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 .
Priority
Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d) to parent Application No. GB2104590.1, filed on 31 March 2021. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 29 September 2023 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Election/Restrictions
Claims 29, 32, 36, 38, & 40-43 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 30 January 2026.
Specification
The title of the invention is not descriptive. A new title is required that is clearly indicative of the invention to which the claims are directed.
The following title is suggested: ACOUSTIC CLUSTER THERAPY FOR TREATMENT OF THE CENTRAL NERVOUS SYSTEM
Claim Objections
Claim 1 is objected to because of lack of antecedent basis for the recited limitation "the CNS" in line 3, and “CNS” is abbreviated without any corresponding long form definition. Appropriate correction is required.
Claim 44 is objected to because of lack of antecedent basis for the recited limitation "the gas" in line 1, and “oil phase” in line 5. Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
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.
Claim 26-28, 30, 33-35, 37, 39, 44, & 49-54 is 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.
With regards to Claim 26, the claim recites “wherein at least one step of ultrasound insonation is performed either non-invasively towards the CNS, invasively towards the CNS or towards the heart or a spinal or carotid artery outside the CNS” (emphasis added). However, steps (iii)(a) & (iv)(a) require the first alternative, steps (iii)(b) & (iv)(b) require the second alternative, and steps (iii)(c) & (iv)(c) require the third alternative. Based on the selected alternative, two of the substeps (a)-(c) are rendered indefinite because their requirement is no longer positively recited. In addition, substep (c) requires at least one of substeps (a) or (c). Moreover, substeps (a)-(c) are separated by “and” instead of “or.” Accordingly, Claim 1 is indefinite.
For the purposes of compact prosecution, the claim will be interpreted based on the “invasively” embodiment along with substep (a). All other embodiments are deemed alternatives and are not considered.
Claims 50-51 & 53 recite similar limitations and are rejected under the same rationale as Claim 1. Dependent claims are rejected by virtue of their dependency to abovementioned claims.
With regards to Claim 30 recites “wherein the ultrasound insonation is performed invasively”; however, invasive insonation is claimed in the alternative, thus, the limitation of Claim 30 requiring invasive insonation is undefined.
For the purposes of compact prosecution, the limitation will be interpreted as “non-invasively.” It should be noted that such an interpretation has not been evaluated for compliance with the written description requirement under 35 U.S.C. 112(a).
Claim 31 recites similar limitations and are rejected under the same rationale as Claim 30.
Similarly, Claim 33 recites “wherein the ultrasound insonation in step (iii) is performed towards the heart or spinal or carotid arteries outside the CNS” which is claimed in the alternative in parent Claim 26. Accordingly, Claim 33 is undefined because it requires step (iii)(c).
For the purposes of compact prosecution, the limitation will be interpreted as “non-invasively.” It should be noted that such an interpretation has not been evaluated for compliance with the written description requirement under 35 U.S.C. 112(a).
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 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.
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 26-27, 30, 33-34, 37, 39, 44, & 49-54 are rejected under 35 U.S.C. 103 as being unpatentable over Åslund et al. (see IDS of 29 September 2023; hereinafter "Åslund").
With regards to Claim 26, a method of treatment of CNS diseases, disorders or injuries of a subject, wherein the method comprises Acoustic Cluster Therapy (ACT) treatment wherein at least one step of ultrasound insonation is performed either non-invasively towards the CNS, invasively towards the CNS or towards the heart or a spinal or carotid artery outside the CNS (non-invasive sonification of animal brain via water tank; see Åslund pg. 25, ¶ 3), wherein the method comprises the steps of:
(i) administering a pharmaceutical composition comprising a microbubble/microdroplet cluster composition to the subject (injecting subject with ACT; see Åslund pf 25, ¶ 4);
(claimed in the alternative; regardless Åslund discloses introduction of ultrasound imaging agent Sonazoid; see Åslund pg. 24, ¶ 4-5);
(iii) activating a phase shift of a diffusible component of the microdroplet of the cluster composition from step (i) by ultrasound insonation at a first frequency and a first mechanical index (For the activation step, the parameters were: MI 0.28, 4 µs pulse length, pulse repetition frequency (PRF) 1 kHz, sonication time 30 s; see Åslund pg. 25, ¶ 4); wherein
a) for the non-invasive insonation, this takes place from at least one transducer positioned outside the brain skull or vertebral column of the subject for insonation through this (non-invasive sonification of animal brain via water tank; see Åslund pg. 25, ¶ 3); and
(claimed in the alternative); and
(claimed in the alternative);
(iv) further insonating with ultrasound at a second frequency and a second mechanical index facilitating extravasation of the at least one imaging agent administered in step (i) at the region of interest in the CNS (For the enhancement step, MI was 0.09, 4 µs pulse length, PRF 1 kHz, sonication time 10 min; see Åslund pg. 25, ¶ 4); wherein
a) for the non-invasive insonation, this takes place from at least one transducer positioned outside the brain skull or vertebral column of the subject for insonation through this (non-invasive sonification of animal brain via water tank; see Åslund pg. 25, ¶ 3); and
(claimed in the alternative);
(claimed in the alternative).
While Åslund disclosing utilizing ACT to deliver MRI imaging agent Gadodiamide, Åslund also teaches that the same ACT microubble formulation is can be designed for co-administration/co-injection of therapeutic agents beyond the BBB (see Åslund pg. 23, ¶ 1 cont. pg. 24, ¶ 1-2 & pg. 28, ¶ 4).
Therefore, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to have modified Åslund to provide at least a therapeutic agent instead of the imaging agent. Doing so would amount to simple substitution of one known element for another to obtain predictable results, i.e. replacing an imaging agent with a therapeutic as taught by Åslund detailed above.
Claims 50-54 recite similar limitations and are rejected under the same rationale as Claim 26.
With regards to Claim 2726, while modified Åslund teaches of wherein the step (iii) is performed non-invasively towards the CNS using a first frequency in the range of 0.2-3 MHz with a first Ml of 0.1 -0.4 (1Mhz center frequency with a MI 0.28, 4 µs pulse length, pulse repetition frequency (PRF) 1 kHz, sonication time 30 s; see Åslund pg. 25, ¶ 4).
With regards to Claim 3026, wherein the ultrasound insonation is performed non-invasively {see rejection under 35 U.S.C. 112(b)} towards the CNS in the step (iii) using a first frequency of 1-10 MHz with a first Ml of 0.1-0.4 (1Mhz center frequency with a MI 0.28, 4 µs pulse length, pulse repetition frequency (PRF) 1 kHz, sonication time 30 s; see Åslund pg. 25, ¶ 4).
With regards to Claim 3326, wherein the ultrasound insonation in step (iii) is performed non-invasively {see rejection under 35 U.S.C. 112(b)} with a first frequency of 1 -10 MHz with a first Ml of 0.1 -0.4 (1Mhz center frequency with a MI 0.28, 4 µs pulse length, pulse repetition frequency (PRF) 1 kHz, sonication time 30 s; see Åslund pg. 25, ¶ 4)(claimed in the alternative).
With regards to Claim 3426, wherein the insonation of step (iii) starts immediately after step (i) and is immediately followed by the insonation of step (iv) (FIG. 1 of Åslund clearly illustrates that the enhancement period is directly after the activation step, which is immediately after the injection).
With regards to Claim 3726, wherein the insonation of step (iii) lasts for 30-120 seconds (For the activation step, the parameters were: MI 0.28, 4 µs pulse length, pulse repetition frequency (PRF) 1 kHz, sonication time 30 s; see Åslund pg. 25, ¶ 4), followed by the insonation of step (iv) which lasts for 3-10 minutes (For the enhancement step, MI was 0.09, 4 µs pulse length, PRF 1 kHz, sonication time 10 min; see Åslund pg. 25, ¶ 4).
With regards to Claim 3926, wherein the same broad band or dual frequency US transducer is used in both the activation insonation of step (iii) and the enhancement insonation of step (iv) (A 1 MHz FUS transducer (Imasonic SAS) with a diameter of 50 mm and a focal length of 125 mm (f-number 2.5) was used for both activation and enhancement; see Åslund pg. 25, ¶ 3-4).
With regards to Claim 4426, wherein the gas of the microbubble is selected from the group of sulphur hexafluoride, perfluoropropane, perfluorobutane, perfluoropentane and perflurohexane or a mix thereof, the microbubble is stabilized by a first stabilizer selected from the group of phospholipids, proteins and polymers (Sonazoid™ (GE Healthcare AS, Norway) is an ultrasound contrast agent comprising perfluorobutane (PFB) microbubbles, stabilized with a hydrogenated egg phosphatidylserine-sodium (HEPS-Na) phospholipid membrane; see Åslund pg. 24, ¶ 4-5);
the oil phase of the microdroples comprises a diffusible component selected from the group of perfluorocarbons, e.g. a perfluorocycloalkane, stabilized with a second stabilizer selected from the group of surfactants, e.g. including phospholipids, polymers and proteins (the microdroplet is perfluoromethylcyclopentane (PFMCP) microdroplets (3 μl/ml) stabilized with a distearoyl-phosphatidylcholine (DSPC) phospholipid membrane with 3% (mol/mol) stearylamine (SA); see Åslund pg. 24, ¶ 4-5).
With regards to Claim 4926, wherein the cluster composition is administered in a time window of 3 hours from combining a first component of microbubbles with a second component of microdroplets preparing the microbubble/microdroplet cluster composition (the ACT bubble stays for typically 10 minutes, prolonging the treatment time window compared to regular contrast microbubbles; see Åslund pg. 24, ¶ 2).
Claims 28 & 31 are rejected under 35 U.S.C. 103 as being unpatentable over modified Åslund as applied to claim 26 above, and further in view of Sontum et al. (“Acoustic Cluster Therapy (ACT) – A novel concept for ultrasound mediated, targeted drug delivery,” (30 November 2015), International Journal of Pharmaceutics, Volume 495, Issue 2, 30 November 2015, Pages 1019-1027; hereinafter "Sontum").
With regards to Claim 2826, while modified Åslund teaches of wherein the step (iv) is performed non-invasively towards the CNS using a second frequency 1MHz with a second Ml of 0.025-0.15 (for the enhancement step, MI was 0.09, 4 µs pulse length, PRF 1 kHz, sonication time 10 min; see Åslund pg. 25, ¶ 4), (claimed in the alternative), it appears that modified Åslund may be silent to a range of 0.2-0.4 Mhz. However, Sontum, as referenced by Åslund as reference [23], teaches of ACT with an enhancement frequency of “e.g. 0.3–1 MHz” (see Santum pg. 1020, ¶ 4).
Modified Åslund and Sontum are both considered to be analogous to the claimed invention because they are in the same field of ACT. Therefore, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to have further modified Åslund to incorporate the above teachings of Santum to provide at least the claimed frequency range. Doing so would aid in “controlled volume oscillations of the large, deposited bubbles and ensuing biomechanical effects to allow for extravasation of drug molecules to the targeted tissue” (see Santum pg. 1020, ¶ 4).
With regards to Claim 3126, wherein step (iv) is performed non-invasively {see rejection under 35 U.S.C. 112(b)} towards the CNS using a second frequency in the range of 0.2-0.4 MHz with a second Ml of 0.025 to 0.15 (for the enhancement step, MI was 0.09, 4 µs pulse length, PRF 1 kHz, sonication time 10 min; see Åslund pg. 25, ¶ 4), (claimed in the alternative).
Claim 35 is rejected under 35 U.S.C. 103 as being unpatentable over modified Åslund as applied to claim 26 above, and further in view of van Wamel et al. (“Acoustic Cluster Therapy (ACT) enhances the therapeutic efficacy of paclitaxel and Abraxane® for treatment of human prostate adenocarcinoma in mice,” (28 August 2016), Journal of Controlled Release, Volume 236, 28 August 2016, Pages 15-21; hereinafter "van Wamel").
With regards to Claim 3526, while modified Åslund discloses all of the limitations of intervening Claim 26 as shown above, it appears that modified Åslund may be silent to wherein the steps (i) to (iv) of the ACT treatment are repeated one to four times. However, van Wamel is cited as reference [25] by modified Åslund and shares many of the same authors as modified Åslund. Van Wamel teaches of performing ACT treatment three consecutive times (see van Wamel pg. 17, ¶ 1).
Modified Åslund and van Wamel are both considered to be analogous to the claimed invention because they are in the same field of ACT. Therefore, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to have further modified Åslund to incorporate the above teachings of van Wamel to provide at least that the ACT treatment are repeated one to four times. Doing so would aid in promoting accumulation (see van Wamel pg. 15, ¶ 2).
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ASHISH S. JASANI whose telephone number is (571) 272-6402. The examiner can normally be reached M-F 9:00 am - 5:00 pm (CST).
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/ASHISH S. JASANI/Examiner, Art Unit 3798
/KEITH M RAYMOND/Supervisory Patent Examiner, Art Unit 3798
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