments, the ultrasound-induced microbubble cavitation is utilized to transiently disrupt (or "open") a targeted blood-brain barrier (BBB) region.”).
With regard to Claim 6, Levy, Vlachos and Janigro disclose the system of claim 3, but do not clearly and explicitly disclose wherein the detection marker and/or the is complexed with a polymer, a liposome, a quantum dot, or a dextran.
Vlachos further discloses wherein the detection marker and/or the is complexed with a polymer, a liposome, a quantum dot, or a dextran (Vlachos, Page 5454, Para 1; “… previous FUS-induced BBB opening studies, employing fluorescence imaging after the administration of fluorescent-tagged 3-kDa dextran (Choi et al 2010).”. In a reference of Vlachos, detection marker used in fluorescence imaging is complexed with dextran). It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Levy, Vlachos and Janigro, as further suggested by Vlachos, in order to complex the detection marker with one of the listed substances. One of ordinary skill in the art would have been motivated to make the modification for the benefit of flexibly controlling the size of the detection marker so as to accurately determine the degree of permeability, or more specifically whether the disrupted opening allows substance (e.g. a therapeutic agent) of a same size to permeate through.
With regard to Claim 9, Levy and Vlachos disclose the system of claim 8. Levy further discloses wherein the degree of permeability is calculated based on: (ii) the measurement inside the target tissue of a detection marker (MRI contrast agent) that is in the size range (Para 0044; “… permeability of molecules having various sizes …”) and administered a subject in which the degree of permeability is calculated (Levy, Para 0046; “By monitoring the contrast change in the MRI images (due to penetration of the MRI contrast agent into the disrupted tissue), a map reflecting tissue permeability based on the size of the MRI contrast agent can be generated.”).
Levy and Vlachos do not clearly and explicitly disclose wherein the degree of permeability is calculated based on: the measurement of a molecule that is in the size range, and present in the target tissue but not in tissues outside the target tissue.
Janigro in the same field of endeavor discloses wherein the degree of permeability is calculated based on: the measurement of a molecule (S100β) that is in the size range, and present in the target tissue but not in tissues outside the target tissue (Janigro, Para 0060; “The upper histogram (FIG. 3A) summarizes concentrations of S100β, GFAP, and NSE, in serum and cerebral spinal fluid (CSF) as derived from the literature …”. Further shown in Fig. 3, in brain tissue with intact BBB, S100β is present in CSF (part of brain) but substantially absent in serum). It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Levy and Vlachos, as suggested by Janigro, in order to determine degree of permeability based on a measurement of a molecule predominantly present in target tissue under normal conditions. One of ordinary skill in the art would have been motivated to make the modification for the benefit of high sensitivity of such measurement of the molecules to change in degree of permeability in target tissue (Janigro, Para 0068; “S100β is the preferred peripheral marker for BBB opening is because there is more S100β in the brain than in the blood under normal conditions. It is not necessary to have damage for production of S100β to have an increased concentration in plasma. All that is necessary is an opening of the barrier.”).
With regard to Claim 10, Levy, Vlachos and Janigro disclose the system of claim 3. Levy further discloses wherein the degree of permeability is compared among at least two applications of sonication on different days administered to the same subject (Levy, Para 0045; “… when the high-permeability mapped region is larger than the defined 3D target volume 202 or when a sensitive organ 406 outside of the target volume 202 has high permeability, … the patient may be required to rest for one or two days until the disrupted tissue is regenerated (thereby reducing the tissue permeability to its normal state) and ready to be disrupted again.”).
Levy, Vlachos and Janigro do not clearly and explicitly disclose wherein the degree of permeability is compared among at least two applications of sonication administered to different subjects.
Vlachos further discloses wherein the degree of permeability is compared among at least two applications of sonication administered to different subjects (Vlachos, Page 5459, Para 3; “The permeability maps showed that Ktrans varies across mice …”). It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Levy, Vlachos and Janigro, as further suggested by Vlachos, in order to compare the degree of permeability across different subjects. One of ordinary skill in the art would have been motivated to make the modification for the benefit of accurately assessing the estimation precision of the degree of permeability by quantifying inter-subject variability induced by physiologic variation (Vlachos, Page 5459, Para 3; “BBB opening depends on the physiological condition of the mouse, apart from the sonication parameters”).
With regard to Claim 11, Levy, Vlachos and Janigro disclose the system of claim 10, but do not explicitly and clearly disclose wherein the degree of permeability is normalized using the measurement of the detection agent or the molecule that is predominantly present in the target tissue but substantially not present in tissues outside the target tissue under normal conditions.
Vlachos and Janigro further disclose wherein the degree of permeability is normalized using the measurement of the detection agent (Vlachos, Page 5456, Para 2; “The second model used for this study was the reference region model (RRM) (Yankeelov et al 2005), which calculates the permeability relative to a reference region with known Ktrans.” Page 5458, Para 1; “The epicranial muscle was selected as the reference region …”. ) or the molecule that is predominantly present in the target tissue but substantially not present in tissues outside the target tissue (Janigro, Para 0075; “… an increase in the level of S100β protein detected in the subject's sample as compared to control samples is an indicator of the degree to which the blood brain barrier has opened.”; Para 0008; “a control sample (e.g., levels found in a normal population)”) under normal conditions. It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Levy, Vlachos and Janigro, as further suggested by Vlachos and Janigro, in order to normalize the degree of permeability to a measurement under normal conditions. One of ordinary skill in the art would have been motivated to make the modification for the benefit of increased accuracy for the estimated degree of permeability by focusing solely on the change in measurement induced by change in the permeability but not on other pathologic factors.
With regard to Claim 12, Levy, Vlachos and Janigro disclose the system of claim 11, but do not explicitly and clearly disclose wherein the target tissue is brain, and the molecule that is predominantly present in the target tissue but substantially not present in tissues outside the target tissue under normal conditions is a brain protein.
Janigro further discloses wherein the target tissue is brain, and the molecule that is predominantly present in the target tissue but substantially not present in tissues outside the target tissue under normal conditions is a brain protein (Janigro, Para 0060; “S100β, in contrast, is predominantly located in the CSF. Upon opening of the BBB this protein is expected to appear into the serum, allowing for peripheral detection of BBB function in absence of neuronal damage. A peripheral marker of BBB leakage or permeability should include most of the following properties: plasma levels in control subjects must be exceedingly low or undetectable … Of the candidates, S100β would appear to be the best peripheral marker in reflecting BBB permeability and/or neuronal damage with regard to those characteristics.” This disclosure discloses the target tissue to be brain, and discloses a brain protein, S100β). It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Levy, Vlachos and Janigro, as further suggested by Janigro, in order to apply the technique to the brain and use a brain protein for the measurement. One of ordinary skill in the art would have been motivated to make the modification for the benefit of transient opening of blood-brain barrier being important for delivering treatment agent from blood to diseased brain tissue (Janigro, Para 0003; “Unfortunately, a plethora of potentially useful therapeutic agents are blood brain barrier impermeant, severely hampering their potential for aggressive treatment of a broad spectrum of neurological disorders”) and enabling non-invasive monitoring of such opening with brain-derived proteins (Janigro, Para 0006; “It would be useful to have a predictable and reliable peripheral marker of blood-brain barrier integrity in order to monitor the neurological status of a subject and to predict outcome and/or to adjust the therapy.”).
With regard to Claim 13, Levy, Vlachos and Janigro disclose the system of claim 12. Levy further discloses wherein the measurement of a substance is used for normalization of the transit of a therapeutic agent with comparable molecular weight (Levy, Para 0046; “… by selecting and injecting into the target region 202 separately resolvable MRI contrast agents having different sizes, the map may indicate various levels of tissue permeability, each level indicating a specific maximal size of molecules capable of entering and diffusing in the tissue.” In this disclosure, the measurement of a substance in combination with ultrasound treatment enables increased tissue permeability for molecules of comparable or smaller size, so intrinsically normalizes the transit of a therapeutic agent of comparable molecular weight).
Levy, Vlachos and Janigro do not explicitly and clearly disclose detecting and measuring NSE or S100B.
Janigro further discloses detecting and measuring NSE or S100B (Janigro, Para 0057; “… several monitoring techniques have been developed to measure brain damage or neuronal distress by measuring plasma levels of various CNS proteins, including S100β protein; glial fibrillary acidic protein (GFAP); neuron specific enolase (NSE); …”; this disclosure indicates that both S100β and NSE can be detected in measuring brain damage. Intrinsically, the detected NSE or S100B in brain is homodimeric and has the specified molecular weight). It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Levy, Vlachos and Janigro, as further suggested by Janigro, in order to detect and measure NSE or S100β. One of ordinary skill in the art would have been motivated to make the modification for the benefit of sensitivity and thus diagnostic value of measurement of the two endogenous substances to brain damage.
Claim 15 is rejected under 35 U.S.C. 103 as being unpatentable over Levy, Vlachos and Janigro, in view of Wei et al (US 20120095325 A1; hereafter Wei).
With regard to Claim 15, Levy, Vlachos and Janigro disclose the system of claim 11. Levy further discloses wherein the detection marker is in a defined molecular weight range corresponding to the molecular weight range of a therapeutic agent (Levy, Para 0007; “An MRI contrast agent having substantially the same molecular weight (or other size metric) as the therapeutic agent (i.e., 1,000 Daltons in this example) may then be injected into the target region in order to generate the tissue permeability map.”).
Levy, Vlachos and Janigro do not clearly and explicitly disclose conjugating a polymer or complexing a liposome to the detection marker.
Wei in the same field of endeavor discloses conjugating a polymer or complexing a liposome to the detection marker (Wei, Para 0052; “… a magnetic nanoparticle formed of an iron-based core and a shell encapsulating the iron-based core, the shell comprising a biological compatible polymer …”). It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Levy, Vlachos and Janigro, as suggested by Wei, in order to complex or conjugate the detection marker to a polymer or a liposome. One of ordinary skill in the art would have been motivated to make the modification for the benefit of flexibly controlling the size of the detection marker so as to accurately determine the degree of permeability, or more specifically whether the disrupted opening allows substance (e.g. a therapeutic agent) of a same size to permeate through.
Claims 54-56 are rejected under 35 U.S.C. 103 as being unpatentable over Epelbaum et al (Alzheimers Res Ther 14(1):40; hereafter Epelbaum), in view of Janigro.
With regard to Claim 54, Epelbaum discloses a method of comparing a degree of permeability of a target tissue in a subject among at least two applications of focused ultrasound treatment on different days, the method comprising:
(i) providing a measurement from the subject (Epelbaum, Page 3, Column 2, Para 4; “MRI imaging was performed following the BBB opening procedure during the first and third sessions …”. The disclosed MRI performed during a first session corresponds to the first measurement for a subject) that received a first application of sonication to a target volume to cause disruption of the target tissue therein and thereby increase a permeability thereof (Epelbaum, Page 3, Column 1, Para 2; “The SonoCloud-1 implantable ultrasound device (Carthera, Paris, France) was used for sonications …”. The disclosed application of ultrasound in the first session (the first red point on the timeline in Fig. 3) corresponds to a first application of sonication in the claim),
(iii) monitoring a degree of permeability of the target tissue caused by the disruption (Epelbaum, Page 4, Column 1, Para 2; “To evaluate BBB disruption efficacy, the map of Gd-DOTA concentration was calculated …”. The disclosed map of Gd-DOTA concentration corresponds to the degree of permeability);
(iv) providing a second measurement from the subject (Epelbaum, Page 3, Column 2, Para 4; “MRI imaging was performed following the BBB opening procedure during the first and third sessions …”. The disclosed MRI performed during the third session corresponds to a second measurement for a subject) that received a second application of sonication on a different day to a target volume to cause a second disruption of the target tissue therein and thereby increase a second permeability thereof (Epelbaum, Page 3, Column 1, Para 2; “The SonoCloud-1 implantable ultrasound device (Carthera, Paris, France) was used for sonications …”. The disclosed application of ultrasound in the third session (the second red point on the timeline in Fig. 3) corresponds to a second application of sonication in the claim),
(vi) monitoring a degree of permeability of the target tissue caused by the second disruption (Epelbaum, Page 4, Column 1, Para 2; “To evaluate BBB disruption efficacy, the map of Gd-DOTA concentration was calculated …”. The disclosed map of Gd-DOTA concentration corresponds to the degree of permeability); and
(vii) comparing a degree of permeability of the target tissue in a subject among at least two applications of sonication on different days (Epelbaum, Page 8, Column 2, Para 2; “No significant difference or trend was found when comparing the two sessions with MRI data available (session 1 and session 3) for the same patient”).
Epelbaum does not clearly and explicitly disclose a method comprising:
providing a biological sample from a subject, or
measuring the amount in the biological sample of a molecule that is present in the target tissue but substantially not present in tissues outside the target tissue under normal conditions.
Janigro in the same field of endeavor discloses a method comprising:
providing a biological sample from a subject (Janigro, Para 0010; “… a method for diagnosis of blood brain barrier permeability by means of detecting levels of S100β protein in a sample of biological fluid, preferably a blood sample, from a patient …”), or
measuring the amount in the biological sample of a molecule that is present in the target tissue but substantially not present in tissues outside the target tissue under normal conditions (Janigro, Para 0060; “The upper histogram (FIG. 3A) summarizes concentrations of S100β, GFAP, and NSE, in serum and cerebral spinal fluid (CSF) as derived from the literature …”. Further shown in Fig. 3, in brain tissue with intact BBB, S100β is present in CSF (part of brain) but substantially absent in serum).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Epelbaum, as suggested by Janigro, in order to measure the amount of a molecule, which is predominantly present in target tissue under normal conditions, in a biological sample. One of ordinary skill in the art would have been motivated to make the modification for the benefit of high sensitivity of such measurement of the molecules to change in degree of permeability in target tissue (Janigro, Para 0068; “S100β is the preferred peripheral marker for BBB opening is because there is more S100β in the brain than in the blood under normal conditions. It is not necessary to have damage for production of S100β to have an increased concentration in plasma. All that is necessary is an opening of the barrier.”).
With regard to Claim 55, Epelbaum and Janigro disclose the method of claim 54. Epelbaum further discloses wherein the target tissue is brain and/or the biological sample is blood (Epelbaum, Page 3, Column 1, Para 2; “The device was placed in a 12-mm diameter burr hole in the left parietotemporal junction targeting the left supramarginal gyrus”).
With regard to Claim 56, Epelbaum and Janigro disclose the method of claim 54, but do not explicitly and clearly disclose wherein the molecule that is present in the target tissue but substantially not present in tissues outside the target tissue under normal conditions is a brain protein.
Janigro further discloses wherein the molecule that is present in the target tissue but substantially not present in tissues outside the target tissue under normal conditions is a brain protein (Janigro, Para 0008; “The present invention is based on monitoring and measuring markers of blood brain barrier permeability, particularly S100β as a peripheral marker …”). It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Epelbaum and Janigro, as further suggested by Janigro, in order to measure the amount of a brain protein. One of ordinary skill in the art would have been motivated to make the modification for the benefit of high sensitivity of such measurement of the molecules to change in degree of permeability in target tissue (Janigro, Para 0068; “S100β is the preferred peripheral marker for BBB opening is because there is more S100β in the brain than in the blood under normal conditions. It is not necessary to have damage for production of S100β to have an increased concentration in plasma. All that is necessary is an opening of the barrier.”).
Conclusion
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/L.Z./Examiner, Art Unit 3798
/PASCAL M BUI PHO/Supervisory Patent Examiner, Art Unit 3798