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 .
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1, 6-7, and 10-15, 19-22, and 26-29 are rejected under 35 U.S.C. 103 as being unpatentable over Levy et al (US 20200139158 A1, hereinafter referred to as Levy) in view of Davalos et al (US20160338758A9; hereinafter referred to as Davalos)
Regarding Claim 1, Levy discloses a method for delivery of a therapeutic agent across a blood brain barrier (BBB) in a subject ("Systems and methods for applying ultrasound sonication to temporarily disrupt a patient's blood-brain barrier" [Abstract] ,"Thereafter, a therapeutic agent may penetrate from the bloodstream to the targeted brain cells via the opened BBB region." [0055]) comprising:
treating the subject with the therapeutic agent comprising paclitaxel ("Thereafter, a therapeutic agent may penetrate from the bloodstream to the targeted brain cells via the opened BBB region...The therapeutic agent may include...Paclitaxel" [0055]),
and disrupting the blood-brain barrier within the brain of the subject by the use of an ultrasound device ("The present invention provides systems and methods for inducing microbubble cavitation with ultrasound in order to disrupt a target BBB region in a controlled and reversible manner." [0007], "The transducer array 102 is coupled to the beamformer 106, which drives the individual transducer elements 104 so that they collectively produce a focused ultrasonic beam or field." [0036]),
the disruption of the blood-brain barrier increases a concentration of therapeutic agent in the brain of the subject as compared to the concentration of paclitaxel in the brain without blood-brain barrier disruption (“Those skilled in the art can select a drug and a BBB opening regime optimized to enhance drug absorption across the BBB within patient safety constraints.” [0056]).
wherein the step of treating the subject comprises administration of the therapeutic agent intravenously ("The drug may be administered intravenously" [0056]),
and wherein disruption of the blood-brain barrier comprises coincident application of the ultrasound device and intravenous microbubble injection ("The present invention provides systems and methods for inducing microbubble cavitation with ultrasound in order to disrupt a target BBB region in a controlled and reversible manner." [0007], "In some embodiments, microbubbles are introduced into the patient's bloodstream, and may either be injected systemically into the patient's brain or locally into the target BBB region 204 using an administration system 124" [0039]).
Levy does not specifically disclose that the therapeutic agent that is Cremophor EL free paclitaxel and comprises albumin-bound paclitaxel.
However, in the similar field of BBB Disruption, Davalos teaches providing electrical energy based methods for temporarily disrupting the blood-brain-barrier for increasing intracellular delivery of drugs across the blood-brain barrier [0002].
Davalos also teaches the therapeutic agent that is Cremophor EL free paclitaxel and comprises albumin-bound paclitaxel (“the skilled artisan may rely on such data to determine an appropriate dosage, route of administration, and timing of administration of the bioactive agent to provide a therapeutic concentration of the agent in blood during the duration of blood-brain-barrier disruption.” [0080], “the bioactive agent is at least one cancer therapeutic agent selected from the group consisting of… ABRAXANE (Paclitaxel Albumin-stabilized Nanoparticle Formulation)” [0084]).
It would have been obvious to an ordinary skilled person in the art before the effective filing
date of the claimed invention to modify the system of Levy as outlined above with the therapeutic agent that is Cremophor EL free paclitaxel and comprises albumin-bound paclitaxel as taught by Davalos, because it may yield improved tumor control and enhances delivery of chemotherapeutic drugs for glioblastoma treatment [0005].
Regarding Claim 6, Levy discloses that the ultrasound device directs blood-brain barrier disruptions in a peri-tumoral region of the brain of the subject to increase the concentration of the therapeutic agent in the peri-tumoral region of the brain ("In this regard, it is known that the BBB is actually already disrupted in the core of many tumors, allowing partial penetration of antitumor drugs; but the BBB is widely intact around the ‘brain adjacent to tumor’ (BAT) region where invasive/escaping GBM cells can be found, and which cause tumor recurrence. Overcoming the BBB for better drug delivery within the tumor core and the BAT can be accomplished using ultrasound as described herein." [0056]).
Regarding Claim 7, Levy discloses that the ultrasound device applies ultrasonic waves transcranially ("FIG. 1 illustrates an exemplary ultrasound system 100 for focusing ultrasound within a patient's brain (e.g., a target BBB region) through the skull." [0034]).
Regarding Claim 10, Levy discloses that the disruption of the blood-brain barrier comprising repeatedly activating, or pulsating the ultrasound device ("transmitting, using a phased array of transducers, one or more ultrasound pulses converging at a focus that includes the target BBB regions" [0021]).
Regarding Claim 11, Levy discloses that the ultrasound device is applied externally ("In various embodiments, the system 100 includes a phased array 102 of transducer elements 104, a beamformer 106 driving the phased array 102, a controller 108 in communication with the beamformer 106, and a frequency generator 110 providing an input electronic signal to the beamformer 106." [0034], “The array 102 may have a curved (e.g., spherical or parabolic) shape suitable for placing it on the surface of the skull”, [0035], See 104 in Fig 1).
Regarding Claim 12, Levy discloses that the step of treating the subject comprises treating a central nervous system tumor is glioblastoma, malignant glioma, diffuse or anaplastic astrocytoma, or any other primary or secondary central nervous system malignancy ("Thereafter, a therapeutic agent may penetrate from the bloodstream to the targeted brain cells via the opened BBB region. The therapeutic agent may include any drug that is suitable for treating a brain tumor. For example, for treating glioblastoma (GBM)" [0055]).
Regarding Claim 13, Levy discloses that the step of treating the subject comprises treating recurrent glioblastoma ("Thereafter, a therapeutic agent may penetrate from the bloodstream to the targeted brain cells via the opened BBB region. The therapeutic agent may include any drug that is suitable for treating a brain tumor. For example, for treating glioblastoma (GBM)" [0055, treating glioblastoma once would inherently teach treating recurrent glioblastoma]).
Regarding Claim 14, Levy discloses all limitations noted above except that the step of treating the subject comprises treating both a central nervous system tumor and a second tumor at a second location in the body of the subject.
However, in the similar field of BBB Disruption, Davalos teaches that the step of treating the subject comprises treating both a central nervous system tumor and a second tumor at a second location in the body of the subject ("The target tissue within the volume of brain tissue is preferably undesirable tissue such as a tumor… Brain tumors may also include metastases from primary tumors originating from tissues and organs outside the brain, including but not limited to breast, ovary, prostate, lung, liver, colon, bladder, kidney, and skin.” [0059] ).
It would have been obvious to an ordinary skilled person in the art before the effective filing
date of the claimed invention to modify the system of Levy as outlined above with the step of treating the subject comprises treating both a central nervous system tumor and a second tumor at a second location in the body of the subject as taught by Davalos, because it may yield improved tumor control and enhances delivery of chemotherapeutic drugs for glioblastoma treatment [0005].
Regarding Claim 15, Levy discloses a method of treating primary or secondary central nervous system tumors in a subject ("Systems and methods for applying ultrasound sonication to temporarily disrupt a patient's blood-brain barrier" [Abstract] ,"Thereafter, a therapeutic agent may penetrate from the bloodstream to the targeted brain cells via the opened BBB region... The therapeutic agent may include any drug that is suitable for treating a brain tumor. For example, for treating glioblastoma (GBM)" [0055], glioblastoma is a primary or secondary central nervous system tumor) comprising:
treating the subject with a therapeutic agent comprising paclitaxel ("Thereafter, a therapeutic agent may penetrate from the bloodstream to the targeted brain cells via the opened BBB region...The therapeutic agent may include...Paclitaxel" [0055]),
and disrupting a blood-brain barrier within the brain of the subject by the use of an ultrasound device ("The present invention provides systems and methods for inducing microbubble cavitation with ultrasound in order to disrupt a target BBB region in a controlled and reversible manner." [0007], "The transducer array 102 is coupled to the beamformer 106, which drives the individual transducer elements 104 so that they collectively produce a focused ultrasonic beam or field." [0036]),
the disruption of the blood-brain barrier increases the concentration of therapeutic agent in the brain of the subject as compared to the concentration of paclitaxel in the brain without blood-brain barrier disruption (“Those skilled in the art can select a drug and a BBB opening regime optimized to enhance drug absorption across the BBB within patient safety constraints.” [0056]).
and the therapeutic agent is useful for ameliorating the primary or secondary central nervous system tumor ("Thereafter, a therapeutic agent may penetrate from the bloodstream to the targeted brain cells via the opened BBB region... The therapeutic agent may include any drug that is suitable for treating a brain tumor. For example, for treating glioblastoma (GBM)" [0055], glioblastoma is a primary or secondary central nervous system tumor),
wherein the step of treating the subject comprises administration of the therapeutic agent intravenously ("The drug may be administered intravenously" [0056]),
and wherein disruption of the blood-brain barrier comprises coincident application of the ultrasound device and intravenous microbubble injection ("The present invention provides systems and methods for inducing microbubble cavitation with ultrasound in order to disrupt a target BBB region in a controlled and reversible manner." [0007], "In some embodiments, microbubbles are introduced into the patient's bloodstream, and may either be injected systemically into the patient's brain or locally into the target BBB region 204 using an administration system 124" [0039]).
Levy does not specifically disclose that the therapeutic agent that is Cremophor EL free paclitaxel and comprises albumin-bound paclitaxel.
However, in the similar field of BBB Disruption, Davalos teaches providing electrical energy based methods for temporarily disrupting the blood-brain-barrier for increasing intracellular delivery of drugs across the blood-brain barrier [0002].
Davalos also teaches the therapeutic agent that is Cremophor EL free paclitaxel and comprises albumin-bound paclitaxel (“the skilled artisan may rely on such data to determine an appropriate dosage, route of administration, and timing of administration of the bioactive agent to provide a therapeutic concentration of the agent in blood during the duration of blood-brain-barrier disruption.” [0080], “the bioactive agent is at least one cancer therapeutic agent selected from the group consisting of… ABRAXANE (Paclitaxel Albumin-stabilized Nanoparticle Formulation)” [0084], as mentioned in the applicants specification and applicants remarks this limitation is representing Abraxane).
It would have been obvious to an ordinary skilled person in the art before the effective filing
date of the claimed invention to modify the system of Levy as outlined above with the therapeutic agent that is Cremophor EL free paclitaxel and comprises albumin-bound paclitaxel as taught by Davalos, because it may yield improved tumor control and enhances delivery of chemotherapeutic drugs for glioblastoma treatment [0005].
Regarding Claim 19, Levy discloses that the central nervous system tumor is glioblastoma, malignant glioma, diffuse or anaplastic astrocytoma, or any other primary or secondary central nervous system malignancy ("Thereafter, a therapeutic agent may penetrate from the bloodstream to the targeted brain cells via the opened BBB region. The therapeutic agent may include any drug that is suitable for treating a brain tumor. For example, for treating glioblastoma (GBM)" [0055]).
Regarding Claim 20, Levy discloses all limitations noted above except that the central nervous system tumor is a lower grade glioma or a metastatic tumor of a subject with breast or lung cancer.
However, in a similar field of endeavor, Davalos teaches that the central nervous system tumor is a lower grade glioma or a metastatic tumor of a subject with breast or lung cancer (“The target tissue within the volume of brain tissue is preferably undesirable tissue such as a tumor. Examples of tumors that may be treated with the present invention include, without limitation.. Oligondendroglial tumors (e.g. Oligodendroglioma, Anaplastic oligodendroglioma)… Other neuroepithelial tumors (e.g. Angiocentric glioma, Chordoid glioma of the third ventricle)… Ganglioglioma, Anaplastic ganglioma” [0059].
It would have been obvious to an ordinary skilled person in the art before the effective filing
date of the claimed invention to modify the system of Levy as outlined above with the central nervous system tumor is a lower grade glioma or a metastatic tumor of a subject with breast or lung cancer as taught by Davalos, because it may yield improved tumor control and enhances delivery of chemotherapeutic drugs for glioblastoma treatment [0005].
Regarding Claim 21, Levy discloses that treating the subject comprises treating recurrent glioblastoma ("Thereafter, a therapeutic agent may penetrate from the bloodstream to the targeted brain cells via the opened BBB region. The therapeutic agent may include any drug that is suitable for treating a brain tumor. For example, for treating glioblastoma (GBM)" [0055, treating glioblastoma once would inherently teach treating recurrent glioblastoma]).
Regarding Claim 22, Levy discloses a method for delivery of a therapeutic agent across a blood brain barrier (BBB) in a subject ("Systems and methods for applying ultrasound sonication to temporarily disrupt a patient's blood-brain barrier" [Abstract] ,"Thereafter, a therapeutic agent may penetrate from the bloodstream to the targeted brain cells via the opened BBB region." [0055]) comprising:
treating the subject with the therapeutic agent comprising paclitaxel, wherein the therapeutic agent crosses the blood brain barrier to deliver the therapeutic agent ("Thereafter, a therapeutic agent may penetrate from the bloodstream to the targeted brain cells via the opened BBB region...The therapeutic agent may include...Paclitaxel" [0055]),
wherein the step of treating the subject comprises administration of the therapeutic agent intravenously ("The drug may be administered intravenously" [0056]),
and wherein disruption of the blood-brain barrier comprises coincident application of the ultrasound device and intravenous microbubble injection ("The present invention provides systems and methods for inducing microbubble cavitation with ultrasound in order to disrupt a target BBB region in a controlled and reversible manner." [0007], "In some embodiments, microbubbles are introduced into the patient's bloodstream, and may either be injected systemically into the patient's brain or locally into the target BBB region 204 using an administration system 124" [0039]).
Levy does not specifically disclose that the therapeutic agent that is Cremophor EL free paclitaxel and comprises albumin-bound paclitaxel.
However, in the similar field of BBB Disruption, Davalos teaches providing electrical energy based methods for temporarily disrupting the blood-brain-barrier for increasing intracellular delivery of drugs across the blood-brain barrier [0002].
Davalos also teaches the therapeutic agent that is Cremophor EL free paclitaxel and comprises albumin-bound paclitaxel (“the skilled artisan may rely on such data to determine an appropriate dosage, route of administration, and timing of administration of the bioactive agent to provide a therapeutic concentration of the agent in blood during the duration of blood-brain-barrier disruption.” [0080], “the bioactive agent is at least one cancer therapeutic agent selected from the group consisting of… ABRAXANE (Paclitaxel Albumin-stabilized Nanoparticle Formulation)” [0084], as mentioned in the applicants specification and applicants remarks this limitation is representing Abraxane).
It would have been obvious to an ordinary skilled person in the art before the effective filing
date of the claimed invention to modify the system of Levy as outlined above with the therapeutic agent that is Cremophor EL free paclitaxel and comprises albumin-bound paclitaxel as taught by Davalos, because it may yield improved tumor control and enhances delivery of chemotherapeutic drugs for glioblastoma treatment [0005].
Regarding Claim 26, Levy discloses that treating the subject comprises treating a central nervous system tumor that is glioblastoma, malignant glioma, diffuse or anaplastic astrocytoma, or any other primary or secondary central nervous system malignancy ("Thereafter, a therapeutic agent may penetrate from the bloodstream to the targeted brain cells via the opened BBB region. The therapeutic agent may include any drug that is suitable for treating a brain tumor. For example, for treating glioblastoma (GBM)" [0055]).
Regarding Claim 27, Levy discloses that treating the subject comprises treating recurrent glioblastoma ("Thereafter, a therapeutic agent may penetrate from the bloodstream to the targeted brain cells via the opened BBB region. The therapeutic agent may include any drug that is suitable for treating a brain tumor. For example, for treating glioblastoma (GBM)" [0055, treating glioblastoma once would inherently teach treating recurrent glioblastoma]).
Regarding Claim 28, Levy discloses all limitations noted above except that treating the subject comprises treating both a central nervous system tumor and a second tumor at a second location in the body of the subject.
However, in the similar field of BBB Disruption, Davalos teaches that treating the subject comprises treating both a central nervous system tumor and a second tumor at a second location in the body of the subject ("The target tissue within the volume of brain tissue is preferably undesirable tissue such as a tumor… Brain tumors may also include metastases from primary tumors originating from tissues and organs outside the brain, including but not limited to breast, ovary, prostate, lung, liver, colon, bladder, kidney, and skin.” [0059] ).
It would have been obvious to an ordinary skilled person in the art before the effective filing
date of the claimed invention to modify the system of Levy as outlined above with treating the subject comprises treating both a central nervous system tumor and a second tumor at a second location in the body of the subject as taught by Davalos, because it may yield improved tumor control and enhances delivery of chemotherapeutic drugs for glioblastoma treatment [0005].
Regarding Claim 29, Levy discloses a method of treating primary or secondary central nervous system tumors in a subject ("Systems and methods for applying ultrasound sonication to temporarily disrupt a patient's blood-brain barrier" [Abstract] , "Thereafter, a therapeutic agent may penetrate from the bloodstream to the targeted brain cells via the opened BBB region. The therapeutic agent may include any drug that is suitable for treating a brain tumor. For example, for treating glioblastoma (GBM)" [0055]) comprising:
treating the subject having a primary or secondary central nervous system tumor by intravenously administrating a therapeutic agent comprising paclitaxel, ("Thereafter, a therapeutic agent may penetrate from the bloodstream to the targeted brain cells via the opened BBB region...The therapeutic agent may include...Paclitaxel" [0055], "The drug may be administered intravenously" [0056]),
wherein the therapeutic agent crosses the blood-brain barrier to deliver the therapeutic agent to the primary or secondary central nervous system tumor ("Thereafter, a therapeutic agent may penetrate from the bloodstream to the targeted brain cells via the opened BBB region. The therapeutic agent may include any drug that is suitable for treating a brain tumor. For example, for treating glioblastoma (GBM)" [0055]).
Levy does not specifically disclose that the therapeutic agent comprises an albumin-bound paclitaxel.
However, in the similar field of BBB Disruption, Davalos teaches that the therapeutic agent comprises an albumin-bound paclitaxel (“the skilled artisan may rely on such data to determine an appropriate dosage, route of administration, and timing of administration of the bioactive agent to provide a therapeutic concentration of the agent in blood during the duration of blood-brain-barrier disruption.” [0080], “the bioactive agent is at least one cancer therapeutic agent selected from the group consisting of… ABRAXANE (Paclitaxel Albumin-stabilized Nanoparticle Formulation)” [0084], as mentioned in the applicants specification and applicants remarks this limitation is representing Abraxane).
It would have been obvious to an ordinary skilled person in the art before the effective filing
date of the claimed invention to modify the system of Levy as outlined above with the therapeutic agent comprising an albumin-bound paclitaxel as taught by Davalos, because it may yield improved tumor control and enhances delivery of chemotherapeutic drugs for glioblastoma treatment [0005].
Claim 3 is rejected under 35 U.S.C. 103 as being unpatentable over Levy in view of Davalos as applied to Claim 1, and further in view of Aslund et al (A. K. O. Aslund et al., “Efficient enhancement of blood-brain barrier permeability using Acoustic Cluster Therapy (ACT),” Theranostics, vol. 7, no. 1, pp. 23–30, Jan. 2017. doi:10.7150/thno.16577; hereinafter referred to as Aslund)
Regarding Claim 3, Levy in view of Davalos discloses that the step of treating the subject comprises administration of the therapeutic agent intravenously ("The drug may be administered intravenously" [Levy 0056]).
Levy in view of Davalos does not specifically disclose that the step of disrupting a blood brain barrier occurs at a period of time after intravenous administration of the therapeutic agent.
However, in the similar field of Focused Ultrasound BBB Disruption, Aslund teaches methods for an efficient opening of the BBB using the Acoustic Cluster Therapy (ACT) in combination with Abraxane® to successfully treat subcutaneous tumors [Abstract]
Aslund also teaches that the step of disrupting a blood brain barrier occurs at a period of time after intravenous administration of the therapeutic agent (“Immediately after injection, the ultrasound treatment was initiated.” [Ultrasound Setup and Treatment Regimen])
It would have been obvious to an ordinary skilled person in the art before the effective filing
date of the claimed invention to modify the system of Levy in view of Davalos as outlined above with the step of disrupting a blood brain barrier occurring at a period of time after intravenous administration of the therapeutic agent as taught by Aslund, because with the new ACT approach, it is possible to generate bubbles, in-situ, that more effectively deliver small and large model drugs into the brain. In addition, the applied ultrasound pressure in this study is 5 to 10 times lower than typical levels used with regular microbubbles, potentially making the treatment safer [Introduction].
Claim(s) 8 and 9 are rejected under 35 U.S.C. 103 as being unpatentable over Levy in view of Davalos as applied to Claim 1 above, and further in view of Horodyckid et al (C. Horodyckid et al., “Safe long-term repeated disruption of the blood-brain barrier using an implantable ultrasound device: A multiparametric study in a primate model,” Journal of Neurosurgery, vol. 126, no. 4, pp. 1351–1361, Apr. 2017. doi:10.3171/2016.3.jns151635; hereinafter referred to as Horodyckid)
Regarding Claim 8, Levy in view of Davalos disclose all limitations noted above except that the ultrasound device is implantable in a cranial window of the skull of the subject.
However, in the similar field of ultrasound BBB disruption, Horodyckid teaches that the application of pulsed ultrasound (US), in combination with the intravenous injection of microbubbles, can temporarily disrupt the BBB to deliver drugs that normally cannot reach brain tissue, the device described in the current work emits US energy using an unfocused transducer implanted in the skull thickness [Objective].
It would have been obvious to an ordinary skilled person in the art before the effective filing date of the claimed invention to modify the system of Levy in view of Davalos as outlined above with the ultrasound device being implantable in a cranial window of the skull of the subject as taught by Horodyckid, because this method avoids distortion of the US energy by the skull bone and allows for simple, repetitive, and broad disruption of the BBB without the need for MRI monitoring [Objective]
Regarding Claim 9, Levy in view of Davalos and further in view of Horodyckid teaches that the implantation of the ultrasound device is surgical and is coincident with tumor removal (“The device can be implanted either at the end of a regular resection or surgical biopsy procedure, or during a unique dedicated surgical procedure under local anesthesia.” [Horodyckid Page 2]).
It would have been obvious to an ordinary skilled person in the art before the effective filing date of the claimed invention to modify the system of Levy in view of Davalos and further in view of Horodyckid as outlined above with the implantation of the ultrasound device being surgical and coincident with tumor removal as taught by Horodyckid, because this method avoids distortion of the US energy by the skull bone and allows for simple, repetitive, and broad disruption of the BBB without the need for MRI monitoring [Objective]
Response to Arguments
Applicant's arguments filed 01/26/2026 have been fully considered but they are not persuasive.
Regarding the U.S.C. 103 rejection of claim(s) 1,3,6-15,19-22 and 26-29, the applicant argues the following:
Applicant respectfully traverses the rejection of independent claims 1, 15, 22, and 29 and their dependent claims under 35 U.S.C. §103 at least for reasons that the Levy and Davalos are not reasonably combinable and teach away from each other.
Regarding independent claims 1, 15, 22, and 29, the Office acknowledges that "Levy does not specifically disclose that the therapeutic agent that is Cremophor EL free paclitaxel and comprises albumin-bound paclitaxel" and relies on Davalos para. [0084] for allegedly teaching ABRAXANE (Paclitaxel Albumin-stabilized Nanoparticle Formulation). However, the rejection as a whole relies on combination of Levy and Davalos is improper for several reasons.
First, Levy and Davalos address different and incompatible blood-brain barrier (BBB) disruption paradigms. Levy is directed to controlled, reversible blood-brain barrier opening using ultrasound-induced microbubble cavitation, with continuous monitoring and threshold-based control to avoid permanent tissue or BBB damage. See Levy, para. [0006], [0008], and [0053]. In contrast, Davalos is directed to irreversible electroporation (IRE) using electrical pulses delivered through implanted electrodes, intentionally producing an ablation zone of dead tissue, with temporary BBB disruption occurring only incidentally in surrounding tissue. See Davalos, Abstract. A person of ordinary skill in the art would not look to an ablative electroporation reference to modify or inform Levy's non-ablative, cavitation-controlled ultrasound system.
Levy and Davalos teach away from each other. Levy's controlled, non-ablative approach. Levy emphasizes avoiding uncontrolled cavitation and permanent tissue damage, suspending treatment when safety thresholds are exceeded. Davalos, by design, applies electrical pulses sufficient to cause irreversible electroporation and tissue ablation. Levy repeatedly and clearly teaches that the BBB opening is reversible and temporary, achieved by modulated ultrasound exposure with real-time cavitation feedback control. See Levy, para. [0007], [0034], [0051], [0052], and [0057]. Levy's concept is directly opposed to irreversible electroporation or destructive BBB disruption seen in Davalos.
The hypothetical combination of Levy and Davalos exhibits drastic timing and logistic mismatch. Davalos requires coordinating drug administration so that Cmax (maximum or peak concentration) coincides within ~10-60 min of the IRE pulses because BBB opening can be on
the order of minutes-tied to a surgical, electrode-based session. See Davalos, para. [0080]. That's a poor fit for Levy's non-invasive, feedback-gated ultrasound sessions that Cremophor EL free paclitaxel comprising albumin-bound paclitaxel is dosed over many cycles. A person of ordinary skill in the art would not be motivated to combine these incompatible timing/clinical workflows. Furthermore, there is no drug-specific motivation in Levy toward Cremophor EL free paclitaxel comprising albumin-bound paclitaxel. Levy is device-centric and drug-agnostic (focused on sonication control), providing no pointer toward paclitaxel formulations-and certainly not toward solving Cremophor EL neurotoxicity (the very problem the subject application solves by using Cremophor EL free paclitaxel comprising albumin-bound paclitaxel). That further undercuts any reason to graft Davalos' invasive IRE onto Levy just to deliver.
The two references rely on different physical mechanisms, different devices, different safety constraints, and different clinical objectives. Accordingly, Davalos is not a compatible secondary reference for Levy.
For all of these reasons, Applicant respectfully submits that independent claims 1 15, 22, and 29 are novel and inventive in the context of 35 U.S.C. § 103 and therefore Applicant respectfully requests the withdrawal of the rejection of independent claims 1, 15, 22, and 29 and their dependent claims under 35 U.S.C. § 103 as being unpatentable over the prior art of record.
In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007).
In this case, it is first noted that the use of Davalos is strictly for the limitation of “the therapeutic agent that is Cremophor EL free paclitaxel and comprises albumin-bound paclitaxel.” At no point is the blood brain disruption system of Davalos incorporated into the combination. Davalos is also not entirely silent on ultrasound being a potential modality, Davalos specifically cites “A technique that uniformly increases BBB permeability and therefore delivery of cytotoxic agents into tumors, may yield improved tumor control (Liu H L, Hua M Y, Chen P Y, Chu P C, Pan C H, et al., (2010) Blood-brain barrier disruption with focused ultrasound enhances delivery of chemotherapeutic drugs for glioblastoma treatment.” [0005]. Davalos also identifies multiple drugs which can cross a disrupted blood brain barrier including “the bioactive agent is at least one cancer therapeutic agent selected from the group consisting of Abiraterone Acetate, ABITREXATE (Methotrexate), ABRAXANE (Paclitaxel Albumin-stabilized Nanoparticle Formulation),… TAXOL (Paclitaxel)” [0084].
Levy teaches a blood brain barrier disruption system which can use generic Paclitaxel formulations as a therapeutic agent (“The present invention provides systems and methods for inducing microbubble cavitation with ultrasound in order to disrupt a target BBB region in a controlled and reversible manner.” [0007], “Thereafter, a therapeutic agent may penetrate from the bloodstream to the targeted brain cells via the opened BBB region. The therapeutic agent may include any drug that is suitable for treating a brain tumor. For example, for treating glioblastoma (GBM), the drug may include or consist of, e.g., one or more of Busulfan, Thiotepa, CCNU (lomustine), BCNU (carmustine), ACNU (nimustine), Temozolomide, Methotrexate, Topotecan, Cisplatin, Etoposide, Irinotecan/SN-38, Carboplatin, Doxorubicin, Vinblastine, Vincristine, Procarbazine, Paclitaxel,” [0055]).
When Levy and Davalos are taken together in combination, a POSITA would recognize that the blood barrier disruption system of Levy allows for Paclitaxel based formulations to cross the blood brain barrier and would thus use Abraxane, which Davalos teaches as being a known therapeutic agent in the art, since it would yield a predictable result of crossing the blood brain barrier.
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 STEVEN MALDONADO whose telephone number is 703-756-1421. The examiner can normally be reached 8:00 am-4:00 pm PST M-Th Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at
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/Steven Maldonado/
Patent Examiner, Art Unit 3797
/CHRISTOPHER KOHARSKI/Supervisory Patent Examiner, Art Unit 3797
Prosecution Insights