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 Amendment
This action is in response to the remarks filed on 12/15/2025.
The amendments filed on 12/15/2025 have been entered. Accordingly claims 23-32 remain pending. Claims 23-32 are presently amended.
The previous rejections of the claims under 35 U.S.C 112(b) have been withdrawn in light of applicant's amendments to the claims.
Response to Arguments
Applicant's arguments filed 12/15/2025 regarding the prior art rejections of the claims have been fully considered but they are not persuasive.
Applicant argues, see page 6 of the remarks, the following.
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Healey discloses in paragraph [0074]:
“The clusters are activated to produce large bubbles by application of external ultrasound energy, such as from a clinical ultrasound imaging system, under imaging control. The large phase shift bubbles produced are typically of a diameter of 10 μm or more (see Examples 1, 2, 3 and 4)”
Therefore, Healey does disclose exposing at least one microbubble-microdroplet cluster to an effective exposure of ultrasound to oscillate, expand, and fuse individual microbubble-microdroplet clusters into a single entity providing an ablation-assisting bubble. Healey also discloses in [0110] that “The presence of the large phase shift bubbles increases the local rate of thermal delivery using ultrasound hyperthermia treatment and/or tissue ablation” and therefore is an ablation-assisting bubble. Finally, Healey discloses in e.g., paragraph [0075]: “the application of low frequency ultrasound, close to the resonance frequencies of the large, activated bubbles (i.e. frequency components in the range 0.05 to 2 MHz, preferably in the range 0.1 to 1.5 MHz, most preferably in the range of 0.2 to 1 MHz), can be used to produce mechanical and/or thermal bio-effect mechanisms to increase the local permeability of the vasculature and/or sonoporation and/or endocytosis” .
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 23-27 and 29-32 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Healey et al. (US 2016/0243234, August 25, 2016).
Regarding claim 23, Healey discloses a method of enhancing ablation at a target region (“power ultrasound (High Intensity Focused Ultrasound, HIFU) [Lukka, H. et al., Clinical Oncology 23 (2011) 117-127] is applied to the tissue region containing the large, activated bubbles. The presence of the large phase shift bubbles increases the local rate of thermal delivery using ultrasound hyperthermia treatment and/or tissue ablation.” [0110]), the method comprising:
intravenously administering (“intravenous administration” [0260]; also see [0066]) a microbubble-microdroplet cluster composition, wherein the microbubble- microdroplet cluster composition comprises groups of negatively charged microbubbles and positively charged microdroplets permanently held together by their opposing electrostatic attractive forces to form a single, agglomerated entity (“the term “clusters” refers to groups of microbubbles and microdroplets permanently held together by electrostatic attractive forces, in a single particle, agglomerated entity.” [0067]; also see [0078]);
exposing at least one microbubble-microdroplet cluster to an effective exposure of ultrasound to oscillate, expand, and fuse individual microbubble-microdroplet clusters into a single entity providing a resulting ablation-assisting bubble (“The clusters are activated to produce large bubbles by application of external ultrasound energy, such as from a clinical ultrasound imaging system, under imaging control. The large phase shift bubbles produced are typically of a diameter of 10 μm or more (see Examples 1, 2, 3 and 4)” [0074]; also see “The presence of the large phase shift bubbles increases the local rate of thermal delivery using ultrasound hyperthermia treatment and/or tissue ablation” [0110]).
Regarding claim 24, Healey discloses further comprising exposing the resulting ablation-assisting bubble to ultrasound at a predetermined intensity to oscillate and/or cavitate to induce mechanical and/or thermal stress on the target region to increase ablation efficiency in the target region (“the application of low frequency ultrasound, close to the resonance frequencies of the large, activated bubbles (i.e. frequency components in the range 0.05 to 2 MHz, preferably in the range 0.1 to 1.5 MHz, most preferably in the range of 0.2 to 1 MHz), can be used to produce mechanical and/or thermal bio-effect mechanisms to increase the local permeability of the vasculature and/or sonoporation and/or endocytosis and hence increase delivery and retention of drugs” [0075]).
Regarding claim 25, Healey discloses wherein the resulting ablation-assisting bubble is configured to induce mechanical and/or thermal stress, comparable to an induced mechanical and/or thermal stress from direct ultrasound insonation on the target region, wherein the predetermined intensity is equal to an intensity for non-bubble assisted ultrasound ablation divided by a factor of between 12 and 24 (“frequency components in the range 0.05 to 2 MHz, preferably in the range 0.1 to 1.5 MHz, most preferably in the range of 0.2 to 1 MHz” [0075]).
Regarding claim 26, Healey discloses wherein the microbubble-microdroplet cluster composition is formed from: a cluster dispersion of microdroplets, having a median diameter of 2 to 3mm, stabilised with a lipid membrane with a net positive surface charge; and microbubbles, having a median diameter of 2 to 3 mm, and stabilised with a lipid shell with a net negative surface charge (“The term ‘microbubble’ or ‘regular, contrast microbubble’ is used in this text to describe microbubbles with a diameter in the range from 0.2 to 10 microns, typically with a mean diameter between 2 to 3 μm.” [0021]; also see “The cluster composition, i.e. comprising the combination of the first and second components, is comprised of a bi-phasic micro particle system engineered to cluster and phase shift in a controlled manner. Drug may be incorporated into low boiling point, micron sized oil microdroplets of the second component, which are stabilised e.g. with a positively charged phospholipid membrane. Before administration, the drug loaded oil microdroplets of the second component are mixed with micron sized gas microbubbles in the first component. Such gas microbubbles may consist of, for example but not limited to, a low solubility perfluorocarbon gas core stabilised with a negatively charged phospholipid membrane.” [0078]).
Regarding claim 27, Healey discloses wherein the net positive surface charge of the microdroplets and the net negative surface charge of the microbubbles provides the electrostatic forces which enable the at least one microbubble-microdroplet cluster to be formed (“where the microbubbles and microdroplets of said first and second components have opposite surface charges and form said clusters via attractive electrostatic interactions” [0065]).
Regarding claim 29, Healey discloses wherein a gas of the microbubbles of the at least one microbubble-microdroplet cluster comprises sulphur hexafluoride or a C3-6 perfluorocarbon or mixtures thereof ([0081], [0082], claim 2).
Regarding claim 30, Healey discloses wherein an oil phase of the microdroplet of the at least one microbubble-microdroplet cluster comprises a partly or fully halogenated hydrocarbon or a mixture thereof ([0285], claim 5).
Regarding claim 31, Healey discloses for use in treatment of one or more of the group consisting of tumours, space occupying masses, thrombolysis and neurological diseases ([0095], [0140], [0254]).
Regarding claim 32, Healey discloses a method of mechanical tissue ablation ([0075], [0110]) comprising:
intravenously administering to a subject (“intravenous administration” [0260]; also see [0066]) a composition comprising a microbubble-microdroplet cluster composition, wherein the microbubble-microdroplet cluster composition comprises groups of negatively charged microbubbles and positively charged microdroplets permanently held together by their opposing electrostatic attractive forces to form a single, agglomerated entity (“the term “clusters” refers to groups of microbubbles and microdroplets permanently held together by electrostatic attractive forces, in a single particle, agglomerated entity.” [0067]; also see [0078]); and
activating a phase shift transition of the microdroplet component of at least one microbubble-microdroplet cluster by ultrasound insonation to create at least one ablation-assisting bubble in a target region (“The clusters are activated to produce large bubbles by application of external ultrasound energy, such as from a clinical ultrasound imaging system, under imaging control. The large phase shift bubbles produced are typically of a diameter of 10 μm or more (see Examples 1, 2, 3 and 4)” [0074]; also see “The presence of the large phase shift bubbles increases the local rate of thermal delivery using ultrasound hyperthermia treatment and/or tissue ablation” [0110]),
wherein an expansion from the transition of the at least one microbubble-microdroplet cluster to the at least one ablation-assisting bubble provides a mechanical stress on the target region to aid ablation on target tissue in the target region (“produce mechanical and/or thermal bio-effect mechanisms to increase the local permeability of the vasculature and/or sonoporation and/or endocytosis and hence increase delivery and retention of drugs” [0075]; also see [0110]).
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim 28 is rejected under 35 U.S.C. 103 as being unpatentable over Healey.
Regarding claim 28, Healey discloses the limitations of claim 27 as stated above but fails to explicitly disclose wherein the resulting formed clusters have a diameter in the range of 4 to 8 mm. Instead Healey teaches that the resulting formed clusters have a diameter in the range of 4 to 80 mm ([0190]). However, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the diameter to in the range of 4 to 8 mm, because it has been held before that “it is not inventive to discover the optimum or workable ranges by routine experimentation" (see MPEP 2144.05.II.A), no criticality is given for the claimed ranges, one of ordinary skill in the art could have made the modification with known methods with no change in their respective functions, and the combination would have yielded nothing more than predictable results to one of ordinary skill in the art before the effective filing date of the claimed invention.
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.
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/A.A./Examiner, Art Unit 3797
/SHAHDEEP MOHAMMED/Primary Examiner, Art Unit 3797