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 .
Response to Arguments
Applicant’s argument on Page 6 regarding the rejection of Claims 9-15 under 35 U.S.C. 112(b) has been fully considered. The rejection of Claims 9-15 under 35 U.S.C. 112(b) is withdrawn in view of the amendment.
Applicant’s argument on Pages 6-9 regarding the rejection of Claim 9 under 35 U.S.C. 103 over Tyler in view of During has been fully considered but is not persuasive under new grounds of rejection as below.
Applicant’s argument on Pages 9-13 regarding the rejection of Claim 17 under 35 U.S.C. 103 over Carpentier in view of Tyler and Hoelscher has been fully considered but is not persuasive under new grounds of rejection as below.
Regarding the rejection of all remaining corresponding claims, applicant’s argument submitted on Pages 12-13 relies on the supposed deficiencies with respect to the rejection of parent Claim 9. Applicant’s argument is moot for the same reasons detailed above.
Claim Objections
Claim 9 is objected to because of the following informalities: minor error in antecedent basis. The claim should be amended to “[…] over the entire brain tissue of [[a]] said subject […]” in order to establish proper antecedent basis. Appropriate correction is required.
Claim 17 is objected to because of the following informalities: minor error in antecedent basis. The claim should be amended to “A method for improving [[the]] bioavailability […] a subject for [[the]] treatment of a central nervous system disease […] applying a device to at least a portion of [[the]] a head of said subject […] reversibly break [[the]] a blood-brain barrier of [[a]] said subject by emitting ultrasound over the entire brain tissue of [[a]] said subject […]” in order to establish proper antecedent basis. Appropriate correction is required.
Claim 18 is objected to because of the following informalities: minor error in antecedent basis. The claim should be amended to “[…] on [[the]] a surface of [[the]] a scalp of [[a]] said subject […]” in order to establish proper antecedent basis. Appropriate correction is required.
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 9-15 and 17-18 are rejected under 35 U.S.C. 103 as being unpatentable over Lee et al. (US 20180333593) in view of Tyler (US 20120289869) and Su et al. (“Controllable permeability of blood-brain barrier and reduced […]”).
Regarding Claim 9, Lee teaches a device configured to selectively and reversibly break a blood- brain barrier of a subject by emitting ultrasound, ([0025] “system 100 may be use a low intensity focused ultrasound (optionally combined with microbubbles) to transiently disrupt the BBB”), comprising:
a) at least two ultrasonic transducers coupled to said structure and configured to emit ultrasound with diagnostic intensity over the entire brain tissue of a subject ([0030] “the transducer array 111 can be configured to insonify the region of interest 132 using ultrasonic or acoustic energy, and the region of interest 132 can include a tissue region (e.g., a blood vessel region, or one or more other locations). […] target 186 may correspond to a brain of a subject” and Claim 17 “wherein: the region of interest comprises a brain of the imaging subject”); and
b) wherein said at least two ultrasonic transducers are configured to deliver an ultrasound frequency of between 1 and 4 MHz, ([0043] “the system included an MR-compatible, pre-focused, 8-element annular array comprising 1.5 MHz transducers 111”).
However, Lee does not explicitly teach a structure configured to be placed on at least a portion of a head of a user; wherein said at least two ultrasonic transducers are of capacitive micromachined, piezoelectric micromachined or piezoelectric type wherein said at least two ultrasonic transducers are configured to deliver at a power of between 400 and 800 mW/cm2, said at least two ultrasonic transducers being adapted to increase bioavailability in brain tissues of at least one agent against inflammation mediators by causing microbubbles previously injected into said subject to enter into oscillation and increase vascular porosity over the entire brain tissue of said subject's brain, the microbubbles having a diameter of between 2 and 11µm.
In an analogous modulating brain activity field of endeavor, Tyler teaches a device configured to selectively and reversibly break a blood- brain barrier of a subject by emitting ultrasound, ([0101] “The application of ultrasound through treatment devices may be used to regulate the cerebrovascular dynamics of the brain such that the blood-brain barrier is modified in order to allow the better absorption of one or more active agents, such as drugs or pharmaceuticals, to specific brain regions,” which is interpreted as selectively and reversibly breaking the blood-brain barrier, and [0111] “The term “treating” refers to inhibiting, preventing, curing, reversing, attenuating, alleviating, minimizing, suppressing or halting the deleterious effects of a disease and/or causing the reduction, remission, or regression of a disease.”), comprising:
a) a structure configured to be placed on at least a portion of a head of a user (Fig. 1A);
b) wherein said at least two ultrasonic transducers are of capacitive micromachined, piezoelectric micromachined or piezoelectric type ([0031] “Devices of the present invention comprise a device operably connected to the subject comprising one or more components for generating ultrasound waves, herein referred to as transducers, and including but not limited to, ultrasonic emitters, transducers or piezoelectric transducers, piezocomposite transducers, […] CMUTs (capacitive micromachined ultrasound transducers), and which may be provided as single or multiple transducers or in array configurations.”).
It would have been obvious to one of ordinary skill in the art at the time of applicant’s filing to modify Lee with the teachings of Tyler because the modification ensures the ability of an operator to modulate the brain’s activities, and to alter or control physiological or behavioral responses by the body of the subject, as taught by Tyler in [0030].
However, Lee modified by Tyler does not explicitly teach wherein said at least two ultrasonic transducers are configured to deliver at a power of between 400 and 800 mW/cm2, said at least two ultrasonic transducers being adapted to increase bioavailability in brain tissues of at least one agent against inflammation mediators by causing microbubbles previously injected into said subject to enter into oscillation and increase vascular porosity over the entire brain tissue of said subject's brain, the microbubbles having a diameter of between 2 and 11µm.
In an analogous controllable permeability of blood-brain barrier field of endeavor, Su teaches a device configured to selectively and reversibly break a blood-brain barrier of a subject by emitting ultrasound, (Abstract “It has been shown that the blood-brain barrier (BBB) can be locally disrupted by focused ultrasound (FUS) in the presence of microbubbles (MB) while sustaining little damage to the brain tissue” and Materials and Methods, Pulsed ultrasound set-up “Pulsed FUS exposures were generated by a 1.0-MHz, single-element focused transducer (A392S, Panametrics, Waltham, MA, USA) with a diameter of 38 mm and a radius of curvature of 63.5 mm.”), comprising: wherein said at least two ultrasonic transducers (as discussed above) are configured to deliver at a power of between 400 and 800 mW/cm2, (Materials and Methods, Pulsed ultrasound set-up “LIPUS was applied […] at an acoustic power of 0.51 W (corresponding to a spatial-peak temporal-average intensities (ISPTA) of 528 mW/cm2).”), said at least two ultrasonic transducers being adapted to increase bioavailability in brain tissues of at least one agent against inflammation mediators by causing microbubbles previously injected into said subject to enter into oscillation and increase vascular porosity over the entire brain tissue of said subject's brain, the microbubbles having a diameter of between 2 and 11µm (Materials and Methods, Pulsed ultrasound set-up “Ultrasound contrast agent was injected […]. This agent contains phospholipid-coated MB with a mean diameter = 2.5 µm”).
It would have been obvious to one of ordinary skill in the art at the time of applicant’s filing to further modify with Su because the modification allows for controllable release of drugs into the brain, as taught by Su in Abstract.
Regarding Claim 10, the modified device of Lee teaches all limitations of Claim 9, as discussed above. Furthermore, Tyler teaches wherein said structure consists of a helmet, a cup, a hood or a headband ([0052] “The body of a device may be a chassis that is insertable into other head gear, or a body may be head gear such as a cap, a headband, a helmet, a protective head covering, a hood, a stretchable material, a flexible material similar to a scarf that can be tied on the head, or other head gear that may be adapted to hold components for generating sound waves and/or other components”).
It would have been obvious to one of ordinary skill in the art at the time of applicant’s filing to further modify with Tyler because the modification contains the components within a singular, wearable device, which provides a compact design and ease of use and comfortability for the patient.
Regarding Claim 11, the modified device of Lee teaches all limitations of Claim 9, as discussed above. Furthermore, Tyler teaches wherein said at least two ultrasonic transducers are positioned in at least a frontal plane or a sagittal plane (as shown in Fig. 1A, reproduced above).
It would have been obvious to one of ordinary skill in the art at the time of applicant’s filing to further modify with Tyler because the placement ensures the complete and comprehensive visualization of anatomical structures along a specific direction, which allows for accurate treatment planning.
Regarding Claim 12, the modified device of Lee teaches all limitations of Claim 9, as discussed above. Furthermore, Tyler teaches wherein said at least two ultrasonic transducers are movable along at least a frontal axis or a sagittal axis ([0065] “FIG. 7 illustrates an exemplary device having movable or rotatable components, such as a movable or rotatable ultrasound transducer. The ultrasound fields may be adjusted manually or automatically, either locally or remotely controlled, by using transducers mounted on a 1-, 2-, 3-spatial axis motion controller” and Fig. 7).
It would have been obvious to one of ordinary skill in the art at the time of applicant’s filing to further modify with Tyler because the placement ensures the complete and comprehensive visualization of anatomical structures along a specific direction, which allows for accurate treatment planning.
Regarding Claim 13, the modified device of Lee teaches all limitations of Claim 9, as discussed above. Furthermore, Lee teaches wherein said device further comprises a control device coupled to the at least two ultrasonic transducers and configured to control the ultrasound frequency and power of the ultrasound emitted by the at least two ultrasonic transducers ([0028] “The region of interest 132 can also or alternatively be disrupted using focused ultrasound by first processor circuit 122 instructing one or more transducers 111 to transmit a low-intensity ultrasound signal.”).
Regarding Claim 14, the modified device of Lee teaches all limitations of Claim 9, as discussed above. Furthermore, Tyler teaches wherein said at least two ultrasonic transducers rest on a surface of a scalp of the user ([0053] “A device of the present invention comprises a device that is wearable by a subject and used for providing at least ultrasound waves to the brain of the subject, comprising a body which covers at least a portion of a subject's head and/or scalp, when worn by the subject, and a plurality of components, wherein at least one component is an ultrasound component.”).
It would have been obvious to one of ordinary skill in the art at the time of applicant’s filing to further modify with Tyler because the modification allows for non-invasive delivery of acoustic energy to open the BBB, while being able to be re-used for repetitive planning or treatment.
Regarding Claim 15, the modified device of Lee teaches all limitations of Claim 9, as discussed above. Furthermore, Tyler teaches wherein said device comprises a plurality of ultrasonic transducers forming an array of transducers on a surface of a scalp of the user (Fig. 1A, reproduced above, [0031] “Devices of the present invention comprise a device operably connected to the subject comprising one or more components for generating ultrasound waves, herein referred to as transducers, and including but not limited to, ultrasonic emitters, transducers or piezoelectric transducers, piezocomposite transducers, piezopolymers, CMUTs (capacitive micromachined ultrasound transducers), and which may be provided […] in array configurations” and [0053] “A device of the present invention comprises a device that is wearable by a subject and used for providing at least ultrasound waves to the brain of the subject, comprising a body which covers at least a portion of a subject's head and/or scalp, when worn by the subject, and a plurality of components, wherein at least one component is an ultrasound component.”).
It would have been obvious to one of ordinary skill in the art at the time of applicant’s filing to further modify with Tyler because the modification allows for non-invasive delivery of acoustic energy to open the BBB, while being able to be re-used for repetitive planning or treatment.
Regarding Claim 17, Lee teaches a method for improving the bioavailability of therapeutical agents against inflammation mediators in a subject for the treatment of a central nervous system disease selected from Alzheimer's disease, Parkinson's disease, cerebrovascular diseases, including stroke, migraine, multiple sclerosis, nervous system infections, brain tumors, traumatic nervous system disorders, depression and malnutrition-related neurological disorders, ([0035] “computer system 126 may determine that the neurological disease in a first section corresponds to epilepsy or a movement disorder.”), comprising the steps of:
a) administering to said subject a therapeutically effective amount of at least one therapeutical agent against inflammation mediators being selected among anti-inflammatory agents or immunomodulators ([0035] “computer system 126 may select to administer a therapeutic agent that includes a neurotoxin to the first section of region of interest 132.”);
b) injecting microbubbles of gas to said subject, ([0031] “The phrase “microbubbles” can generally refer to lipid-shelled perfluorocarbon gas bubbles that may be used as ultrasound contrast agents for medical imaging” and [0032] “biotinylated gas-filled microbubbles may be produced by an insonification protocol from decafluorobutane gas by dispersing gas in a lipid micellar mixture of distearoyl phosphatidylcholine, polyethylene glycol stearate, and biotin-PEG3400-distearoylphosphatidylethanolamine in normal saline to create microbubbles coated with a lipid monolayer shell.”); and
c) emitting focused ultrasound onto at least one site of the brain of said subject with said device, at an ultrasound frequency of between 1 and 4 MHz ([0043] “the system included an MR-compatible, pre-focused, 8-element annular array comprising 1.5 MHz transducers 111”).
However, Lee does not explicitly teach the microbubbles having a diameter of between 2 and 11 µm; applying a device to at least a portion of the head of said subject, said device being configured to selectively and reversibly break the blood-brain barrier of a subject by emitting ultrasound over the entire brain tissue of a subject and comprising: a structure configured to be placed on at least a portion of the head of the subject, at least two ultrasonic transducers coupled to said structure and configured to emit ultrasound with diagnostic intensity, wherein said at least two ultrasonic transducers are of capacitive micromachined, piezoelectric micromachined or piezoelectric type, and emitting focused ultrasound onto at least one site of the brain of said subject with said device, at a power of between 400 and 800 mW/cm2 thereby causing microbubbles to enter into oscillation and increase vascular porosity over the entire brain tissue said subject's brain so that the bioavailability in brain tissues of the at least one therapeutical agent against inflammation mediators is increased.
In an analogous modulating brain activity field of endeavor, Tyler teaches a method for improving the bioavailability of therapeutical agents, (Abstract “The present invention relates to a method for transiently disrupting a region of the blood-brain barrier”), against inflammation mediators in a subject for the treatment of a central nervous system disease selected from Alzheimer's disease, (0095] “In some embodiments, the treatment of a brain disease consists solely to the application of US beams as described above (i.e., without the additional delivery of a therapeutic agent). Indeed, the progression of some brain diseases, such as for instance Alzheimer, may be slowed down or stopped after application of US.”), Parkinson's disease ([0083] “Examples of neurodegenerative diseases include Parkinson disease”), cerebrovascular diseases, including stroke, migraine, multiple sclerosis, ([0085] “In the context of the invention, the targeted brain diseases also encompass inflammatory and/or auto-immune diseases, such as multiple sclerosis”), nervous system infections, brain tumors, ([0077] “only a region of the BBB surrounding damaged brain tissue, such as a tumor, is targeted.”), traumatic nervous system disorders, ([0014] “A further object of the invention concerns a method for treating a brain disease, preferably a neurodegenerative disorder”), depression, and malnutrition-related neurological disorders comprising the steps of: applying a device to at least a portion of the head of said subject, (Fig. 1), said device being configured to selectively and reversibly break the blood-brain barrier of a subject, (Abstract “The present invention relates to a method for transiently disrupting a region of the blood-brain barrier”), by emitting ultrasound over the entire brain tissue of a subject, ([0043] “the expression “brain” may designate all […] of the cerebral lobes” and [0049] “the US beams are applied to the brain of the patient”), and comprising:
a) a structure configured to be placed on at least a portion of the head of the subject, at least two ultrasonic transducers coupled to said structure and configured to emit ultrasound with diagnostic intensity, (Fig. 1, [0060] “several transducers, such as several implantable medical devices, are fixed to the skull of the patient, to cover different areas or a wider area of the brain” and [0062] “the method comprises the application one or more pulses, or bursts, comprising from 100 to 100,000 successive cycles, preferably from 1,000 to 75,000, more preferably from 10,000 to 50,000, even more preferably from 20,000 to 30,000.”), and
b) wherein said at least two ultrasonic transducers are of capacitive micromachined, piezoelectric micromachined or piezoelectric type, ([0031] “Devices of the present invention comprise a device operably connected to the subject comprising one or more components for generating ultrasound waves, herein referred to as transducers, and including but not limited to, ultrasonic emitters, transducers or piezoelectric transducers, piezocomposite transducers, […] CMUTs (capacitive micromachined ultrasound transducers), and which may be provided as single or multiple transducers or in array configurations.”).
It would have been obvious to one of ordinary skill in the art at the time of applicant’s filing to modify Lee with the teachings of Tyler because the modification ensures the ability of an operator to modulate the brain’s activities, and to alter or control physiological or behavioral responses by the body of the subject, as taught by Tyler in [0030].
However, Lee modified by Tyler does not explicitly teach the microbubbles having a diameter of between 2 and 11 µm; and emitting focused ultrasound at a power of between 400 and 800 mW/cm2 thereby causing microbubbles to enter into oscillation and increase vascular porosity over the entire brain tissue said subject's brain so that the bioavailability in brain tissues of the at least one therapeutical agent against inflammation mediators is increased.
In an analogous controllable permeability of blood-brain barrier field of endeavor, Su teaches a method for improving the bioavailability of therapeutical agents against inflammation mediators in a subject, (Abstract “It has been shown that the blood-brain barrier (BBB) can be locally disrupted by focused ultrasound (FUS) in the presence of microbubbles (MB) while sustaining little damage to the brain tissue” and Materials and Methods, Pulsed ultrasound set-up “Pulsed FUS exposures were generated by a 1.0-MHz, single-element focused transducer (A392S, Panametrics, Waltham, MA, USA) with a diameter of 38 mm and a radius of curvature of 63.5 mm.”), comprising:
a) the microbubbles having a diameter of between 2 and 11 µm (Materials and Methods, Pulsed ultrasound set-up “Ultrasound contrast agent was injected […]. This agent contains phospholipid-coated MB with a mean diameter = 2.5 µm”); and
b) emitting focused at a power of between 400 and 800 mW/cm2 thereby causing microbubbles to enter into oscillation and increase vascular porosity over the entire brain tissue said subject's brain so that the bioavailability in brain tissues of the at least one therapeutical agent against inflammation mediators is increased (Materials and Methods, Pulsed ultrasound set-up “Ultrasound contrast agent was injected […]. This agent contains phospholipid-coated MB with a mean diameter = 2.5 µm […]. […] LIPUS was applied […] at an acoustic power of 0.51 W (corresponding to a spatial-peak temporal-average intensities (ISPTA) of 528 mW/cm2).”).
It would have been obvious to one of ordinary skill in the art at the time of applicant’s filing to further modify with Su because the modification allows for controllable release of drugs into the brain, as taught by Su in Abstract
Regarding Claim 18, the modified method of Lee teaches all limitations of Claim 17, as discussed above. Furthermore, Tyler teaches wherein the at least two ultrasonic transducers rest on the surface of the scalp of a subject ([0053] “A device of the present invention comprises a device that is wearable by a subject and used for providing at least ultrasound waves to the brain of the subject, comprising a body which covers at least a portion of a subject's head and/or scalp, when worn by the subject, and a plurality of components, wherein at least one component is an ultrasound component.”).
It would have been obvious to one of ordinary skill in the art at the time of applicant’s filing to further modify with Tyler because the modification allows for non-invasive delivery of acoustic energy to open the BBB, while being able to be re-used for repetitive planning or treatment.
Conclusion
THIS ACTION IS MADE FINAL. 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MARIA CHRISTINA TALTY whose telephone number is (571)272-8022. The examiner can normally be reached M-Th 8:30-5:30 EST.
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/MARIA CHRISTINA TALTY/ Examiner, Art Unit 3797
/MICHAEL J CAREY/ Supervisory Patent Examiner, Art Unit 3795