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 . Claims included in the prosecution are claims 32-39, 41-48, 50, 51 and 54.
Applicants' arguments, filed 02/13/2026, have been fully considered. Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
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 32-39, 41-48, 50, 51 and 54 are rejected under 35 U.S.C. 103 as being unpatentable over Rapoport et al. (US 2009/0117177, May 7, 2009) (hereinafter Rapoport) in view of Johnson et al. (US 2010/0143241, Jun. 10, 2010) (hereinafter Johnson).
Rapoport discloses a class of polymeric drug carriers that simultaneously serve as ultrasound imaging contrast agents and enhancers of ultrasound-mediated micelle disruption. These nanoparticles, or microbubbles, formed in situ from a microemulsion composition with microdroplets stabilized by diblock, triblock copolymers, or mixtures thereof, may be used for the image-guided intratumoral treatment of tumors (¶ [0017]). In a preferred embodiment, microbubbles or nanobubbles are composed of perfluorocarbons (PFCs). An exemplary PFC is C5F12 (perfluoropentane) (material that expands upon the application of ultrasound), which is liquid at room temperature but converts into highly echogenic nano/microbubbles at higher temperatures, such as physiological temperatures. These substances may be called liquid/gas (¶ [0018]). Examples of block copolymers used for the formation of the microbubbles include PEG-PCL (poly(ethylene oxide)-block-poly(caprolactone)) (expandable polymer). The size of the droplets can be controlled by copolymer concentration and concentration of liquid/gas (¶ [0020]). Such microbubbles may be loaded with chemotherapeutic agents (¶ [0027]). Agents useful in the treatment of tumors and cancers include propofol (¶ [0078]). Microbubbles also include nanoemulsions (¶ [0084]). Nanoemulsions have a droplet size of 100-1000 nm (¶ [0082]). Example 9 discloses poly(ethylene oxide)-block-poly(caprolactone) (PEG2000-PCL2000) stabilized nanodroplets comprising perfluoropentane (PFP) (Table 6). Nanobubbles produced from the nanodroplets are ultrasound-responsive (¶ [0109]). A local ultrasonic irradiation of the tumor, after injection of the drug encapsulated by the microbubble composition, triggers drug release from the microbubble within the tumor volume and enhances the intracellular drug uptake by the tumor cells (¶ [0043]). The microbubble composition may be injected intravenously (¶ [0027]). Ultrasound may be applied extracorporeally, intraluminally, or interstitially. The mode of ultrasound application be determined depending on the locations of the tumors. HIFU (high intensity focused ultrasound) treatment (tumor ablation) uses extracorporeal ultrasound transducers. However, ultrasound can also be applied intraluminally via specifically designed needle applicators (i.e., claimed tip sonicator). These applicators are in the market and are known in the art (¶ [0016]). The amount of the ultrasonic irradiation to be applied against any tumor will depend on several variables such as the type of tissue the tumor originates from, location of the tumor or tumors in the subject, the size of tumor thickness or width of any other dimension, the amount of drug or biologically active agent to be injected, and other environmental variables able to be determined by one of ordinary skill in the art (¶ [0127]).
Rapoport differs from the instant claims insofar as not disclosing wherein the nanobubble/microbubble and ultrasound are applied to the brain and wherein the ultrasound is MR-guided focused ultrasound.
However, Johnson discloses a method for opening the blood-brain barrier of a subject comprising the steps of: (a) administering a microbubble agent into the blood-stream of said subject, and (b) applying either (i) an unfocused ultrasound to the whole brain of said subject to open the blood brain barrier in the whole brain, or (ii) an electronically focused ultrasound beam to a portion of the brain (claim 1). The method further comprises a step of administering a diagnostic or therapeutic agent to the blood of the subject before step (b) (claim 7). The therapeutic agent may be a chemotherapeutic agent (claim 8). The therapeutic agent crosses the blood brain barrier to treat a patient (¶ [0018]). The microbubbles may be injected intravenously (¶ [0062]). Focused ultrasound (FUS) can open the BBB without necessarily causing tissue damage. Focused ultrasound may be MRI-guided (¶ [0059]).
Accordingly, it would have been prima facie obvious to one of ordinary skill in the art to have administered the nanobubble/microbubble and ultrasound of Rapoport to the brain since it was known in the art that chemotherapeutic agents are needed for the brain as taught by Johnson. One of ordinary skill in the art would have had a reasonable expectation of success since microbubbles and ultrasound may be administered to the brain as taught by Johnson.
It would have been prima facie obvious to one of ordinary skill in the art to have applied MRI-guided focused ultrasound since this is a known and effective ultrasound for the brain as taught by Johnson.
In regards to instant claims 32, 44 and 54 reciting wherein the method does not damage or injure tissue in the brain, such as brain parenchyma, as discussed in the rejection, Johnson discloses wherein focused ultrasound can open the BBB without necessarily causing tissue damage.
In regards to instant claims 33 and 45 reciting wherein the nanoparticle has a diameter and applying the ultrasound expands the diameter in the range of 5 to 6 times forming an expanded nanoparticle that releases pharmaceutical agent from the nanoparticle compared to when ultrasound is not applied to the nanoparticle, the nanobubble (i.e., claimed nanoparticle) of Rapoport comprises substantially the same material that expands upon the application of ultrasound as the claimed invention (i.e., perfluoropentane). Therefore, one of ordinary skill in the art would reasonably expect that the diameter of the nanobubble of Rapoport would expand by the same amount as the claimed invention after applying ultrasound.
In regards to instant claims 32, 42, 49 and 51 reciting wherein the ultrasound is applied at about 1 MHz, between about 1.0 MPa to about 1.5 MPa, and at 1 MHz using 10 ms pulses every 1 sec for up to 2 min, as discussed above, Rapoport discloses that the amount of the ultrasonic irradiation to be applied against any tumor will depend on several variables such as the type of tissue the tumor originates from, location of the tumor or tumors in the subject, the size of tumor thickness or width of any other dimension, the amount of drug or biologically active agent to be injected, and other environmental variables able to be determined by one of ordinary skill in the art (¶ [0127]). Therefore, it would have taken no more than the relative skills of one of ordinary skill in the art through routine experimentation to have arrived at the claimed frequency, pressure, and interval of ultrasound depending on the type of tissue the tumor originates from, the location of the tumor or tumors in the subject, the size of tumor thickness or width of any other dimension, the amount of drug or biologically active agent to be injected, and other environmental variables which may be determined by one of ordinary skill in the art as taught by Rapoport. Where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. See MPEP 2144.05(II)(A).
Response to Arguments
Applicant argues that a lack of evidence of damage or injury of the brain parenchyma, indicates that the blood-brain barrier was not damaged or injured, i.e., opened, by the presently claimed methods.
The Examiner does not find Applicant’s argument to be persuasive. Johnson discloses in paragraph [0059] wherein opening the BBB with focused ultrasound does not cause tissue damage. As such, Applicant’s argument is unpersuasive since Johnson does not teach away from the claimed invention as opening the blood brain barrier does not cause damage or injury to the brain.
Applicant argues that the nanoparticle size in the present invention inherently precludes transit of the nanoparticles across the BBB to the brain.
The Examiner does not find Applicant’s argument to be persuasive. Although this statement was made in the Declaration, Declarant made this statement without providing objective evidence or a scientific explanation supporting the statement. Therefore, it is unclear whether the statement is merely Declarant’s opinion or whether it is factual. As such, Applicant’s argument is unpersuasive.
Applicant argues that the release of the therapeutic agent and subsequent delivery of the agent to the brain in the present invention occur intravascularly as opposed to the method of Rapoport in which the nanoparticles are deposited directly in the tumor, after which the therapeutic agent is released.
The Examiner does not find Applicant’s argument to be persuasive. Rapoport discloses in paragraph [0027] and claim 9 wherein the microbubbles may be injected intravenously. As such, applicant’s argument is unpersuasive.
Applicant argues that even if the nanoparticles of Rapoport could be transported through the BBB by the method of Johnson, i.e., opening the BBB, there would be a likelihood of injury to the BBB of the subject.
The Examiner does not find Applicant’s argument to be persuasive. As discussed above, Johnson discloses in paragraph [0059] wherein opening the BBB with focused ultrasound does not cause tissue damage. As such, Applicant’s argument is unpersuasive.
Applicant argues that modifying John such that the BBB is not opened to arrive at the instant invention would render Johnson inoperable for its intended purpose.
The Examiner does not find Applicant’s argument to be persuasive. The rejection does not suggest to not open the BBB. As such, Applicant’s argument is unpersuasive.
Applicant argues that the subject matter of the instant invention was accepted within the scientific community, which is an indicia of non-obviousness.
The Examiner does not find Applicant’s argument to be persuasive. It is unclear what exactly was presented to the scientific community and how much of it relates to the claimed invention. Therefore, non-obviousness has not shown and Applicant’s argument is unpersuasive.
Response to Declaration
Declarant’s arguments have been addressed above and are unpersuasive.
Conclusion
Claims 32-39, 41-48, 50, 51 and 54 are rejected.
Claims 28-31 have been withdrawn.
No claims are allowed.
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.
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/TRACY LIU/Primary Examiner, Art Unit 1614